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OBM Integrative and Complementary Medicine The Importance of Rapport in Hypnotic Clinical Practice
This article is based on the assumption that the therapist's focused attention, open awareness and kind intention are the basic ingredients for creating a relationship of trust with the patient from the first session. He also stresses that when the attention of a genuine therapist, without prejudice or judgment, is centered on how the patient expresses him/herself and on the contents s/he proposes, the patient relies more easily on the competent care of the therapist. The author argues that to empower patients it is essential to accept their vulnerability, awaken hidden resources and define realistic therapeutic goals. In this way, each session focuses on the perceptual, cognitive, emotional and behavioral changes that the patient can undertake during the session and implement after the session, by himself or herself. Through the presentation of some cases, the article shows the importance of concentrating the patient's attention in the present moment with the resources s/he has in his/her current life, from which to observe significant episodes from the past. The revision of the past from the point of view of the present, which is the future of the past, helps the patient to observe what happened with different perceptions, thoughts and emotions, thus reformulating his representative memory of what happened. The article proposes the transcription of a typical induction that the author usually uses to establish a relationship based on a secure attachment to evoke a feeling of calm and trust in the patient. It also provides the transcription of several inductions used during some highlights of a therapy session of the selected cases. Each case and each induction has been chosen to show how attachment theory concepts have been used in hypnotic practice as an indispensable tool for building and maintaining a therapeutic relationship based on mutual trust.
The article proposes the transcription of a typical induction that the author usually uses to establish a relationship based on a secure attachment to evoke a feeling of calm and trust in the patient.It also provides the transcription of several inductions used during some highlights of a therapy session of the selected cases.Each case and each induction has been chosen to show how attachment theory concepts have been used in hypnotic practice as an indispensable tool for building and maintaining a therapeutic relationship based on mutual trust.
Rapport; attachment; trust; hypnotic inductions
The objective of this article is to stimulate reflection on the importance of developing rapport in hypnotic clinical practice.A combination of attachment theory with several hypnotic techniques such as utilization and reframing has been proposed in this article.
This article starts with some questions such as "Is rapport a predictor of therapeutic success?", "Is rapport the guardian of the quality of the therapeutic process?", and "Is rapport a guarantee of the trust between therapist and patient?".This article illustrates building and maintaining a therapeutic alliance based on "focused attention, open awareness, and kind intention" in order to develop a relationship of mutual trust and reciprocal understanding [1].
Rapport is defined by the author as the unconditional acceptance of patients' vulnerability, the empathic attunement with whom they are and the empowerment of their strengths before defining any therapeutic goal and suggesting any kind of change.Rapport is the perception of the patients experienced while the therapists employ their verbal and analogical communication to connect their conscious and unconscious minds [2].
Based on M. H. Erickson's suggestion, a therapeutic alliance is established, irrespective of patients' behavior, by illustrating them that they are completely accepted as they are.Rapport is when the patient has the feeling of being accepted, understood, and connected, whereby, s/he can develop trust in the therapist and therefore, count on the therapist's care.Rapport facilitates therapists to address any emotion experienced by patients, to reduce their intensity or duration, to calm them during the session, to assist them to improve their executive functions, thereby, mitigating their fear of the future [2].
In this article, three cases are offered to illustrate those points in action.
Building Rapport from the First Session
Patients seeking therapeutic help are mostly in a vicious circle: they fear to be unable to overcome a past experience, to be incapable of achieving their goals and are unaware of the solution to the problem.This fear indulges in immobilization which again reinforces fear [3].
Restoration of the active and effective defensive responses is achieved by the therapist by interrupting the vicious circle, reinforced by the patient's emotions, such as anger, sadness, guilt, shame [4].An emotionally corrective experience is offered by the therapists to the patients, guiding them to reduce negative feelings and rejuvenate the sense of self-confidence in a world filled with volatility, uncertainty, complexity, and ambiguity [1].
To initiate the first session, it is essential for the patient to comprehend the therapist as competent, genuine, caring, and non-judgemental.The initial acceptance of patients' behavior, followed by their collaborative response, orchestrates the path of therapeutic change paved by the relationship based on trust [2].
Hypnotists, in their first meet, convey one of the main messages to their patients that they are in a safe place where they can awaken their dormant resources.Patients are empowered by the hypnotic therapists to respect and protect their vulnerability, to increase their resources in facing challenges, to connect body and mind, heart, brain, muscle, bones, and to install lasting changes in their emotional and cognitive processes, as well as in their behavior [5].
Hypnotic techniques engage the therapist to collect and calibrate verbal and non-verbal messages sent by the patient.The process of mutual influence develops a bond and maintains a good attunement.The therapists' kind intention, motivation, and commitment to listening/helping/sustaining patients to achieve their well-being in an efficient and effective way bridge the gap between the therapists and the patients.
Rapport in hypnotic clinical settings helps patients to develop the internal locus of control, selfesteem, self-efficacy, independence, and interdependence.Patients are encouraged to depart the land where they have enacted the role of victim and explore a realm where they act as agent, as problem solvers, and improve their ability to use their critical thinking, creative imagination, and planning how to promote evolutive changes [2,6].
At the end of the therapeutic process, patients divert their attention from problematic events of the past to projections of open future, curious to explicitly define their goals, reinforced by their aspirations, motivation, and perseverance [7].
Rapport is mainly built and maintained by nurturing the communication style of the patients.Utilization is nothing more than making good use of what happens during the session and matching what patients bring to therapy: breathing, posture, gestures, body changes, words, metaphors, tone of voice, beliefs, interests, values, and priorities [8,9].An important role is also played by the reframing, which is incorporating new and empowering perspective to the patient teaching skills and providing experiences that uplift his/her life [10].
The Role of Hypnosis in Building and Maintaining Rapport
At the beginning of the session, the consequences of the hypnotic induction are to stabilize and calm patients making them feel seen, safe, protected, calm, and secure.Once the patients realize that they are recognized for what they are, the therapists aid them in shifting their attention to their resources and regaining confidence in their future.
Therapists specialized in hypnosis are conscious regarding the importance of expressing their linguistic competence and verbal fluency.Delivering congruent messages of attunement through their body language and their tone of voice is also essential for treating patients.Eye contact of the hypnotist with the patient along with a pleasant smile, relaxed and soft body posture, warm and gentle gestures are essential in order to provide the patients a comfortable environment and to make them feel that they are acceptable as they are.Voice modulation according to the emotional strings they wish to touch is essential to deal with such patients.The modulation of facial expressions of the therapist reflecting congruence with what the patient is narrating is a technique to portray their resonance.
An empathic resonance is established with the patient's narrative through these therapeutic sessions.Empathic resonance means not only feeling what patients feel, but also encompasses their perspective, visualizing through their eyes according to their cognitive schemes, imagining their mental experience, their attributions to what happened, and their representation of the world.Therapists who show attunement, resonance, and willingness to take care of patients' wellbeing, also share the happiness for their achievements [1].
Staying focused on the present therapy helps patients to concentrate on the experience of the session, aware of being in the future of their past and thus relate their story from the point of view of the present, separating the past, present, and future.The patients are asked to retrospect the past incidents that might be related to the current suffering.Unearthing a "problematic episode" that seemed to be the starting point of the suffering of their current life, help them differentiate between past and present.
Furthermore, the therapist invites patients to realize what they learned that they did not know before and that they could not have learned in any other way [7,11].
Rapport Based on Secure Attachment
A secured bond involving the same attachment patterns studied by John Bowlby [12] is carefully established by the therapist in order to develop and sustain a rapport based on trust.It is important that patients in therapy feel seen, soothed, and safe, like a child with a caregiver.This helps strengthen the sense of security in the patients.They learn to maintain hope and improve their resilience even during adverse situations.[9] My usual initial induction begins in this way, changing it according to the uniqueness of each patient.
At this moment, you are here in my office and today is … day, month, year.
This is a safe place for you. With eyes closed you can perceive the luminosity of the room which is subjected to change based on the hide and seek clouds play with the sun; you hear the sound of my voice, the tic-tac of the clock reminding you of the inexorable passing of time. Time passes even if you stay still and do nothing but concentrate on finding a relaxing position. The passing of time is an alarm to remind you that the only place you are going to is the future. You can also smell the fragrance in the room. You may feel a residual taste in your mouth. And now you can start focusing your attention on all the contact points of your body, such as your feet touching the ground, thighs, and bottom on the chair, your back resting on the back of the chair, your arms supported by the arms of the chair, and your hands on your lap. Even with your eyes closed, you can sense my full presence focused on your wellbeing while we are together in this secured place. I just noticed that your breathing is becoming calmer and calmer, and your facial expression is becoming more relaxed so that you experience that the more you relax your body the more you relax your mind; the more you relax your mind the more you relax your body.
Synchronization with the feelings, thoughts, and body language responses of the patients with the therapist generate a sense of security among the patients.They feel that they are seen, heard, held, and healed by a therapist.Distressed patients learn to calm down when they realize their therapist is able to transmit calm.Thus they feel they are protected from danger, kept safe, and cared for by their therapist, who will educate them on how to soothe themselves.
Right from the beginning the hypnotists try to impose an emotionally corrective experience of secure attachment with the patients, by seeding verbal and non-verbal messages such as "I'm with you in the here and now ..., I'm in tune with you…, You are in a safe place..., I resonate with you..., I understand you…, You can learn now how to calm down..., In this safe place you can recognize that you have all the resources you need at this moment in your life..." A rapport based on secure attachment helps the therapists to utilize hypnosis to diminish patients' sense of alertness, simultaneously empowering their sense of security and confidence.A safe environment incorporates a sense of protection and fearlessness among patients.This can pave the way to discover the pleasure of exploring a new world full of opportunities, play new games, and cultivate their imagination in creating new projects that can reform their lives.
Here are the three cases.
The Case of Monica
Monica, a 32-year-old woman, is afraid of crickets and does not know what to do when she encounters them.She recently shifted to her newly purchased house with a garden.In her previous condominium apartment, she did not face the problem of crickets.However, now she finds it when she returns home from work.She is very much attached to her new house and the garden.She does not want to indulge in the risk that her fear will ruin her return to home in the evenings when she spends a lot of time hunting for crickets in every corner.
During our first session, I followed a metaphorical model of mine namely "The Five Petals of Identity", useful for discovering strengths and vulnerabilities in each petal, so that a suffering petal can receive help from the others [7,11].The first petal represents the qualities of body identity characterized by gender, age, and physical appearance; the second concerns the power of belonging coming from social identity.The third petal deals with a sense of self-efficacy attributed to professional identity.The fourth signifies our transcendent spiritual parts connected to virtues and values, morals and ethics.The fifth embodies secrets regarding every aspect of the previous petals.
After reaching the state of trance post-induction, I started sending these therapeutic suggestions to Monica.
At this moment you can focus your attention on the five petals of your identity.You can start with becoming aware of the body you've lived in since your birth.You might also recall all changes that have occurred since you were born until today since you weighed a few kilos and were a few centimeters long until your current weight and height.
Just as you can remember the changes that have taken place in your social relationships, from the time you were mainly the daughter of your parents to the time you started going to school and met friends, from primary school to secondary school to university where you contacted people and made new friends.Over the years, your knowledge has also undergone modification, improvement, and refinement.You At the end of the induction, Monica told me that she had experienced the differences between her and a cricket and sensed a calm which motivated self-efficacy.At the conclusion of the first meeting, Monica was keen for a second session, which we agreed would be scheduled three weeks from the first one.
In our second meeting, Monica told me that she was no longer afraid of crickets.She was able to handle them calmly and efficiently.So I was curious to know why she came back.She replied that she was in search of the origin of the fear.
The second hypnotic intervention aimed at bringing Monica back to her past to find the episode of the first time she experienced she was afraid of crickets.After the initial induction, I said: Now that you are here and now in this safe place, be aware of all the resources you have and when you are ready, leave your unconscious mind free to select the oldest memory connected with that fear of crickets.After discovering that episode, when you are ready, you can open your eyes and tell me what I need to know to continue to help you.Monica opened her defocused eyes and told me that she had gone back to when she was a little girl (about 3-4 years old), playing in the garden of her parent's house and at one point, a cricket jumped on her.She screamed in fear, drawing her mother's attention.When the mother went to the garden and realized that her daughter had been attacked by a cricket, she invited Monica to go inside the house, telling her that she would take care of the insect.There were no further comments from her mother.
Once I received this information, I reminded Monica of the resources she had discovered during the first session.I, then, recommended her to go back to the little Monica to teach her what she now knew and help her manage the emotions of the past.
With the full awareness that you are in the future of what has happened in your past be ready to go back now, dressed as you are today to help little Monica of a long time ago, when she was only 3-4 years old, her body was the body of a 3-4-year-old girl, her experience was of a 3-4-year-old girl, her knowledge was of a 3-4-year-old girl.The woman who is in front of me right now is 29 years old and has a body of a 29-year-old, knowledge and experiences of a 29-year-old woman.Now The experiences she gathered from the retrospective view of the childhood memory, Monica acquired two types of awareness: the one that kept implicit traces of her child self in the past and the other that recognized her adult resources in the present.She was a little girl whose mother was unable to teach her the difference between fright and fear and pursue a simple reality test: you are stronger and bigger than a small cricket.
The episode that emerged in Monica's explicit memory belonged to an implicit memory layer that had restored in her brain the primary imprint of a fearful experience.The hypnotic interventions assisted Monica to transform her implicit memory contained in sensations, emotions, images, thoughts, and behavior provoked by the old fear of the cricket into an explicit narration where she sees herself able to treat the harmless insect in an adult and efficient manner.
The Case of Elena
Elena, a seventy-year-old, came to therapy encouraged by a former patient of mine who was anxious about Elena's depression and her desire to die.In six months Elena lost her brother and a close friend, which justified her depression.Were there any reasons to want to die?Elena isolated herself, confined herself in her house and was unwilling to carry out the normal daily activities.Despite being full of resources, she felt she did not deserve to live.Termination of her life seemed to be the best solution for Elena.
During our first session, her desperation and a lack of confidence in the therapy provoked me to apply mainly conversational hypnosis.The development of a trusting alliance was the main objective for the first session so that she could attend the second session with the anticipation that she would be benefitted from our meetings.For this reason, I watered the roots of hope by inviting her to remember her past life when she had bounced back from depression by awakening the resources required to deal with her present situation.At the end of the first session, she was convinced to see me for another encounter.
During the second session, I asked her to freely talk about her desire to die.She shared her life story regarding her family where she was neglected by both her parents because their attention and expectations were toward her brother.For the purpose of this article, only an emblematic example of her narration has been selected.Her parents were ignorant regarding her studies, though she was a good student.Elena was inclined toward culture, literature, and art.She got a job to support her college expenses and when she finally graduated she told them, "Today I graduated cum laude".The father's first answer was, "What a pity your brother left college and did not graduate."Not even her mother uttered words of satisfaction, pride or congratulations.Despite the discriminatory and unfair attitude of her parents, Elena developed the ability to recover and continue to love them and she looked after them until their deaths.She also took care of her brother until his death.After the death of her brother, however, she felt guilty.
She was of the opinion that, if her parents had still been alive, they would have preferred her death to her brother's.Thus I decided to work on her guilt.
After eliciting a hypnotic state, I suggested to Elena: Let your unconscious mind remind you of some episodes of your life with your brother.Go back to the time when you wanted to study simply because you loved to spend your time reading books of literature, of art, of history, while your brother loved doing different things.Now is the time to be true to yourself and explore carefully if you did anything wrong that refrained your brother from studying.Be honest and explore now if you did anything wrong that prevented him from studying instead of doing what he liked best.I started my induction by highlighting the differences between her and her brother regarding studying, to let her experience that she had not committed any sin.Then I shifted her attention to her brother's last period of life.
Now go back to the period when your brother was ill and you took good care of him. Go there with him, talk to him, spend all the time you need to tell your brother how much you loved him. And you can also listen to what your brother is willing to tell you before passing away.
With these suggestions, I wanted Elena to realize that she had done her best to look after her brother and helped him to die in peace.Since she loves culture, I proceeded with the Greek myth of Admetus, Alcestis, and Apollo, as a particularly useful metaphor at this moment.
Let me now tell you the Greek story of Admetus, Alcestis, and Apollo that you may already know.The God Apollo expressed gratitude toward Admetus because he had hosted God during his exile.When Apollo learned that Admetus was to die, God gave him one more day of life to allow him to find someone willing to die in his place.Neither his father nor his mother wished to die in his place: the only one who accepted the exchange was his wife Alcestis.When Alcestis reached the underworld, God Thanatus was so impressed by her generosity and love that he sent her back to earth to live.You know that these things happen only in Greek mythology.In reality, nobody can bargain with any God for the life or death of someone else.Even though you would like to accept death on behalf of your brother, you know that this was impossible.Your brother accepted his fate to die before you, so you have to accept your fate to live longer than him.This was a cultural way to remind her that she was unable to prevent the death of her brother.So she need not be guilty in this matter.At the end of the second session, Elena fixed another appointment.
During our third session, we shifted attention to the distressing demise of her friend.This death was also associated with guilt: the two friends shared many activities.They sang in a choir, were part of a group of creative reading and writing, visited painting and sculpture lessons, and to films and exhibitions.As her friend was unable to participate in these events, Elena developed the limiting belief that, by continuing to do alone what she previously had done with her friend, might end up in deceiving her friend.
After the initial induction, I told Elena Now you can go back to the days when you and your friend spent your time together, singing in the choir, going to creative writing and other activities that you liked so much.Be there with her now and enjoy doing what you liked best.Imagine you are with your friend and you are talking to her as you used to do when you were together.Now that you feel her presence here and now, you can also sense her presence next time you sing in the choir, next time you paint or sculpt, next time you write or read a poem.You know that even though she is not anymore on this earth you can still be with her.Just go inside of you and feel her spiritual presence close to you.Imagine that your friend is happy and grateful that you are still bringing her with you, continuing to carry out the same activities, honoring your friendship.Just imagine having her at your side, continuing to be with her, dedicating her the art and beauty you are surrounded by.Elena attended two more sessions with the aim to strengthen her resources.In the meantime, she started going back to painting class, singing in the chorus and engaged herself in writing poems.I expressed my sympathetic joy when I came to know that she accepted sketching portraits of children.Having consolidated her new attitude toward life, she realized that she was lucky to be alive.She acknowledged the fact that she would disrespect her friend's memory if she ceases doing what she used to do with her friend.She reached the conclusion that, in order to illustrate her love for her brother and friend and to honor their memory, she had to continue doing what gave meaning to her life.
Hypnosis helped Elena to gain awareness regarding the association between different experiences and integrated them into a coherent story.When she frankly discussed the veiled desire to kill herself, she confessed that it was not what she really wanted.She was looking for a life she deserved to live in her own way, surrounded by justice, art, and beauty.
The induction technique similar to the one with Elena is usually employed for a patient, lamenting the death of a loved one.This can achieve the purpose of integrating the natural phenomenon of life and death and of saying goodbye to the dead person.
Elena's case demonstrated how the hypnotic utilization of her favorite "medicine" -culture, art, and beauty -along with her attachment for the dead loved ones enlightened a new purpose in her life.I moved a "tree trunk" full of guilt to encourage Elena to proceed lighter toward the path of her well-being.Just as the river begins to flow again after the tree trunk, blocking its path, has been eradicated, patients also continue to improve spontaneously when they start integrating problematic memories.
The Case of Marilia
A 28-year-old girl named Marilia lost both her parents within one month.She was the single child of her parents.The apparently healthy father died suddenly two weeks before her mother, who was suffering from terminal cancer.The shocks induced by these two deaths indulged her to come for treatment.In the first session, Marilia stated that she missed her parents so much that she desired to reach them, as early as possible.Ignoring this veiled threat of suicide, I tried to divert her attention to her body and enquired if she ate and slept regularly.She replied she did not eat, which was not astonishing for me, considering her circumstances.She also told me that she was unable to sleep, which instead I thought needed to be solved.I, therefore, asked her what abstained her from sleeping.She replied that she felt such a heavy burden on her chest that she was unable to breathe properly.
After eliciting a hypnotic state, I employed the strategy of pain dislocation and told her: Now image it is already the end of today (naming the precise day, month, and year) and prepare to go to bed.Just do the usual ritual of taking off your clothes worn today, putting away the thoughts thought today, ignoring the sensations felt today.Get ready to take off everything you do not need to bring to bed to ensure a deep restful night's sleep.When you realize that you have taken off all that you do not need to carry into the sleeping world, feel the weight you said you felt on your chest.With your own times and your own rhythms, now imagine shifting that weight from your chest toward the shoulder and then slowly from the shoulder down your arm, until it reaches the palm of your hand.Now feel the difference in your chest, free of the weight that has now been relocated on the palm of your hand.When you're ready, move that weight from the palm of your hand to the bedside table.Make sure to place it right on your bedside table.It is important to know that when you fall asleep, you are sure that the weight is there, comfortable and quiet, so that the next morning when you wake up, you find it on the bedside table.In this way, when you wake up, you take the weight in your hand and make it move up on your arm until it reaches the shoulder and then, put it back in its old place on the chest.This induction worked and Marilia reported that she had slept enough when she arrived for the second session.To address the suicidal threat in Marilia, I began my second therapeutic intervention with a direct and provocative question: "Why do you want to kill your parents?"To this question, she replied that they were already dead.I repeated: "I know.If you think you want to die, it's like wanting to kill them a second time.Your death will delete the only proof that they existed on this earth and that they were good parents." After this explicit reframe, I took advantage of her state of confusion and recommended to her to close her eyes and dive inside herself.I told her: I know how much you love your parents and how much you miss them.The best way to portray how much you love them and that you continue to love them even though they are no longer here, is to honor the life they gave you.Only if you live a meaningful life, you can show that you really loved them.Now take all the time you need to be with your parents, to talk to them telling them what you never told them before and also listen to what they are willing to tell you right now.The reframing proposed a change of values: if you live a good life, you show that you had good parents who taught you that the most important thing is giving meaning to your own.The communication with her dead parents helped Marilia to keep the connection with them.
Ending Remarks
Put your sorrow into words.The grief you keep inside you will whisper in your heart until it breaks.
W. Shakespeare Establishment of a relationship of trust with the patient from the first session and not being afraid to ask patients to give words to their pain, help them transform their suffering into a narrated story.This, in turn, aims to develop a distance between the patient and the past incidence.Translating their sorrow into words helps resolve any residual passivity, any guilt for what they think has committed or omitted, any shame for what wrong they think they did or any rancor for what others were not able to do.Illustrating their story with their adult voice also helps patients identify that they are no longer a victim of what happened: they are now empowered by understanding and the lesson they have learned from the past incidence.
When attention goes to the learning process initiated after a problematic event, patients discover that they do not need to dramatize the effect of what happened (Elena's and Marilia's cases), nor trivialize the meaning of it (Monica's case), nor justify the misbehavior of others (Elena's case).Thus they learn to accept the incidence as something that occurred in their past and is part of their story.They also recognize that they are more than their story.
In each person, there is a stratification of pain, some layers are distant, while others are more recent [1].The pain narrates the patient's story: sometimes bringing limitations, other times conveying resilience.Some pains are part of the memory of the mind (Monica), other pains of the memory of the heart (Elena), and still others of the memory of the body (Marilia) [3,4,13] Therapists welcome each pain and each memory, in turn, teaching the patients the art of acceptance of the incidence that cannot be changed and the awareness that, after therapy, they can illuminate their old story with new words, describing new emotions and new thoughts.
A therapeutic alliance developed on a rapport based on attachment and trust established in the first session assists the patients to start perceiving themselves as empowered and legitimized to use their strengths and resources without ignoring their own vulnerability.They change their role from a victim to an agent or person ready to plan for their future, with the full right to live their lives without fear, guilt or shame, because these emotions are not necessary anymore.
The therapeutic work with Monica, Elena, and Marilia showed that the hypnotic induction imposed on them helped them to evaluate the characteristics of the past events, improve their current management and adaptation skills (coping styles), develop their self-regulation, and their ability to calm down.I empowered them by transferring my therapeutic sensitivity into their hands so that they could begin to love themselves and their lives.
Hypnotic induction started with the utilization of the problem confronted by the patient and proceeded with reframing it [2,8].The induction was based on accepting and utilizing what the patients brought to therapy, inviting each of them to identify their vulnerabilities as well as their Page 12/13 strengths.Placing the past in the past is a way to make peace with what happened and cannot be altered.Placing the past in the past is a way to fully live their present; living the present is their awareness that they are going toward the future they are creating in the present [7].
now know how many things you have learned that have changed your way of thinking and observing the world.Until you entered the world of work, first with one role, then with another role, then with another role.You are now aware of the alterations you went through in your job and all the skills you have improved day by day, week by week, month by month, year by year.Following the five petals metaphoric model, I asked Monica to recollect all the changes she came across in her life from the anagraphical, social, and professional perspectives.I modulated my voice to underline the word change.I went on to say: With this awareness now imagine being in front of a cricket and perceive what you see, what you hear, what you feel, what you think, and what you do.You can now divert your attention to what you are thinking right now, knowing that thoughts are only thoughts, they come and go.You can now move your attention to what you are feeling right now, also knowing that emotions are only emotions, they came and go.Now that you have explored your sensations, thoughts, and feelings you can start being curious about noticing how you perceive yourself in the presence of a cricket.With this awareness now imagine being in front of a cricket and notice that something has changed in your way of seeing, thinking, and feeling and that you are capable of doing something different.
that you are in the future of what happened to little Monica I ask you to go back to her and talk to her.You are the only person who knows what little Monica would have needed at that moment.You are the only person who knows what little Monica would have liked to hear and now you can tell her.After the induction, Monica told me that she had taught little Monica to calm down and to behave accordingly.
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Weights in Neural Network
I am reading : https://towardsdatascience.com/how-to-build-your-own-neural-network-from-scratch-in-python-68998a08e4f6
I saw following code:
import numpy as np
def sigmoid(x):
return 1.0/(1+ np.exp(-x))
def sigmoid_derivative(x):
return x * (1.0 - x)
class NeuralNetwork:
def __init__(self, x, y):
self.input = x
self.weights1 = np.random.rand(self.input.shape[1],4)
self.weights2 = np.random.rand(4,1)
self.y = y
self.output = np.zeros(self.y.shape)
def feedforward(self):
self.layer1 = sigmoid(np.dot(self.input, self.weights1))
self.output = sigmoid(np.dot(self.layer1, self.weights2))
def backprop(self):
# application of the chain rule to find derivative of the loss function with respect to weights2 and weights1
d_weights2 = np.dot(self.layer1.T, (2*(self.y - self.output) * sigmoid_derivative(self.output)))
d_weights1 = np.dot(self.input.T, (np.dot(2*(self.y - self.output) * sigmoid_derivative(self.output), self.weights2.T) * sigmoid_derivative(self.layer1)))
# update the weights with the derivative (slope) of the loss function
self.weights1 += d_weights1
self.weights2 += d_weights2
if __name__ == "__main__":
X = np.array([[0,0,1],
[0,1,1],
[1,0,1],
[1,1,1]])
y = np.array([[0],[1],[1],[0]])
nn = NeuralNetwork(X,y)
for i in range(1500):
nn.feedforward()
nn.backprop()
print(nn.output)
Shouldn't the weights be a 4x4 random matrix because we have 4 neurons in hidden layers and 4 input values so the total number of weight should be 16 but the following code assigns a matrix of 2x4 in the init function and creates a dot product?
there is only one hidden layer and one output layer in this network, not four.
Sorry I meant 4 neurons in hidden layer.
Your input matrix X suggests that number of samples is 4 and the number of features is 3. The number of neurons in the input layer of a neural network is equal to the number of features*, not number of samples. For example, consider that you have 4 cars and you chose 3 features for each of them: color, number of seats and origin country. For each car sample, you feed these 3 features to the network and train your model. Even if you have 4000 samples, the number of input neurons do not change; it's 3.
So self.weights1 is of shape (3, 4) where 3 is number of features and 4 is the number of hidden neurons (this 4 has nothing to do with the number of samples), as expected.
*: Sometimes the inputs are augmented by 1 (or -1) to account for bias, so number of input neurons would be num_features + 1 in that case; but it's a choice of whether to deal with bias seperately or not.
Thank you this helps a lot, Multiple tutorials online using same number of input as number of neurons in input layer. I learned from your answer that its the features which is number of columns in input which defined the input layer size. Let me know if I understood it correctly.
Yes, it is always number of features that determines the number of input neurons. The usual convention for the design matrix X is to have shape (num_samples, num_features) so yes, it is generally the number of columns of the input matrix. Seems you got it.
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How do I see ALL the versions of a package on NPM?
I've been using bower info package and npm view package to see which package manager has more versions of numerous packages and have found that bower goes much farther back to older versions of the packages. Do old verions simply 'expire' on npm and cannot be installed through npm after a period of type? Or is there a way for me to see older versions?
Packages do not expire. Maybe those versions have simply never been published to the npm registry? Maybe they have since been removed by their authors?
that's strange that those packages have not been removed on bower though
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User:The Legend of Zelda Freak
Home Consoles
NES
- Super Mario Bros. - Super Mario Bros. 2 - Super Mario Bros. 3 - The Legend of Zelda
SNES
N64
Gamecube
Handhelds
Gameboy;Gameboy Color
- Super Mario Land - Super Mario Land 2 - Wario Land 2
Nintendo DS
- Mario Kart DS - New Super Mario Bros.
Relations to Link
Wario
Mario Kart
He likes every Mario Kart Game. His favorite Characters are Wario and Luigi.
Mario Party
Nintendo 64
His favorite Game is Ocarina of Time, which he plays untill today in the Master Quest.
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needed as a preliminary to any such enquiry. Meanwhile let us consider a few cases of the forms of cells, either sohtary, or in such simple aggregates that their individual form is httle disturbed thereby. Let us clearly understand that the cases we are about to consider are those where the perfect sjnnmetry of the sphere is replaced by another symmetry, less complete, such as that of an ellipsoidal or cylindrical cell. The cases of asymmetrical deformation or dis placement, such as are illustrated in the production of a bud or the development of a lateral branch, are much simpler; for here we need only assume a slight and locahsed variation of surface tension, such as may be brought about in various ways through the heterogeneous chemistry of the cell. But such diffused and graded asymmetry as brings about for instance the ellipsoidal shape of a yeast-cell is another matter.
If the sphere be the one surface of complete symmetry and therefore of independent equilibrium, it follows that in every cell which is otherwise conformed there must be some definite cause of its departure from sphericity; and if this cause be the obvious one of resistance offered by a solidified envelope, such as an egg-shell or firm cell-wall, we must still seek for the deforming force which was in action to bring about the given shape prior to the assumption of rigidity. Such a cause may be either external to, or may lie within, the cell itself. On the one hand it may be due to external pressure or some form of mechanical restraint, as when we submit our bubble to the partial restraint of discs or rings or more compHcated cages of wire ; on the other hand it maybe due to intrinsic causes, which must come under the head either of differences of internal pressure, or of lack of homogeneity or isotropy in the surface or its envelope*.
* A case which we have not specially considered, but which may be found to deserve consideration in biology, is that of a cell or drop suspended in a liquid of varying density, for instance in the upper layers of a fluid (e.g. sea-water) at whose surface condensation is going on, so as to produce a steady density-gradient. In this case the normally spherical drop will be flattened into an oval form, with its maximum surface-curvature lying at the level where the densities of the drop and the surrounding liquid are just equal. The sectional outline of the drop has been shewn to be not a true oval or ellipse, but a somewhat complicated quartic curve. (Rice, Phil. Mag. Jan. 1915.) A more general case, which also may well deserve consideration by the biologist, is that of a charged bubble in (for instance) a uniform field of force : which will expand or elongate in the direction of the lines of force, and become a spheroidal surface in continuous transformation with the original sphere.
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If $\sin^{-1}\frac{2a}{1+a^2}-\cos^{-1}\frac{1-b^2}{1+b^2}=\tan^{-1}\frac{2x}{1-x^2}$ then what is value of x?
If $\sin^{-1}\frac{2a}{1+a^2}-\cos^{-1}\frac{1-b^2}{1+b^2}=\tan^{-1}\frac{2x}{1-x^2}$ then what is value of x?
Solution
$\tan^{-1}x=\tan^{-1}a-\tan^{-1}b=\tan^{-1}\frac{a-b}{1+ab}$
x=$\frac{a-b}{1+ab}$
i have a doubt what is $\tan^{-1}a$ and $\tan^{-1}b$ and how come $\tan^{-1}x=\tan^{-1}a-\tan^{-1}b$?
Related : http://math.stackexchange.com/questions/1339791/solve-for-x-from-an-equation-containing-inverse-trigonometric-functions
Hint:
Assume a=tan(y) and similarly for x and b .
Solve the identity and replace y with $tan^{-1}$b .
You will get your expression.
Use this ,this and this from here for help with those identities.
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using System.Collections;
using System.Collections.Generic;
using UnityEngine;
public class PlayerHairMasking : MonoBehaviour
{
public SpriteRenderer Renderer;
public BodyGear HeadGear;
public void Update()
{
if(HeadGear.GetGearItem() != null)
{
Renderer.maskInteraction = HeadGear.GetGearItem().HidesHair ? SpriteMaskInteraction.VisibleInsideMask : SpriteMaskInteraction.None;
}
else
{
Renderer.maskInteraction = SpriteMaskInteraction.None;
}
}
}
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Talk:Lower-Sunbury
It's not likely that anyone will enter 'Lower-Sunbury' (with the hyphen) but if they do, they will want the 'Lower Sunbury' article, which has a link to Sunbury-on-Thames if needed. treesmill 21:22, 24 January 2006 (UTC)
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Charles T. Oakes vs. Manufacturers’ Fire & Marine Insurance Company.
Suffolk.
Jan. 16.
June 27, 1883.
Field & W. Allen, JJ., absent.
In an action upon a policy of insurance, conditioned to be void if the property insured should be “ sold or conveyed in whole or in part,” oral evidence is admissible to prove that the plaintiff informed the defendant that there had been a conveyance of the property, at the same time that he informed the defendant of the existence of an outstanding mortgage on the property made before the policy was issued; and that the defendant thereupon indorsed on the policy its consent to pay the insurance in case of loss to the mortgagee named in the mortgage, and redelivered the policy to the plaintiff.
Holmes, J.
This is an action upon a policy of insurance conditioned to be void if the property should be “ sold or conveyed in whole or in part.” The plaintiff subsequently conveyed through a third person to his wife, and the answer sets up the conveyance as a breach of condition. It has already been decided that the condition was broken by the conveyance. Oakes v. Manufacturers’ Ins,. Co. 131 Mass. 164. But at a second trial the plaintiff offered to prove that he went to the office of the defendant company, and orally notified it of the conveyance and of a mortgage, which was made before the policy and was still outstanding, and requested the defendant to cure the defect in the policy caused by the conveyance, and handed the policy to the defendant for that purpose; and that, at that time, and upon said request, the defendant made the following indorsement on the policy: “ Boston, Aug. 29, 1877. Pay the within insurance of Sixteen Hundred Dollars on House in case of loss to the Andover Savings Bank. Chas. T. Oakes. Assented to Aug. 30, 1877. Jas. J, Goodrich, Secretary.” That, said policy was then redelivered by the defendant to the plaintiff, and no return of premium, or any portion thereof, was made. The court excluded the evidence, and directed a verdict for the defendant.
The plaintiff’s insurable interest is admitted, and the defendant supports this ruling and direction on the single ground that the plaintiff’s offer was an attempt to modify and enlarge the effect of the written indorsement by evidence of contemporaneous oral dealings, and to import into it, or establish alongside of it, a larger scope or transaction than can be gathered from its words. No other question is raised.
In the opinion of the court, the evidence was admissible. To begin at a little distance from the ground of the chief contention, the highest authorities have declared that the condition against alienation does not take away the defendant’s power to waive a breach and to continue the insurance in force, and that a new consideration is not necessary for this purpose. Titus v. Glen Falls Ins. Co. 81 N. Y. 410, 419. Wheeler v. Watertown Ins. Co. 131 Mass. 1, 8. Insurance Co. v. Norton, 96 U. S. 234. A condition subsequent can rarely be meant to deprive the party for whose benefit it is inserted of his choice in this respect. Hence a contract which is subject to such a condition is usually construed to provide by its own terms that it shall remain in force after a breach, unless by some overt act the contractor shall manifest his election to avoid it, or if by some overt act he shall manifest his election to affirm it, as the case may be. It follows that, if he elects to remain bound, he remains so by force of the original contract, and on the original consideration.
It might be said that this reasoning applies to a condition subsequent, strictly so called, which goes to the whole contract, and which, if insisted on, avoids it ab initia, but that the proviso in this case only limits the scope of the promise and the extent of the risk assumed. And then it might be argued further, that the scope of a promise cannot be enlarged without a new consideration. The answer is, that, even taking it that way, by the same settled construction that reads “ void ” as “ voidable,” the limitation of the promise is itself conditional, and that the original promise is to insure throughout the term, in spite of an alienation, in case the insurer manifests an election to keep the insurance on foot.
Whether it be said that the contract remains subject to affirmance after an alienation, or that the promise is alternative to insure up to or beyond that event, at the election of the promisor, all that is necessary to impose the greater burden on the insurer is an overt act directed toward the insured and manifesting an election to assume that burden. And it is enough that the act implies that the insurance is to continue, although its immediate purpose is some further result.
Thus, where, as here, the thing set up as manifesting the election is a writing, the election need not be expressed in the words used. The writing may contain no reference to the breach of condition, yet if the undertaking which it does set forth carries with it, as the necessary premise, that the insurer was content to remain bound, he will remain bound as certainly as if he had written out that such was his intention.
Of course, however, if the act thus relied on as an indirect election be shown to have been done in ignorance of the breach of condition, it will not continue the insurance unless in the exceptional case where the insurer has acted with indifference to what the facts might be, and has assumed to act with equal effect however they might turn out. Parol evidence is therefore admissible to show that the insurer knew of the breach at the time of the act relied on.
The application of the foregoing principles to this case is obvious. The defendant had the power to continue the insurance if it chose. When, at the request of the plaintiff, it indorsed upon the policy its consent to pay the insurance, in case of loss, to the mortgagee, it did an act which. necessarily assumed that the contract remained in force; for by such an indorsement it necessarily admitted and affirmed that, in case of loss, money would be due and payable to some one under the contract. Such an affirmation was an overt act of election to continue the insurance, provided the act was done with knowledge that the condition had been broken. But this indirect effect of the indorsement as an act of election depended upon the defendant’s having such knowledge. Hence evidence that the conveyance had been communicated to the company was most material, not as tending to enlarge the writing or add a further agreement, but as showing that the condition attached by the law to the operation of the indorsement as an act of election had been satisfied.
Barrett v. Union Ins. Co. 7 Cush. 175, was cited on behalf of the defendant. In that case, a policy was issued by a mutual company, subject to a by-law, which formed part of the contract, to the effect that all policies upon property previously insured should be void, unless such previous insurance was mentioned in the policy at the time it was issued. There was previous insurance not mentioned in the policy; and it was rightly held that, in an action on the policy, paroi evidence was inadmissible to show that this had been made known to the company and assented to by it. The evidence would have directly contradicted the written instrument declared on. The policy in effect stipulated that its delivery should not make a contract if there was previous insurance not mentioned. The evidence went to show that delivering the policy made a contract, notwithstanding such insurance; or, in other words, that the condition precedent was not insisted on at the very moment when, by the words of the policy, it was insisted on. The other cases cited do not require special notice.
P. West, (J. F. Andrew with him,) for the plaintiff.
E. W. Hutchins & H. Wheeler, for the defendant.
To avoid misapprehension, it may be well to add that this case is not affected by the clause providing that the policy may continue for the benefit of the purchaser, if the company consents, &c. The plaintiff claims in his own name, under the contract made with him, which he made voidable by his act, but which he says he can prove the company elected to affirm. The power of the company to elect in favor of the contract is not dependent upon any printed clause, but is given to it as legally incident to a condition subsequent. Exceptions sustained.
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Mortal Kombat Zero
Synopsis
Playable
* Fatality 1: TBD
* Fatality 2: TBD
* Fatality 1: TBD
* Fatality 2: TBD
* Fatality 1: TBD
* TBD
* TBD
* TBD
* TBD
* TBD
* TBD
* TBD
* TBD
* TBD
* TBD
* TBD
* TBD
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* TBD
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* TBD
* TBD
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* TBD
* TBD
* TBD
* TBD
* TBD
* Fatality 1: TBD
* Fatality 1: TBD
Misc.
* Fatality 1: TBD
Non-playable
* TBD
Gameplay
TBD
Stages
* TBD
* TBD - TBD
* TBD - TBD
* TBD - TBD
* TBD
* TBD
Arcade endings
See /Arcade endings/.
Alternate costumes
See /Alternate costumes/.
Trivia.
[[Category:M]]
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Harry Miller, et ux., v. Bay-to-Gulf, Inc., The Maderia Construction Company, Inc., The Maderia Holding Company, Inc., Mae V. Brush, a Widow, and A. B. Archibald.
193 So. 425
Division B
Opinion Filed January 26, 1940
W. G. Ramseur, for Appellants;
Edwin R. Dickenson and Robert W. Patton, for Appellees.
Per Curiam.
This cause of action involves a small strip of land located on Maderia Island near St. Petersburg, Florida, and bordering on the Gulf of Mexico. In 1927 The Maderia Holding Company, Inc., was the owner of a large tract of land on the aforementioned Maderia Island. The company caused a partial plat to be made of the property, showing Blocks and Lots thereon, and known as Maderia Beach Subdivision. This plat shows the westerly boundary of Blocks 5, 7, 9 and 13 abutting the waters of the Gulf of Mexico, while the westerly boundary of Blocks 1 and 3 are shown abutting on a strip of land approximately 100 feet in width, lying between Blocks 1 and 3 and the waters of the Gulf.
The herein disputed property is a part of that unplatted strip of land lying between the westerly boundary lines of Blocks 1 and 3 of the subdivision and the waters of the Gulf of Mexico.
In 1931, A. B. Archibald, then president of Maderia Holding Company, Inc., entered into an agreement with the appellants for the sale of Lot 6 of Block 3 of Maderia Beach Subdivision. Appellants immediately entered into possession of the premises and moved five cottages onto the property.
Appellants received a warranty deed to the property from Maderia Holding Company, Inc., on April 19, 1932. The descriptions in both the contract of sale and in the deed being according to the plat of Maderia Beach Subdivision. Although there was no mention of the fact made in the purchase agreement it is shown upon the face of the deed that the plat was unrecorded.
The appellants were subsequently informed by the tax collector that in order to pay taxes on their property it would be necessary to have a description of. the premises by metes and bounds because the plat of Maderia Beach Subdivision had never been recorded. Appellants then demanded and received on May 7, 1935, a deed from Maderia Holding Company, Inc., conveying Lot 6 of Block 3 by metes and bounds.
Due to erosion along the shore of the Gulf, Miller in 1932 or 1933 erected a bulkhead about two feet west of his westerly boundary line. Again in 1935 Miller caused a second bulkhead or sea wall to be erected on the land now controverted. This second wall is slightly more than five feet west of appellants’ westerly boundary.
In 1936, appellee Maderia Holding Company, Inc., sold the strip of land between appellants’ westerly boundary line and the Gulf to Mae V. Brush, and received from the vendee a purchase money mortgage covering the property described in the deed. Mae V. Brush, joined by her husband, C. H. Brush, and Bay-to-Gulf, Inc., entered into an agreement whereby Mae V. Brush was to convey the property involved to Bay-to-Gulf, Inc., upon the performance of certain conditions by the corporation.
In 1937 appellants were notified by appellees Maderia Construction Company j Inc., acting as agent for appellee Bay-to-Gulf, Inc., to remove the sea wall within five days or legal steps would be taken to remove the sarnie.
Appellants filed their bill of complaint against appellees praying for an injunction restraining appellees from demolishing the bulkhead and that appellant’s title be quieted against any claim of appellees. Appellees filed answers in which they sought to restrain appellants from further maintaining the bulkhead upon the lands of appellees.
At the close of the testimony the chancellor entered his decree permanently enjoining appellants from interfering with or attempting to interfere with the rights of appellees to the use and enjoyment of the strip of land in question.
Appellants insist that the final decree attempted to quiet title to the lands in favor of appellees upon an unsworn answer when' the lands were in actual possession of appellants and when no proper predicate was laid by necessary averments in such answer to justify such relief. In answer to this we state that the final decree adjudicated that the appellants had no right, title or interest in the lands and that appellants should thereafter be permanently enjoined from interfering with the rights of appellees.
The lower court was clearly within its province when it allowed the relief that was granted in this case. If, after hearing all the testimony, the chancellor had only dismissed the suit, it would have then been necessary for appellees to relitigate the same issues in order to gain possession of the rights which the lower court decided the appellees were entitled to. The answer in the instant case contained all the necessary averments along with a prayer for general relief. It is a well settled principle of law, and oft stated by this court, that a court of equity once having properly taken jurisdiction of the parties and the subject matter of a cause, will determine all matters properly presented in relation thereto and will grant full relief. Switow v. Sher, 136 Fla. 284, 296, 186, South. Rep. 519, 524.
Any relief may be granted under a general prayer which is warranted by the case made by the pleadings an'd proof and not inconsistent with the relief specifically prayed for. Pinellas Packing Co. v. Clearwater Citrus Growers’ Ass’n, 75 Fla. 247, 78 South. Rep. 16. The relief in the instant case would not have been' full and complete without the granting of the injunction to appellees.
Appellants present several theories seeking to establish title to the controverted property in themselves.
The first theory is that this strip of land had been impliedly dedicated as a street or passage way, the public having been' actually using it as such. The unrecorded plat of Maderia Beach Subdivision does not show any markings on the space representing the strip of land which would indicate an intention to dedicate the strip for any purpose.
In order to constitute a dedication there must be (1) an intention, on the part of the proprietor of the land, to dedicate the property to public use and (2) an acceptance by the public. The proof of both of these facts must be clear, satisfactory and unequivocal. City of Miami v. Florida East Coast Ry. Co., 79 Fla. 539, 84 South. Rep. 726; City of Palmetto v. Katsch, 86 Fla. 506; 98 South. Rep. 352. The mere user by the public, without the consent or objection of the owner, does not show an intention to dedicate. City of Palmetto v. Katsch, supra. In the instant case the record fails to show, by clear an'd satisfactory proof, any intent on the part of appellees to dedicate the land to public use. Therefore, it follows that this contention of appellants is without merit.
Appellants’ second contention is that all of the appellees, are estopped from seeking any affirmative relief due to the fraudulent misrepresentations of the appellee Archibald that the property was water front land. The chancellor, in his findings of fact, held that appellants had failed to prove the existence of any fraud. It is true that the testimony on this point is conflicting, but the Judge of the lower court had the opportunity to observe as well as hear the witnesses and his decree will not be reversed on findings of fact supported by the evidence unless it is made clearly to appear that such finding is erroneous. Schonfeld v. Engler, 119 Fla. 138, 160 South. Rep. 879; Boyte v. Stoer, 114 Fla. 395, 153 South. Rep. 845; Frickling Properties, Inc., v. Smith, 123 Fla. 556, 167 South. Rep. 42; Walter J. Dolan Properties, Inc., v. Vonnegut, 117 Fla. 830, 158 South. Rep. 457; Sabin v. City of Daytona, 130 Fla. 62, 177 South. Rep. 229; Nolen v. Nolen, 121 Fla. 130, 163 South. Rep. 401; Johns v. Gillian, 134 Fla. 575, 184 South. Rep. 140. There is ample evidence in the record to support the finding of the chancellor that there was no fraud in' connection with the sale of the land to appellants.
The third contention of appellants is that they became vested with the title to the land in question by reason of a gradual erosion of the beach to such an extent that the ordinary or high water mark of the Gulf had reached a point east of appellants’ westerly boundary line.
In disposing of this contention it will be necessary to determine exactly what is meant by ordinary high mater mark or ordinary high tide, as it is essential that appellants show the ordinary high water mark or ordinary high tide of the Gulf of Mexico extended to their westerly boundary in order for them to be entitled to any sort of riparian rights, Martin v. Busch, 93 Fla. 535, 112 South. Rep. 274; Adams v. Elliott, 128 Fla. 79, 174 South. Rep. 731, and any claim of title to property due to erosion of tidal waters must be as strictly or even more strictly construed.
The determination' of the exact meaning of “ordinary high water mark” has never been passed upon by this Court. However, in ascertaining just what were and were not tide lands in the State of Florida, this Court stated:
“Lands within the limits of the State of Florida that are covered and uncovered by the ordinary daily tides of public navigable waters are shore or tide lands, and the title to them is held by the State * * *
“* * * Overflowed lands are those that are covered by non-navigable waters * * * (not including lands between' high and low water marks of navigable streams or bodies of water, nor lands covered and uncovered by the ordinary daily ebb and flow of normal tides of navigable waters), * * (Emphasis added.) State ex rel. Ellis v. Gerbing, 56 Fla. 603, 615, 47 South. Rep. 343.
In arriving at the true meaning of the terms above designated it is appropriate to make a few comments on the tide and how it is influenced. At times of a new moon an'd full moon the tidal forces of moon and sun are acting in the same direction. High water then rises higher and low water falls lower than usual. The tides at such times are called “spring tides.” When the moon is in its first and third quarters, the tidal forces of moon and sun are opposed and the tides do not rise so high nor fall so low. At such times the tides are called “neap tides.”
The varying distance of the moon from the earth likewise affects the range of the tide. In its movement around the earth the moon describes an ellipse in a period of approximately 27y2 days. When the moon is in' perigee or nearest the earth, its tide-producing power is increased, resulting in an increased rise and fall of the tide. These tides are known as “perigean tides.” When the moon' is farthest from the earth, its tide-producing power is diminished, the tides at such time exhibiting a decreased rise and fall. These tides are called “apogean tides.” Thus if a new or full moon is in perigee (High-sprin'g or Equinoctial tide) the rise and fall of the tide will be greater than during the ordinary “spring tide.” See Marmer’s Tidal Datum Planes, U. S. Coast and Geodetic Survey, Department of Commerce, Pub. No. 135.
The term “ordinary high tide” does not refer to the limit which the monthly spring tides reach. The limit of the spring tides is, in one sense, the usual high-water mark, for as often as those tides occur, to that limit the flow extends; however, it is not the limit to which we refer when we speak of “ordinary high-water mark” or “ordinary high tide.” By the latter terms of phrases is meant the limit reached by the daily ebb and flow of the tide, the usual tide, or the neap tide that happens between the full and change of the moon. See State ex rel. Ellis v. Gerbing, supra. This meaning of ordinary high tide has the support of eminent authority. See Teschemacher v. Thompson, 18 Cal. 11, 79 Am. Dec. 151; Forgeus v. Santa Cruz County, 24 Cal. App. 193, 140 Pac. 1092; Taylor Sands Fishing Co. v. State Land Board, 36 Ore. 157, 108 Pac. 126; Cape Romain Land & Improvement Co. v. Georgia-Caroline Canning Co., 148 S. C. 428, 146 S. E. 434; Howard v. Ingersoll, 54 U. S. (8 How.) 381, 423, 14 L. Ed. 189; Thompson on Real Property, Vol. 4, Sec. 3220, p. 325; Gould on Waters (3d Ed.) Sec. 27, p. 61; Chapter VI, Hale’s De Jure Maris, quoted in 16 Am. Rep. 60.
The evidence offered by appellants in support of their contention and that offered by appellees in refutation thereof is conflicting. The witnesses for appellants testified that they had seen the waters of the Gulf of Mexico up to and over the westerly boundary line of the Millers’ property, while those of the appellees testified that the waters of the Gulf had not encroached upon the land of appellants at all. It is worthy of note, however, that several witnesses for appellants, testifying that they had seen the water up over the land of appellants and even up under the Millers’ houses or cottages, admitted on cross-examination that their observations were made during a “spring tide or extremely high tide” and it was nowhere maintained that the usual or neap tide came up over the property of appellants in' its every day ebb and flow.
The lower court in its final decree found that there had never been such erosion of the lands or that the waters of tire Gulf had never encroached on appellants’ land in such a manner as to make them riparian owners. This was a question of fact, and appellants have failed to show that the findings of the court below in this respect are clearly erroneous.
For fourth contention the appellants argue that the unrecorded plat referred to in their first deed shows an' obvious intention to lay out a subdivision along the open coast in such a manner as to make it attractive to people to purchase lots therein, and that the lot purchased at all times would have free access to the waters of the Gulf. The evidence in the record does n'ot support this contention. There is nowhere in the record evidence to justify a finding of title to this controverted strip of land in the appellants.
In addition to the foregoing comments it might not be amiss for us to point out in conclusion that both instruments of conveyance in this case contained very exact, full, complete and definite descriptions' of the premises. The first being according to a plat and the second by metes and bounds. Both of these instruments conveyed a piece of land whose bounds were determined. The disputed strip of land was not included in either conveyance and the appellants have shown no right to claim any right, title or interest in or to the premises.
We have carefully examined all other questions presented by appellants in their briefs; but, in view of our above conclusion, do not deem it necessary to discuss them at present.
The decree of the lower court is affirmed.
Affirmed.
Whitfield, P. J., and Brown and Chapman, J. J., concur.
Terrell, C. J., concurs in opinion and judgment.
Justices Buford and Thomas not participating as authorized by Section 4687, Compiled General Laws of 1927, and Rule 21-A of the Rules of this Court.
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Talk:Cartoon Crossover (revival)/@comment-24063931-20140215002405
KM, Bagel, Hagel, Wario (the Wikia user), Chrome and MattBoo are also in the movie.
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v3.4: add file preview
Since invenio-previewer has not been migrated to Semantic-UI, the code to display the file preview in the record.html has been commented out for the time being.
blocked because invenio-previewer is not migrated https://github.com/inveniosoftware/invenio-previewer/issues/124
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Crusader Pistol
The Crusader pistol is a ranged weapon
Characteristics
Crafting
* -|Level 50=
* -|Level 45=
* -|Level 35=
* -|Level 30=
Weapon modifications
Weapon modification plans are bought for 200 gold bullion from Regs.
Locations
* Crafted at a weapons workbench.
Behind the scenes
Gallery
Пистолет воителя
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Sponge in form of a mass of thick flabellate or digitate fronds arising from a common base ; with circular sphinctrate oscules., each about 1 cm. in diameter, situated at the summits or along the upper edges of the branches, the canals into which tliey lead extending nearly to the base of the branches. General surface of the sponge covered with circular pore areas each about 4 mm. in diameter, the oval or circular pores being about 90 fi in diameter, and the strands of the poral reticulum about 30 /i in breadth. Colour in spirit pale brown. Consistence soft and fleshy, being easily torn.
Skeleton . — Choanosomal skeleton formed of loosely agglo merated compound, longitudinal, or main bundles about 1 mm. in diameter, curving out to the surface as they pass upwards ; the separate fibres of the main bundles about 80 /x thick. The main bundles joined at right angles by secondary fibres 1-3 spicules thick. Spongin not perceptible. Ecto somal skeleton formed of circles of strongyles, the spicules isolated or in fan-like wisps, arranged partly vertically, partly tangentially, round the pore-areas ; the vertical spicules usually isolated and the tangential ones in wisps. On drying the sponge the edges of the pore-areas stand up sharply, the areas themselves sinking in, giving a pock-marked aspect to the surface.
Spicules. — Megascleres : choanosomal styles, 402x13 |tt, curved at about one fourth of the length from the round end, smooth, but occasionally with a few spines about the head. Ectosomal strongyles, 261 X 6'5 ix, smooth, occasionally slightly swollen at each end.
18 cm. and the breadth 13 cm.
The arrangement of the pores in circular areas each sui-rounded by a zone of ectosomal spicules is not common in Tedania ; it occurs in the second new species described belovv, and something of the kind is found in Tedania tenuicajntata^ Kidley, from the Straits of Magellan. lu the present species
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1. Introduction {#sec1-ijerph-20-03366}
Finland has a general law of conscription. Military (or non-military) service is obligatory for every Finnish male citizen between 18 to 60 years of age. Voluntary military service was made possible for women in 1995. Conscript service is usually carried out at the age of 19 years, and it lasts for 165, 255 or 347 days. During the service, a conscript may be exposed to impulse noise from various firearms as the shooting conditions vary both in the field circumstances and at a shooting range \[[@B1-ijerph-20-03366],[@B2-ijerph-20-03366],[@B3-ijerph-20-03366],[@B4-ijerph-20-03366]\]. Various types of hearing protectors (earmuffs, earplugs) are available for all exercises, drills, and shooting range activities at the Finnish Defence Forces (FDF), and their protection capacity is reportedly good \[[@B4-ijerph-20-03366],[@B5-ijerph-20-03366],[@B6-ijerph-20-03366],[@B7-ijerph-20-03366]\].
There are many possibilities for the exposure to impulse-noise in military environment, including various small arms \[[@B5-ijerph-20-03366]\]. Measurements of acoustical energy of shots from rifle-caliber weapons have shown that the peak pressure levels within the shooter's ear vary from 156 to 170 dB (rifles, pistols) \[[@B1-ijerph-20-03366]\]. In these measurements, the (A-) duration was around 0.3 ms. The attenuation (insertion loss) of impulse noise measured with an ear-canal-placed miniature microphone varied from 16 to 23 dB for earplugs, 10 to 20 dB for earmuffs, and 24 to 34 dB for the combined use of plugs and muffs \[[@B5-ijerph-20-03366],[@B6-ijerph-20-03366],[@B7-ijerph-20-03366],[@B8-ijerph-20-03366],[@B9-ijerph-20-03366]\]. If the limit for the C-weighted peak level is 135--137 dB for unprotected ears or 140 dB for protected ears (EU directive against noise-induced hearing loss), then protection against low-frequency noise is provided for up to 156 dB by earplugs, up to 150 dB by earmuffs, and up to 165 dB by combined use of plugs and muffs \[[@B8-ijerph-20-03366]\].
The hearing protection guidelines in the FDF date back to 1968, when hearing protectors (ear plugs) were instructed to be used at shooting ranges. Earmuffs became mandatory a decade later (FDF 1979) for sheltered shooting-range conditions. However, the use of ear plugs only was allowed when shooting at battle shooting situations or at open shooting ranges. According to these regulations, the used hearing protection may not risk general safety or cause undue harm in military operations. It remains obvious that these limitations and the discomfort of various types of ear plugs led to insufficient hearing protection among soldiers. Therefore, the supplementary and revised regulations (FDF 1985) ordered the use of at least earplug protectors for all shooting situations. Further, later regulations (FDF 1989, FDF 1992) gave instructions regarding protector types and safety distances for persons responsible for military education and training.
A strong acoustic trauma will induce histological changes in the cochlea and auditory nerve. Cochlear outer hair cell loss and damage of inner hair cell stereocilia and axonal loss and myelin sheath disorganization of the auditory nerve will consequently lead to permanent hearing loss \[[@B10-ijerph-20-03366]\].
Typically, hearing loss after acute acoustic trauma (AAT) can first be seen at 6 kHz frequency, and then at 8 kHz and 4 kHz \[[@B9-ijerph-20-03366],[@B11-ijerph-20-03366]\]. High frequency AAT-induced hearing loss is most typical, but also flat or low-frequency losses can be seen \[[@B9-ijerph-20-03366],[@B11-ijerph-20-03366]\]. Tinnitus is the most common symptom related to AAT. In most cases it is even more disturbing than the hearing loss itself \[[@B11-ijerph-20-03366],[@B12-ijerph-20-03366],[@B13-ijerph-20-03366],[@B14-ijerph-20-03366]\]. Hyperacusis, distorted sounds or pain in the ear are symptoms that can be present at early phase of cases with AAT \[[@B13-ijerph-20-03366],[@B14-ijerph-20-03366]\].
There are no reports on the occurrence of AAT in the FDF since the study by Mrena et al. (2004) including a selective series of 163 AAT patients treated at the Central Military Hospital during the year 2000 \[[@B14-ijerph-20-03366]\]. Most of the AATs (87.5%) in their study occurred in patients with unprotected ears, the assault rifle being the typical causative weapon \[[@B14-ijerph-20-03366]\]. Of note, prior to military service all Finnish recruits are examined with a screening test for their hearing. The quality of these hearing screening tests has proved to be of good quality \[[@B15-ijerph-20-03366]\].
The primary aim of the present study was to investigate the population-based occurrence of AATs after exposure to assault rifle noise during conscript training in the FDF. The secondary aim was to evaluate the possible causes for such accidents.
2. Materials and Methods {#sec2-ijerph-20-03366}
In the FDF a conscript is instructed to immediately report a suspected AAT and fill in a questionnaire ([Appendix A](#app1-ijerph-20-03366){ref-type="app"}), which starts a process that includes hearing screening tests and an evaluation of further actions in the healthcare system. A selected group of conscripts will annually get monetary compensation for a consequent and verified hearing loss. These incidents are also included in the annual reporting at military unit and national level.
This retrospective nationwide population-based study consists of two cohorts covering the years 1997--2003 and 2008--2010. Information on 2004--2007 does not exist, based on organizational causes. The large population consists of all FDF conscripts in service during these two time periods (\>220,000). The inclusion criterium was that if the conscript complained of changed hearing after exposure to assault rifle noise, then a questionnaire was filled in and later an audiometric analysis was performed. All conscripts who had filled in the questionnaire were thus included in this study. It was still possible that the audiometric analysis later showed only a rather limited hearing threshold shift. The study cohort comprised all conscripts (1456) during the same time periods who claimed to have symptoms of an AAT, i.e., ear pain, dullness, tinnitus or a subjective hearing deficit after exposure to assault rifle noise. These subjective symptoms, combined with a hearing threshold change of at least 10 dB for one frequency in the speech area (frequencies 500 Hz--4 kHz) or a change of at least 15 dB for the other frequencies, compared with a prior audiogram, were considered an AAT-induced hearing deficit.
The subjects were asked to fill in a questionnaire including the following parameters: type of weapon and cartridge, user of the weapon (own weapon or belonging to another shooter), distance from the weapon, type of hearing protection used, reason for not wearing hearing protection, prior instruction on the use of hearing protection. A written description of the incident was also obtained ([Appendix A](#app1-ijerph-20-03366){ref-type="app"}). These reporting forms were signed by the conscript, the trainer and the healthcare provider.
All Finnish conscripts are screened for their hearing at the beginning of their military service. In this screening examination, a 20 dB hearing level is measured at frequencies of 0.5, 1, 2, 3, 4, 6 and 8 kHz in a standardized auditory booth. If the hearing threshold is higher than 20 dB, then the hearing threshold of this frequency is examined more carefully. After a noise incident, accurate hearing thresholds are always examined.
In cases of an AAT-induced hearing loss, it is compulsory to consult an ENT (ear-nose-throat) specialist for evaluation of further care. If the AAT-related deficit exceeds 10 dB at 0.5--2 kHz or more than 35 dB at 3--8 kHz, then the conscript is ordered to receive hyperbaric oxygen treatment. Currently, corticosteroids and hyperbaric oxygen therapy are the standard treatment of acoustic trauma in the FDF. However, during the study periods, normobaric or hyperbaric oxygen only was used. Milder deficits are monitored with a control audiogram after two weeks. In addition, the conscript is ordered not to attend noise-causing service for a certain period of time.
Sound pressure levels (SPLs) of weapons can be measured by using sound level meters, hearing loss dB is measured by using audiometers, and attenuation of hearing protectors by using an insertion loss factor in field conditions with sound-level meters (microphone outside and inside hearing protector). However, the information data on hearing protector attenuation values are measured in laboratory conditions by using the human threshold of hearing (dB).
The study proposal received approval from the Research Ethics Committee of the Helsinki and Uusimaa Hospital District Occupational Health Ethics Committee (Dnro 315/E2/03/27.6.2003) and from the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District (Dnro 41/13/03/00/2012). Study permissions were granted by FDF on 7 May 2003 (Dnro R680/8/E/II) and 29 March 2012 (Dnro 2148/26/2012/AI6100).
3. Results {#sec3-ijerph-20-03366}
3.1. AATs {#sec3dot1-ijerph-20-03366}
During the investigated periods (total 10 years) the total number of conscripts with a new hearing loss due to AAT in the FDF was 1617 (annual variation of cases of HL from rifle-caliber noise, 67--258). There were 161 AATs after exposure to noise from large-caliber weapons and explosions. Altogether, 1456 (90%) of all hearing losses were caused by rifle-caliber weapons. This is around 0.7--1.5% of the annual number of conscripts (mean annual number of forms filled in 145.6, health information 428--438, and annual variation, 19,000--30,000). Altogether, 1150 rifle-caliber AATs were registered during the first study period (1997--2003, Group I) and 306 during the second period (2008--2010, Group II). The audiograms of Group I were measured on the same day of the incident in 73%, on the following day in 15%, later in 3%, and the timepoint was unknown in 9%. The audiograms of Group II were measured during the same day in 44%, the following day in 17 %, later in 4%, and on an unknown day in 35%. There were 1439 (99%) males in the study cohort and 17 females (1%).
There were 841 (73% of the Group I) unexpected shots in the Group I and 230 (75%) in the Group II. Normal cartridges caused 16 (1%) AATs in the Group I and 5 (2%) AATs in the Group II.
The annual numbers of AATs from assault rifle-caliber weapons in the FDF showed a slightly diminishing trend during the study periods ([Figure 1](#ijerph-20-03366-f001){ref-type="fig"}).
3.2. Weapons {#sec3dot2-ijerph-20-03366}
Rifle-caliber weapons consisted of assault rifles, pistols and light machine guns. Acute acoustic traumas were mostly noted in February and November, which relates to the first shooting practices that the conscripts perform in their service. Most hearing losses were due to firing an assault rifle with a blank cartridge during military drills (1286, 88% of all 1456 AATs caused by rifle-caliber weapons). When using normal cartridges, there was a recorded AAT-related hearing loss information only in 1% of the cases, typically at shooting ranges. Typically, in 593 (41%) out of the 1456 cases the neighboring conscript was shooting. Among the whole cohort of 1456 persons, the distance was less than 2 m for 973 (67%), 2--5 m for 257 (18%), more than 5 m for 84 (6%), and unknown for 142 (10%).
3.3. Hearing Protectors {#sec3dot3-ijerph-20-03366}
In 1266 (87%) out of the 1456 cases having completed the questionnaire, there was no protector in use. Typically, the situation was either unexpected or the protector had fallen off. In only 42 (3%) incidents had the conscript used a well-fitting hearing protector. In the remaining 142 (10%) cases there was a poor fit of the protector or another reason. In six questionnaires, no answer was given to this question.
3.4. Hearing Loss and Tinnitus {#sec3dot4-ijerph-20-03366}
Tinnitus was the most prominent symptom, and the most typical hearing loss after AAT was seen at the frequency of 6 kHz. Tinnitus and other hearing symptoms were asked about separately from the conscripts in Group II. Tinnitus occurred after AAT in 201 (66%) out of the 306 subjects in this group, and other ear symptoms (pain, buzzing, ringing, whizzing, headache, balance-disturbance etc.) in 144 (47%). Both types of symptoms occurred in 125 (41%) among the 306 conscripts.
Noise caused damages for various group types of conscripts around the shot in 235 incidents. Most typically, two subjects (101 incidents), or 3--5 subjects (21--33 incidents depending on the group size) were exposed. Incidents with 6--12 subjects were encountered least frequently. For machine gun noise exposure, the most usual incident affected 2--6 conscripts (eight incidents). One example of an incident with a group of 27 conscripts without hearing protection was caused by six combat vehicles driving near the group and starting to shoot with machine guns with blank cartridges.
4. Discussion {#sec4-ijerph-20-03366}
We conducted a retrospective population-based 10-year study among all conscripts in the Finnish Defence Forces (FDF) during the years 1997--2003 and 2008--2010 to find out the frequency of acute acoustic trauma (AAT) after exposure to rifle-caliber noise exposure.
The main finding was that most AAT-related hearing losses occurred after unexpected firing of an assault rifle. Most incidents occurred at the distance of less than two meters, with a neighboring conscript shooting and because no hearing protectors were used. The distances were evaluated by the victims who claimed to have adverse effects. The distances were sometimes later certified by training officers. The AATs were usually not serious (10--20 dB), although maximum hearing losses varied between 50 to 80 dB.
The most prominent hearing loss after AAT in the present series typically affected the frequency band of 6 kHz. The same has been noted for the Finnish professional soldiers \[[@B9-ijerph-20-03366]\]. The exact comparison of hearing results before and after the AAT incidents is not possible, because the audiograms at the beginning of the service were measured by a screening audiometer only.
Although the hearing protectors are ordered to be used, the unexpected shots took place in circumstances where nobody in the training had hearing protectors. This forms a major challenge for the military training noise control. More importantly, it remains the responsibility of the training personnel to emphasize this even more in the rifle-handling of the conscripts. Unfortunately, false arguments still exist claiming that blank cartridges would not cause hearing loss. Developmental work to obtain blank cartridges with less noise emission from the muzzle of the rifle should be supported. There has been continuous product development in the muzzle brakes and wooden bullet breakers to enhance these efforts \[[@B16-ijerph-20-03366],[@B17-ijerph-20-03366]\].
Communication hearing protectors are important in drill or shooting range activities, because there is always a risk of a shooting accident. There are many types of communication protectors when using earmuffs or plugs, and the variety is increasing.
Although technical orders for training sessions have been established according to the safety precautions, noise-related accidents still occur, and these can cause even permanent hearing deficits. It seems that the human control factors should be emphasized even in crisis simulation conditions. The impact of a hearing disorder on a conscript's future career and communication skills is evident and should thus not be underestimated.
The present results are in accordance with earlier studies in Finland, Sweden and elsewhere \[[@B17-ijerph-20-03366],[@B18-ijerph-20-03366],[@B19-ijerph-20-03366],[@B20-ijerph-20-03366]\]. For example, Muhr concluded that the incidence of decreased hearing thresholds was elevated during military service compared to the previous figures \[[@B13-ijerph-20-03366]\]. However, Holma pointed out that the risk of receiving a hearing loss during military service is variable \[[@B9-ijerph-20-03366]\].
Around 0.7--1.5% of the conscripts experience an AAT during their service in the FDF. Vanmaele et al. \[[@B21-ijerph-20-03366]\] studied military AAT-related hearing losses in Belgium and found a prevalence of 0.6%. In the French armed forces, the AATs decreased during the period from 2007 to 2014. The AAT incidence rate varied between 4.0 cases per 1000 person-years in 2011 and 3.4 in 2013 \[[@B22-ijerph-20-03366]\]. In the Republic of Korea 2.8% of all military personnel reported a hearing loss \[[@B23-ijerph-20-03366]\], and the use of hearing protection was modest. The present data regarding the FDF are in accordance with these studies. Further, in an earlier questionnaire study involving 416 conscripts in the FDF, personal experience of tinnitus was related both to longer service time and high levels of noise exposure \[[@B4-ijerph-20-03366]\].
Our study includes certain limitations. Audiometric analysis results can occasionally be dependent on the attitude of conscripts at the end of their military service period as some individuals may seek compensation for their AAT-induced hearing loss. On the other hand, it is also possible that some conscripts did not complain of their hearing symptoms after noise exposure, and thus the damage was not registered. The amount of missing data was a minor factor in the present study. Furthermore, the possibility of combined effects on the background of the registered AAT, i.e., simultaneous heavy weapon shooting, blows on the ear, leisure time noise exposure, etc., remains. Our results on AAT-induced hearing loss and tinnitus are impossible to verify using a control group. The present series comprised 1674 of a cohort of 220,000 conscripts. In Finland currently about 70--80% of the male population undergo military training, and therefore it is difficult to obtain a control group for comparison. Furthermore, those with an earlier permanent sensorineural hearing loss or other major health problems get an exemption from military service.
5. Conclusions {#sec5-ijerph-20-03366}
We conclude that around 0.7--1.5% of conscripts experience an AAT during their service with the Finnish Defence Forces. Most incidents occur after an accidental shot with an assault rifle, when persons around the weapon do not use hearing protection. Firing a blank cartridge as an accidental shot seems to be most typical at these occasions. Faults in weapon handling and carelessness regarding hearing protection in the battlefield military training form the basis for these. Training, control measures, and raising the awareness of possible consequences of ATT are the most important possibilities to reduce the incidence of these accidents.
Conceptualization, M.T., R.P., A.A. and A.A.M.; methodology, M.T., R.P., A.A. an A.A.M.; formal analysis, M.T. and R.P.; original draft preparation, M.T., R.P., R.N., A.A. and A.A.M.; writing M.T., R.P., R.N., A.A. and A.A.M.; review and editing, M.T., R.P., R.N., A.A. and A.A.M.; supervision, R.P., A.A. and A.A.M. All authors have read and agreed to the published version of the manuscript.
The study proposal received an approval from the Research Ethics Committee of the Helsinki and Uusimaa Hospital District Occupational Health Ethics Committee (Dnro 315/E2/03/27.6.2003) and from the Coordinating Ethics Committee of the Helsinki and Uusimaa Hospital District (Dnro 41/13/03/00/2012). Study permissions were granted by FDF on 7 May 2003 (Dnro R680/8/E/II) and 29 March 2012 (Dnro 2148/26/2012/AI6100).
Informed consent was obtained from all subjects involved in the study.
The authors declare no conflict of interest.
Evaluation form of a suspected hearing loss
Arrival date to FDF
Distance from the weapon
Ordered to use
Use of the hearing protector
Did not have time
Muff and plug
Training for its use
Not sufficiently trained
Not sufficiently practiced
Description of the incident
; Conscript, chief of the military unit and medical officer
::: {#ijerph-20-03366-f001 .fig}
Annual number (n) of conscripts with a new hearing loss after an exposure to assault-rifle noise during 1997--2003 and 2008--2010.
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[Congressional Record (Bound Edition), Volume 158 (2012), Part 10]
[House]
[Page 14361]
PERMISSION FOR MEMBER TO BE ADDED AS COSPONSOR OF H.R. 2994
Ms. BONAMICI. Mr. Speaker, I ask unanimous consent to be added as a
cosponsor to H.R. 2994, the Marine and Hydrokinetic Renewable Energy
Promotion Act. The original sponsor is no longer in Congress.
The SPEAKER pro tempore. Is there objection to the request of the
gentlewoman from Oregon?
There was no objection.
____________________
|
# Install Metacontroller using Helm
## Building the chart
The chart can be built from metacontroller source:
```shell
git clone https://github.com/metacontroller/metacontroller.git
cd metacontroller
helm package deploy/helm/metacontroller --destination deploy/helm
```
## Installing the chart
```shell
helm install metacontroller deploy/helm/metacontroller-v*.tgz
```
## Configuration
| Parameter | Description | Default |
|-------------------------------------------|-----------------------------------------------|---------------------------------------------------------|
| `rbac.create` | Create and use RBAC resources | `true` |
| `image.repository` | Image repository | `metacontrollerio/metacontroller` |
| `image.pullPolicy` | Image pull policy | `IfNotPresent` |
| `image.tag` | Image tag | `""` (`Chart.AppVersion`) |
| `imagePullSecrets` | Image pull secrets | `[]` |
| `nameOverride` | Override the deployment name | `""` (`Chart.Name`) |
| `namespaceOverride` | Override the deployment namespace | `""` (`Release.Namespace`) |
| `fullnameOverride` | Override the deployment full name | `""` (`Release.Namespace-Chart.Name`) |
| `serviceAccount.create` | Create service account | `true` |
| `serviceAccount.annotations` | ServiceAccount annotations | `{}` |
| `serviceAccount.name` | Service account name to use, when empty will be set to created account if `serviceAccount.create` is set else to `default` | `""` |
| `podAnnotations` | Pod annotations | `{}` |
| `podSecurityContext` | Pod security context | `{}` |
| `securityContext` | Container security context | `{}` |
| `resources` | CPU/Memory resource requests/limits | `{}` |
| `nodeSelector` | Node labels for pod assignment | `{}` |
| `tolerations` | Toleration labels for pod assignment | `[]` |
| `affinity` | Affinity settings for pod assignment | `{}` |
| `zap.logLevel` | Zap Level to configure the verbosity of logging | `4` |
| `zap.devel` | Development Mode or Production Mode | `"production"` |
| `zap.encoder` | Zap log encoding (‘json’ or ‘console’) | `"json"` |
| `zap.stacktraceLevel` | Zap Level at and above which stacktraces are captured (one of ‘info’ or ‘error’) | `"info"` |
| `discoveryInterval` | How often to refresh discovery cache to pick up newly-installed resources | `"20s"` |
| `cacheFlushInterval` | How often to flush local caches and relist objects from the API server | `30m` |
|
Papillary thyroid cancer (PTC) is the most common type of thyroid cancer, and the majority of PTCs exhibit a relatively good prognosis ([@B1], [@B2]). However, it has been observed recently that some PTCs may dedifferentiate in some situations. When PTC appears to be dedifferentiated, its prognosis becomes very poor, and conventional surgical treatment cannot achieve good therapeutic effects. Such patients often experience relapse or metastasis in a short period of time ([@B3]--[@B5]). At present, the treatment methods for poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are limited, and their progression mechanism is still unclear.
It has been shown that many ATC and PDTC result from dedifferentiation of DTC ([@B6]). In addition, some genetic abnormalities such as *TERT* and *TP53* mutation may play an important role ([@B7], [@B8]). A considerable number of studies have shown that occurrence and development of PDTC and ATC are closely related to immune microenvironment and epigenetic changes ([@B9]--[@B12]). Our previous study also revealed that some genes may have a significant impact on the initiation and progression of dedifferentiated thyroid cancer (DDTC) through metabolism-related pathways ([@B13]). However, considering that dedifferentiation of DTC is accompanied by a great increase in the degree of malignancy, it is likely that dedifferentiation must involve more than one mechanism. The mechanisms of how genes affect DTC dedifferentiation remain to be studied.
This study was oriented toward mining out differentially expressed genes among PDTC, PTC, and normal thyroid (NT) at the level of transcriptome and then classifying them into different groups based on their biological functions to explore possible dedifferentiation-related processes. We expect that our findings could provide a plausible basis for further study of PDTC, thereby helping to indicate prognosis and development of PTC and exploring the possibility of reversing dedifferentiation or re-differentiation.
Six NT, five PTC, and five PDTC specimens were obtained from eight patients who underwent surgical management in the Fudan University Shanghai Cancer Center (FUSCC) ([Supplementary Table 1](#SM1){ref-type="supplementary-material"}). The information of the eight patients and 16 samples was described in our previous study ([@B13]). These 16 samples were included in a discovery cohort and used for high-throughput RNA sequencing (RNA-seq) to identify differentially expressed genes. Written informed consent was obtained from each patient before his/her specimens were used in this study, and the study was approved by the Medical Ethics Committee of the FUSCC. All procedures performed in this study were in accordance with the Declaration of Helsinki.
Total RNA was extracted from all samples using TRIzol reagent (Life Technologies, Carlsbad, CA). We used RiboMinus eukaryote kit (Qiagen, Valencia, CA) to remove ribosomal RNA of total RNA (\~3 mg) before RNA-seq libraries construction. Strand-specific RNA-Seq libraries were prepared using the Illumina workflow (New England BioLabs, Beverly, MA). Next, the samples were fragmented, reverse-transcribed, and ligated to Illumina adaptors. We purified the ligated cDNA products to remove second-strand cDNA. After 13--15 cycles of amplification, libraries were controlled for quality and quantified using with an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA) and sequenced by a HiSeq 2000 sequencing system (Illumina, San Diego, CA) on a 100-bp paired-end run. Clustal Omega was used for sequence alignment. Human genome version GRCh38.100 was used throughout. RNA-seq data were normalized by fragments per kilobase per million (FPKM). Significant differences were determined by Limma package (version 3.11; <https://bioconductor.org/packages/limma/>).
The Cancer Genome Atlas and Gene Expression Omnibus Cohorts
The Cancer Genome Atlas (TCGA) mRNA expression data (FPKM) was sourced from the University of California Santa Cruz (UCSC) Cancer Browser ([@B14]). The raw data of Gene Expression Omnibus (GEO) combined GEO cohort including the GSE29265 cohort (20 NTs, 20 PTCs, and 9 ATCs) ([@B15]), GSE33630 ([@B16]), GSE53157 ([@B17]), GSE65144 ([@B18]), and GSE76039 ([@B19]) were obtained from the GEO database ([@B20], [@B21]) and were background adjusted and normalized. The ComBat method was performed to remove batch effects by the R package "sva." According to the annotation file, probes were matched with gene symbol, and probes that were not matched to gene symbol were deleted. When more than one probe matched the same gene symbol, average value was calculated as the final expression value. We performed a correlation analysis on expression matrix of PDTC and ATC samples in the combined GEO cohort, and we found that PDTC and ATC are highly correlated ([Supplementary Figure 1](#SM5){ref-type="supplementary-material"}). Therefore, we used the GSE29265 cohort and GSE33630 cohort as verification cohorts to verify the effectiveness of gene signatures. All patients were staged by the 8th edition of the TNM staging system published by the American Joint Committee on Cancer. Only samples for which all clinical data and thyroid differentiation score (TDS) could be obtained were included in the analysis.
Gene Function Annotation and Interaction Analysis
Gene Set Enrichment Analysis (GSEA) was performed using GSEA software. C5 collection \[Gene Ontology (GO)\] was utilized to identify GO terms that were differentially regulated in different comparisons. GO and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed by DAVID online function annotation tool ([@B22], [@B23]) to classify differentially expressed genes into functional categories. The enriched group was ranked by *p-*value (*p* \< 0.05) and false discovery rate (FDR \< 0.25). The GeneMANIA prediction server was used for interaction analysis between genes ([@B24]).
Weighted Gene Co-expression Network Analysis
Weighted gene co-expression network analysis (WGCNA) was performed by the R WGCNA package ([@B25]) (v1.66) to identify TDS-related modules and their gene members. The modules were identified by Dynamic Hybrid Tree Cut algorithm. We chose the yellow module with the highest correlation coefficient to screen out hub genes.
A comparison of categorical variables was performed using chi-square test and Fisher\'s exact test. Descriptive statistics are presented in the tables. TDS was proposed by TCGA project. It summarizes the expression of 16 genes (*DIO1, DIO2, DUOX1, DUOX2, FOXE1, GLIS3, NKXX2-1, PAX8, SLC26A4, SLC5A5, SLC5A8, TG, THRA, THRB, TPO*, and *TSHR*) related to thyroid metabolism and function, which can be an index to determine the degree of thyroid-specific differentiation. We have eliminated these genes in subsequent calculations to avoid bias ([@B26]). According to median of TDS, TCGA dataset was divided into two groups: highly differentiated and poorly differentiated. Least absolute shrinkage and selection operator (LASSO) regression was performed on each function group to reduce the number of variables. Multivariate logistic regression was used to determine genes to be finally included in the signature; expression levels of the differential genes as signatures in each patient were integrated into a risk score fitted by logistic regression ([Table 1](#T1){ref-type="table"}). Non-parametric receiver operating characteristic (ROC) analysis was performed for each signature, and we calculated area under the ROC curve (AUC) to test its indicative power for dedifferentiation. The Kaplan--Meier method was used to construct the disease-free survival (DFS) curve. Two-side *p* \< 0.05 was considered statistically significant. Statistical analysis and visualization were carried out through SPSS (v25.0; IBM Corporation, Armonk, NY) and R (v3.6.3; R Foundation for Statistical Computing, Vienna, Austria) software.
::: {#T1 .table-wrap}
Function based differential gene grouping.
Cell differentiation and rhythm *CIPC, HHEX, NFIA, TCTN1, ARNTL2*
Substance and signal transduction *ADCY9, ANK3, BMPR1A, CACNA1I, CHD6, CIRBP, CLIC3, DOP1A, DYNLL2, ERLIN2, FZD5, GPX3, ILDR1, KCNJ16, KCNQ1, KLHDC1, LMBRD2, NEBL, OBSL1, PCYOX1, PEBP1, PLLP, RAB30, RALGPS1, RIC3, SEC11C, SELENBP1, SLC20A2, SLC22A17, SLC48A1, TEF, TMEM50B, TOM1L2, TXNL1, AQP9, GAS2L3, GNA12, GPR173, KCNK6, KPNA2, MSR1, MYO1F, PPP1R18, PSTPIP2, SLC36A1, WASF1*
Transcription and epigenetic modification *PRDM16, RORA, RORC, SALL2, SECISBP2L, SMAD6, SP4, TBX3, TPMT, ZBTB4, ZNF154, ZNF19, ZNF208, ZNF471, ZSCAN18*
Protein modification *PTPN21, RNF146, RNF170, RNF180, USP51, USP54, ZNF10*
Cilia formation and movement *BBOF1, BBS1, CFAP70, DNAH7, IQCA1, MAATS1, PIFO, TAPT1, TEKT2*
Extracellular matrix *ADAM19, ANGPTL2, COLGALT1, PDGFA, RCN3, S100A3, SERPINH1, SH2D2A, SH3PXD2A, SLC8A1, SRPX2, TNC, TRPV2, AMIGO1, CPQ, CRHBP, NPNT, PARM1, PEF1, RGN, STX12*
Apoptosis *ARL4C, BRIP1, EME1, EXO1, FANCI, FEN1, FHL3, GNA15, LMNB1, LMNB2, MAP4K4, MCM10, MELK, RAD51, SLC20A1, SPOCD1, TOP2A, TPX2, AKTIP, ARHGEF5, BCL2, BEX4, BTG2, C2orf40, CDS1, GABARAPL2, GPRASP1, LAMTOR3, MPPE1, STK33, TENT5C, TERF2IP, TMEM192,*
Proliferation *ANLN, ASF1B, ASPM, AURKB, BUB1, CDC45, CDCA5, CDCA8, CDK2, CDT1, CENPF, CENPI, CENPL, CENPW, CEP55, CHEK1, CHTF18, CLIP2, DIAPH3, DNMT1, DTL, E2F1, E2F7, E2F8, ECT2, FOXM1, GINS1, GINS4, GTSE1, HASPIN, HJURP, IQGAP3, KIF11, KIF14, KIF23, KIF2C, KIF4A, MAD2L1, MARVELD1, MCM2, MCM4, MCM5, MIS18A, MKI67, NCAPG, NCAPG2, NCAPH, NDC80, NEK6, NTMT1, NUF2, NUSAP1, ORC1, ORC6, PDCD11, PHF19, PIMREG, PPP1R14B, PRC1, RACGAP1, RNASEH2A, SCO2, SGO1, SKA3, SMC4, SNRPB, SPC24, TCF19, TRIO, TRIP13, TUBA1B, TUBB6, UBE2C, UBE2T, UHRF1, WDHD1, ZWILCH, ZWINT, NAP1L5, NEK11, RCBTB1, RPRD2, STRBP, TMEM30B, VEZT*
Invasion *ANPEP, COL1A2, COL7A1, CORO1C, CTHRC1, EZH2, FMNL1, GREM1, LGALS1, NHSL1, PLAUR, PLXNA1, TPBG, TPM4, TWIST1, CD164, DMTN, EPB41L4B, EPB41L5, HOOK2, ID4, MARVELD2, MPP5, OCLN, PIK3CB, RBM47, RUFY3, SFTA3, SLIT3, ZFP3*
Metabolism *ACOT7, ADAMTSL1, ARSI, B4GALT2, ENO1, GALNT6, HK3, KIF20A, MTHFD2, PKM, PLPP4, PYGL, RALA, RRM2, SLC7A5, TK1, TYMS, UGCG, ACE2, ACOX2, ADHFE1, AK8, AK9, ALDH5A1, ALDH9A1, CCDC28A, CERS4, CHPT1, CROT, CYP2C8, ENOSF1, EPHX2, EPM2AIP1, ETFRF1, FAM174B, GKAP1, GPD1L, HSD17B8, IDNK, INPP5J, ITM2B, IYD, LHPP, LPCAT2, MAN1C1, MDH1B, MTMR10, NAPEPLD, NME5, NT5C2, PDE1A, PLPP3, RALGAPA2, SLC16A11, SLC25A23, SLC25A4, SORD, ST3GAL1, ST6GAL2, TM7SF2*
Immunity *ADGRE2, C5AR1, CCR1, CD276, CD300A, CEACAM4, CSF1R, CXCL1, CXCL5, ELF4, FCGR2A, FCGR2B, FPR2, LILRB2, MICB, NCF2, NFKBIE, NLRC4, NOD2, OSCAR, PSMD2, RAP2B, RELB, SECTM1, SIGLEC1, SIRPA, SIRPB2, SLAMF8, SPHK1, TNFAIP6, VSIG4, BMP7, CRBN, DUOXA1, METTL7A, PBXIP1, PRKCQ, SASH1, TRIM2, TXNDC11*
Ungrouped *C12orf75, CMSS1, C11orf71, C15orf56, C16orf46, C1orf210, CCDC191, CCDC85A, ZNF273, ZNF334, ZNF415, ZNF483, ZNF518B, ZNF585B, ZNF626, ZNF680, ZNF763, CYB5D1, ERMP1, FAM189A2, FAM8A1, FBXO16, IGSF22, IQCK, KIAA1671, KLHDC2, KLHL14, LNX1, LYRM9, PLEKHB1, PLEKHH1, PPIL6, PPP1R21, PXK, SPATA6L, THAP6, TMEM132B, TMEM245, ZMAT1, ZMYND12, KIAA0930, TCP11L1, TMEM51, VMO1, ARMCX4*
Identification of Genes Related to Differentiation Status in Dedifferentiated Thyroid Cancer
To identify genes that may relate to dedifferentiation of DTC, we first analyzed changes in high-throughput transcriptome expression profile of five PDTCs, five PTCs, and six NTs from the FUSCC cohort. Then, 1,465 deregulated genes (690 upregulated and 775 downregulated, fold change ≥ 2, *p* \< 0.05) were found among three groups ([Figure 1A](#F1){ref-type="fig"}). Then we found out the corresponding expression values of these genes in two GEO datasets (GSE29265 and GSE33630) and confirmed their differential expression (307 upregulated genes and 313 downregulated genes, fold change ≥ 1, *p* \< 0.05), as shown in Venn diagrams and heat maps, which finally validated our target gene set for an in-depth study ([Figures 1B--F](#F1){ref-type="fig"}).
::: {#F1 .fig}
Identification of deregulation of genes in DDTC. **(A)** Volcano maps: left map, 1,728 downregulated genes (green dots) and 988 upregulated genes (red dots) in PDTCs compared with NT tissues; right map, 2,630 downregulated genes (green dots) and 1,246 upregulated genes (red dots) in PDTCs compared with PTCs; fold change (FC) ≥ 2, *p* \< 0.05. **(B)** Compared with PTC and NTs, overlap of abnormal expressed genes in PDTC. **(C)** The Venn diagram showed that 1,465 genes abnormally expressed in the FUSCC cohort were validated into GSE29265 and GSE33630, and 313 downregulated genes and 307 upregulated genes were screened out. **(D--F)** The heat map shows the expression data of 620 dysregulated genes in the FUSCC cohort, GSE29265 cohort, and GSE33630 cohort. DDTC, dedifferentiated thyroid cancer; PDTC, poorly differentiated thyroid cancer; NT, normal thyroid; PTC, papillary thyroid cancer; FUSCC, Fudan University Shanghai Cancer Center.
Weighted Gene Co-expression Network Analysis Obtained a Co-expression Module Containing Seven Hub Genes
The WGCNA of 620 valid genes was carried out. Seven gene co-expression modules were detected. WGCNA assigned colors to name each module, and the yellow module showed the highest correlation with TDS ([Figures 2A--D](#F2){ref-type="fig"}). Then we screened genes by direct correlation between genes and specified traits, module identity, and weighted correlation; *METTL7A, KCNQ1, ALDH9A1, C16orf46, PLAUR, BCL2*, and *TPMT* were defined as the hub genes. The expression levels of these seven hub genes in each patient were fitted to a dedifferentiation risk score through logistic regression. The AUC value of this risk score in TCGA cohort reached 0.91([Figure 2F](#F2){ref-type="fig"}) and 0.73 in GEO combined cohort ([Supplementary Figure 2](#SM6){ref-type="supplementary-material"}). However, after the patients were divided into two groups based on the risk score, the difference in DFS between two groups was not significant ([Figure 2E](#F2){ref-type="fig"}).
::: {#F2 .fig}
Gene modules identified by weighted gene co-expression network analysis (WGCNA) and indicative ability of hub gene signature constructed by logistic regression for PTC differentiation and disease free survival rate. **(A)** Cluster the gene dendrograms according to topological overlap and assign different colors to each module. Finally, seven co-expression modules were constructed. The size of these modules varies according to the number of genes they contain. **(B)** Module--TDS associations. Each row corresponds to a module eigengene; each column corresponds to TDS. Each cell contains the corresponding correlation and *p*-value. **(C)** Using heat map plots to visualize gene networks. The heat map depicts the topological overlap matrix (TOM) between all genes in the analysis. **(D)** Heat map of module adjacency. Red indicates high adjacency (positive correlation), and blue indicates low adjacency (negative correlation). **(E)** The receiver operating characteristic (ROC) shows indicative ability of hub gene signature for TDS. **(F)** Hub gene signature fails to distinguish DFS well. PTC, papillary thyroid cancer; TDS, thyroid differentiation score; DFS, disease-free survival.
Functional Classification of Differentially Expressed Genes
The seven hub genes obtained by WGCNA showed no good results in functional enrichment and thus cannot fully reflect the impact of abnormally expressed genes on differentiation. Therefore, we screened 620 genes through univariate logistic regression analysis and found 396 genes that significantly correlated with TDS. Next, we tried to group these genes into functional groups based on the results of GSEA. We found that the results of GSEA were mostly concentrated in proliferation, immunity, metabolism, and other related pathways ([Supplementary Tables 2](#SM2){ref-type="supplementary-material"}, [3](#SM3){ref-type="supplementary-material"}). The most significant phenotype of tumor cells after dedifferentiation was the proliferation ability ([@B27], [@B28]); as a result, some phenotypes of interest may have been masked by proliferation during GSEA.
Therefore, we combined the results of GSEA and data from the literature to divide all deregulated genes into 11 groups including cell differentiation and rhythm, substance and signal transduction, transcription and epigenetic modification, protein modification, cilia formation and movement, extracellular matrix (ECM), apoptosis, proliferation, invasion, metabolism, and immunity ([Table 2](#T2){ref-type="table"}). In addition, there were 44 genes that cannot be clearly functionally classified ([Table 1](#T1){ref-type="table"}; [Supplementary Table 4](#SM4){ref-type="supplementary-material"}).
::: {#T2 .table-wrap}
Risk score for each functional group.
**Group** **Risk score**
Cell differentiation and rhythm Risk score = (0.006 × *HHEX*) + (0.057 × *CIPC*) + (−0.381 × *NFIA*) + (−0.506 × *TCTN1*) + (0.056 × *ARNTL2*)
Substance and signal transduction Risk score = (−0.497 × *KLHDC1*) + (−0.006 × *PEBP1*) + (−0.363 × *FZD5*) + (−0.106 × *KCNQ1*) + (0.048 × *SLC48A1*) + (0.529 × *ILDR1*) + (−0.729 × *ANK3*) + (−0.248 × *TOM1L2*)
Transcription and epigenetic modification Risk score = (−0.079 × *TMPT*) + (0.087 × *ZSCAN18*) + (−0.405 × *SMAD6*) + (−0.660 × *PRDM16*) + (0.029 × *TBX3*)
Protein modification Risk score = (−0.091 × *USP54*) + (−0.194 × *RNF180*) + (−0.251 × *ZNF10*)
Cilia formation and movement Risk score = (−0.854 × *TAPT1*) + (−9.068 × *DNAH7*) + (3.525 × *BBS1*)
Extracellular matrix Risk score = (−0.200 × *SH3PXD2A*) + (0.112 × *SLC8A1*) + (−0.056 × *CPQ*) + (−0.067 × *PEF1*) + (0.023 × *TNC*)
Apoptosis Risk score = (0.721 × *TMEM192*) + (−0.412 × *ARHGEF5*) + (−0.381 × *BCL2*) + (0.240 × *SLC20A1*)
Proliferation Risk score = (0.245 × *CLIP2*) + (−0.724 × *NEK11*) + (0.648 × *NTMT1*) + (4.155 × *IQGAP3*)
Invasion Risk score = (1.278 × *NHSL1*) + (0.327 × *OCLN*) + (−0.075 × *EPB41L4B*) + (0.096 × *PLAUR*) + (0.201 × *PIK3CB*) + (−0.192 × *EPB41L5*) + (−0.019 × *ID4*) + (−0.050 × *TPM4*) + (−0.525 × *MARVELD2*)
Metabolism Risk score = (0.131 × *CHPT1*) + (−0.054 × *PDE8B*) + (−0.110 × *HSD17B8*) + (−1.226 × *ADAMTSL1*) + (−0.052 × *ST3GAL1*) + (0.074 × *SLC7A5*) + (0.900 × *ACOT7*) + (−0.225 × *PYGL*)
Immunity Risk score = (0.059 × *SECTM1*) + (−0.125 × *RAP2B*) + (0.121 × *ELF4*) + (0.131 × *CRBN*) + (−0.140 × *NFKBIE*) + (−0.030 × *SASH1*) + (1.109 × *CEACAM4*) + (0.032 × *OSCAR*)
Gene Signatures of Signal and Substance Transport, Transcription and Epigenetic Modification, Extracellular Matrix, and Metabolism Group Can Indicate Dedifferentiation of Papillary Thyroid Cancer
Among the 396 genes obtained in multivariate regression analysis, many genes have been extensively studied. For example, *EZH2*, a methyltransferase, is closely related to tumor metastasis and proliferation ([@B29], [@B30]). *TNC*, an extracellular matrix protein, plays an important role in tumor cell invasion and metastasis ([@B31], [@B32]). *PRDM16*, which also plays an important role in protein modification, is also closely related to fat metabolism and tumor growth ([@B33], [@B34]). In addition, there are many important tumor-related genes. We have further screened them in each group to construct a functionally related gene signature.
We first used LASSO regression to screen each group of genes ([Supplementary Figure 3](#SM7){ref-type="supplementary-material"}) and then performed multivariate logistic regression analysis adjusted by T stage, lymph node metastasis (LNM), and *BRAF*^*V*600*E*^ on each group of genes selected to determine genes to be incorporated into the signature, and we evaluated the indicative ability of each signature by calculating the AUC value in the training set (TCGA cohort) and validation set (GEO combined cohort). We found that the AUC value in the group signal and substance transport, transcription and epigenetic modification, ECM, and metabolism was \>0.75 in both the training set and validation set ([Figure 3](#F3){ref-type="fig"}). It was worth noting that in two datasets, the AUC values of the invasion group reached 0.919297 and 0.746622, and the cilia formation and movement group also reached 0.805777 and 0.709767 ([Supplementary Figure 4](#SM8){ref-type="supplementary-material"}).
::: {#F3 .fig}
The AUC of four signatures of metabolism, signal and substance transport, transcription and epigenetic modification, and extracellular matrix. **(A--D)** The AUC of the group metabolism, signal and substance transport, transcription and epigenetic modification, and extracellular matrix was \>0.75 in both the training set and validation set. AUC, area under the receiver operating characteristic curve.
Correlations of the Gene Signatures With Clinical Features of Papillary Thyroid Cancer
In further analyses, we investigated the clinicopathological significance of the gene signatures associated with dedifferentiation to reveal their further research priority and translational potential.
Based on the gene signature of each group, we divided all TCGA patients into high-risk and low-risk groups, and we analyzed their survival differences. We found that although some risk score of gene signatures can reflect degree of differentiation well, they cannot accurately reflect the patient\'s tumor recurrence status. Among all gene signatures, there were significant differences in DFS between the high-risk and low-risk groups including transcription and epigenetic modification, cilia formation and movement, and proliferation ([Figure 4](#F4){ref-type="fig"}; [Supplementary Figure 5](#SM9){ref-type="supplementary-material"}). Next, we further analyzed the relationships between high or low risk and clinical parameters in TCGA cohort ([Table 3](#T3){ref-type="table"}), and we found significant differences in *BRAF*^*V*600*E*^ mutation, TNM stage, T stage, and TDS. In addition, in the cilia formation group, the risk score and LNM also had a significant correlation ([Figure 5](#F5){ref-type="fig"}).
::: {#F4 .fig}
Gene signatures were tested for DFS analyses in patients with thyroid cancer. **(A--C)** There were significant differences in DFS between the high-risk group and low-risk group in cilia formation and movement, transcription and epigenetic modification, and proliferation groups. DFS, disease-free survival.
::: {#T3 .table-wrap}
Clinicopathologics of PTC patients in TCGA cohort.
**TCGA (*N* = 354)**
------------------------------- ------------------------ -------
Age, years, mean ± SD (range) 47.53 ± 15.79 (15--89)
Male 91 25.71
Female 263 74.29
Yes 100 28.25
No 254 71.75
T1/T2 229 64.69
T3/T4 125 35.31
N0 208 58.76
N1 146 41.24
I/II 340 96.05
III/IV 14 3.95
Yes 210 59.32
No 144 40.68
Low 177 50.00
High 177 50.00
*PTC, papillary thyroid cancer; TCGA, The Cancer Genome Atlas; ETE, extrathyroidal extension; LNM, lymph node metastasis*.
::: {#F5 .fig}
Correlation of risk score with clinical parameters in TCGA cohort. **(A)** The risk score in cilia formation and movement group was significantly correlated with TDS, *BRAF*^*V*600*E*^ mutation, LNM, T stage, and extrathyroidal extension (ETE). **(B)** The risk score in the transcription and epigenetic modification group was significantly correlated with TDS, *BRAF*^*V*600*E*^ mutation, LNM, T stage, and ETE. **(C)** The risk score in the proliferation group was significantly correlated with TDS, *BRAF*^*V*600*E*^ mutation, T stage, and ETE. \**p* \< 0.05, \*\**p* \< 0.01, and \*\*\**p* \< 0.001. TCGA, The Cancer Genome Atlas; TDS, thyroid differentiation score; LNM, lymph node metastasis.
Undifferentiated thyroid cancer is relatively rare, but it has a very high degree of malignancy, which brings great difficulties in exploring its pathogenesis. In recent years, many studies have explored undifferentiated thyroid cancer at pre-transcription, transcription, and translation levels, revealing that a considerable number of undifferentiated cancers develop from dedifferentiation of DTC. Studies have shown that dedifferentiation of colorectal cancer is closely related to TGF-β, Wnt, and Hedgehog signaling pathways ([@B35]), while dedifferentiation of glioblastoma is closely related to hypoxia ([@B36]). Our previous studies have also shown that metabolic pathways play an important role in dedifferentiation of thyroid cancer ([@B13]). Most of these studies focused on a certain pathway or mechanism; however, according to previous experience, the occurrence and development of malignant tumors, including dedifferentiation, involve multiple mechanisms and a large number of abnormal gene expressions. Moreover, research on the mechanism of dedifferentiation of DTC is still not comprehensive. In order to explore the potential mechanism of dedifferentiation of DTC from a broader perspective, we retrospectively obtained 16 samples of eight patients with DDTC who had undergone surgical treatment in our institution (FUSCC cohort). We used intermittent sampling to obtain tissue samples with a gradient of differentiation. Through the joint analysis of 16 samples of high-throughput sequencing data, TCGA cohort, and GEO chip data, we obtained 620 differentially expressed genes related to dedifferentiation of PTC, and all of them were subjected to further analysis.
First, we performed WGCNA on all 620 genes and divided them into seven modules according to their expression. Among them, the yellow module demonstrated the strongest correlation with TDS. After screening genes by direct correlation between genes and specified traits, module identity, and weighted correlation, seven genes including *METTL7A, KCNQ1, ALDH9A1, C16orf46, PLAUR, BCL2*, and *TMPT* have been certified as hub genes. Through analysis of GeneMANIA prediction server, we found that these seven hub genes and their interacting genes directly or indirectly interact and co-localize, but they were not functionally enriched together ([Supplementary Figure 6](#SM10){ref-type="supplementary-material"}). Thus, we believe that the results of WGCNA cannot fully explain the dedifferentiation process of DTC.
In order to reflect the differentiation status more comprehensively from multiple angles, we first performed GSEA on all genes and found that the pathways related to TDS were mostly enriched on proliferation and apoptosis, which is consistent with the biological performance of PDTC. Many studies also focused on pathways related to cell proliferation, invasion, and immunity ([@B26], [@B37]--[@B39]); but also many new tumor-related phenotypes, such as ECM, cilia formation and movement, and epigenetic modification, have attracted our interest ([@B40]--[@B43]). However, these phenotypes have been rarely studied in thyroid cancer, so there is a certain value for further research ([@B9], [@B44], [@B45]).
We evaluated the gene signature of each group by calculating AUC, and we verified it in the combined GEO cohort. Finally, we identified gene signatures in group signal and substance transport, transcription and epigenetic modification, ECM, invasion, and metabolism groups, which showed very good indicative performance. In the gene signature of signal and substance transport group, *PEBP1, FZD5, KCNQ1*, and *TOM1L2* play a role in protein kinase binding together ([Supplementary Figure 7A](#SM11){ref-type="supplementary-material"}), while *PEBP1* is also associated with autophagy and ferroptotic death ([@B46]). In the transcription and epigenetic modification group, *SMAD6* and *PRDM16* showed a high degree of consistency in function ([Supplementary Figure 7B](#SM11){ref-type="supplementary-material"}), as functions of these two genes are concentrated on TGF-β/SMAD ([@B47], [@B48]), a pathway that plays an important role in cell differentiation. *SMAD6* is a component of this pathway; and its importance is self-evident, as *PRDM16*, an important methyltransferase and transcription factor, has also been reported as a repressor of the TGF-β/SMAD pathway ([@B49]). In the ECM group, *TNC* was in a central position, and its main interaction target was Integrin Alpha V (*ITGAV*), a protein expressed in thyroid tissues higher than in other tissues in the human body, suggesting that it specifically influences the differentiation of thyroid cancer through the phenotype of extracellular matrix ([Supplementary Figure 7C](#SM11){ref-type="supplementary-material"}). As a traditional malignant tumor phenotype, the gene signature of the invasion group consisted of *NHSL1, OCLN, EPB41L4B, PLAUR, PIK3CB, EPB41L5, ID4, TPM4*, and *MARVELD2*. *TPM4* showed the opposite effects in colon cancer and lung cancer. In our analysis, its high expression corresponded to better differentiation, which is consistent with the research results in colon cancer ([@B50], [@B51]). In the metabolism group, *CHPT1, PDE8B, HSD17B8, ADAMTSL1, ST3GAL1, SLC7A5, ACOT7*, and *PYGL* were combined to make up a signature. *PDE8B, HSD17B8, ST3GAL1*, and *ACOT7* also appeared in a signature constructed in our previous study ([@B13]).
Through the STRING database, we found that some genes have an interaction relationship, including intra-group and inter-group interactions ([@B52]) ([Supplementary Figure 8](#SM12){ref-type="supplementary-material"}). In the transcription and epigenetic modification group, there are gene fusion and co-expression between *TBX3* and *SMAD6* ([@B53]). *OCLN* and *MARVELD2* are both invasion-related genes, and they share a protein homology ([@B54]). *MARVELD2* also has a co-expression relationship with the signal and substance transport gene *ILDR2* ([@B54]). *KLHDC1* in the signal and substance transport group, and *IQGAP3* in the proliferation group also has co-expression ([@B55]). These possible interactions indicate that the joint effect of these genes may have a more important impact on differentiation of DTC. Since they have not been studied in thyroid cancer, it is worthy of further investigation.
At the same time, we also paid due attention to the relationship between risk scores and other clinical parameters. We found that the cilia formation group could better reflect the condition of LNM than other groups. Other studies have shown that cilia formation is closely related to autophagy ([@B56]); therefore, high expression of cilia formation-related proteins (*DNAH7, TAPT1*, and *BBS1*) in the low-risk group may be due to exuberant autophagy activity ([Supplementary Figure 7D](#SM11){ref-type="supplementary-material"}). Additionally, the formation and movement of cilia are also very important to the movement of cells, which in turn affect the tumor cell migration and invasion ([@B57]). In recent years, studies have found that the sensitivity of ATC to chemotherapy drugs is closely related to autophagy ([@B58]--[@B61]); therefore, we believe that genes involved in cilia formation and movement are promising as targets for drug therapy and should be further researched.
Our research also had certain limitations. First, we selected traditional malignant tumor-related phenotypes and some phenotypes that we were interested in as groupings, so this method is not very objective. There may be some important phenotypes that we did not include in the groups. This has also led to 44 genes that could not be included in specific group. At the same time, it should be noted that a more detailed and comprehensive grouping may divide the genes too finely, resulting in some interactions that cannot be reflected in intergroup. Second, limited by the number of cases and difficulty of obtaining material, the distinction between PDTC and PTC in the sequenced samples is not fine enough. We plan to collect more samples and use more precise microdissection methods for the next step of research.
In conclusion, we analyzed the genes that may affect the differentiation of thyroid cancer from 11 different perspectives and constructed gene signatures, revealing the possibility of multiple mechanisms that lead to dedifferentiation of DTC.
Data Availability Statement {#s5}
The datasets presented in this study can be found in online repositories. The name of the repository and accession number can be found below: National Center for Biotechnology Information (NCBI) BioProject, <https://www.ncbi.nlm.nih.gov/bioproject/>, PRJNA702648.
Ethics Statement {#s6}
This study was approved by the Medical Ethics Committee of the FUSCC. All procedures performed in our study were in accordance with the ethical standards of our institutional research **c**ommittee and the Declaration of Helsinki.
Author Contributions {#s7}
WX, CL, BM, and WW contributed to conception and design of the study. HJ, XW, and YY organized the data. WX, CL, and YucW performed the statistical analysis. All authors contributed to writing and review of the manuscript and approved the final submitted version.
Conflict of Interest {#conf1}
The UCSC Xena Platform for cancer genomics datasets, the GEO platform of the National Center for Biotechnology Information, and the Science and Technology Commission of Shanghai Municipality are gratefully acknowledged. We were also very grateful to Haihan Chen for his help in the current research.
**Funding.** This work was supported by the National Natural Science Foundation of China (Grants 81572622 and 81772854 to QJ and 82072951 to YuW) and the Natural Science Foundation of Shanghai (Grant 19ZR1410900 to WW).
Supplementary Material {#s8}
The Supplementary Material for this article can be found online at: <https://www.frontiersin.org/articles/10.3389/fonc.2021.641851/full#supplementary-material>
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[^1]: Edited by: Gong Zhang, Jinan University, China
[^2]: Reviewed by: Wanting Liu, Jinan University, China; Zexian Liu, Sun Yat-sen University Cancer Center (SYSUCC), China
[^3]: This article was submitted to Cancer Genetics, a section of the journal Frontiers in Oncology
[^4]: †These authors have contributed equally to this work
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});
$("#mapToolTip").tooltip({
html : true
});
//$("#mapToolTip").tooltip('show');
//force to change the view
//this.onCategoryChange();
this.computeMapHeight();
var vMapLayoutY = $("#mapLayout").offset().top;
var vMapLayoutW = $("#mapLayout").width();
var vMapLayoutH = $("#mapLayout").height();
//We want map always visible when classified ad list is displayed.
//listen scroll for map and its position may be fixed
$(window).scroll(function()
{
var vNumResultDisplayed = $("#resultLayout").children().length;
if (vNumResultDisplayed > 0) {
var lScrollPosition = $(window).scrollTop();
vMapLayoutW = $("#mapLayout").width();
if (lScrollPosition >= vMapLayoutY) {
lThis.mWegeooMapFixed = true;
//put map to fixed
$("#mapLayout").css("position", "fixed");
$("#mapLayout").css("top", "0");
$("#mapLayout").css("width", vMapLayoutW);
//set the same height to the map replacement, otherwise all elements above will go up
$("#mapReplacementLayout").height(vMapLayoutH);
$("#mapReplacementLayout").css("margin-top" , "10px");
$("#mapReplacementLayout").css("margin-bottom" , "10px");
} else {
lThis.mWegeooMapFixed = false;
//put map to relative
$("#mapLayout").css("position", "relative");
$("#mapLayout").css("top", "");
$("#mapLayout").css("width", "");
//reset the map replacement height
$("#mapReplacementLayout").height(0);
$("#mapReplacementLayout").css("margin-top" , "0");
$("#mapReplacementLayout").css("margin-bottom" , "0");
}
}
});
$(window).resize(function()
{
lThis.computeMapHeight();
if (lThis.mWegeooMapFixed) {
$("#mapLayout").width($("#mapReplacementLayout").width());
vMapLayoutW = $("#mapLayout").width();
vMapLayoutH = $("#mapLayout").height();
$("#mapReplacementLayout").height(vMapLayoutH);
}
});
var lParams = {};
//set the div "resultLayout" to a infiniteScroll
this.mInfiniteScrollParams = {
'contentPage' : 'services.php',
'contentData' : {},
'contentDataStep' : this.mStepDisplayedClassifiedAds,
'scrollTarget' : $(window),
'heightOffset' : 10,
'beforeLoad' : function()
{
this.contentData = lThis.onBeforeLoadInfiniteScroll();
},
'afterLoad' : function(elementsLoaded)
{
lThis.onAfterLoadInfiniteScroll();
$('#loading').fadeOut();
var i = 0;
lThis.mInfiniteScrollParams["contentData"] = lParams;
// $(elementsLoaded).fadeInWithDelay();
if ($('#content').children().size() > 100) {
$('#nomoreresults').fadeIn();
$('#content').stopScrollPagination();
}
}
};
$('#resultLayout').infiniteScroll(this.mInfiniteScrollParams);
$('#resultLayout').disableInfiniteScroll();
$("#search_town_input").autocomplete({
displayValue : function(inValue, inData)
{
return inData.libelle + " (" + inData.postal_code + ")";
}
});
//init town
if ( Wegeoo.FrontController.getInstance().getStateParserFunction())
{
var lHref = window.location.href;
var lState = lHref.substring(lHref.indexOf("/", 7));
var lStateInfos = Wegeoo.FrontController.getInstance().getStateParserFunction().call(null,lState);
if ( lStateInfos.hasOwnProperty("town"))
{
var lTown = lStateInfos["town"];
if ( lTown.hasOwnProperty("value"))
{
var lTownValue = lTown["value"];
if ( lTownValue.hasOwnProperty("name") && lTownValue.hasOwnProperty("postal_code") )
{
var lTownName = lTownValue["name"];
var lTownPostalCode = lTownValue["postal_code"];
$("#search_town_input").setSelectedTown(lTownName , lTownPostalCode);
}
}
}
}
};
///////////////////////////////////////////////////////////////////////////////////////////
//////////////////////////////////////////////////////////////////////////// DISPLAY CLASSIFIED AD
Wegeoo.PublicationPageViewController.prototype.displayAdsFromSelectedMarkers = function()
{
var lSelectedReferences = this.mWegeooMap.getSelectedReferences();
Wegeoo.FrontController.getInstance().setSelectedReferences(lSelectedReferences);
};
///////////////////////////////////////////////////////////////////////////////////////////
//////////////////////////////////////////////////////////////////////////// INFINITE SCROLL UTILS
Wegeoo.PublicationPageViewController.prototype.onBeforeLoadInfiniteScroll = function()
{
//get beginIndex and endIndex
var lBeginIndex = this.mNumClassifiedAdsDisplayed;
var lEndIndex = lBeginIndex + this.mStepDisplayedClassifiedAds;
this.mNumClassifiedAdsDisplayed = lEndIndex;
//limit on EndIndex
if (lEndIndex > this.mSelectedClassifiedAds.length)
lEndIndex = this.mSelectedClassifiedAds.length;
//get current references to load
var lCurrentReferences = this.mSelectedClassifiedAds.slice(lBeginIndex, lEndIndex);
//create ajax params for theses references.
var lParams = {};
lParams["operation"] = Wegeoo.Operation.GET_CLASSIFIED_AD_LIST_VIEW;
lParams["classifiedAdReferences"] = JSON.stringify(lCurrentReferences);
lParams["orderBy"] = $('#resultLayoutSortList').selectpicker("val");
return lParams;
};
Wegeoo.PublicationPageViewController.prototype.onAfterLoadInfiniteScroll = function()
{
this.mNumClassifiedAdsDisplayed = $('#resultLayout').children().length;
if (this.mNumClassifiedAdsDisplayed >= this.mSelectedClassifiedAds.length) {
$('#resultLayout').disableInfiniteScroll();
}
};
///////////////////////////////////////////////////////////////////////////////////////////
///////////////////////////////////////////////////////////////////////////////////////////
Wegeoo.PublicationPageViewController.prototype.computeMapHeight = function()
{
var vMapLayoutH = Math.min(300, $(window).height() / 2);
$("#map_canvas").height(vMapLayoutH);
};
///////////////////////////////////////////////////////////////////////////////////////////
/////////////////////////////////////////////////////////////////////// ON SEARCH BUTTON CLICKED
Wegeoo.PublicationPageViewController.prototype.onSearchButtonClicked = function(pEvent)
{
pEvent.preventDefault();
//town
var lSelectedTown = $("#search_town_input").getSelectedTown();
if (lSelectedTown) {
if (Wegeoo.FrontController.getInstance().getStateCreatorFunction()) {
var lState = Wegeoo.FrontController.getInstance().getStateCreatorFunction().call(null);
Wegeoo.FrontController.getInstance().setState(lState);
} else {
console.log("");
alert("");
}
} else {
BootstrapDialog.show({
type : BootstrapDialog.TYPE_WARNING,
message : "Vous devez sélectionner une ville pour lancer une recherche."
});
}
};
///////////////////////////////////////////////////////////////////////////////////////////
///////////////////////////////////////////////////////////////////////////////////////////
Wegeoo.PublicationPageViewController.prototype.cleanAllAboutTown = function()
{
$("#search_town_input").val("");
_twoFirstTownCharacters = "";
displayTowns(null);
};
Wegeoo.PublicationPageViewController.prototype.onTownChange = function(inE)
{
_isTownSelectionCorrect = false;
var vTown = inE.target.value.toString();
if (vTown.length <= 2)
_lastResults = null;
var isThereAnyBracket = vTown.indexOf("(") >= 0 || vTown.indexOf(")") >= 0;
if (vTown) {
if (isThereAnyBracket == false) {
try {
var lParams = new Array();
lParams["townFirstLetters"] = vTown;
var lService = new Wegeoo.Service();
lService.addEventListener(Wegeoo.ServiceEvent.COMPLETE, this.onTownsLoadComplete.bind(this));
lService.sendRequest(Wegeoo.Operation.SEARCH_TOWNS, lParams);
} catch(vError) {
alert(vError);
}
} else {
this.displayTowns(_lastResults);
}
}
};
Wegeoo.PublicationPageViewController.prototype.onTownsLoadComplete = function(pEvent)
{
pEvent.getTarget().removeEventListener(Wegeoo.ServiceEvent.COMPLETE, this.onTownsLoadComplete);
var lData = pEvent.getData();
this.displayTowns(lData);
};
Wegeoo.PublicationPageViewController.prototype.displayTowns = function(pResults)
{
if (pResults == null)
return;
//format data for the component
var lResults = new Array();
$.each(pResults, function(j, item)
{
lResults.push({
value : item.uppercaseName,
data : {
id : item.id,
postal_code : item.postal_code,
uppercaseName : item.uppercaseName,
libelle : item.libelle,
codgeo : item.codgeo,
region_name : item.region_name,
department_name : item.department_name
}
});
});
_lastResults = lResults;
$("#search_town_input").autocomplete("destroy");
try {
$("#search_town_input").autocomplete({
data : lResults,
multiple : true,
matchInside : false,
useFilter : false,
showResult : function(inValue, inData)
{
return inData.libelle + " (" + inData.postal_code + ")";
},
displayValue : function(inValue, inData)
{
return inData.libelle + " (" + inData.postal_code + ")";
},
onItemSelect : function(inData, inAutoCompleter)
{
//Wegeoo.FrontController.getInstance().registerSearchTownData(inData.data);
//$('input[name="town"]').val(inData.value);
//$('input[name="postal_code"]').val(inData.data.postal_code);
//$('input[name="insee"]').val(inData.data.insee);
_isTownSelectionCorrect = true;
}
});
} catch(e) {
alert(e);
}
};
///////////////////////////////////////////////////////////////////////////////////////////
///////////////////////////////////////////////////////////////////////////////////////////
Wegeoo.PublicationPageViewController.prototype.onPriceClick = function(e)
{
var vValue = ($(e.target).val());
if ($(e.target).attr("id") == "search_pricefrom_input") {
if (vValue == "min") {
$(e.target).val("");
}
} else if ($(e.target).attr("id") == "search_priceto_input") {
if (vValue == "max") {
$(e.target).val("");
//annonceId=<?php echo $vAnnonceId; ?>
}
}
};
Wegeoo.PublicationPageViewController.prototype.onPriceFocusOut = function(e)
{
var vValue = ($(e.target).val());
if ($(e.target).attr("id") == "search_pricefrom_input") {
if (vValue == "") {
$(e.target).val("min");
}
} else if ($(e.target).attr("id") == "search_priceto_input") {
if (vValue == "") {
$(e.target).val("max");
}
}
};
///////////////////////////////////////////////////////////////////////////////////////////
///////////////////////////////////////////////////////////////////////////////////////////
Wegeoo.PublicationPageViewController.prototype.onMarkersSelectionChanged = function(pEvent)
{
//clear classified ads
this.clearClassifiedAds();
//add new classified ads
var lClassifiedAdReferences = pEvent.getData();
this.displayClassifiedAds(lClassifiedAdReferences);
};
Wegeoo.PublicationPageViewController.prototype.clearClassifiedAds = function()
{
//@TODO
this.mNumClassifiedAdsDisplayed = 0;
};
Wegeoo.PublicationPageViewController.prototype.displayClassifiedAds = function(pClassifiedAdReferences)
{
this.mSelectedClassifiedAds = pClassifiedAdReferences;
$('#resultLayout').infiniteScroll(this.mInfiniteScrollParams);
Wegeoo.FrontController.getInstance().scrollToPosition(this.mOriginalMapPositionY);
};
///////////////////////////////////////////////////////////////////////////////////////////
///////////////////////////////////////////////////////////////////////////////////////////
Wegeoo.PublicationPageViewController.prototype.highlightMarker = function(pReference)
{
this.mWegeooMap.highlightMarker(pReference);
};
|
Assessment of biorisk management implementation in NIHRD laboratory as national referral laboratory of emerging infectious diseases in Indonesia
Background: NIHRD laboratory was appointed as a national referral laboratory to perform laboratory detection for emerging infectious disease (EID). Because of its important role, NIHRD laboratory must implement biorisk management system. A reliable high containment laboratory is crucial to perform laboratory diagnosis for EIDs and to avoid further spread of EIDs. The protection of laboratory workers, environment, and biological agents is achieved by addressing laboratory biorisk management consist of laboratory biosafety and biosecurity measures. This study aims to find gaps related the implementation of biorisk management with standard. Methods: This study was carried out by Professional Assessor in 2015 by conducting document checking and interviewing BSL-3 Technical Managers and BSO who were considered to have in-depth information regarding biosafety and biosecurity activities in NIHRD laboratory. Questionnaire developed based on CWA 15793:2011, which contain 160 questions provided from 16 elements of the standard. Analysis of the scores was interpreted between ranges of 0-2. Score 0 means full conformity and score 2 means doesn’t meet the required standard. Results: The study showed that only 3 out of 16 elements have full conformity with the standard. They were good microbiological technique, clothing and personal protective equipment, laboratory equipment and maintenance. The highest gap was in security elements with the score: 1.16. No elements has a noncompliance with the standard or score 2. Conclusion: Overall the NIHRD laboratory has a strong biorisk management system already established which is working well in many areas. However, important action is needed in several elements in order to comply with the standard. (Health Science Journal of Indonesia 2018;9(2):70-5)
The World Health Organization's revised Inter national Health Regulations (IHR) in 2005 and each country members to develop the core capacities needed to detect, assess, report, and respond to events that could constitute a public health emergency of international concern (PHEIC). 1 In terms of IHR, one of the core elements is Laboratory which provided vital support and facilitates the initiation and monitoring of public health interventions. 2 Therefore strengthening laboratory services must have more attention to provide accurate and reliable outcome. NIHRD laboratory was appointed as a national referral laboratory to perform laboratory diagnosis for Emerging infectious Disease (EID), such as Avian Influenza (H5N1), H7N9, MERS-CoV, Ebola Virus Diseases (EVD) as well as other EIDs (Ministry of Health Decree no. 658/2009). 3 A high containment (BSL 3) laboratory in NIHRD has been established and put into operation for this purpose. NIHRD is also tasked to be the National Influenza Centre (NIC) as part of the Global Influenza Surveillance and Response System (GISRS) to monitor influenza trends and provide early detection of novel influenza viruses. 4 Laboratory in capacity to detect microorganisms related to PHEIC must be implemented a safe and secure workplace, in order to protect workers from diseases infection occurred at laboratory or released from laboratory to environment intentionally. 5 Management of safety and secure at the laboratory called biosafety and biosecurity, where biosafety is refer to containment or a safe handling of pathogens, in order to reduce the risk of unintentional exposure or accidental release, while biosecurity means all necessary action to reduce the risk of unauthorized access, loss, theft, misuse, diversion or intentional release of valuable biological material (VBM). 6 Both, biosafety and biosecurity in combination are often called biorisk, and to assure all element of biosafety and biosecurity are in place, biorisk management should be applied in Laboratory. NIHRD laboratory have obligation to implement biorisk management system because it's important role in national health system as referral EID detection laboratory. 3 Laboratories that handle dangerous pathogens need to manage it biorisk to prevent any occurrence of human error intentionally or unintentionally in laboratory, implementing biorisk management approach and ethical responsibility. 7 Equipment and facility may also contribute to the safety of laboratory according their level of pathogen handling. 8 A reliable high containment laboratory is crucial to perform laboratory diagnosis for EIDs and to avoid further spread of EIDs. 9 Especially with the existence of dual-use research issues that has the potential to be misused, addressing laboratory biorisk management has considered to be an action to prevent from bioweapon release from containment. 10 There are a lot of tools to consider to measures the performance of laboratory in biosafety and biosecurity terms, in order to have specific needs based on its function. 11,12,13 However, in terms of NIHRD Laboratory, Assessor was considering to use CEN Workshop Agreement (CWA) 15793:2011. This standard was use as an international guideline for laboratory biorisk management. It was developed by 73 stakeholders, facilitated by Comitee Europeen De Normalisation (CEN) on 2008 and revised in 2011. 14 The CWA 15793:2011 was based on management system and risk based approach. Requirement of this standard were basic and applicable in laboratory handling biological agent/ toxin in all level, likewise, the guidelines for how to implement according to standards have also been made in Indonesia. 15,16 Assessment using CWA 15793:200 was needed to acknowledge how biorisk policy, objectives and processes to achieve on policy commitment was implemented in order to improve its performance. This study aims to find gaps related the implementation of biorisk management in NIHRD laboratory according to CWA 15793:2011. This study finding is important to develop policies and preventives procedures for the safe and secure work in NIHRD laboratory.
METHODS
This study was carried out by Professional Assessor from Robert Heckert Consulting supported by WHO in October 2015. Total 160 questions were determined by the Assessor based on the 16 elements and 61 sub elements of CWA 15793 standards as a guideline and assessment benchmark. The elements consist of managerial of biorisk in laboratory, risk assessment, inventory of pathogen and toxin, general safety, personnel and competency, good microbiological technique, clothing and personal protective equipment, human factors, health care, emergency response and contingency planning, accident/ incident investigation, facility physical requirement, equipment and main tenance, decontamination, disinfection and sterilization, transport procedure and security. The complete assessment has been done by interviewing two person involved closely with biorisk management in NIHRD laboratory, Biosafety Officer (BSO) and Biosafety Laboratory Level 3 (BSL-3) Technical Manager. They were appointed based on Head of Biomedical and Basic Health Technology Center decree number HK.02.04/ II/56/2015. Both personnel was considered to have in-depth data in documentation and information related to biosafety and biosecurity activities in the NIHRD laboratory. Laboratory document records were also validated in place. The assessment system of scoring was used 1= fully met; 2 = partially met/ in progress; 3 = not met/not started. Implementation scores and gap analysis was interpreted using following formula : The number 1 in the gap score formula represents ideal assessment score (fully met). Therefore, if the implementation of all biorisk management subelements is in conformity with the CWA 15793 standard, the gaps score will be zero (0) or in other word, there is no gap between real implementation with the standard. Vice versa, if gaps score is 2.0 then the implementation of all biorisk management sub-elements doesn't meet the required standard.
RESULTS
Elements of biorisk management in CWA 15793 were based on 16 elements, and every element consists of sub-elements that represent all requirement of the standard. Result of the assessment showed that Satisfactory implemented elements were consider no gaps (gap score 0) in all the activities found in three elements: good microbiological technique, clothing and personal protective equipment and equipment and maintenance. No element found that did not conform to the standard (gap score 2). Average gap score of elements was between 0 and 1, which means that each element has already implemented, but some of the sub-element still needs improvement. Only two elements were scored over than 1, they were emergency response and contingency planning and security. It means that in these element most of the sub-elements doesn't meet required standard and much more improvement was needed. (Table 1) The assessment indicated that more than half activities of NIHRD biorisk management programs are in place, but still there are some elements in specific sub element need to be improved. As in first element, Both personnel was considered to have in-depth data in documentation and information related to biosafety and biosecurity activities in the NIHRD laboratory. Laboratory document records were also validated in place. The assessment system of scoring was used 1= fully met; 2 = partially met/in progress; 3 = not met/not started. Implementation scores and gap analysis was interpreted using following formula : The number 1 in the gap score formula represents ideal assessment score (fully met). Therefore, if the implementation of all biorisk management subelements is in conformity with the CWA 15793 standard, the gaps score will be zero (0) or in other word, there is no gap between real implementation with the standard. Vice versa, if gaps score is 2.0 then the implementation of all biorisk management sub-elements doesn't meet the required standard.
RESULTS
Elements of biorisk management in CWA 15793 were based on 16 elements, and every element consists of sub-elements that represent all requirement of the standard. Result of the assessment showed that Satisfactory implemented elements were consider no gaps (gap score 0) in all the activities found in three elements: good microbiological technique, clothing and personal protective equipment and equipment and maintenance. No element found that did not conform to the standard (gap score 2). Average gap score of elements was between 0 and 1, which means that each element has already implemented, but some of the sub-element still needs improvement. Only two elements were scored over than 1, they were emergency response and contingency planning and security. It means that in these element most of the sub-elements doesn't meet required standard and much more improvement was needed. (Table 1) The assessment indicated that more than half activities of NIHRD biorisk management programs are in place, but still there are some elements in specific sub element need to be improved. As in first element, Health Science Journal of Indonesia Biorisk management system, which have 13 sub elements to be addressed, and scores in sub elements was showed that policy, roles and responsibility, audits and inspection has become a shortcoming of these elements. Some sub-elements that are seen with high scores compared to the questions indicate that there is a significant inconsistency with the standard. They are monitoring and control in element number 3, contingency plans in element number 10, commissioning and decommissioning in element number 12, Information security and personnel control in element number 16. In terms of general requirement and policy, the study found that almost all aspect of important requirement were fulfilled, however the lack of documentation records were occurred in many elements and implementation of routine audit were not fulfilled. The gap score indicates that the highest value element is an element that needs to be prioritized to improve, and in this study, we found that the highest gaps score which has more than 1 score was element security and the second highest is emergency respond and contingency.
DISCUSSION
Biorisk management approach is built on the concept of continual improvement through a cycle of planning, do, correct and act (PDCA) in order to achieve conformity with the standard. 17 It is intended to effectively identify, monitor and control the laboratory biosafety and biosecurity activities. Many standard was built base on international agreement and guideline such as CWA 15793:2011, WHO, CDC and ISO. 6,18,19 Some countries will adopt them as a national guidelines. in Indonesia, regulations related to biorisk management are made based on international guidelines as well, with a few modifications that are appropriate to the conditions of the country. 16,9 Every laboratory has different issues regarding their actual implementation of standard. Most standard was referring to ideal condition which will be different with the actual condition of each laboratory must encounter, like environment or culture. However, Laboratory management should create roles and responsibilities to biorisk policies, rules and regulations according to it scope of work, with any special emphasis regarding their issues to protecting workers, environment and the product. 20,21 Biorisk management system, which have 13 sub elements to be addressed, and scores in sub elements was showed that policy, roles and responsibility, audits and inspection has become a shortcoming of these elements. Some sub-elements that are seen with high scores compared to the questions indicate that there is a significant inconsistency with the standard. They are monitoring and control in element number 3, contingency plans in element number 10, commissioning and decommissioning in element number 12, Information security and personnel control in element number 16. In terms of general requirement and policy, the study found that almost all aspect of important requirement were fulfilled, however the lack of documentation records were occurred in many elements and implementation of routine audit were not fulfilled. The gap score indicates that the highest value element is an element that needs to be prioritized to improve, and in this study, we found that the highest gaps score which has more than 1 score was element security and the second highest is emergency respond and contingency.
DISCUSSION
Biorisk management approach is built on the concept of continual improvement through a cycle of planning, do, correct and act (PDCA) in order to achieve conformity with the standard. 17 It is intended to effectively identify, monitor and control the laboratory biosafety and biosecurity activities. Many standard was built base on international agreement and guideline such as CWA 15793:2011, WHO, CDC and ISO. 6,18,19 Some countries will adopt them as a national guidelines. in Indonesia, regulations related to biorisk management are made based on international guidelines as well, with a few modifications that are appropriate to the conditions of the country. 16,9 Every laboratory has different issues regarding their actual implementation of standard. Most standard was referring to ideal condition which will be different with the actual condition of each laboratory must encounter, like environment or culture. However, Laboratory management should create roles and responsibilities to biorisk policies, rules and regulations according to it scope of work, with any special emphasis regarding their issues to protecting workers, environment and the product. 20,21 Assessment of biorisk management conducted in Laboratory Hospital in Bangkok, Thailand using biosafety practices tools adopted from Centers for Diseases Control (CDC) and National Institutes of Health (NIH) guidelines. 18,22 The study found that appropriate of protective barriers were need to be strengthened. 23 It means that there are issues in their facilities and equipment needed according to biosafety requirements. In Singapore, audits for biosafety requirement was conducted in University Laboratories and in Nanyang Technological University, using WHO Biosafety Manual and NTU safety manual for biological work and local requirement, and found that issues regarding consistency of biosafety commitments in laboratory. 12 In Indonesia, the assessments study of biosafety and biosecurity was also conducted in University of Indonesia, using adopted tools from WHO guidelines and the National University of Singapore (University NUS) laboratory manual for 38 laboratories worked with pathogen. It found that action of improvement was in human resource (good microbiological techniques and recommended work practices) and emergency response. 24 NIHRD laboratory in cooperation with WHO was also assessed biosecurity in seven regional and central reference labs in 2010, with the result that physical security, employee management and information security have not been adequately implemented. 25 Our study finding was mainly in the area of policy and documentation. Policy statement from top management was not socialize and noticed within laboratory staff, since the institution guideline was not published yet. While, The challenge with the security element is the need to improvement of the personnel reliability policy and competency. The procedure of laboratory staff recruitment was not controlled by the laboratory management but administered by higher level in Institution causing inadequate test for personal performance and competency. There were no written standard operating procedures has been documented yet for the response and contingency planning and system, where in the event of emergency, adequate contingency measures is needed to be address.
Corrective actions that must be carried out prioritized those that are important and urgent according to assessor were as follow: 1) develop a policy statement from top management regarding biorisk management based upon the elements found in CWA 15793 and 16393; 2) develop a biorisk management manual based upon the CWA 15793 elements as a guide and table of contents; 3) ensure that NIHRD is in compliance with all Indonesian regulatory requirements regarding the operation and risks associated with the activities carried out in the institute; 4) begin an audit/inspection process of all labs based upon a biosafety guideline (US, Canadian, WHO, etc.) to determine the status of biorisk implementation; 5) develop, implement and document a formal risk assessment process; 6) begin better documentation of risk management decisions at all levels and in all areas; 7) ensure that only staff with the full immunization and required protective titers are allowed to work with pathogens being protected against; 8) establish a uniform incident/ accident reporting system for all laboratories and encourage reporting of all incidents and near misses; 9) define and implement a personnel reliability policy.
In conclusion, overall the NIHRD laboratory has a strong biorisk management system already established which is working well in many areas. However, some elements need to prioritized and important actions must be taken to follow the recommendations of the assessor to comply with the standards, in order to assess the performance of the system and NIHRD needs to establish an assessment review using the same CWA 15793 checklist which can be repeated to ensure that the elements are improving, in order to have safe and secure laboratory.
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options should be optional
Currently I have to write var layzr = new Layzr({}); to use all the default options, which is weird.
@wong2 no doubt about it, great catch. will merge shortly
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Thread:<IP_ADDRESS>/@comment-5691350-20130504083252
Hi, welcome to ! Thanks for your edit to the NC6 Gauss SAW page.
Please leave me a message if I can help with anything!
|
package com.vaadin.cdi.tutorial;
import javax.annotation.PostConstruct;
import javax.enterprise.event.Observes;
import javax.inject.Inject;
import com.vaadin.cdi.CDIViewProvider;
import com.vaadin.cdi.NormalUIScoped;
import com.vaadin.navigator.Navigator;
import com.vaadin.ui.UI;
@NormalUIScoped
public class NavigationServiceImpl implements NavigationService {
@Inject
private CDIViewProvider viewProvider;
@Inject
private ErrorView errorView;
@Inject
private UI ui;
@PostConstruct
public void initialize() {
if (ui.getNavigator() == null) {
Navigator navigator = new Navigator(ui, ui);
navigator.addProvider(viewProvider);
navigator.setErrorView(errorView);
}
}
@Override
public void onNavigationEvent(@Observes NavigationEvent event) {
try {
ui.getNavigator().navigateTo(event.getNavigateTo());
} catch (Exception e) {
throw new RuntimeException(e);
}
}
}
|
#include "block.h"
static ivec2s get_texture_location(struct World *world, ivec3s pos, enum Direction d) {
switch (d) {
case UP:
return (ivec2s) {{ 4, 2 }};
case DOWN:
return (ivec2s) {{ 2, 0 }};
default:
return (ivec2s) {{ 5, 2 }};
}
}
void podzol_init() {
struct Block podzol = BLOCK_DEFAULT;
podzol.id = PODZOL;
podzol.get_texture_location = get_texture_location;
BLOCKS[PODZOL] = podzol;
}
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Ochlocracy
Ochlocracy, also called Mob Rule, is the ideology representing Off-Compass Democracy.
History
Personality and Behaviour
How to Draw
Ochlocracy_flag.svg
* 1) Draw a ball,
* 2) In the centre, draw a blue circle,
* 3) Draw a white pitchfork inside the circle, coming up from the bottom of the circle,
* 4) Draw the eyes, and you're done!
* 5) (Optional) Colour the eyes red.
Friends
* [[File:Reddit.png]] Reddit - Echochamber gang!
* [[File:Pcba_twit.png]] Twitter - Basically me as a website... Based!
* [[File:Pop.png]] Populism - If the people want to...
Frenemies
Enemies
* [[File:Oligarchy.png]] Oligarchy - The opposite a mob controlled society. Cringe.
* [[File:Nooc.png]] Noocracy - Same as above.
* [[File:Auto.png]] Autocracy - [comment removed by moderator]
* [[File:PolState.png]] Police Statism - Just let me do some crime, damn it!
Literature
* The Menace of the Herd, or Procrustes at Large by [[File:Monarch.png]] Erik von Kuehnelt-Leddihn
Articles
* Ochlocracy
* Tyranny of the Majority
* Mobbing
* Gang Rape
* Lynching
* Herd Mentality
* Bandwagon Effect
* Argumentum ad Populum
Online Communities
* All social media communities.
|
Board Thread:Roleplay/@comment-26380985-20150720212015/@comment-26380985-20150822160239
Kaoru: A passage opened. Stand back!
The kaoru troops begin to leave the enclosure.
Captain: Do not let them escape.
|
Marshmallow Sky
Paused
Collect black orbs ⚫ as fast as possible.
Turn with with mouse. LMB click to accelerate (costs 1 orb), RMB click to slow down (free).
You also get a "free" speed boost each time you collect an orb. Crashing teleports you up, but costs 5 orbs.
Space toggles pause. Q toggles quality. R restarts game.
|
//#ifndef FORCE_DEBUG
//#define NDEBUG
//#endif
#include <string>
#include <algorithm>
#include "analysis/DNAVector.h"
#include "analysis/KmerTable.h"
#include "base/CommandLineParser.h"
extern "C"
{
#include <fcntl.h>
#ifndef WIN32
#include <unistd.h>
#endif
}
static bool DEBUG_FLAG = false;
using namespace std;
bool Exists(const string & s)
{
FILE * p = fopen(s.c_str(), "r");
if (p != NULL) {
fclose(p);
return true;
}
// cout << "FATAL ERROR: Could not open file for read: " << s << endl;
// cout << "Please make sure to enter the correct file name(s). Exiting now." << endl;
return false;
}
void SortPrint(FILE * pReads, svec<IDS> & ids, const vecDNAVector & seq)
{
long long i;
Sort(ids);
int lastID = -1;
int id = -1;
int start = -1;
int edge = -1;
int lastStart = -1;
int lastEdge = -1;
int ori;
string line;
char tmp[1024 * 10];
int lastStartTemp = -1;
int lastOri = 1;
for (i = 0; i<ids.lsize(); i++) {
id = ids[i].ID();
ori = ids[i].Ori();
start = ids[i].Start();
edge = ids[i].Edge();
//cout << id << "\t" << start << "\t" << edge << endl;
if (id != lastID
#ifndef NO_REVERSE_OUT
|| ori != lastOri
#endif
) {
if (lastID != -1) {
sprintf(tmp, "%d\t%d\t", lastStart, lastEdge);
line += tmp;
if (lastStart > lastStartTemp) {
fprintf(pReads, "%s\t", line.c_str());
//const DNAVector &d = seq[lastID];
#ifndef NO_REVERSE_OUT
DNAVector d = seq[lastID];
if (lastOri == -1) {
d.ReverseComplement();
//cout << "Reversing" << endl;
}
else {
//cout << "Forward" << endl;
}
#endif
for (int j = 0; j<d.isize(); j++) {
tmp[1] = 0;
tmp[0] = d[j];
fprintf(pReads, "%s", tmp);
}
if (lastOri == -1)
fprintf(pReads, "\t-");
else
fprintf(pReads, "\t+");
fprintf(pReads, "\n");
}
//fprintf(pReads, "%d\t%d\n", lastStart, lastEdge);
line = "";
}
//fprintf(pReads, "%s\t%d\t%d\t", seq.Name(id).c_str(), start, edge);
sprintf(tmp, "%s\t%d\t%d\t", seq.Name(id).c_str(), start, edge);
line = tmp;
lastStartTemp = start;
}
lastID = id;
lastStart = start;
lastEdge = edge;
lastOri = ori;
}
if (id != -1) {
sprintf(tmp, "%d\t%d\t", start, edge);
line += tmp;
if (lastStart > lastStartTemp) {
fprintf(pReads, "%s\t", line.c_str());
DNAVector d = seq[id];
if (ori == -1)
d.ReverseComplement();
for (int j = 0; j<d.isize(); j++) {
tmp[1] = 0;
tmp[0] = d[j];
fprintf(pReads, "%s", tmp);
}
if (lastOri == 1)
fprintf(pReads, "\t+");
else
fprintf(pReads, "\t-");
fprintf(pReads, "\n");
}
//fprintf(pReads, "%d\t%d\n", start, edge);
}
}
//========================================================================
//========================================================================
//========================================================================
bool Irregular(char l)
{
if (l == 'A' || l == 'C' || l == 'G' || l == 'T')
return false;
//cout << "Irregular char: " << l << endl;
return true;
}
string ReadsExt(const string & in)
{
char tmp[1024 * 10];
strcpy(tmp, in.c_str());
int n = strlen(tmp);
for (int i = n - 1; i >= 0; i--) {
if (n - i > 6) {
break;
}
if (tmp[i] == '.') {
tmp[i] = 0;
string out = tmp;
out += ".reads";
return out;
}
}
string out = in + ".reads";
return out;
}
class KmerEntryCompare
{
const vecDNAVector& master;
size_t kmer_length;
DNAVector target;
public:
KmerEntryCompare(const vecDNAVector& m, size_t k) : master(m), kmer_length(k)
{
}
const DNAVector& GetDNA(KmerEntry kmer)
{
return kmer.Index() < 0 ? target : master[kmer.Index()];
}
int operator()(KmerEntry a, KmerEntry b)
{
const DNAVector &me = GetDNA(a);
const DNAVector &you = GetDNA(b);
//ML: perform the actual comparison on the raw char array
const char* me_str = (&(me[0])) + max(a.Pos(), 0);
const char* you_str = (&(you[0])) + max(b.Pos(), 0);
for (size_t i = 0; i<kmer_length; i++) {
if (me_str[i] > you_str[i])
return false;
if (me_str[i] < you_str[i])
return true;
}
return false;
}
void set_target(const DNAVector& d)
{
target = d;
}
};
void add_kmers(const vecDNAVector & all, int K, vector<KmerEntry>& result)
{
for (size_t j = 0; j<all.size(); j++) {
const DNAVector & d = all[j];
for (int i = 0; i <= d.isize() - K; i++) {
result.push_back(KmerEntry(j, i));
}
}
KmerEntryCompare comparer(all, K);
sort(result.begin(), result.end(), comparer);
}
long long BasesToNumberCountPlus(const vector<KmerEntry>& kmers,
svec<IDS> & ids,
long long & count,
const DNAVector & d,
int edge,
const vecDNAVector& reads,
int kmer_length) {
KmerEntryCompare comparer(reads, kmer_length);
comparer.set_target(d);
KmerEntry dummyKmer;
vector<KmerEntry>::const_iterator iter = lower_bound(kmers.begin(), kmers.end(), dummyKmer, comparer);
if (iter == kmers.end() || comparer(dummyKmer, *iter))
return -1;
size_t ret = iter - kmers.begin();
count = 0;
for (size_t i = ret; i<kmers.size(); i++) {
if (comparer(kmers[i], kmers[ret]))
break;
if (comparer(kmers[ret], kmers[i]))
break;
ids.push_back(IDS(kmers[i].Index(), kmers[i].Pos(), edge));
count++;
}
// cerr << "Searched: " << d.AsString() << "\tcount: " << count << endl;
return ret;
}
int main(int argc, char** argv)
{
commandArg<string> aStringCmmd("-i", "read fasta file");
commandArg<string> gStringCmmd("-g", "graph file");
commandArg<string> oStringCmmd("-o", "graph output");
commandArg<int> kCmmd("-k", "kmer size", 24);
commandArg<bool> strandCmmd("-strand", "strand specific", false);
commandArg<long> maxReadsCmd("-max_reads", "max number of reads to map to graph", -1);
commandArg<bool> debugCmmd("-debug", "verbosely describe operations", false);
commandArg<bool> no_cleanupCmmd("-no_cleanup", "retain input files on success", false);
commandLineParser P(argc, argv);
P.SetDescription("Assembles k-mer sequences.");
P.registerArg(aStringCmmd);
P.registerArg(gStringCmmd);
P.registerArg(oStringCmmd);
P.registerArg(kCmmd);
P.registerArg(strandCmmd);
P.registerArg(maxReadsCmd);
P.registerArg(debugCmmd);
P.registerArg(no_cleanupCmmd);
P.parse();
string aString = P.GetStringValueFor(aStringCmmd); // reads
string gString = P.GetStringValueFor(gStringCmmd); // graph input
string oString = P.GetStringValueFor(oStringCmmd); // graph output
bool sStrand = P.GetBoolValueFor(strandCmmd);
int k = P.GetIntValueFor(kCmmd) + 1;
long max_reads = P.GetLongValueFor(maxReadsCmd);
bool NO_CLEANUP = P.GetBoolValueFor(no_cleanupCmmd);
DEBUG_FLAG = P.GetBoolValueFor(debugCmmd);
if (Exists(oString) && (!Exists(gString)) && (!Exists(aString))) {
cerr << "Quantify graph previously finished successfully on " << aString << ". Not rerunning here." << endl;
return(0);
}
else if (!(Exists(gString) && Exists(aString))) {
cerr << "ERROR: missing either: " << gString << " or " << aString << ", cannot run QuantifyGraph here." << endl;
return(1);
}
int i, j;
vecDNAVector seq;
if (max_reads > 0) {
// std::cerr << "*Restricting number of input reads to " << max_reads << endl;
seq.setMaxSeqsToRead(max_reads);
}
seq.Read(aString, false, true, true, 1000); // parse the reads from the fasta file
vector<KmerEntry> kmers;
add_kmers(seq, k, kmers);
size_t m = kmers.size();
FlatFileParser parser; // read the raw graph
parser.Open(gString);
FILE * pOut = fopen(oString.c_str(), "w"); // output graph
string reads = ReadsExt(oString);
FILE * pReads = fopen(reads.c_str(), "w"); // output reads in context of graph
svec<IDS> ids;
ids.reserve(seq.size());
svec<char> first;
first.resize(100000, 'N');
// do an initial scan to set up the node identities and linkage info
while (parser.ParseLine()) {
if (parser.GetItemCount() >= 4) {
const string & s = parser.AsString(3); // kmer
int node = parser.AsInt(0);
int prevNode = parser.AsInt(1);
const char * p2 = s.c_str();
if (node >= first.isize())
first.resize(node + 10000, 'N');
first[node] = p2[0]; // first letter of the kmer stored
}
}
// now, do a second pass:
parser.Open(gString);
while (parser.ParseLine()) {
if (parser.GetItemCount() < 4) {
fprintf(pOut, "%s\n", parser.Line().c_str()); // component header line
// processing of component data from previously processed component
if (ids.lsize() > 0) {
SortPrint(pReads, ids, seq);
}
fprintf(pReads, "%s\n", parser.Line().c_str());
ids.clear();
continue;
}
const string & s = parser.AsString(3); // kmer
int node = parser.AsInt(0);
int prevNode = parser.AsInt(1);
const char * p2 = s.c_str();
long long edge = prevNode;
long long n1 = 0;
long long n2 = 0;
if (prevNode >= 0) {
// building the whole kmer sequence in 'sub'
DNAVector sub;
sub.resize(strlen(s.c_str()) + 1);
const char * p = s.c_str();
for (i = 0; i<sub.isize() - 1; i++)
sub[i + 1] = p[i];
if (first[prevNode] == 'N')
cout << "ERROR!! first[prevNode] where prevNode = " << prevNode << " unset" << endl;
sub[0] = first[prevNode];
BasesToNumberCountPlus(kmers, ids, n1, sub, edge, seq, k);
if (!sStrand) {
sub.ReverseComplement();
long long from = ids.lsize();
BasesToNumberCountPlus(kmers, ids, n2, sub, edge, seq, k);
if (n1 + n2 < 0x7FFFFFFF) {
for (long long x = from; x<ids.lsize(); x++) {
ids[x].SetOri(-1);
int len = seq[ids[x].ID()].isize();
int pos = ids[x].Start() + 1;
//cout << "len=" << len << " pos=" << pos;
#ifndef NO_REVERSE_OUT
ids[x].SetStart(len - pos - k + 1);
//cout << " new=" << len-pos-k+1 << endl;
#else
ids[x].SetStart(pos + 1);
#endif
}
}
else {
cout << "WARNING: k-mer overflow, n=" << n1 + n2 << ". Discarding." << endl;
n1 = n2 = 0;
}
}
}
for (i = 0; i<parser.GetItemCount(); i++) {
if (i>0)
fprintf(pOut, "\t");
if (i == 2) {
fprintf(pOut, "%d", (int)(n1 + n2));
}
else {
fprintf(pOut, "%s", parser.AsString(i).c_str());
}
}
fprintf(pOut, "\n");
}
if (ids.lsize() > 0) {
SortPrint(pReads, ids, seq);
}
fclose(pOut);
fclose(pReads);
// only remove the input files once the outputs have been successfully generated.
if (!NO_CLEANUP) {
// remove inputs to reduce file counts.
#ifdef WIN32
_unlink(aString.c_str());
_unlink(gString.c_str());
#else
unlink(aString.c_str());
unlink(gString.c_str());
#endif
}
return 0;
}
|
Indo-Greek
Noun
* 1) a proposed branch within the Indo-European language family, of which the Hellenic and Indo-Iranian branches are sub-branches.
|
Board Thread:Roleplaying/@comment-27915391-20170802215608/@comment-29611741-20170807005446
Isaira sighs. She then grabs a boomerang from her bag and gives it to Cefalo.
Isaira: If you change your mind about our camp, toss this lightly to the sky, OK?
|
Allow to see the rejection reason the previous user chose
It would help if I could see the rejection reason already selected from other user in the dialog box that I see when I choose to reject a suggested edit; it would be similar to what happen when I vote to close a question, and other users already voted to close the same question.
For example, if the suggested edit has been rejected as minor edit, and I didn't notice anything wrong with the it, I can check again the edit, and verify if effectively the edit just correct less things than it should.
This has now been implemented in the same way as for close votes:
You can see the rejection reason if you click on the "permalink to this edit suggestion" link.
The rejection reason is displayed in the "Reviewer stats" section under the suggested edit.
But I agree that having it work like the close vote dialog would be a bit more practical.
+1 for this. My feature-request suggested either showing the rejection reason when you hover over the "Reject" button, or showing something like this (inspired from the 10k flag queue);
My reasoning behind this was because you want to see the other reason before casting your vote.
On the other-hand, when you're voting to close a question you've more than likely already decided why you want to close it; if you had to click the "Reject" button to bring up the popup to see the rejected-reason, you'd end up closing the popup to double check whether the initial vote was correct first.
Either way, any improvement on the current UI would be welcomed!
|
'use strict';
var EventEmitter = require('eventman');
var inherits = require('inherits');
var amgui = require('../amgui');
var UnitInput = require('./UnitInput');
var StringInput = require('./StringInput');
var SelectInput = require('./SelectInput');
var ColorInput = require('./ColorInput');
var CheckboxInput = require('./CheckboxInput');
var defineCompactProperty = require('./defineCompactProperty');
function OptionLine(opt) {
EventEmitter.call(this);
this.inputs = {};
this.buttons = {};
this._indent = 0;
this._lineH = amgui.LINE_HEIGHT;
this._hidden = false;
this._createDomElem();
this._createHighlight();
this._subOptionLines = [];
if (opt.separator) {
amgui.createSeparator({parent: this._deHeadCont});
}
if (opt.parent) {
opt.parent.appendChild(this.domElem);
}
if (opt.contextMenuOptions) {
this.dropdown = amgui.createDropdown({
options: opt.contextMenuOptions,
});
amgui.bindDropdown({
asContextMenu: true,
deTarget: this._deHeadCont,
deMenu: this.dropdown,
});
}
if (opt.tgglChildren) {
this.buttons.tgglChildren = amgui.createToggleIconBtn({
iconOn: 'angle-down',
iconOff: 'angle-right',
onClick: opt.tgglChildren.onClick,
parent: this._deHeadCont
});
}
else if (opt.keepSpaceForTgglChildren) {
this._deHighlight.style.marginRight = '16px';
}
this._createIndent();
if (opt.indent) {
this.indent = opt.indent;
}
if (opt.title) {
this._deTitle = amgui.createLabel({
text: typeof opt.title === 'string' ? opt.title : (opt.title.text || ''),
parent: this._deHeadCont,
});
this._deTitle.style.marginRight = '3px';
}
this._inputCont = amgui.createDiv({
parent: this._deHeadCont,
display: 'flex',
flex: '1',
});
this._btnCont = amgui.createDiv({
parent: this._deHeadCont,
display: 'inline-block'
});
if (opt.inputs) {
opt.inputs.forEach(this.addInput, this);
}
if (opt.tgglMerge) {
this.addButton({
domElem: amgui.createToggleIconBtn({
iconOn: 'flow-line',
iconOff: 'flow-parallel',
onClick: opt.tgglMerge.onClick,
}),
name: 'tgglMerge',
});
}
if (opt.btnKey) {
this.addButton({
domElem: amgui.createStepperKey({
onClick: opt.btnKey.onClick,
onClickPrev: opt.btnKey.onClickPrev,
onClickNext: opt.btnKey.onClickNext,
}),
name: 'key',
});
}
if (opt.onDblclick) {
this.domElem.addEventListener('dblclick', opt.onDblclick);
}
if (opt.data) {
this.data = opt.data;
}
if (opt.highlight) {
this.highlight = opt.highlight;
}
}
inherits(OptionLine, EventEmitter);
var p = OptionLine.prototype;
module.exports = OptionLine;
Object.defineProperties(p, {
title: {
set: function (v) {
this._deTitle.text = v;
},
get: function () {
this._deTitle.text;
},
},
highlight: {
set: function (v) {
this._deHighlight.style.opacity = v ? 1 : 0;
if (typeof(v) === 'string') {
this._deHighlight.style.backgroundColor = v;
}
},
},
indent: {
set: function (v) {
v = parseInt(v);
if (v === this._indent) return;
this._indent = v;
this._deIndent.style.width = this._indent * 6 + 'px';
},
get: function () {
return this._indent;
},
},
hidden: {
set: function (v) {
v = !!v;
if (v === this._hidden) return;
this._hidden = v;
this.domElem.style.display = v ? 'none' : '';
},
get: function () {
return this._hidden;
}
}
});
defineCompactProperty(p, [
{name: 'bgHighlight', type: 'boolean', onChange: function (v) {
this._deHeadCont.style.backgroundColor = v ? amgui.color.bg1 : amgui.color.transparent;
}}
]);
p.addInput = function (opt) {
var input;
opt = _.assign({
onChange: opt.onChange,
flex: '1',
}, opt);
switch (opt.type) {
case 'unit':
input = new UnitInput(opt);
break;
case 'select':
input = new SelectInput(opt);
break;
case 'color':
input = new ColorInput(opt);
break;
case 'checkbox':
input = new CheckboxInput(opt);
break;
default:
case 'string':
input = new StringInput(opt);
}
if (opt.name) {
this.inputs[opt.name] = input;
}
this._inputCont.appendChild(input.domElem);
};
p.addButton = function (opt) {
if ('childIdx' in opt && this._btnCont.children[opt.childIdx]) {
this._btnCont.insertBefore(opt.domElem, this._btnCont.children[opt.childIdx]);
}
else {
this._btnCont.appendChild(opt.domElem);
}
opt.domElem.style.display = 'inline-block';
opt.domElem.style.verticalAlign = 'top';
if (opt.name) {
this.buttons[opt.name] = opt.domElem;
}
if (opt.hoverMode) {
opt.domElem.style.visibility = 'hidden';
this.domElem.addEventListener('mouseenter', () => {
opt.domElem.style.visibility = 'visible';
});
this.domElem.addEventListener('mouseleave',() => {
opt.domElem.style.visibility = 'hidden';
});
}
};
p.addOptionLine = function (optionLine) {
this._subOptionLines.push(optionLine);
this._deSubcont.appendChild(optionLine.domElem);
optionLine.indent = this.indent + 1;
if (this._isBorrowingChildInputs) {
this.returnChildInputs();
this.borrowChildInputs();
}
};
p.removeOptionLine = function (optionLine) {
var idx = this._subOptionLines.indexOf(optionLine);
if (idx === -1) return;
this._subOptionLines.splice(idx, 1);
this._deSubcont.removeChild(optionLine.domElem);
if (this._isBorrowingChildInputs) {
this.returnChildInputs();
this.borrowChildInputs();
}
};
p.removeAllOptionLines = function () {
this._subOptionLines.slice().forEach(ol => this.removeOptionLine(ol));
};
p.showSublines = function () {
this._deSubcont.style.display = '';
};
p.hideSublines = function () {
this._deSubcont.style.display = 'none';
};
p.walkChildren = function (fn) {
this._subOptionLines.forEach(subOptionLine => {
fn(subOptionLine, this);
subOptionLine.walkChildren(fn);
});
};
p.borrowChildInputs = function () {
//TODO: do this two somehow better
this._isBorrowingChildInputs = true;
this._subOptionLines.forEach(line => {
if (line.hidden) return;
Object.keys(line.inputs).forEach(inpName => {
this._inputCont.appendChild(line.inputs[inpName].domElem);
});
});
};
p.returnChildInputs = function () {
this._isBorrowingChildInputs = false;
var deInputs = _.toArray(this._inputCont.children);
this._subOptionLines.forEach(line => {
Object.keys(line.inputs).forEach(inpName => {
var idx = deInputs.indexOf(line.inputs[inpName].domElem);
if (idx === -1) return;
line._inputCont.appendChild(deInputs[idx]);
});
});
};
p._createDomElem = function() {
this.domElem = amgui.createDiv();;
this.domElem.style.width = '100%';
this.domElem.style.overflow = 'hidden';
this._deHeadCont = amgui.createDiv();;
this._deHeadCont.style.position = 'relative';
this._deHeadCont.style.display = 'flex';
this._deHeadCont.style.width = '100%';
this._deHeadCont.style.height = this._lineH + 'px';
this.domElem.appendChild(this._deHeadCont);
amgui.createSeparator({parent: this._deHeadCont});
this._deSubcont = amgui.createDiv({
parent: this.domElem,
width: '100%',
});
};
p._createHighlight = function () {
this._deHighlight = amgui.createDiv();;
this._deHighlight.style.display = 'inline-block';
this._deHighlight.style.width = '2px';
this._deHighlight.style.height = this._lineH + 'px';
this._deHighlight.style.background = amgui.color.selected;
this._deHighlight.style.opacity = 0;
this._deHeadCont.appendChild(this._deHighlight);
};
p._createIndent = function () {
this._deIndent = amgui.createDiv();;
this._deIndent.style.display = 'inline-block';
this._deIndent.style.width = '0px';
this._deHeadCont.appendChild(this._deIndent);
};
p.dispose = function () {
//TODO
};
|
John Fay and another, Respondents, v. John T. Lynch, Appellant, Impleaded, etc.
—Judgment affirmed. Opinion by
Daniels, J.
|
Grease
From Player's Handbook, page 246.
Description
1st-level conjuration
* Casting Time: 1 action
* Range: 60 feet
* Components: V, S, M (a bit of pork rind or butter)
* Duration: 1 minute
Learned By
* Classes: Artificer, Sorcerer (OCF), Wizard
* Subclasses: Fighter (Eldritch Knight), Rogue (Arcane Trickster)
* Feats: Artificer Initiate, Magic Initiate, Strixhaven Initiate
|
require 'omniauth-oauth2'
require 'faraday'
require 'net/https'
require 'json'
require 'pp'
# #The Dailycred Omniauth Strategy
module OmniAuth
module Strategies
class Dailycred < OmniAuth::Strategies::OAuth2
# default options
option :client_options, {
:site => "https://www.dailycred.com",
:authorize_url => '/connect',
:token_url => '/oauth/access_token'
}
# allows parameters to be passed through
AUTH_PARAMS = ["action","identity_provider","referrer", "access_token"]
option :authorize_options, OmniAuth::Strategies::Dailycred::AUTH_PARAMS
uid { user['uid'] }
info do
user
end
alias :old_request_phase :request_phase
def authorize_params
super.tap do |params|
params[:state] ||= {}
end
end
# this step allows auth_params to be added to the url
def request_phase
p session['omniauth.state']
OmniAuth::Strategies::Dailycred::AUTH_PARAMS.each do |param|
val = session['omniauth.params'][param]
if val && !val.empty?
options[:authorize_params] ||= {}
options[:authorize_params].merge!(param => val)
end
end
old_request_phase
end
private
# This is the phase where the gem calls me.json, which returns information about the user
def user
return @duser if [email protected]?
connection = Faraday::Connection.new options.client_options[:site], :ssl => options.client_options[:ssl]
response = connection.get("/graph/me.json?access_token=#{access_token.token}")
json = JSON.parse(response.body)
pp json if options[:verbose]
@duser = {'token' => access_token.token}
@duser['provider'] = 'dailycred'
@duser['uid'] = json['id'] || json['user_id']
json.each do |k,v|
@duser[k] = v
end
json["identities"].each do |k, v|
@duser[k] = v
@duser[k][:access_token] = json["access_tokens"][k]
end if !json["identities"].nil?
pp @duser if options[:verbose]
created = json['created'] / 1000
@duser['created'] = DateTime.strptime(created.to_s, '%s')
@duser.delete("id")
@duser
end
end
end
end
|
using System;
using System.Collections.Generic;
using System.Reflection;
using Autofac;
using Net.Autofac;
using Net.Collections;
namespace SampleLibrary
{
public class AutofacBusInstanceConfiguration : IConfigureBus
{
internal IList<Assembly> ConsumerAssemblies { get; private set; }
internal IList<Type> ConsumerTypes { get; private set; }
internal IList<Action<ContainerBuilder>> RegisterServices { get; private set; }
internal IList<Action<IContainer>> ContainerCreatedActions { get; private set; }
internal Action<RegistrationModule> ConfigureModule { get; private set; }
internal string NamedInstance { get; set; }
internal bool BusEnabled { get; set; }
internal bool IsGuiInstance { get; set; }
internal bool IsWebInstance { get; set; }
public bool IsDebugging { get; set; }
public AutofacBusInstanceConfiguration()
{
RegisterServices = new List<Action<ContainerBuilder>>();
ContainerCreatedActions = new List<Action<IContainer>>();
ConsumerAssemblies = new List<Assembly>();
ConsumerTypes = new List<Type>();
BusEnabled = true;
var entryAssembly = Assembly.GetEntryAssembly();
if (entryAssembly != null)
{
NamedInstance = entryAssembly.GetName().Name;
ConsumerAssemblies.Add(entryAssembly);
}
}
IConfigureBus IConfigureBus.ContainerCreated(Action<IContainer> container)
{
ContainerCreatedActions.Add(container);
return this;
}
IConfigureBus IConfigureBus.ConfigureContainer(Action<ContainerBuilder> builder)
{
RegisterServices.Add(builder);
return this;
}
IConfigureBus IConfigureBus.LoadConsumersFrom(params Assembly[] assemblies)
{
ConsumerAssemblies.AddRange(assemblies);
return this;
}
IConfigureBus IConfigureBus.LoadConsumers(params Type[] consumerTypes)
{
ConsumerTypes.AddRange(consumerTypes);
return this;
}
IConfigureBus IConfigureBus.Name(string name)
{
NamedInstance = name;
return this;
}
IConfigureBus IConfigureBus.DisableBus(bool disable)
{
BusEnabled = !disable;
return this;
}
IConfigureBus IConfigureBus.IsGuiInstance(bool isGuiInstance)
{
IsGuiInstance = isGuiInstance;
return this;
}
IConfigureBus IConfigureBus.IsWebInstance(bool isWebInstance)
{
IsWebInstance = isWebInstance;
return this;
}
IConfigureBus IConfigureBus.EnableDebugging(bool isDebuggingEnabled)
{
IsDebugging = isDebuggingEnabled;
return this;
}
IConfigureBus IConfigureBus.ConfigureModule(Action<RegistrationModule> module)
{
ConfigureModule = module;
return this;
}
}
}
|
User:Thuguely/Sandbox11
Information Recorded in the Records
Baptisms
Marriages
Marriage registers can give:
Burials
Burial registers may give:
Step 2: Digital Copies of Church Records in the FamilySearch Catalog
* a. Click on the [STATE LINK records of STATE].
* b. Click on Places within STATE and a list of counties will appear.
* c. Click on your county if it appears.
* d. Click on the "Church records" topic. Click on the blue links to specific record titles.
* e. Click on Places within COUNTY and a list of towns will appear.
* g. Click on the "Church records" topic. Click on the blue links to specific record titles.
Step 4: Correspond with or Visit Church Archives and/or Local Churches.
Writing to Local Churches
Mennonite Church Finder
Writing to Local Churches
* Episcopal Church Find a Church
Writing to Local Churches
* USAChurches.org Baptist Church Directory
Writing to Local Churches
* Christian Reformed Church Finder
* Reformed Church in America Church Finder
Online Resources
Writing to Local Churches
Community of Christ Church Finder
Writing to Local Churches
* National Association of Congregational Christian Churches Member Churches Map
Writing to Local Churches
* Jehovah's Witnesses Find a Meeting (Congregation)
Writing to Local Churches
* ELCA Evangelical Lutheran Church in America Congregation Finder
* AFLC Association of Free Lutheran Congregations Church Finder
* NALC North American Lutheran Church Congregations
* AALC American Association of Lutheran Churches Church Finder
* CLC Church of the Lutheran Confession Church Finder
* ELCM Evangelical Lutheran Conference & Ministerium of North America Church Finder
* ELDONA Evangelical Lutheran Diocese of North America Parish Finder
* LCR Lutheran Churches of the Reformation Congregations
* ELS Evangelical Lutheran Synod Church Finder
* LCMS The Lutheran Church-Missouri Synod Church Finder
* LCMC Lutheran Congregations in Mission for Christ Church Finder
Writing to Local Churches
* United Methodist Church Find a Church
* USA Churches Methodist Church Directory
Writing to Local Churches
* Church Angel Orthodox Churches Directory
* Parishes Greek Orthodox Churches in America
* Orthodox Church in America Parish Finder
* Ukrainian Orthodox Church of America Directory of Parishes
* Russian Orthodox Church Finder
Writing to Local Churches
* USAChurches.org Pentecostal Church Directory
* ChurchAngel.com Listing of Assemblies of God
* ChurchAngel.com Evangelical Church Directory
Writing to Local Churches
* Presbyterian Church in America Church Directory
Writing to Local Churches
* Friends General Conference Quaker Directory
Writing to Local Churches
The Catholic Directory
* Catholic Churches of the Maronite Rite
* Melkite Greek Catholic Church Parish Locator
Writing to Local Churches
* Adventist Church Finder
Writing to Local Churches
* FIND A UNITARIAN UNIVERSALIST CONGREGATION
Writing to Local Churches
|
Thread:Squivolarious/@comment-4403388-20170813031800
(This is an automated message, so please do not reply to this.)
Enjoy your time at !
|
Root-shoot relationships in four strains of field-grown Erianthus arundinaceus at seedling stage
Abstract The production of cellulosic bioethanol from non-edible plants is a potential countermeasure against global warming. Erianthus species provide cellulosic raw material for bioethanol because they have high biomass productivity and high tolerance to environmental stress, associated with their large, deep root systems. However, it is difficult to select Erianthus species for breeding by direct observation of their root systems because the roots are widely dispersed in the soil. Instead, we examined shoot morphological traits that could be closely related to root morphology to find effective reference indices for selection. The potential to evaluate root structure and function in Erianthus according to bleeding rate was also examined. An analysis of root–shoot relationships in seedlings indicated that root number and mean length were closely related to stem number and diameter, respectively. These results suggest that root–shoot relationships may provide useful criteria for selective breeding of root systems in Erianthus.
Erianthus arundinaceus is a perennial C4 grass that produces numerous tillers (Hattori et al., 2010). It is anticipated that E. arundinaceus will be grown as a raw material for cellulosic bioethanol because of its large shoot biomass (Amalraj et al., 2008). Although a few strains (cultivars) have been released for practical use (Uwatoko & Gau, 2013), additional strains with higher biomass production and stress tolerance are required to improve bioethanol production.
Erianthus species have high biomass production and high tolerance to environmental stresses probably because of their large, deep root systems (Matsuo et al., 2002;Sekiya et al., 2013). Thus, breeding Erianthus cultivars according to structural and functional characteristics of the root system should improve biomass yield in poor and problem soils. However, direct observation and measurement of Erianthus roots for breeding purposes is difficult because the root system is extensive and deep. If shoot traits, which are easy to measure, correspond closely to the structural and functional characteristics of the root system, they could provide effective reference indices for selecting plants to accelerate breeding new cultivars.
Rice (Oryza sativa) is classified into two morphological types: panicle-number and panicle-weight types. Paniclenumber types, including IR8, form many small heads and thin tillers, whereas panicle-weight types such as Takanari and Lemont have fewer thick tillers with large panicles (Imbe et al., 2004;Morita et al., 1995;Sakai et al., 2009). Each of these plant types has a characteristic root system. Panicle-number types have more nodal roots and a relatively shallow root system, and panicle-weight types have a deep root system with long and thick nodal roots (Abe et al., 1998;Morita et al., 1995;Kato et al., 2007). These differences suggest that panicle-number and panicle-weight plant types may have different strategies for developing root biomass, which could be determined by the combination of nodal root number and mean root weight or length.
Although E. arundinaceus strains vary from stem-number type (analogous to panicle-number type in rice) to stem-weight type (analogous to panicle-weight type in rice) (Matsunami et al., 2014), there is little information on root-shoot relationships among strains of this species. In the present study, root-shoot relationships were examined in four E. arundinaceus strains of different plant types, and these relationships are discussed with reference to root physiological activity examined by bleeding rate. Although Erianthus are perennial plants, we investigated the morphology of three-month-old seedlings because it is feasible to perform measurements on seedlings, which OPEN ACCESS
Field experiment
A field experiment was conducted at the Institute for Sustainable Agro-ecosystem Services, University of Tokyo, Nishitokyo, Japan (lat 35°43′N, long 139°32′E). We aimed to investigate whether the root traits at 91 DAP (pot experiment) were related to root function after the roots were widely dispersed in the soil. The top 30 cm of the soil is Andosol, and the subsoil is Tachikawa loam (Yamagishi et al., 2003); both originated from volcanic ash. Before planting seedlings, the field was fertilized with chemical fertilizer at rates 72 kg ha −1 N, 108 kg ha −1 P 2 o 5 , and 96 kg ha −1 K 2 o. The plot size was 4 m × 4 m with three replications for each strain (12 plots in total). Seedlings of the four strains (86 DAP), prepared as for the pot experiment, were transplanted at a density of one plant per m 2 (1 m × 1 m spacing) on June 9, 2010. Weeds were removed manually.
At 76 days after transplanting (162 DAP; August 24, 2010) bleeding rate was measured (Morita & Abe, 2002). Shoots were removed at approximately 15 cm above the soil surface for application of weighed cotton (ca. 20 g) at 10:00 h. The cotton was wrapped with polyethylene film and sealed with a vinyl band to prevent evaporative loss. The cotton was removed after 1 h to quantify xylem sap. The bleeding rate was measured for 3-6 plants per plot (a total of 10-13 plants per strain). Stem numbers were recorded and shoot weight was measured after drying at 80 °C for 3 days.
Differences in bleeding sap rates among the strains were examined with Turkey's multiple range tests. Because the Erianthus strains are not genetically pure and show considerable variation, data for individual plants were used for correlations.
Results and discussion
The morphological characteristics of shoots and roots in the pot experiment are shown in Table 1. Stem number, total root length, and root dry weight varied significantly among E. arundinaceus strains. The relationships between are easy to handle; this may enhance the selection process for future breeding.
Pot experiment
Seeds of four strains of E. arundinaceus (IK1, IK2, IK3, and IK4) were sown in a nursery box (60 cm × 30 cm × 3.6 cm) filled with fertilized soil on March 15, 2010 and grown in a greenhouse at the National Agricultural Research Center for Kyushu okinawa Region (Kumamoto, Japan). IK1 is a synthetic1 between two clones derived from strain JW630 (originally collected from Shizuoka Prefecture; Tsuruta et al., 2012) and one clone derived from Ko2 (preserved in Kyushu National Agricultural Experiment Station). IK2 is a synthetic1 between two clones derived from JW4 (originally collected in okinawa Prefecture; Tsuruta et al., 2012). IK3 is a selfed line of a clone derived from the second-generation selfed lines of JW4. IK4 is a selfed line of clone of JW630. Seedlings of each strain were transplanted to a 128-cell tray (cell size: 30 × 30 × 44 mm) using tweezers at 21 days after planting (DAP). The seedlings were transplanted to plastic pots (7.5 cm diameter × 9.0 cm height; 1 plant per pot) at 52-55 DAP.
At 91 DAP, the stem and root numbers of 12 plants per strain were recorded. The diameter of the main stem with leaf sheaths (average of the major and minor axes) was measured at the topmost root-emerging node, whereas the diameter of nodal roots (average of the major and minor axes) was measured at the base of individual nodal roots using a digital caliper. In addition, images of roots were scanned at 200 dpi using an image scanner (Epson Expression 10000XL) for the measurement of root length including laterals, which was performed using a WinRHIZo Regular (Regent Instruments Inc.). The total root length including laterals was divided by the number of roots (seminal and nodal roots) to calculate mean root length. Thereafter, the shoots and roots were dried at 80 °C for 3 days and weighed, and specific root length (ratio of total root length to total dry weight) was calculated. 3.3 ± 0.4 bc 13.2 ± 1.0 a 17.4 ± 1.0 b 9.5 ± 0.6 ab 1.23 ± 0.09 a 3.03 ± 0.17 a 53.8 ± 4.9 ab 0.76 ± 0.10 b 75.3 ± 4.8 b shoot and root traits in these strains were similar to those reported for rice (Abe et al., 1998;Morita et al., 1995). Root number was closely correlated with stem number (r = .722, n = 48; p < .001) when all plants of all strains were analyzed together. Mean root length was correlated with stem diameter (r = .385, n = 48; p < .01). IK2, IK3, and IK4 were stem-weight type that had a small number of stems and a large diameter of main stems, consistent with the panicle-weight type in rice. Those strains, especially IK3 and IK4, had a large mean root length, resulting in a large total root length (Table 1), like Lemont in rice (Morita et al., 1995). IK1, like panicle-number rice types, formed approximately twice as many thin stems and short roots than did the other three strains. Stem thickness could relate to root thickness and growth direction in rice (Abe & Morita, 1994;Kato et al., 2006;Morita et al., 1997), and panicle-weight types with thick stems tend to develop large, deep root systems. IK1 had the lowest total root length despite its large number of stems and roots. These results suggest that IK3 and IK4, with fewer but thicker stems (similar to panicle-weight type cultivars in rice), presumably have the advantage of developing large root systems, but further studies with more strains are required.
Shoot growth and bleeding rate of the four strains in the field experiment are summarized in Table 2. Plant height at 156 DAP (August 18) was 215 ± 3.7 (IK1), 226 ± 4.6 (IK2), 223 ± 8.8 (IK3), and 250 ± 3.6 cm (IK4), respectively. Significant differences were observed among the strains in the number of stems and bleeding rate despite similar shoot dry weight. IK4 had a significantly greater bleeding rate per plant, whereas IK1 had the smallest bleeding rate despite the presence of many stems. Bleeding rate per plant can be explained by the product of the number of stems and the bleeding rate per stem (Morita & Abe, 1999). Here, bleeding rate per stem contributed more than stem number to the bleeding rate per plant (see partial correlation coefficients in Figure 1), which suggests an advantage of strains with thick stems (similar to panicle-weight types in rice) in terms of physiological activity of the root system in E. arundinaceus. The results of the two experiments suggest the relationship between root morphology at the seedling stage and root function at Figure 1. relationships between the number of stems and bleeding rate per plant (a), and between bleeding rate per stem and bleeding rate per plant (B) in Erianthus arundinaceus. the broken line in a indicates the linear regression among iK2, iK3, and iK4. the solid line in B indicates the linear regression among all the four strains. r: correlation coefficient among all the four strains. r iK1 : correlation coefficient in iK1. r iK2-4 : correlation coefficient among iK2, iK3, and iK4. Notes. ***correlation is significant at p < .001. rʹ a : Partial correlation coefficient eliminating the influence of bleeding rate of each stem. rʹ B : Partial correlation coefficient eliminating the influence of the total number of stems.
a later stage. For instance, IK3 and IK4 had a large total root length due to a large mean root length at the seedling stage (Table 1) and had high bleeding rates at later growth stages (Table 2), whereas IK1, which had a higher number of small stems, had numerous small roots at the seedling stage and showed a lower bleeding rate in the field. These results suggest that strains with large stems at the seedling stage (stem-weight type), rather than strains with numerous tillers (stem-number type), can form large root systems with high viability in the field, which is advantageous for biomass production under stressful conditions. Upland rice cultivars with high drought tolerance are often panicle-weight types with thick stems and deep root systems (Kato et al., 2006). IK3 and IK4, strains with a small number of thick stems, might have deep root systems that are tolerant to drought (Uga, 2013), although root systems in the field were not investigated in this study. The shoot characteristics of IK3 and IK4 may relate to the depth of the root system and the total quantity of roots. This analysis of root system morphology with reference to root physiological activity, including its possible relationship to shoot morphological traits, provides useful data for breeding new, better performing cultivars of Erianthus.
|
#!/bin/bash -x
################################################################################
# misc/mk-doxygen-travis.sh
#
# Script to automatically generate doxyen documentation on Travis and upload it
# to Github Pages.
#
# Based on https://gist.github.com/vidavidorra/548ffbcdae99d752da02
#
# Part of tlx - http://panthema.net/tlx
#
# Copyright (C) 2017 Timo Bingmann <[email protected]>
#
# All rights reserved. Published under the Boost Software License, Version 1.0
################################################################################
set -e
GH_REPO_REF=github.com/tlx/tlx.github.io
# GH_REPO_TOKEN=<set-by-travis>
# Get the current github doxygen repo
rm -rf doxygen-html
git clone https://git@${GH_REPO_REF} doxygen-html
### Clean directory -- works with lots of files
CURRENTCOMMIT=`git -C doxygen-html rev-parse HEAD`
# Reset working tree to initial commit
git -C doxygen-html reset --hard base
# Move HEAD back to where it was
git -C doxygen-html reset --soft $CURRENTCOMMIT
echo 'Generating Doxygen code documentation...'
doxygen 2>&1 | tee doxygen-html/doxygen.log
if [ -f "doxygen-html/index.html" ]; then
echo 'Uploading documentation to Github Pages...'
pushd doxygen-html
git add --all
git \
-c user.name="mk-doxygen (Travis CI)" \
-c user.email="[email protected]" \
commit \
-m "Deploy code docs to GitHub Pages Travis build: ${TRAVIS_BUILD_NUMBER}" \
-m "Commit: ${TRAVIS_COMMIT}"
git \
-c push.default=simple \
push --force \
"https://${GH_REPO_TOKEN}@${GH_REPO_REF}" > /dev/null 2>&1
popd
else
echo '' >&2
echo 'Warning: No documentation (html) files have been found!' >&2
echo 'Warning: Not going to push the documentation to GitHub!' >&2
exit 1
fi
################################################################################
|
Page:The Melanesians Studies in their Anthropology and Folklore.djvu/433
.]
Mera-mbuto prepared food for himself, and then he invited Tagaro to come that they might eat together. So Tagaro came to him in his house; and the food of Mera-mbuto was exceedingly bad, and as they ate Tagaro did not eat at all, but he wrapped the food up to deceive Mera-mbuto, and went and threw it away, and then went back to his house. Afterwards Tagaro sent after him saying, Mera-mbuto, come here to my house. Mera-mbuto came and they two ate. And the food was good; Mera-mbuto liked Tagaro's food very much; he had made his own not at all good. So Mera-mbuto considered silently, What sort of thing is this we two are eating? So he asked Tagaro, and Tagaro said to him, I have grated up my barrow pig. So Mera-mbuto went and grated up his barrow pig, and in due course they two ate it. After this Tagaro invited Mera-mbuto to eat with him in return in his house. So he asked him again, What food is this we two are eating? And Tagaro was tired of being asked, and deceived Mera-mbuto, saying to him, My mother; I cooked her in the oven. So Mera-mbuto went home and cooked his mother in the oven. After this Tagaro said to him, Light a fire over me. So Mera-mbuto came, and tied up the door of Tagaro's house, bound it very tight, and set fire to Tagaro's house. Then Tagaro wept; Mera-mbuto said to him, Don't cry, you deceived me formerly, now you are soon to die for it. He thought that Tagaro was dead; but not at all, he had dug a hole, and stayed in it. In the morning thinking that he was dead he came, and Tagaro had been long sitting ready for him. So Mera-mbuto asked him, Are you sitting like this? Tagaro said, Yes. So Mera-mbuto said to him, My turn now, to-night you set fire to my house. So Tagaro set fire to his house, and the fire burnt him up.
|
package main
import (
"encoding/json"
"fmt"
"os"
"github.com/sdotz/apple-news-format/pkg/convert"
"gopkg.in/alecthomas/kingpin.v2"
)
var (
convertCmd = kingpin.Command("convert", "Convert content to apple news format")
url = convertCmd.Flag("url", "A URL to download and convert to apple news format").String()
siteConfigPath = convertCmd.Flag("siteConfig", "Path of site config json file").String()
)
func main() {
cmd := kingpin.Parse()
switch cmd {
case "convert":
siteConfig, err := convert.GetSiteConfig(*siteConfigPath)
if err != nil {
fmt.Fprintln(os.Stderr, err)
}
if siteConfig == nil {
siteConfig = &convert.SiteConversionConfig{
SectionConversionSelectors: []string{"body"},
}
}
article, err := convert.ConvertUrlToAnf(*url, siteConfig)
if err != nil {
fmt.Println(err)
os.Exit(1)
}
b, err := json.Marshal(article)
if err != nil {
fmt.Println(err)
os.Exit(1)
}
fmt.Println(string(b))
}
}
|
Electrical stimulation device and method for the treatment of dysphagia
ABSTRACT
An electrical stimulation device and method for the treatment of dysphagia is disclosed. In a preferred embodiment, the electrical stimulation device includes one or more channels of electrodes each of which includes a first electrode positioned in electrical contact with tissue of a target region of a patient and a second electrode positioned in electrical contact with tissue of a posterior neck region or a posterior thoracic region of the patient. A series of electrical pulses are then applied to the patient through the one or more channels of electrodes in accordance with a procedure for treating dysphagia. The series of electrical pulses may comprise: a plurality of cycles of a biphasic sequential pulse train pattern; a plurality of cycles of a biphasic overlapping pulse train pattern; a plurality of cycles of a triphasic sequential pulse train pattern; a plurality of cycles of a triphasic overlapping pulse train pattern; a functional pulse train pattern; a low-frequency pulse train pattern; or a frequency-sequenced pulse burst train pattern. Various exemplary embodiments of the invention are disclosed.
CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is generally directed to the treatment ofdysphagia, and is more specifically directed to an electricalstimulation device and method for applying a series of electrical pulse sto one or more channels of electrodes in accordance with a procedure for treating dysphagia.
2. Description of Related Art
Swallowing is a complicated action whereby food is moved from the mouth through the pharynx and esophagus to the stomach. The swallowing act is usually divided into several stages that require the integrated action of the respiratory center and motor functions of multiple cranial and cervical nerves, as well as the coordination of the autonomic system.
The first stage (commonly referred to as the oral stage) involvesmastication, bolus formation and bolus transfer. The food, which hasbeen brought to the mouth, is chewed and combined with saliva to form abolus that is moved to the back of the oral cavity and prepared for swallowing. The performance of the oral phase requires proper lip closure, cheek tensing, multidimensional tongue movement and chewing.
The second stage (commonly referred to as the oropharyngeal stage)involves the coordinated contractions of several muscles of the tongue,pharynx and larynx, whereby the bolus is moved to the back of the throat and into the esophagus. The tongue propels the bolus to the posterior mouth into the pharynx. The bolus passes through the pharynx, which involves relaxation and constriction of the walls of the pharynx,backward bending of the epiglottis, and an upward and forward movement of the larynx and trachea. The bolus is prevented from entering the nasal cavity by elevation of the soft palate and from entering thelarynx by closure of the glottis and backward inclination of theepiglottis. During the oropharyngeal stage, respiratory movements are inhibited by reflex.
The third stage (commonly referred to as the esophageal stage) involves the movement of the bolus down the esophagus and into the stomach. This movement is accomplished by momentum from the prior stage, peristalticcontractions and gravity.
Dysphagia is generally defined as difficulty in swallowing. For example,dysphagia may occur when one cannot create a good lip seal/closure(which results in the leaking of the mouth contents) or ineffective tongue plunger action. Also, poor cheek tensing may result in thepocketing of food between the teeth and cheek. The patient may sometimes be unable to complete chewing due to muscle fatigue of the tongue andthe muscles involved in mastication.
Classic neurologically-based dysphagia is described as a dystonia orincoordination of the oropharyngeal stage sequencing of multiple muscles controlled by the central pattern generator located in the brainstem.This level of dysphagia may manifest itself as the bolus being lodged inthe throat after swallowing. The patient may even regurgitate the food or most dangerously aspirate into the airway.
Dysphagia has a variety of causes. These include obstructive/mechanical,damage to the central neuron pools (pattern generators) for swallowing following traumatic injury, or neurologic disease (as in stroke), nerve compression, neuromuscular junction atrophy or damage, and muscular atrophy and spasticity. Dysphagia may also be a sign of underlying disease of the esophagus, which may be due to strictures,gastroesophogeal reflux disease, peptic ulcers, cancer, thyroid disease,stroke, Parkinson's disease, ALS, myasthenia gravis, muscular dystrophy,muscular atrophy, torticollis, or a number of other diseases. Dysphagiamay also be medication-induced.
In the past, patients suffering from dysphagia have been subjected to dietary changes or thermal and mechanical stimulation treatments to regain adequate swallowing reflexes. Thermal stimulation involvesimmersing a mirror or probe in ice or another cold substance and stimulating the tonsillar fossa with the cold mirror or probe. Upon such stimulation, the patient is directed to close his mouth and attempt to swallow. While dietary changes and exercise rehabilitation using thermal stimulation may be effective for treating dysphagia, some patients may require weeks or months of therapy. It is also difficult to distinguish patients who require such treatments from patients who recover spontaneously.
Electrical stimulation of various body parts has also been used in orderto treat dysphagia. For example, Ka ada and other researchers have reported that low-frequency transcutaneous nerve stimulation on the hands resulted in relief from dysphagia. See Ka ada, Successful treatment of esophageal dysmotility and Raynaud's phenomenon in systemic sclerosis and achalasia by transcutaneous nerve stimulation: Increase in plasma VIP concentration, Scand. J. Gastroenterol. 1987 Nov. 22(9):1137-46;Ka ada, Systemic sclerosis: successful treatment of ulcerations, pain,Raynaud's phenomenon, calcinosis, and dysphagia by transcutaneous nerve stimulation: A case report, Acupunct. Electro ther. Res. 1984 9(1):31-44;Guelrud et al., Transcutaneous electrical nerve stimulation decrease slower esophageal sphincter pressure in patients with achalasia, Dig.Dis. Sci. 1991 Aug. 36(8):1029-33; Chang et al., Effect oftranscutaneous nerve stimulation on esophageal function in normal subjects—evidence for a somatovisceral reflex, Am. J. Chin. Med. 199624(2):185-92. However, other researchers have found no beneficial effects associated with esophageal motility upon applying electrical simulation to the hands. See Me arin et al., Effect of transcutaneousnerve stimulation on esophageal motility in patients with achalasia andscleroderma, Scand. J. Gastroenterol. 1990 Oct. 25(10):1018-23.
More recently, electrical stimulation has been applied to the oral cavity for the treatment of dysphagia. See Park et al., A pilot exploratory study of oral electrical stimulation on swallow function following stroke: an innovative technique, Dysphagia. 1997 Summer12(3):161-6. Other researchers have reported improved swallowing withthe use of transcutaneous electrical stimulation applied to the anterior portion of the neck (i.e., the region bounded on the upper side by themandible and on the lower side by the clavicles and the manubrium of thesternum). See Freed et al., U.S. Patent Application No. 2004/0220645entitled “Treatment of oropharyngeal disorders by application of neuromuscular electrical stimulation”; Freed et al., U.S. Pat. No.5,725,564; Freed et al., U.S. Pat. No. 5,891,185; Freed et al., U.S.Pat. No. 5,987,359; and Freed et al., U.S. Pat. No. 6,198,970. The Freed method may pose a safety hazard to the patient if the electrodes and stimulation are inadvertently placed over the carotid sinus (which may alter blood pressure and/or cardiac contractility). In addition, a risk occurs if the electrodes and stimulation are applied anteriorly over thelaryngeal or pharyngeal muscles (which may cause a blockage of thepatient's airway and cause difficulty in breathing due to electrical activation of the muscles causing a strong contraction). Further, whenthe electrodes are placed on the anterior neck and the chin is tucked for swallowing, the electrodes may contact each other shorting out and causing uncomfortable or dangerous surges in current. Loose skin,adipose tissue and facial hair further limit the placement and adhesion of electrodes to the target treatment area. Thus, there is a need in the art for an improved or alternative method for treating dysphagia.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to an electrical stimulation device and method for the treatment of dysphagia. In general, the electricalstimulation device includes an electronic control unit connected to one or more channels of electrodes, such as transcutaneous or percutaneouselectrodes. Each channel comprises two electrodes (i.e., a relative positive electrode and a relative negative electrode), wherein one electrode is positioned in electrical contact with tissue of a target region of the patient (preferably to stimulate a motor point of one or more muscles involved in the oral, oropharyngeal and/or esophageal stages of swallowing or a combination of the swallowing stages) and theother electrode is positioned in electrical contact with tissue of a posterior neck region or a posterior thoracic region of the patient. The electronic control unit applies a series of electrical pulses to thepatient through the one or more channels of electrodes in accordance with a procedure for treating dysphagia.
In the present invention, the electrodes are preferably placed on thepatient in a manner that stimulates the central pattern generators associated with swallowing. In this regard, it will be appreciated thatthe cranial roots of the accessory nerve (XI) convey most of the fibers from the recurrent laryngeal nerve to the vagus nerve (X), which provides most of the motor fibers distributed in the pharyngeal andre current laryngeal branches of the vagus nerve. The activation and sequencing of these nerves are under the control of the swallowing central pattern generator associated with swallowing. The cranial root of the accessory nerve (XI) can be accessed in the posterior neck region between the C1-C4 cervical vertebrae and in the trapezius muscle (whichis innervated by the spinal branch of the accessory nerve) using the relative negative electrode.
Thus, for example, in the present invention, placement of one electrode at the posterior neck region or posterior thoracic region of the patient and placement of another electrode near the buccinator, orbicularisoris, masseter, pterygoids, tongue, trapezius, median nerve, and/or first dorsal interosseous muscles of the patient will re educate the central pattern generator associated with the various stages and related muscles involved in swallowing. The relative positive and negative electrodes contain both phases of the current and, thus, the electrode placement is generally determined by the sensitivity of the neural structures and the proximity of the nerve to the superficial tissue.Thus, the relative negative electrode is generally placed para spin ally over the accessory and spinal nerves, which are deeper and more difficult to activate than, for example, the motor points of thebuccinator, orbicularis oris, masseter, pterygoids, tongue, trapezius,median nerve, and/or first dorsal interosseous muscles.
In one aspect, stimulation of the cervical para spinal muscles with the relative negative electrode and stimulation of the motor point of the right and/or left buccinator and/or orbicularis oris muscle with the relative positive electrode has been shown to improve swallowing duringthe oral phase, especially that associated with proper lip seal and tongue movement.
In another aspect, stimulation of the cervical para spinal muscles withthe relative negative electrode and stimulation of the motor point ofthe right and/or left masseter muscle and/or pterygoid muscle with the relative positive electrode has been shown to improve swallowing duringthe oral phase, especially that involving chewing.
In still another aspect, stimulation of the cervical para spinal muscles with the relative negative electrode and stimulation of the motor point of the tongue with the relative positive electrode has been shown toimprove the oral and oropharyngeal phases of swallowing associated with multidimensional movement of the bolus to the pharynx by the tongue.
In yet a further aspect, stimulation of the cervical para spinal muscles with the relative negative electrode and stimulation of the motor point of the right and/or left trapezius muscle with the relative positive electrode has been shown to improve the oropharyngeal phase of swallowing.
In still another aspect, stimulation of the cervical para spinal muscles with the relative negative electrode and stimulation of the left and/or right median nerves in the vicinity of the anterior surface of the wrist and/or stimulation of the motor point of the left and/or right first dorsal interosseous muscle with the relative positive electrode has been shown to improve the oropharyngeal and esophageal phases of swallowing.This stimulation is thought to modulate the gag reflex in patients who may have hypersensitivity or neurologic inhibition of the gag reflex dueto central pattern generator damage in which case the stimulation re educates the correct pattern for the reflex. This tracks theinnervation of the cervical esophagus at the C1-C8 cervical afferent andefferent nerves and spinal interneuron loops located at the levels ofthe C1-C7 spinal vertebrae. In addition, there is supplementary accessible innervation through the median and ulnar nerves at the first dorsal interosseous muscle through the nerve roots located at the levels of the C5-C7 vertebrae.
In still another aspect, stimulation of the thoracic para spinal muscles with the relative negative electrode and stimulation of the left and/or right median nerves in the vicinity of the anterior surface of the wrist and/or stimulation of the motor point of the left and/or right first dorsal interosseous muscle with the relative positive electrode has been shown to improve the oropharyngeal and esophageal phases. Again, the therapy is thought to modulate the gag reflex due to central pattern generator abnormalities. This tracks the innervation of the mid to lower esophagus at the T4-T6 thoracic afferents, interneurons, and efferentswith suprasegmental (cervical and brainstem) input.
Lastly, stimulation of the cervical para spinal muscles (e.g., the C1-C4or C5-C7 cervical vertebrae) with the relative negative electrode and stimulation of the thoracic para spinal muscles (e.g., the T4-T6 thoracicvertebrae) has been shown to improve the esophageal phase of swallowing.
The series of electrical pulses applied to the one or more channels of electrodes may comprise a variety of different types of pulse train patterns. For example, a plurality of cycles of a biphasic sequential or overlapping pulse train pattern may be used, in which a first phase of electrical pulses is applied to a first channel of electrodes and asecond phase of electrical pulses is applied to a second channel of electrodes. Using the biphasic sequential pulse train pattern, the second phase of electrical pulses commences after termination of thefirst phase of electrical pulses such that there is a time delaytherebetween. Using the biphasic overlapping pulse train pattern, the second phase of electrical pulses commences before termination of thefirst phase of electrical pulses such that there is an overlaptherebetween.
In another example, a plurality of cycles of a triphasic sequential or overlapping pulse train pattern may be used, in which a first phase of electrical pulses is applied to a first channel of electrodes, a second phase of electrical pulses is applied to a second channel of electrodes,and a third phase of electrical pulses is applied to the first channel of electrodes. Using the triphasic sequential pulse train pattern, the second phase of electrical pulses commences after termination of thefirst phase of electrical pulses such that there is a time delaytherebetween and, similarly, the third phase of electrical pulses commences after termination of the second phase of electrical pulses such that there is a time delay therebetween. Using the triphasicoverlapping pulse train pattern, the second phase of electrical pulses commences before termination of the first phase of electrical pulses such that there is an overlap therebetween and, similarly, the third phase of electrical pulses commences before termination of the second phase of electrical pulses such that there is an overlap therebetween.
In yet another example, the series of electrical pulses comprises a functional pulse train pattern applied to one or more channels of electrodes. In this example, the pulse train pattern attempts to mimic the electrical sequencing of particular muscles involved in swallowing(e.g., the buccinator muscles, the orbicularis oris muscles, themasseter muscles, the pterygoid muscles, the tongue, and the pharyngealand laryngeal muscles) during normal functioning activity.
In a further example, the series of electrical pulses comprises alow-frequency pulse train pattern applied to one or more channels of electrodes, wherein the individual electrical pulses are generated at a frequency of between 0.1 Hz and 200 Hz to selectively generate the relative selective production neurotransmitters and modulators(endorphins, dynorphins, enkephalin, and serotonin, etc.) based on the frequency selected. Stimulation at specific frequencies is believed tohave beneficial effects in the treatment of dysphagia due to the normalization of hyperactive sensory inputs (which play a role in there-education of the central pattern generators) or triggering descending inhibition to reduce overactive muscle tone and/or spasticity. The useof a single frequency of stimulation may be most effective in targeting a single mechanism of inhibition that may be dysfunctional.
Alternatively, a frequency-sequenced pulse burst train pattern may be applied to one or more channels of electrodes, wherein different sequences of modulated electrical pulses are generated at different burst frequencies. Preferably, the different burst frequencies are selected so as to generate the simultaneous production of endorphins,dynorphins, enkephalin, and serotonin during each of the respective sequences, which is believed to have beneficial effects in the treatment of dysphagia due to the normalization of hyperactive sensory inputs(which play a role in the re-education of the central pattern generators) or triggering descending inhibition to reduce overactivemuscle tone and/or spasticity. The combined effect of the generation of multiple inhibitory or excitatory neurotransmitters may provide a more powerful effect than a single neurotransmitter for use in more difficult cases or as a more generalized approach as compared to the single frequency method.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be described in greater detail in thefollowing detailed description of the invention with reference to the accompanying drawings that form a part hereof, in which:
FIG. 1 is a block diagram of an electrical stimulation device that maybe used in accordance with the method of the present invention;
FIG. 2A is a timing diagram of a biphasic sequential pulse train pattern that may be applied to the output channels of the electrical stimulation device of FIG. 1;
FIG. 2B is a timing diagram of a biphasic overlapping pulse trainpattern that may be applied to the output channels of the electricalstimulation device of FIG. 1;
FIG. 2C is a timing diagram of a triphasic sequential pulse trainpattern that may be applied to the output channels of the electricalstimulation device of FIG. 1;
FIG. 2D is a timing diagram of a triphasic overlapping pulse trainpattern that may be applied to the output channels of the electricalstimulation device of FIG. 1;
FIG. 2E is a timing diagram of a low-frequency pulse train pattern that may be applied to the output channels of the electrical stimulation device of FIG. 1;
FIG. 2F is a timing diagram of a first frequency-sequenced pulse bursttrain pattern that may be applied to the output channels of the electrical stimulation device of FIG. 1;
FIG. 2G is a timing diagram of a second frequency-sequenced pulse bursttrain pattern that may be applied to the output channels of the electrical stimulation device of FIG. 1;
FIG. 2H is a timing diagram of a third frequency-sequenced pulse bursttrain pattern that may be applied to the output channels of the electrical stimulation device of FIG. 1;
FIG. 3A illustrates a method for treating dysphagia in a patient byapplying electrical stimulation in accordance with a first exemplaryembodiment of the present invention, in which the buccinator and/orobicularis oris muscles and the cervical para spinal muscles of thepatient are stimulated;
FIG. 3B illustrates a method for treating dysphagia in a patient byapplying electrical stimulation in accordance with a second exemplaryembodiment of the present invention, in which the masseter and/orpterygoid muscles and the cervical para spinal muscles of the patient are stimulated;
FIG. 3C illustrates a method for treating dysphagia in a patient byapplying electrical stimulation in accordance with a third exemplaryembodiment of the present invention, in which the tongue muscles and the cervical para spinal muscles of the patient are stimulated;
FIG. 3D illustrates a method for treating dysphagia in a patient byapplying electrical stimulation in accordance with a fourth exemplaryembodiment of the present invention, in which the trapezius muscles andthe cervical para spinal muscles of the patient are stimulated;
FIG. 3E illustrates a method for treating dysphagia in a patient byapplying electrical stimulation in accordance with a fifth exemplaryembodiment of the present invention, in which the median nerves or first dorsal interosseous muscles and the cervical para spinal muscles of thepatient are stimulated;
FIG. 3F illustrates a method for treating dysphagia in a patient byapplying electrical stimulation in accordance with a sixth exemplaryembodiment of the present invention, in which the median nerves or first dorsal interosseous muscles and the thoracic para spinal muscles of thepatient are stimulated; and
FIG. 3G illustrates a method for treating dysphagia in a patient byapplying electrical stimulation in accordance with a seventh exemplaryembodiment of the present invention, in which the thoracic para spinalmuscles and the cervical para spinal muscles of the patient are stimulated.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to an electrical stimulation device and method for the treatment of dysphagia. As used herein, the term“electrical stimulation” refers to the passing of various types of current to a patient through transcutaneous or percutaneous electrodes,and includes indirect nerve and/or muscle activation by stimulation ofthe nerves innervating the sensor (cutaneous and position sensors) and muscle fibers associated with central pattern generator inputs or inhibitory mechanism and stimulation of motor efferent fibers which activate the muscles associated with swallowing.
Examples of the types of electrical stimulation that may be used include, but are not limited to, Patterned Electrical Neuromuscular Stimulation (PENS), Transcutaneous Electrical Nerve Stimulation (TENS),Neuromuscular Electrical Stimulation (NMES), and Interferential Current(IFC), Percutaneous Electrical Muscle Stimulation (PEMS), PercutaneousElectrical Nerve Stimulation (PENS), which may use alternating or modulated alternating current waveforms, asymmetrical or symmetricalbiphasic pulsed current waveforms and monophasic pulsed currentwaveforms. Of course, one skilled in the art will appreciate that other types of electrical stimulation may also used in accordance with the present invention.
As used herein, the term “posterior neck region” refers to the region or portion thereof generally bounded by the occiput and the C1 to C7cervical vertebrae and extending along the cervical para spinal muscle sand the trapezius muscle of the patient with afferent and efferentinnervation to the C1-C8 spinal nerves.
As used herein, the term “posterior thoracic region” refers to the region generally bounded by the T1 to T6 thoracic spinous process line and extending along the thoracic para spinal muscles of the patient tothe medial border of the scapulae.
As used herein, the term “motor point” refers to an area of tissue that can be electrically stimulated by lower levels of electricity compared to surrounding areas. The motor point overlies the innervation zone of a muscle where the motor nerve endings are concentrated or where the nerve trunk enters the muscle. The motor point is often used as a placement site for surface electrodes used to stimulate the muscle.
As used herein, the term “tissue” refers to an aggregation ofmorphologically similar cells and associated intercellular matter acting together to perform one or more specific functions in the body,including epithelial, connective, muscle, and neural tissue.
As used herein, the term “treatment” refers to the treatment ofdysphagia in a patient, such as a mammal (particularly a human), which includes preventing, ameliorating, suppressing, or alleviating one ore more of the symptoms of dysphagia.
Referring to FIG. 1, an exemplary embodiment of an electricalstimulation device that may be used in accordance with the method of the present invention is designated generally as reference numeral 10.Electrical stimulation device 10 generally comprises an electronic control unit 12 with a plurality of output connectors 14, 16, which are connected to a plurality of output cables 18, 20 and associated electrode pairs 18 a, 18 b and 20 a, 20 b, respectively. Although two output connectors 14, 16 are shown in FIG. 1, it should be understood that electronic control unit 12 may include any number of output connectors (such as one, two, six or eight output connectors) in accordance with the present invention.
Output cables 18, 20 each comprise any suitable type of insulated conductive cable, such as a coaxial cable. In the illustrated embodiment, output cable 18 includes a back section 22 with a connector24 (such as a male jack) that attaches to output connector 14, and a front section 26 that splits into a first split end 26 a and a second split end 26 b. Similarly, output cable 20 includes a back section 28with a connector 30 (such as a male jack) that attaches to output connector 16, and a front section 32 that splits into a first split end32 a and a section split end 32 b. Of course, it should be understood that each of output cables 18, 20 could alternatively be manufactured out of two separate leads (instead of having a front section with split ends). In addition, output cables 18, 20 could be connected directly to electronic control unit 12 without the use of connectors.
As can be seen in FIG. 1, electrodes 18 a, 18 b are attached to split ends 26 a, 26 b of output cable 18, respectively. Similarly, electrodes20 a, 20 b are attached to split ends 32 a, 32 b of output cable 20,respectively. As such, output cable 18 and electrodes 18 a, 18 b together form a first output channel (referred to hereinafter as“channel A”), and output cable 20 and electrodes 20 a, 20 b together form a second output channel (referred to hereinafter as “channel B”).Although two channels are shown in FIG. 1, it should be understood that any number of channels may be used in accordance with the present invention (provided, of course, that the number of channels corresponds to the number of output connectors of electronic control unit 12).
In the illustrated example, electrodes 18 a and 20 a each comprise a relative positive electrode, and electrodes 18 b and 20 b each comprise a relative negative electrode. As will be described in greater detailhereinbelow, each of the electrical pulses applied to electrodes 18 a,18 b and electrodes 20 a, 20 b may comprise, for example, a monophasicwaveform (which has absolute polarity), a biphasic asymmetric waveform(which has relative polarity), or a biphasic symmetric waveform (which has no polarity). Thus, as used herein, the term “positive electrode”refers to a relative positive electrode and the term “negative electrode” refers to a relative negative electrode (regardless of whether the electrical pulse comprises a monophasic waveform, ana symmetric biphasic waveform, or a symmetric biphasic waveform (which behaves like the relative positive or relative negative electrode during each phase of the waveform)).
Electrodes 18 a, 18 b and 20 a, 20 b are each adapted to be positioned in electrical conduct with tissue of selected regions of a patient, as will be described in greater detail hereinbelow with reference to FIGS.3A-3G. In the illustrated embodiment, each of electrodes 18 a, 18 b and20 a, 20 b comprises a transcutaneous electrode having a surface electrode pad that may be placed on the skin of a patient. As is known in the art, each of electrodes 18 a, 18 b and 20 a, 20 b may be formed of metal or some other physiologically acceptable conductive material and may take on a variety of different sizes and shapes. Of course, one or more of electrodes 18 a, 18 b and 20 a, 20 b may alternatively comprise a percutaneous electrode, such as a needle electrode, or anyother type of suitable electrode in accordance with the present invention.
Electronic control unit 12 also includes internal circuitry (not shown)for selectively generating a series of electrical pulses in accordance with a procedure for treating dysphagia. The series of electrical pulses generated by the circuitry are provided at output connectors 14, 16 and,as such, may be applied to a patient through channel A and/or channel B.The series of electrical pulses may comprise a variety of different types of pulse train patterns, such as: a plurality of cycles of abiphasic sequential pulse train pattern; a plurality of cycles of abiphasic overlapping pulse train pattern; a plurality of cycles of atriphasic sequential pulse train pattern; a plurality of cycles of atriphasic overlapping pulse train pattern; a functional pulse trainpattern; a low-frequency pulse train pattern; or a frequency-sequenced pulse burst train pattern. Each of these pulse train patterns will be described in detail hereinbelow with reference to FIGS. 2A-2H. Ones killed in the art will understand that a variety of different circuit configurations may be used to generate the various pulse train patterns,such as the circuitry described in Palermo U.S. Pat. No. 5,562,718,which is incorporated herein by reference.
A variety of different electrical stimulation devices may be used and/or adapted for use in accordance with the present invention. For example,one could easily incorporate the protocols disclosed herein into theOmnistim® FX² patterned electrical neuromuscular stimulator or theOmnistim® FX² Pro patterned electrical neuromuscular stimulator, both ofwhich are sold by the assignee of the present application. Of course,other types of electrical stimulation devices could also be used, whichare generally available in the industry.
Referring now to FIGS. 2A-2H, examples of the various types of pulse train patterns that may be used in accordance with the present invention will now be described hereinbelow. Each of the pulse train patterns is comprised of a series of individual electrical pulses arranged into a particular pattern. Each of the electrical pulses may comprise either amonophasic or biphasic waveform, which may be, for example, asymmetric,symmetric, square, sinusoidal, and the like. Preferably, each of the electrical pulses comprises a biphasic asymmetric square wave having a pulse duration that ranges between 30 microseconds and 100 microsecondsduring the positive and negative phases and a current amplitude that typically ranges between 25 milliamps and 140 milliamps.
It has been found that electrical pulses having a short pulse duration and high current amplitude selectively trigger p-type calcium channels(preferably having a pulse duration of 30-100 microseconds and a current amplitude of 25-140 milliamps). Activation of p-type calcium channels will in turn trigger the release of nerve growth factor (“NGF”) to sustain axon regeneration and repair. This repeated p-type calcium channel activation increases the calcium pool at the neuromuscular junction, which facilitates enhanced muscle recruitment. Twitch contractions may increase in intensity during the treatment even though the stimulation output is not increased as observed empirically. This additional calcium at the neuromuscular junction lasts for several hours post-treatment, which facilitates voluntary movement. See RegeneronCorp. (Tarrytown N.Y.) Neural stimulation effects presentation, Society for Neuroscience, San Diego 1998 (short and long term nerve growthpotentiation using repetitive electric stimulation).
Biphasic Sequential Pulse Train Pattern
Referring to FIG. 2A, electrical stimulation device 10 may be used to apply a plurality of cycles of a biphasic sequential pulse train pattern to a patient. In a typical biphasic sequential pulse train pattern, afirst phase of electrical pulses is applied to channel A and a second phase of electrical pulses is applied to channel B with a delay periodtherebetween.
In the illustrated example, the first phase of electrical pulses isapplied to channel A for approximately 60 milliseconds to 120milliseconds (and most preferably for 100 milliseconds). At the conclusion of the first phase of electrical pulses, there is a delay period of approximately 0 milliseconds to 100 milliseconds (and mostpreferably 80 milliseconds) before the second phase of electrical pulse sis applied to channel B. Then, the second phase of electrical pulses isapplied to channel B for approximately 60 milliseconds to 120milliseconds (and most preferably for 100 milliseconds). The frequency of the individual electrical pulses in each phase is approximately 30 Hz to 100 Hz (and most preferably 50 Hz).
The biphasic sequential pulse train pattern described above may be repeated approximately every 0.33 seconds (3 Hz) to 3 seconds (0.33 Hz),depending on the stage of swallowing being treated. Preferably, the pulse train pattern is applied to the patient for a total treatment time of approximately 10 minutes to 30 minutes (and most preferably for 20minutes), as desired for a particular treatment.
Biphasic Overlapping Pulse Train Pattern
Referring to FIG. 2B, electrical stimulation device 10 may also be usedto apply a plurality of cycles of a biphasic overlapping pulse trainpattern to a patient. In a typical biphasic overlapping pulse trainpattern, a first phase of electrical pulses is applied to channel A anda second phase of electrical pulses is applied to channel B with an overlap period therebetween.
In the illustrated example, the first phase of electrical pulses isapplied to channel A for approximately 60 milliseconds to 120milliseconds (and most preferably for 100 milliseconds). When the first phase of electrical pulses has reached a time period of between 40milliseconds and 100 milliseconds (and most preferably 80 milliseconds),the second phase of electrical pulses is applied to channel B for approximately 60 milliseconds to 120 milliseconds (and most preferably for 100 milliseconds). Thus, there is an overlap period of approximately20 milliseconds to 80 milliseconds (and most preferably 20 milliseconds)during which both channel A and channel B are providing electricalstimulation to the patient. The frequency of the individual electricalpulses in each phase is approximately 30 Hz to 100 Hz (and mostpreferably 50 Hz).
The biphasic overlapping pulse train pattern described above may be repeated approximately every 0.33 seconds (3 Hz) to 3 seconds (0.33 Hz),depending on the stage of swallowing being treated. Preferably, the pulse train pattern is applied to the patient for a total treatment time of approximately 10 minutes to 60 minutes (and most preferably 20minutes), as desired for a particular treatment.
Triphasic Sequential Pulse Train Pattern
Referring to FIG. 2C, electrical stimulation device 10 may also be usedto apply a plurality of cycles of a triphasic sequential pulse trainpattern to a patient. In a typical triphasic sequential pulse trainpattern, a first phase of electrical pulses is applied to channel A, asecond phase of electrical pulses is applied to channel B, and a third phase of electrical pulses is applied to channel A, wherein there is a delay period between the first and second phases of electrical pulse sand another delay period between the second and third phases of electrical pulses.
In the illustrated example, the first phase of electrical pulses isapplied to channel A for approximately 60 milliseconds to 120milliseconds (and most preferably for 100 milliseconds). At the conclusion of the first phase of electrical pulses, there is a delay period of approximately 0 milliseconds to 100 milliseconds (and mostpreferably 80 milliseconds) before the second phase of electrical pulse sis applied to channel B. Then, the second phase of electrical pulses isapplied to channel B for approximately 60 milliseconds to 120milliseconds (and most preferably for 100 milliseconds). At the conclusion of the second phase of electrical pulses, there is a delay period of approximately 0 milliseconds to 100 milliseconds (and mostpreferably 80 milliseconds) before the third phase of electrical pulse sis applied to channel A. Then, the third phase of electrical pulses isapplied to channel A for approximately 36 milliseconds to 72milliseconds (and most preferably for 60 milliseconds). The frequency ofthe individual electrical pulses in each phase is approximately 30 Hz to100 Hz (and most preferably 50 Hz).
The triphasic sequential pulse train pattern described above may be repeated approximately every 0.33 seconds (3 Hz) to 3 seconds (0.33 Hz),depending on the stage of swallowing being treated. Preferably, the pulse train pattern is applied to the patient for a total treatment time of approximately 10 minutes to 60 minutes (and most preferably 20minutes), as desired for a particular treatment.
Referring to FIG. 2D, electrical stimulation device 10 may also be usedto apply a plurality of cycles of a triphasic overlapping pulse trainpattern to a patient. In a typical triphasic overlapping pulse trainpattern, a first phase of electrical pulses is applied to channel A, asecond phase of electrical pulses is applied to channel B, and a third phase of electrical pulses is applied to channel A, wherein there is an overlap period between the first and second phases of electrical pulse sand another overlap period between the second and third phases of electrical pulses.
In the illustrated example, the first phase of electrical pulses isapplied to channel A for approximately 60 milliseconds to 120milliseconds (and most preferably for 100 milliseconds). When the first phase of electrical pulses has reached a time period of between 40milliseconds and 100 milliseconds (and most preferably 80 milliseconds),the second phase of electrical pulses is applied to channel B for approximately 60 milliseconds to 120 milliseconds (and most preferably100 milliseconds). Thus, there is an overlap period of approximately 0milliseconds to 100 milliseconds (and most preferably 20 milliseconds)during which both channel A and channel B are providing electricalstimulation to the patient. When the second phase of electrical pulses has reached a time period of between 40 milliseconds and 100milliseconds (and most preferably 80 milliseconds), the third phase of electrical pulses is applied to channel A for approximately 36milliseconds to 72 milliseconds (and most preferably 60 milliseconds)(i.e., the third phase of electrical pulses has a shorter time duration than that of the first phase of electrical pulses). Thus, there is an overlap period of approximately 0 milliseconds to 72 milliseconds (and most preferably 20 milliseconds) during which both channel B and channel A are providing electrical stimulation to the patient. The frequency ofthe individual electrical pulses in each phase is approximately 30 Hz to100 Hz (and most preferably 50 Hz).
The triphasic overlapping pulse train pattern described above may be repeated approximately every 0.33 seconds (3 Hz) to 3.0 seconds (0.33Hz), depending on the stage of swallowing being treated. Preferably, the pulse train pattern is applied to the patient for a total treatment time of approximately 10 minutes to 60 minutes (and most preferably 20minutes), as desired for a particular treatment.
Functional Pulse Train Pattern
Electrical stimulation device 10 may also be used to apply a functional pulse train pattern to a patient. The functional pulse train pattern isapplied to channel A and channel B (or to additional channels) so as to mimic the electrical sequencing of particular muscles involved in swallowing during normal functioning activity. One skilled in the art will understand that the functional pulse train pattern for a particular functioning activity (e.g., chewing, moving the bolus or swallowing) maybe obtained through the use of an electromyographic (EMG) recording device. The sequence of firing of the muscles, firing frequencies, andthe duration and frequency of the firing of the muscles may thus be determined for standardized healthy normal subjects and may then be programmed into the appropriate stimulation pattern. Preferably, the functional pulse train pattern is applied to the patient for a total treatment time of approximately 10 minutes to 60 minutes (and mostpreferably 20 minutes), as desired for a particular treatment.
Low-Frequency Pulse Train Pattern
Referring to FIG. 2E, electrical stimulation device 10 may also be usedto apply a low-frequency pulse train pattern to a patient. The low-frequency pulse train pattern may be applied to channel A and/or channel B, wherein the individual electrical pulses are generated on each channel at a frequency of between 0.1 Hz and 200 Hz. Generally, the frequency of the electrical pulses is selected in order to provide the desired response and release of stimulatory or inhibitoryneurotransmitters centrally and spin ally while providing the greatest comfort to the patient. If channel A and channel B are both used, the low-frequency pulse train pattern may be applied simultaneously to channel A and channel B, or, a different frequency may be applied on each channel to a different area associated with various phases of swallowing. Preferably, the low-frequency pulse train pattern is applied to the patient for a total treatment time of approximately 5 minutes to60 minutes (and most preferably 20 minutes), as desired for a particular treatment.
Frequency-Sequenced Pulse Burst Train Pattern
Referring to FIGS. 2F-2H, electrical stimulation device 10 may also beused to apply a frequency-sequenced pulse burst train pattern to a patient. The frequency-sequenced pulse burst train pattern may be applied to channel A and/or channel B, wherein different sequences of modulated electrical pulses are generated at different frequencies.Preferably, the different burst frequencies are selected so as to selectively generate the production of endorphin, dynorphin, andenkephalin/serotonin during each of the respective sequences, which is believed to have beneficial effects in the treatment of dysphagia.
In the example shown in FIG. 2F, the frequency-sequenced pulse bursttrain pattern has a carrier frequency of 500 Hz to 100,000 Hz with afirst sequence of modulated electrical pulses generated at a burstfrequency of approximately 0.1 Hz to 5 Hz for a duration of approximately 1 seconds to 120 seconds, a second sequence of modulated electrical pulses generated at a burst frequency of approximately 5 Hz to 20 Hz for a duration of approximately 1 seconds to 120 seconds, and a third sequence of modulated electrical pulses generated at a burstfrequency of approximately 20 Hz to 250 Hz for a duration of approximately 1 seconds to 120 seconds. Preferably, the frequency-sequenced pulse burst train pattern is applied to the patient for a total treatment time of approximately 1 minute to 60 minutes.Using this therapy, the patient begins to receive the effects of all ofthe neurotransmitters relatively quickly as the frequencies cycle through rapidly. This therapy is also very comfortable and moderately aggressive.
In the example shown in FIG. 2G, the frequency-sequenced pulse bursttrain pattern has a carrier frequency of 500 Hz to 100,000 Hz with afirst sequence of modulated electrical pulses generated at a burstfrequency of approximately 5 Hz to 20 Hz for a duration of approximately1 minute to 10 minutes, a second sequence of modulated electrical pulses generated at a burst frequency of approximately 0.1 Hz to 5 Hz for a duration of approximately 1 minute to 30 minutes, and a third sequence of modulated electrical pulses generated at a burst frequency of approximately 20 Hz to 250 Hz for a duration of approximately 1 minute to 20 minutes. Preferably, the frequency-sequenced pulse burst trainpattern is applied to the patient for a total treatment time of approximately 3 minutes to 50 minutes. This therapy is the most aggressive and least tolerated but provides the longest lasting effect.The initial effect is dynorphin (5-20 Hz), followed by endorphin (1-5Hz), and then by enkephalin/serotonin (20-250 Hz). Since it takes 15 to30 minutes to activate endorphin and only 5-10 minutes to activateenkephalin/serotonin, both are present at the completion of the treatment for maximum effect.
In the example shown in FIG. 2H, the frequency-sequenced pulse bursttrain pattern has a carrier frequency of 500 Hz to 100,000 Hz with afirst sequence of modulated electrical pulses generated at a burstfrequency of approximately 20 Hz to 250 Hz for a duration of approximately 1 minute to 20 minutes, and a second sequence of modulated electrical pulses generated at a burst frequency of approximately 0.1 Hz to 20 Hz for a duration of approximately 1 minute to 20 minutes.Preferably, the frequency-sequenced pulse burst train pattern is applied to the patient for a total treatment time of approximately 20 minutes to40 minutes. This therapy is the least aggressive and best tolerated but provides the shortest lasting effect. The initial effect isenkephalin/serotonin (20-250 Hz) followed by endorphin (1-20 Hz). Since it takes about 15-30 minutes to activate endorphin and only about 5-10minutes to activate enkephalin/serotonin, both are present at the completion of the treatment. However, the enkephalin/serotonin has begun to deplete as it has a relatively short half life (15 minutes to 2hours) compared to endorphin (2-6 hours). Stimulation at higher frequencies is better tolerated and thus more appropriate to start with for more sensitive patients.
Referring now to FIGS. 3A-3E, electrodes 18 a, 18 b and 20 a, 20 b are each adapted to be positioned in electrical contact with tissue of selected regions of a patient. The selected regions are preferably those that will assist in programming the central pattern generators associated with swallowing. These central pattern generators are neuronal ensembles located in the brain stem capable of producing the basic spatiotemporal patterns underlying “automatic” swallowing movements in the absence of peripheral feedback. In the present invention, the muscle contractions produced by the pulse train patterns provide afferent inputs or efferent stimulation that assist inretraining of the central nervous system and spinal motor loops to promote normal muscle function. In particular, it has been found that stimulation of the buccinator, orbicularis oris, masseter, trapezius,median nerve, first dorsal interosseous muscle and mid thoracicpara spinals in conjunction with the posterior neck region or posterior thoracic region may assist in retraining the central pattern generators associated with swallowing.
It will be appreciated that when multiple channels are used (e.g., inthe case of biphasic and triphasic pulse patterns), the first pulse pattern is preferably applied to the muscle most seriously affected. Forexample, if a patient complains of muscle weakness in chewing primarily on the right side of the body, the motor point of the masseter muscle onthe right side of the patient's body preferably receives the pulse pattern on channel A and the motor point of the masseter muscle on the left side of the patient's body preferably receives the pulse pattern on channel B.
The dysphagia treatment methods of the present invention are well-adapted to be used with other conventional therapies for dysphagiatreatment, including changing the diet (such as eating thickened liquids or thin liquids, depending on the type of dysphagia), swallowing exercises, changes in body posture, strengthening exercises, and even surgery. Medications useful for treating dysphagia include, but are not limited to, nitrates (e.g., nitroglycerin, isosorbide), anticholinergics(e.g., dicyclomine, hyoscyamine sulfate), calcium-channel blockers(e.g., nifedipine, diltiazem), sedatives/antidepressants (e.g.,diazepam, trazodone, doxepin), smooth-muscle relaxants (e.g.,hydralazine), and antacids (e.g., cimetidine, ranitidine, nizatidine,famotidine, omeprazole, lansoprazole, metoclopramide).
While several exemplary embodiments of the present invention are discussed below, those skilled in the art will readily appreciate that various modifications may be made to these embodiments, and the invention is not limited to the specific electrode placements and pulse train patterns described therein.
FIRST EXEMPLARY EMBODIMENT
In a first exemplary embodiment of the present invention, as generallyillustrated in FIG. 3A, a pair of electrodes is positioned in electricalcontact with the patient's tissue in order to provide electricalstimulation to one or more of the face muscles used to create proper lip seal during swallowing and to the muscles associated with the posterior neck region. A second pair of electrodes is positioned bilaterally in a similar manner.
More specifically, as shown in FIG. 3A, a first electrode 18 a ispositioned in electrical contact with tissue to stimulate a motor point of the patient's buccinator muscle and/or orbicularis oris muscle. Most preferably, first electrode 18 a comprises a surface electrode that ispositioned on the patient's skin along the distal corner of thepatient's mouth. A second electrode 18 b is positioned is electricalcontact with tissue to stimulate the patient's cervical para spinalmuscles. Most preferably, second electrode 18 b comprises a surface electrode that is positioned on the patient's skin in the posterior neckregion just lateral to the one or more of the cervical vertebrae, mostpreferably near the C1, C2, C3 and/or C4 cervical vertebrae. Another pair of electrodes 20 a, 20 b is provided bilaterally in a similar position as generally illustrated in FIG. 3A.
In this exemplary embodiment, the pulse train pattern comprises abiphasic overlapping pulse train pattern having the followingparameters:
Pulse duration of individual electrical pulses: 50-70 microseconds
Current amplitude of individual electrical pulses: 25-70 milliamps
Duration of first phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of second phase: 100 milliseconds
Frequency of pulse train pattern: 0.6 seconds
Total treatment time: 20 minutes
Total number of treatments: 18 (over six weeks)
Frequency of individual electrical pulses (in each phase): 50 hertz
SECOND EXEMPLARY EMBODIMENT
In a second exemplary embodiment of the present invention, as generallyillustrated in FIG. 3B, a pair of electrodes is positioned in electricalcontact with the patient's tissue in order to provide electricalstimulation to one or more of the face muscles used to chew during swallowing and to the muscles associated with the posterior neck region.A second pair of electrodes is positioned bilaterally in a similar manner.
More specifically, as shown in FIG. 3B, a first electrode 18 a ispositioned in electrical contact with tissue to stimulate a motor point of the patient's masseter muscle and/or pterygoid muscle (medial and/or lateral). Most preferably, first electrode 18 a comprises a surface electrode that is positioned on the patient's skin along the jaw about one inch anterior to the lower angle of the mandible at the prominence of the masseter muscle. A second electrode 18 b is positioned is electrical contact with tissue to stimulate the patient's cervicalpara spinal muscles. Most preferably, second electrode 18 b comprises a surface electrode that is positioned on the patient's skin in the posterior neck region just lateral to the one or more of the cervicalvertebrae, most preferably near the C1, C2, C3 and/or C4 cervicalvertebrae. Another pair of electrodes 20 a, 20 b is provided bilaterallyin a similar position as generally illustrated in FIG. 3B.
In this exemplary embodiment, the pulse train pattern comprises abiphasic overlapping pulse train pattern having the followingparameters:
Pulse duration of individual electrical pulses: 50-70 microseconds
Current amplitude of individual electrical pulses: 20-70 milliamps
Duration of first phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of second phase: 100 milliseconds
Frequency of pulse train pattern: 0.6 seconds
Total treatment time: 20 minutes
Total number of treatments: 36
Frequency of individual electrical pulses (in each phase): 50 hertz
THIRD EXEMPLARY EMBODIMENT
In a third exemplary embodiment of the present invention, as generallyillustrated in FIG. 3C, a probe is positioned in electrical contact withthe patient's tissue in order to provide electrical stimulation to the tongue, which is used to move the bolus to the pharynx in preparation for swallowing and to the muscles associated with the posterior neckregion. As can be seen, the probe (which is preferably used as a common ground) is placed on the tongue and other electrodes are positionedbilaterally along the posterior neck region of the patient.
More specifically, as shown in FIG. 3C, a first electrode 18 a and asecond electrode 20 a are connected to the probe, which is positioned in electrical contact with tissue to stimulate a motor point of thepatient's tongue muscle. Most preferably, the probe includes a conductive ball that is positioned on the patient's tongue about themidpoint. Other electrodes 18 b and 20 b are positioned bilaterally in electrical contact with tissue to stimulate the patient's cervicalpara spinal muscles. Most preferably, electrodes 18 b and 20 b each comprise a surface electrode that is positioned on the patient's skin inthe posterior neck region just lateral to the one or more of the cervical vertebrae, most preferably near the C1, C2, C3 and/or C4cervical vertebrae. The two channels thus use the probe as a common ground for application to the tongue. Of course, as an alternative touse of the probe, it should be understood that electrodes 18 a and 18 b could be placed side-by-side on the midpoint of the patient's tongue.
In this exemplary embodiment, the pulse train pattern comprises abiphasic overlapping pulse train pattern having the followingparameters:
Pulse duration of individual electrical pulses: 50-70 microseconds
Current amplitude of individual electrical pulses: 15-50 milliamps
Duration of first phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of second phase: 100 milliseconds
Frequency of pulse train pattern: 0.6 seconds
Total treatment time: 20 minutes
Total number of treatments: 36
Frequency of individual electrical pulses (in each phase): 50 hertz
FOURTH EXEMPLARY EMBODIMENT
In a fourth exemplary embodiment of the present invention, as generallyillustrated in FIG. 3D, a pair of electrodes is positioned in electricalcontact with the patient's tissue in order to provide electricalstimulation to one or more of the muscles involved in the oropharyngealphase of swallowing and to the muscles associated with the posterior neck region. A second pair of electrodes is positioned bilaterally in a similar manner.
More specifically, as shown in FIG. 3D, a first electrode 18 a ispositioned in electrical contact with tissue to stimulate a motor point of the patient's trapezius muscle. As discussed above, the spinal component of the accessory nerve (XI) innervates the trapezius muscle.The more superficial muscles, such as the trapezius, rhomboideus minor,and/or rhomboideus major associated with maintaining proper posture during swallowing, may also be stimulated. Most preferably, first electrode 18 a comprises a surface electrode that is positioned on thepatient's skin on the rhomboid and mid-trapezius, just lateral to the lower cervical and upper thoracic vertebrae, most preferably near the C7cervical vertebrae and the T1 thoracic vertebrae. A second electrode 18b is positioned in electrical contact with tissue to stimulate thepatient's cervical para spinal muscles. Most preferably, second electrode18 b comprises a surface electrode that is positioned on the patient's skin in the posterior neck region just lateral to the one or more of the cervical vertebrae, most preferably near the C1, C2, C3 and/or C4cervical vertebrae. Another pair of electrodes 20 a, 20 b is providedbilaterally in a similar position as generally illustrated in FIG. 3D.
In this exemplary embodiment, the pulse train pattern comprises abiphasic overlapping pulse train pattern having the followingparameters:
Pulse duration of individual electrical pulses: 50-70 microseconds
Current amplitude of individual electrical pulses: 30-140 milliamps
Duration of first phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of second phase: 100 milliseconds
Frequency of pulse train pattern: 0.6 seconds
Total treatment time: 20 minutes
Total number of treatments: 36
Frequency of individual electrical pulses (in each phase): 50 hertz
FIFTH EXEMPLARY EMBODIMENT
In a fifth exemplary embodiment of the present invention, as generallyillustrated in FIG. 3E, a pair of electrodes is positioned in electricalcontact with the patient's tissue in order to provide electricalstimulation to one or more of the muscles involved in the oropharyngealand esophageal phase of swallowing and to muscles associated with the posterior neck region. A second pair of electrodes is positionedbilaterally in a similar manner.
More specifically, as shown in FIG. 3E, a first electrode 18 a ispositioned in electrical contact with tissue to stimulate the median nerve or first dorsal interosseous muscle. One or more muscles of the arm involved in carrying food to the patient's mouth may also be stimulated, such as the (superficial) flexor carpi radialis, flexorcarpi ulnaris, palma ris longus brachioradialis, (deep) flexor digitorumsuperficalis, or flexor digitorum profundus. Most preferably, first electrode 18 a comprises a surface electrode that is positioned on thepatient's skin on the palmar/anterior side of the forearm at the base ofthe wrist just above the wrist crease. A second electrode 18 b ispositioned in electrical contact with tissue to stimulate the patient's cervical para spinal muscles. Most preferably, the second electrode 18 b comprises a surface electrode that is positioned on the patient's skin in the posterior neck region just lateral to the one or more of the cervical vertebrae, most preferably near the C1, C2, C3 and/or C4cervical vertebrae. Another pair of electrodes 20 a, 20 b is providedbilaterally in a similar position as generally illustrated in FIG. 3E.
In this exemplary embodiment, the pulse train pattern comprises atriphasic overlapping pulse train pattern having the followingparameters:
Pulse duration of individual electrical pulses: 50-70 microseconds
Current amplitude of individual electrical pulses: 30-70 milliamps
Duration of first phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of second phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of third phase: 60 milliseconds
Frequency of pulse train pattern: 0.5-1.5 seconds
Total treatment time: 20 minutes
Total number of treatments: 36
Frequency of individual electrical pulses (in each phase): 50 hertz
SIXTH EXEMPLARY EMBODIMENT
In a sixth exemplary embodiment of the present invention, as generallyillustrated in FIG. 3F, a pair of electrodes is positioned in electricalcontact with the patient's tissue in order to provide electricalstimulation to one or more of the muscles involved in the oropharyngealand esophageal phase of swallowing and to muscles associated with the posterior thoracic region. A second pair of electrodes is positionedbilaterally in a similar manner.
More specifically, as shown in FIG. 3F, a first electrode 18 a ispositioned in electrical contact with tissue to stimulate the median nerve or first dorsal interosseous muscle. One or more muscles of the arm involved in carrying food to the patient's mouth may also be stimulated, such as the (superficial) flexor carpi radialis, flexorcarpi ulnaris, palma ris longus brachioradialis, (deep) flexor digitorumsuperficalis, or flexor digitorum profundus. Most preferably, first electrode 18 a comprises a surface electrode that is positioned on thepatient's skin on the palmar/anterior side of the forearm at the base ofthe wrist just above the wrist crease. A second electrode 18 b ispositioned in electrical contact with tissue to stimulate the patient's thoracic para spinal muscles. Most preferably, the second electrode 18 b comprises a surface electrode that is positioned on the patient's skin in the posterior thoracic region just lateral to the thoracic vertebrae,most preferably near the T4, T5, and/or T6 thoracic vertebrae. Another pair of electrodes 20 a, 20 b is provided bilaterally in a similar position as generally illustrated in FIG. 3F.
In this exemplary embodiment, the pulse train pattern comprises atriphasic overlapping pulse train pattern having the followingparameters:
Pulse duration of individual electrical pulses: 50-70 microseconds
Current amplitude of individual electrical pulses: 30-70 milliamps
Duration of first phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of second phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of third phase: 60 milliseconds
Frequency of pulse train pattern: 0.5-1.5 seconds
Total treatment time: 20 minutes
Total number of treatments: 36
Frequency of individual electrical pulses (in each phase): 50 hertz
SEVENTH EXEMPLARY EMBODIMENT
In a seventh exemplary embodiment of the present invention, as generallyillustrated in FIG. 3G, a pair of electrodes is positioned in electricalcontact with the patient's tissue in order to provide electricalstimulation to one or more of the muscles in the posterior thoracic region involved in the esophageal phase of swallowing and to the muscles associated with the posterior neck region. A second pair of electrode sis positioned bilaterally in a similar manner.
More specifically, as shown in FIG. 3G, a first electrode 18 a ispositioned in electrical contact with tissue to stimulate the patient's thoracic para spinal muscles at T4, T5, and/or T6 thoracic vertebrae.Most preferably, the first electrode 18 a is positioned on the patient's skin in the posterior thoracic region, near the T4, T5, and/or T6thoracic vertebrae. The second electrode 18 b is positioned in electrical contact with tissue to stimulate the patient's cervicalpara spinal muscles. Most preferably, second electrode 18 b comprises a surface electrode that is positioned on the patient's skin in the posterior neck region just lateral to the one or more of the cervicalvertebrae, most preferably near either (1) the C1, C2, C3 and/or C4cervical vertebrae or (2) the C5, C6 and/or C7 cervical vertebrae.Another pair of electrodes 20 a, 20 b is provided bilaterally in a similar position as generally illustrated in FIG. 3G.
In this exemplary embodiment, the pulse train pattern comprises abiphasic overlapping pulse train pattern having the followingparameters:
Pulse duration of individual electrical pulses: 50-70 microseconds
Current amplitude of individual electrical pulses: 30-140 milliamps
Duration of first phase: 100 milliseconds
Duration of overlap: 20 milliseconds
Duration of second phase: 100 milliseconds
Frequency of pulse train pattern: 0.6 seconds
Total treatment time: 20 minutes
Total number of treatments: 36
Frequency of individual electrical pulses (in each phase): 50 hertz
It will also be appreciated that the dysphagia treatment methods of the present invention may readily be adapted by configuring the electrode sin a manner that is asymmetrical or bilateral in nature, depending upon the stage of dysphagia being treated. For example, for patients suffering from oropharyngeal and esophageal dysphagia at the same time,a combination of the Fifth and Seventh exemplary embodiments may beused. That is, for the first channel, the first electrode 18 a may be positioned to stimulate the median nerve or first dorsal interosseusmuscle of the patient by placing the electrode 18 a on thepalmar/anterior side of the forearm at the base of the wrist. The secondelectrode 18 b of the first channel positioned to stimulate thepatient's cervical para spinal muscles in the said posterior neck region near the C1, C2, C3, and/or C4 cervical vertebrae. For the secondchannel, the first electrode 20 a may be positioned so as stimulate the thoracic para spinal muscles in the posterior thoracic region (e.g. near the T4, T5, and/or T6 thoracic vertebrae of said patient). The secondelectrode 20 b of the second channel is positioned so as to stimulate the posterior neck region near the C1, C2, C3, and/or C4 cervicalvertebrae of said patient. It is contemplated that all of the Exemplary embodiments may be combined in a similar manner to fit the patient's needs and symptoms (e.g. first embodiment for the first channel and either the second, third, fourth, fifth, sixth, or seventh embodiments for the second channel, and so on). In each embodiment, however, it is contemplated that at least one of the electrodes in each channel will be positioned in electrical contact with the patient's posterior neckregion or posterior thoracic region.
Case Study #1
This case study involved a 57-year-old female suffering from chronic esophageal dysmotility over the past four years. The patient's medical history includes two strokes involving right fronto-parietal lobe infarction about five years ago and left temporal parietal infarction about four years ago. The patient exhibited excellent upper and lower extremity recovery with some residual left hand weakness. The patient also suffered from chronic gastroesophageal reflux disease (“GERD”),requiring antacids for past four years. While ingestion of liquids andpuree solids had not been a significant problem, the patient had been unable to tolerate chicken and even ground meat without extensive time between swallows. The patient showed evidence of esophagealregurgitation on modified barium swallow. In addition, recent respiratory failure required intubation and ventilation about four weeks prior to treatment as discussed herein.
The patient was treated with Omnistim® FX² electrical stimulation using therapy combination discussed with respect to the Fifth and Seventh Exemplary Embodiments. More specifically, for Channel A, the positive electrode (2″×4″) was applied to the right hand first dorsalinterosseous muscle and the negative electrode was applied to the rightC1-C4 para spinal muscles. For Channel B, the positive electrode was applied to the left intrascapular para spinal/mid thoracic muscles(T4-T6) and the negative electrode was applied to the left C1-C4para spinal muscles.
The intensity was such to create minimal twitch muscle contractions. The pulse train pattern comprises a biphasic overlapping pulse train pattern having the following parameters:
Pulse duration of individual electrical pulses: 50 microseconds
Current amplitude of individual electrical pulses: 60-70 milliamps
Duration of first phase: 100 milliseconds (5 pulses per train)
Duration of overlap: 20 milliseconds (1 pulse)
Duration of second phase: 100 milliseconds (5 pulses per train)
Frequency of pulse train pattern: 0.6 seconds (1.6 Hz)
Total treatment time: 20 minutes
Frequency of individual electrical pulses (in each phase): 50 hertz
After stimulation, the patient had no difficulty swallowing “rather dry”chicken. Further, regurgitation during and after full meal was no longer noted. The effect of treatment noted to be greater than 6 hours initially and extended with repeated daily treatments. No pain was noted during or after treatment.
Case Study #2
This case study involved a 63-year-old male with advanced Parkinson's Disease and severe rigidity affecting both oral and pharyngeal phase of swallowing. The patient was unable to open his mouth sufficiently to take his dopaminergic medication. Further, the patient could not tolerate a nasogastric tube.
The patient was treated with Omnistim® FX² electrical stimulation with a therapy protocol generally discussed with respect to the Fourth Exemplary Embodiment. More specifically, for Channel A, the positive electrode (2″×4″) was applied to the right upper trapezius muscle andthe negative electrode was applied to the right C1-C4 para spinalmuscles. For Channel B, the positive electrode (2″×4″) was applied tothe left upper trapezius muscle, and the negative electrode was applied to the left C1-C4 para spinal muscles.
The intensity was such to create minimal twitch muscle contractions with visible contractions and minimal head movement. The pulse train patterncomprises a biphasic overlapping pulse train pattern having thefollowing parameters:
Pulse duration of individual electrical pulses: 50 microseconds
Current amplitude of individual electrical pulses: 60-80 milliamps
Duration of first phase: 100 milliseconds (5 pulses per train)
Duration of overlap: 20 milliseconds (1 pulse)
Duration of second phase: 100 milliseconds (5 pulses per train)
Frequency of pulse train pattern: 0.6 seconds (1.6 Hz)
Total treatment time: 20 minutes
Frequency of individual electrical pulses (in each phase): 50 hertz
During the final five minutes and following the treatment, the patient was able to voluntarily move his head approximately 20 degrees in each direction. The patient had not been able to do this prior to the stimulation. The patient as then able to open his mouth voluntarily inorder to ingest medication with applesauce. The initial benefit lasted approximately four hours. Repeated daily applications provided progressive improvement to the point that the patient was able to resume feeding with mechanically softened foods and ingest medications without aspiration. After four sessions, the benefit lasted over 12 hours at each application. At discharge from the hospital, the patient used thesystem described above three times per week with continued benefit for three months. Oral and esophageal phases of swallowing continued to be intact during that time.
Case Study #3
This case study involved an 82-year-old male with oral and pharyngealphase dysphagia due to left cerebellar hemorrhage. Aspiration was noted on modified barium swallow. Tongue and pharyngeal dysmotility was noted,including a reduction in the initiation of the swallowing reflex.Gastrostomy tube placement had been required. The patient was readmittedwith marked weakness due to aspiration pneumonia and urinary tract infection exacerbating prior left hemiparesis and ataxia. The patient also reported a pain in the tongue due to candida overgrowth.
The patient was treated with Omnistim® FX² electrical stimulation with a therapy protocol generally set forth in the First Exemplary Embodiment.More specifically, for Channel A, the positive electrode (2″×2″) was applied to the right facial musculature (orbicularis oris andbuccinator) and the negative electrode was applied to the right C1-C4para spinal muscles. For Channel B, the positive electrode (2″×2″) was applied to the left facial musculature (orbicularis oris andbuccinators) and the negative electrode was applied to the left C1-C4para spinal muscles.
The intensity was such to create minimal twitch muscle contractions with visible contractions and minimal head movement. The pulse train patterncomprises a biphasic overlapping pulse train pattern having thefollowing parameters:
Pulse duration of individual electrical pulses: 50 microseconds
Current amplitude of individual electrical pulses: 45-65 milliamps
Duration of first phase: 100 milliseconds (5 pulses per train)
Duration of overlap: 20 milliseconds (1 pulse)
Duration of second phase: 100 milliseconds (5 pulses per train)
Frequency of pulse train pattern: 0.6 seconds (1.6 Hz)
Total treatment time: 20 minutes
Frequency of individual electrical pulses (in each phase): 50 hertz
The patient was able to tolerate progressive increase in intensity to create motor movement both the facial muscles as well as a minimal twitch of the cervical para spinals. Following the first session, thepatient was able to move his facial muscles and tongue better, but was unable to initiate a swallow nor was he able to manipulate ice chips.The patient's speech volume and precision was improved, the patient reported no discomfort from the treatment.
Following the second treatment the following day, the patient was ableto manipulate the ice chips but could not tolerate the intensity of cold at mid-tongue. Softened ice cream was tolerated and he was able to both manipulate the small bolus and swallow. This generated a cough reflex aswell as a double swallowing reflex.
Following the third treatment the following day, patient was able to speak more clearly, clear his throat more easily and generate a swallowing reflex both with a small bolus of ice cream as well as small sips of thickened water. Protective cough reflex was also reestablished.
Case Study #4
This case study involved a 76-year-old female with right middle cerebral artery (“MCA”) ischemic infarction, left hemiparesis and dysphagia.Modified barium swallow after nasogastric tube removed demonstrated decreased oral phase motility and difficulty with initiation of swallowing reflex plus some penetration without aspiration withthickened consistency food.
The patient was treated with Omnistim® FX² electrical stimulation as generally set forth with respect to the First Exemplary Embodiment. More specifically, for Channel A, the positive electrode (2″×2″) was applied to the right facial musculature (orbicularis oris and buccinator) andthe negative electrode was applied to the right C1-C4 para spinalmuscles. For Channel B, the positive electrode (2″×2″) was applied tothe left facial musculature (orbicularis oris and buccinators) and the negative electrode was applied to the left C1-C4 para spinal muscles.
The intensity was such to create minimal twitch muscle contractions with visible contractions and minimal head movement. The pulse train patterncomprises a biphasic overlapping pulse train pattern having thefollowing parameters:
Pulse duration of individual electrical pulses: 50 microseconds
Current amplitude of individual electrical pulses: 40-60 milliamps
Duration of first phase: 100 milliseconds (5 pulses per train)
Duration of overlap: 20 milliseconds (1 pulse)
Duration of second phase: 100 milliseconds (5 pulses per train)
Frequency of pulse train pattern: 0.6 seconds (1.6 Hz)
Total treatment time: 20 minutes
Frequency of individual electrical pulses (in each phase): 50 hertz
The stimulation was well tolerated and patient stated that her face felt“more like my own.” The patient also demonstrated an improvement in oral motility and pharyngeal phase of swallowing after the first session. She also had a complete reduction in choking after three sessions. Lefthemiparesis partially improved after three weeks of inpatient rehabilitation but she no longer noted clinical dysphagia.
Case Study #5
This case study involved a 76-year-old male with idiopathic dysphagiawho demonstrated a progressive decreased ability to activate the swallowing reflex. The patient has suffered increased choking over a three week period, an was referred for a placement of a gastrostomytube. The patient reported that thin and thickened liquids were difficult to swallow. However, no oral phase dysfunction and no esophageal dysmotility was apparent. The patient had lost considerable weight (about 20 pounds) at the time of initiation of stimulation treatment.
The patient was treated with Grass S-88 electrical stimulator as generally set forth with respect to the Fourth Exemplary Embodiment.More specifically, for Channel A, the positive electrode (2″×4″) was applied to the right upper trapezius muscle and the negative electrode applied to the right C1-C4 para spinal muscles. For Channel B, the positive electrode (2″×4″) was applied to the left upper trapeziusmuscle, and the negative electrode was applied to the left C1-C4para spinal muscles.
The intensity was such to create minimal twitch muscle contractions with visible contractions and minimal head movement. The pulse train patterncomprises a biphasic overlapping pulse train pattern having thefollowing parameters:
Pulse duration of individual electrical pulses: 50 microseconds
Current amplitude of individual electrical pulses: 60-80 milliamps
Duration of first phase: 100 milliseconds (5 pulses per train)
Duration of overlap: 20 milliseconds (1 pulse)
Duration of second phase: 100 milliseconds (5 pulses per train)
Frequency of pulse train pattern: 0.6 seconds (1.6 Hz)
Total treatment time: 20 minutes
Frequency of individual electrical pulses (in each phase): 50 hertz
The patient reported that the treatment was well tolerated, and no pain was identified. Immediately after the first session, the patient was able to swallow tap water without difficulty and without choking. The benefit was reported to last about six hours, and subsequent treatment sat a frequency of three times per week over the next three weeks eliminated the dysfunction. The patient had a relapse at about two months and resumed therapy which was immediately responsive requiring only three additional treatments.
At follow-up in three months, the patient continued to do well without requiring additional treatments. At four months post-treatment, however,the patient again had a relapse and continued on intermittent treatment using the Omnistim® FX² without a definitive diagnosis.
Case Study #6
This case study involved an 82-year-old male with Parkinson's plus syndrome causing dysphagia and difficulty with the oral phase of swallowing and chewing. The patient pocketed food in the bilateral cheeks and had difficulty with power of chewing. Also, the patient had difficulty with initiating the swallowing reflex.
The patient was treated with Omnistim® FX² electrical stimulation as generally set forth with respect to the Second Exemplary Embodiment.More specifically, for Channel A, the positive electrode (2″×2″) was applied to the right facial musculature (masseter) and the negative electrode applied to the right C1-C4 para spinal muscles. For Channel B,the positive electrode (2″×2″) was applied to the left facialmusculature (masseter) and the negative electrode was applied to the left C1-C4 para spinal muscles.
The intensity was such to create minimal twitch muscle contractions with visible contractions and minimal head movement. The pulse train patterncomprises a biphasic overlapping pulse train pattern having thefollowing parameters:
Pulse duration of individual electrical pulses: 50 microseconds
Current amplitude of individual electrical pulses: 35-58 milliamps
Duration of first phase: 100 milliseconds (5 pulses per train)
Duration of overlap: 20 milliseconds (1 pulse)
Duration of second phase: 100 milliseconds (5 pulses per train)
Frequency of pulse train pattern: 0.6 seconds (1.6 Hz)
Total treatment time: 20 minutes
Frequency of individual electrical pulses (in each phase): 50 hertz
The patient tolerated three sessions without difficulty. Effects were quite positive in that he was able to chew and swallow with more power and ease of mouth and tongue mobility. The effects lasted for 12 to 48hrs following the treatments.
While the present invention has been described and illustratedhereinabove with reference to several exemplary embodiments, it shouldbe understood that various modifications could be made to these embodiments without departing from the scope of the invention.Therefore, the invention is not to be limited to the exemplary embodiments described and illustrated hereinabove, except insofar as such limitations are included in the following claims.
1. A method for treating dysphagia in a patient by electricalstimulation, said method comprising: positioning a first channel comprising two electrodes, wherein a first electrode of said firstchannel is positioned in electrical contact with tissue of a first target region of said patient and a second electrode of said firstchannel is positioned in electrical contact with tissue of a posterior neck region or a posterior thoracic region of said patient usingtranscutaneous or percutaneous electrodes on said tissue of saidposterior neck region or said posterior thoracic region; positioning asecond channel comprising two electrodes, wherein a first electrode of said second channel is positioned in electrical contact with tissue of asecond target region of said patient and a second electrode of saidsecond channel is positioned in electrical contact with tissue of saidposterior neck region or said posterior thoracic region of said patient using transcutaneous or percutaneous electrodes on said tissue of saidposterior neck region or said posterior thoracic region; applying a series of electrical pulses to said patient through said first and second channels in accordance with a procedure for treating dysphagia.2. The method of claim 1, wherein said first electrode of said firstchannel is positioned so as to stimulate a motor point of a firstbuccinator muscle of said patient and said first electrode of saidsecond channel is positioned bilaterally so as to stimulate a motor point of a second buccinator muscle of said patient.
3. The method ofclaim 2, wherein said second electrode of said first channel and saidsecond electrode of said second channel are positioned bilaterally so as to stimulate the cervical para spinal muscles in said posterior neckregion near the C1, C2, C3, and/or C4 cervical vertebrae of said patient.
4. The method of claim 1, wherein said first electrode of said first channel is positioned so as to stimulate a motor point of a firstmasseter muscle of said patient and said first electrode of said secondchannel is positioned bilaterally so as to stimulate a motor point of asecond masseter muscle of said patient.
5. The method of claim 4,wherein said second electrode of said first channel and said secondelectrode of said second channel are positioned bilaterally so as tostimulate the cervical para spinal muscles in said posterior neck region near the C1, C2, C3, and/or C4 cervical vertebrae of said patient. 6.The method of claim 1, wherein said first electrode of said firstchannel and said first electrode of said second channel are positioned so as to stimulate a tongue muscle of said patient.
7. The method ofclaim 6, wherein said second electrode of said first channel and saidsecond electrode of said second channel are positioned bilaterally so as to stimulate the cervical para spinal muscles in said posterior neckregion near the C1, C2, C3, and/or C4 cervical vertebrae of said patient.
8. The method of claim 1, wherein said first electrode of said first channel is positioned so as to stimulate a motor point of a firsttrapezius muscle of said patient and said first electrode of said secondchannel is positioned bilaterally so as to stimulate a motor point of asecond trapezius muscle of said patient.
9. The method of claim 8,wherein said second electrode of said first channel and said secondelectrode of said second channel are positioned bilaterally so as tostimulate the cervical para spinal muscles in said posterior neck region near the C1, C2, C3, and/or C4 cervical vertebrae of said patient. 10.The method of claim 1, wherein said first electrode of said firstchannel is positioned so as to stimulate a first median nerve of said patient and said first electrode of said second channel is positionedbilaterally so as to stimulate a second median nerve of said patient.11. The method of claim 10, wherein said second electrode of said firstchannel and said second electrode of said second channel are positionedbilaterally so as to stimulate the cervical para spinal muscles in saidposterior neck region near the C1, C2, C3, and/or C4 cervical vertebraeof said patient.
12. The method of claim 10, wherein said secondelectrode of said first channel and said second electrode of said secondchannel are positioned bilaterally so as to stimulate the cervicalpara spinal muscles in said posterior neck region near the C4, C5, C6,and/or C7 cervical vertebrae of said patient.
13. The method of claim10, wherein said second electrode of said first channel and said secondelectrode of said second channel are positioned bilaterally so as tostimulate the thoracic para spinal muscles in said posterior thoracic region near the T4, T5, and/or T6 thoracic vertebrae of said patient.14. The method of claim 1, wherein said first electrode of said firstchannel is positioned so as to stimulate a motor point of a firstly located first dorsal interosseous muscle of said patient and said first electrode of said second channel is positioned bilaterally so as tostimulate a motor point of a secondly located first dorsal interosseousmuscle of said patient.
15. The method of claim 14, wherein said secondelectrode of said first channel and said second electrode of said secondchannel are positioned bilaterally so as to stimulate the cervicalpara spinal muscles in said posterior neck region near the C1, C2, C3,and/or C4 cervical vertebrae of said patient.
16. The method of claim14, wherein said second electrode of said first channel and said secondelectrode of said second channel are positioned bilaterally so as tostimulate the cervical para spinal muscles in said posterior neck region near the C4, C5, C6, and/or C7 cervical vertebrae of said patient. 17.The method of claim 14, wherein said second electrode of said firstchannel and said second electrode of said second channel are positionedbilaterally so as to stimulate the thoracic para spinal muscles in saidposterior thoracic region near the T4, T5, and/or T6 thoracic vertebraeof said patient.
18. The method of claim 1, wherein said first electrode of said first channel and said first electrode of said second channel are positioned bilaterally so as to stimulate the thoracic para spinalmuscles in said posterior thoracic region near the T4, T5, and/or T6thoracic vertebrae of said patient.
19. The method of claim 18, whereinsaid second electrode of said first channel and said second electrode of said second channel are positioned bilaterally so as to stimulate the cervical para spinal muscles in said posterior neck region near the C1,C2, C3, and/or C4 cervical vertebrae of said patient.
20. The method ofclaim 18, wherein said second electrode of said first channel and saidsecond electrode of said second channel are positioned bilaterally so as to stimulate the cervical para spinal muscles in said posterior neckregion near the C5, C6, and/or C7 cervical vertebrae of said patient.21. The method of claim 1, wherein said first electrode of said firstchannel is positioned to stimulate a motor point of a firstly located first dorsal interosseous muscle of said patient and said secondelectrode of said first channel is positioned so as to stimulate saidposterior neck region near the C1, C2, C3, and/or C4 cervical vertebraeof said patient, and said first electrode of said second channel ispositioned so as stimulate the thoracic para spinal muscles in saidposterior thoracic region near the T4, T5, and/or T6 thoracic vertebraeof said patient and said second electrode of said second channel ispositioned so as to stimulate the posterior neck region near the C1, C2,C3, and/or C4 cervical vertebrae of said patient.
22. The method ofclaim 1, wherein said series of electrical pulses comprises a plurality of cycles of a biphasic sequential pulse train pattern.
23. The method of claim 22, wherein said biphasic sequential pulse train patterncomprises a first phase of electrical pulses applied to said firstchannel and a second phase of electrical pulses applied to said secondchannel, wherein said second phase of electrical pulses commences after termination of said first phase of electrical pulses.
24. The method ofclaim 1, wherein said series of electrical pulses comprises a plurality of cycles of a biphasic overlapping pulse train pattern.
25. The method of claim 21 wherein said biphasic overlapping pulse train patterncomprises a first phase of electrical pulses applied to said firstchannel and a second phase of electrical pulses applied to said secondchannel, wherein said second phase of electrical pulses commences before termination of said first phase of electrical pulses.
26. The method ofclaim 1, wherein said series of electrical pulses comprises a plurality of cycles of a triphasic sequential pulse train pattern.
27. The method of claim 26, wherein said triphasic sequential pulse train patterncomprises a first phase of electrical pulses applied to said firstchannel, a second phase of electrical pulses applied to said secondchannel, and a third phase of electrical pulses applied to said firstchannel, wherein said second phase of electrical pulses commences after termination of said first phase of electrical pulses and wherein said third phase of electrical pulses commences after termination of saidsecond phase of electrical pulses.
28. The method of claim 1, whereinsaid series of electrical pulses comprises a plurality of cycles of atriphasic overlapping pulse train pattern.
29. The method of claim 28,wherein said triphasic overlapping pulse train pattern comprises a first phase of electrical pulses applied to said first channel, a second phase of electrical pulses applied to said second channel, and a third phase of electrical pulses applied to said first channel, wherein said second phase of electrical pulses commences before termination of said first phase of electrical pulses and wherein said third phase of electricalpulses commences before termination of said second phase of electricalpulses.
30. The method of claim 1, wherein said series of electricalpulses comprises a functional pulse train pattern applied to said first and second channels so as to mimic electrical sequencing of particular muscles involved in swallowing during normal functioning activity. 31.The method of claim 1, wherein each of said electrical pulses has a pulse duration of between 30 microseconds and 100 microseconds.
32. The method of claim 1, wherein each of said electrical pulses has a current amplitude of between 25 milliamps and 140 milliamps.
33. A method for treating dysphagia in a patient by electrical stimulation, said method comprising: positioning at least one channel comprising two electrodes,wherein a first electrode is positioned in electrical contact with tissue of a target region of said patient and a second electrode ispositioned in electrical contact with tissue of a posterior neck region or a posterior thoracic region of said patient using transcutaneous orpercutaneous electrodes on said tissue of said posterior neck region or said posterior thoracic region; and applying a series of electricalpulses to said patient through said channel in accordance with a procedure for treating dysphagia.
34. The method of claim 33, whereinsaid first electrode is positioned so as to stimulate a motor point of abuccinator muscle of said patient.
35. The method of claim 33, whereinsaid first electrode is positioned so as to stimulate a motor point of amasseter muscle of said patient.
36. The method of claim 33, whereinsaid first electrode is positioned so as to stimulate a tongue muscle of said patient.
37. The method of claim 33, wherein said first electrode is positioned so as to stimulate a motor point of a trapezius muscle of said patient.
38. The method of claim 33, wherein said first electrode is positioned so as to stimulate a median nerve of said patient.
39. The method of claim 33, wherein said first electrode is positioned so as tostimulate a motor point of a first dorsal interosseous muscle of said patient.
40. The method of claim 33, wherein said first electrode ispositioned so as to stimulate a thoracic para spinal muscle of said patient.
41. The method of claim 33, wherein said second electrode ispositioned so as to stimulate the cervical para spinal muscles in saidposterior neck region near the C1, C2, C3 and/or C4 cervical vertebraeof said patient.
42. The method of claim 33, wherein said secondelectrode is positioned so as to stimulate the cervical para spinalmuscles in said posterior neck region near the C5, C6, and/or C7cervical vertebrae of said patient.
43. The method of claim 33, whereinsaid second electrode is positioned so as to stimulate the thoracicpara spinal muscles in said posterior thoracic region near the T4, T5,and/or T6 thoracic vertebrae of said patient.
44. The method of claim33, wherein said series of electrical pulses comprises a low-frequency pulse train pattern.
45. The method of claim 44, wherein said low-frequency pulse train pattern comprises individual electrical pulses generated at a frequency of between 0.1 Hz and 200 Hz.
46. The method ofclaim 33, wherein said series of electrical pulses comprises a frequency-sequenced pulse burst train pattern with a carrier frequency of between 500 Hz and 100,000 Hz.
47. The method of claim 46, whereinsaid frequency-sequenced pulse burst train pattern comprises a first sequence of modulated electrical pulses generated at a burst frequency of between 0.1 Hz and 5 Hz, a second sequence of modulated electricalpulses generated at a burst frequency of between 5 Hz and 20 Hz, and a third sequence of modulated electrical pulses generated at a burstfrequency of between 20 Hz and 250 Hz.
48. The method of claim 46,wherein said frequency-sequenced pulse burst train pattern comprises afirst sequence of modulated electrical pulses generated at a burstfrequency of between 5 Hz and 20 Hz, a second sequence of modulated electrical pulses generated at a burst frequency of between 0.1 Hz and 5Hz, and a third sequence of modulated electrical pulses generated at a burst frequency of between 20 Hz and 250 Hz.
49. The method of claim 46,wherein said frequency-sequenced pulse burst train pattern comprises afirst sequence of modulated electrical pulses generated at a burstfrequency of between 20 Hz and 250 Hz, and a second sequence of modulated electrical pulses generated at a burst frequency of between0.1 Hz and 5 Hz.
50. The method of claim 33, wherein each of said electrical pulses has a pulse duration of between 30 microseconds and100 microseconds.
51. The method of claim 33, wherein each of said electrical pulses has a current amplitude of between 25 milliamps and140 milliamps.
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<?php
use Illuminate\Support\Facades\Schema;
use Illuminate\Database\Schema\Blueprint;
use Illuminate\Database\Migrations\Migration;
class CreateCoinpaymentsTransactionsTable extends Migration
{
/**
* Run the migrations.
*
* @return void
*/
public function up()
{
Schema::create('coinpayments_transactions', function (Blueprint $table) {
$table->bigIncrements('id');
$table->string('address', 100);
$table->double('amount', 25, 8);
$table->integer('confirms');
// $table->string('currency', 10);
$table->integer('currency_id');
$table->string('deposit_id', 100);
$table->double('fee', 25, 8);
$table->double('fiat_amount', 25, 8);
$table->string('fiat_coin', 50);
$table->double('fiat_fee', 25, 8);
$table->string('ipn_id', 100);
$table->string('ipn_mode', 10);
$table->string('ipn_type', 10);
$table->string('ipn_version', 10);
// $table->string('label', 100);
$table->integer('label');
$table->string('merchant', 100);
$table->integer('status');
$table->string('status_text', 100);
$table->string('txn_id', 100);
/*
[currency] => BTC
[fiat_coin] => USD
*/
// ALTER TABLE `coinpayments_transactions` ADD `log` LONGTEXT NOT NULL AFTER `txn_id`;
// ALTER TABLE `coinpayments_transactions` ADD `ipn_log` JSON NOT NULL AFTER `txn_id`;
$table->timestamps();
});
}
/**
* Reverse the migrations.
*
* @return void
*/
public function down()
{
Schema::dropIfExists('coinpayments_transactions');
}
}
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The Compound Power Situation...
So we can now drag a compound power from a character sheet into a folder that sets up an automatic folder structure.
However the compound powers in the folder seems to have broken the structure of the compound power to no longer act as it should. You can't transfer a compound power equipment from 1 PC to another. Also the new hero designer prefab import doesn't work with the new way of moving compound powers around.
The bottom line is there needs to be a way you can move a compound power around without it being broken up into pieces. Unless there is a button that lets you choose what you want to add back into it.
If this was meant to only be part of the implementation and refinement is coming, then feel free to ignore this post.
Thanks for all your hard work. I nag because I care. :)
I worked on this today and made several improvements that will be part of the next/3.0.81 release. I think the drag from actor to actor is fixed. So are compound powers in a framework. Not sure about the prefab upload as I don't have a complicated prefab to test with.
I was look in at the attacks tab when I drug it over. It was adding everything correctly it seems. Even dragging the folder worked.
The only thing that still needs work is the .hdp compatibility with the new rule.
Sorry my bad.
Yup, I confirmed that a combo power within a framework is not loading correctly into the prefab compendium. I'm looking into that.
Next release should handle complex prefabs.
You guys are the best keep up the great work.
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New games! PlayTrivia andBirthle.
PILOT
Olga Sanfirova
1917 - 1944
Olga Sanfirova
Olga Aleksandrovna Sanfirova (Russian: Ольга Александровна Санфирова; 2 May [O.S. 19 April] 1917 – 13 December 1944) was a captain and squadron commander in the 46th Taman Guards Night Bomber Aviation Regiment during World War II. Read more on Wikipedia
Since 2007, the English Wikipedia page of Olga Sanfirova has received more than 40,570 page views. Her biography is available in 20 different languages on Wikipedia. Olga Sanfirova is the 33rd most popular pilot, the 1,186th most popular biography from Russia and the 6th most popular Russian Pilot.
Memorability Metrics
• 41k
Page Views (PV)
• 50.79
Historical Popularity Index (HPI)
• 20
Languages Editions (L)
• 4.98
Effective Languages (L*)
• 2.11
Coefficient of Variation (CV)
Page views of Olga Sanfirova by language
Among PILOTS
Among pilots, Olga Sanfirova ranks 33 out of 48Before her are Bessie Coleman, Amy Johnson, Leyla Mammadbeyova, Helmut Wick, Pyotr Nesterov, and Maguba Syrtlanova. After her are Janina Lewandowska, Polina Osipenko, Touria Chaoui, Jacqueline Auriol, Mariya Dolina, and Jean Mermoz.
After her are Zainab al Ghazali, Domenico Bartolucci, David Tomlinson, Asima Chatterjee, Robert Byrd, and Knut Haugland. Among people deceased in 1944, Olga Sanfirova ranks 188Before her are Stefan Rowecki, Prince Gustav of Denmark, Erich Salomon, Georges Mandel, Hana Brady, and Hans-Jürgen von Blumenthal. After her are Gabriel Hanotaux, Krzysztof Kamil Baczyński, Leonid Mandelstam, Tokutaro Ukon, Dénes Kőnig, and Edith Durham.
After her are Dmitry Lelyushenko (1901), Alla Kushnir (1941), Ekaterina Maximova (1939), Pavel Durov (1984), Andrei Bitov (1937), and Alexander Serov (1820).
Among PILOTS In Russia
Among pilots born in Russia, Olga Sanfirova ranks 6Before her are Marina Raskova (1912), Valery Chkalov (1904), Vladimir Ilyushin (1927), Pyotr Nesterov (1887), and Maguba Syrtlanova (1912). After her are Mariya Dolina (1922), Vladimir Kokkinaki (1904), Anna Yegorova (1916), Nikolai Kamanin (1908), and Viktor Talalikhin (1918).
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Summary
Toy beret-style hat made by Mrs Johanna Harry Hillier, nee Gyles, circa 1929-1935, in which was stored toys made from MacRobertson's Max Mint wrappers of waxed paper, printed with a diamond shape in blue and orange with a background of red and blue zig-zag lines.
Mrs Hillier came to Australia from England in 1881. She was a milliner by trade and made a set of these toys for each of three grandchildren. She began by making the fans and then progressed to a variety of other toys. A set of 56 figures, pieces of furniture, costume and costume accessories was donated to Museums Victoria by one of her granddaughters.
Physical Description
Doll sized hat made from Max Mints confectionary wrappers attached to a cardboard band. Hat is "pin cushion" style with a stitched and pleated crown. A pink ribbon with a bow trims the band.
More Information
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Engineering strategy and vector library for the rapid generation of modular light-controlled protein-protein interactions
Optogenetics enables the spatio-temporally precise control of cell and animal behaviour. Many optogenetic tools are driven by light-controlled protein-protein-interactions (PPIs) that are repurposed from natural light-sensitive domains (LSDs). Applying light-controlled PPI to new target proteins is challenging because it is difficult to predict whether one the many available LSDs will yield robust light regulation. As a consequence, fusion protein libraries need to be prepared and tested, but methods and platforms to facilitate this process are currently not available. Here, we developed a genetic engineering strategy and vector library for the rapid generation of light-controlled PPIs. The strategy permits fusing a target protein to LSDs efficiently and in two orientations. The public and expandable library contains 29 vectors with blue, green or red light-responsive LSDs many of which have been previously applied ex vivo and in vivo. We demonstrate the versatility of the approach and the necessity for sampling LSDs by generating light-activated caspase-9 (casp9) enzymes. Collectively, this work provides a new resource for optical regulation of a broad range of target proteins in cell and developmental biology.
INTRODUCTION
Optogenetics has revolutionized research in neuroscience, cell biology and developmental biology by allowing the 'remote control' of cell and animal behaviour with extraordinary precision (1)(2)(3)(4)(5). This precision is achieved by utilizing light as a stimulus that offers unique advantages over pharmacological and genetic manipulation strategies. For instance, light permits unparalleled control in time (e.g., to modulate animal behaviour acutely or to target selected developmental or disease stages; Figure 1A) and in space (e.g., to target selected compartments in a cell or selected cells in a tissue; Figure 1B). Also, light can be readily applied and withdrawn given a sufficiently transparent matrix. Finally, light-activated molecular tools can be paired with genetic targeting to allow an even higher level of precision for specific cell types, tissues or developmental stages (6)(7)(8)(9)(10).
Optogenetics first flourished in the hands of neuroscientists that utilized animal and microbial opsins to dissect neural circuits through the bidirectional control of neuronal bioelectrical activity (8,11). More recently and in cell types other than neurons, light control of gene regulation and cellular signalling, together with associated cell behaviours, has emerged (12,13). The optogenetic tools that can regulate cell bioelectricity are fundamentally different from those applied to control biochemical and enzymatic processes. In the former case, ion conducting opsins, such as channelrhodopsin or halorhodopsin, turn neurons on or off by changing their membrane potential through an intrinsic light-gated ion channel or pump activity (7,8,14). In the latter case, a wide range of cellular processes have been rendered light-inducible by using LSDs that do not harbour catalytic activity but regulate intraor intermolecular binding events ( Figure 1C).
The plethora of cellular processes governed by PPIs currently far exceeds the number of available optogenetic tools. This is in part because generating functional fusion proteins of LSDs and target proteins is a non-trivial task. For instance, multiple LSD genes need to be obtained and validated to find a suited domain. Furthermore, the location of the fusion site as well as the length of linkers can be critical parameters that determine fusion protein function (35,36). As a consequence of combinatorial complexity, many genetic constructs need to be generated and tested, and currently no methods or libraries are available to facilitate this process.
Here, we developed a genetic engineering strategy and a vector library for the rapid and modular generation of light-controlled PPIs. The engineering strategy can produce LSD-target protein fusions in several domain orientations and with linkers in a single cloning step (a universal restriction enzyme digest followed by ligation) using inexpensive and readily available materials. The publicly available vector library contains a collection of prominent LSDs that are responsive to blue, green or red light and have been applied in the past ex vivo and in vivo. The design of the strategy and library allows for easy expansion either with further LSDs, targeting sequences or markers. Using this resource, we generated light-activated casp9 enzymes.
Cassette design
Cassettes were introduced in pcDNA3.1-(Invitrogen/Life Technologies) to generate the vectors named pOVC1-3 (optogenetic vector core 1-3, Figure S4). A XmaI restriction site was removed from the backbone using site-directed mutagenesis (oligonucleotides 1 and 2, Table S2). Inverse polymerase chain reactions (PCR) (oligonucleotides 3 and 4, 5 and 6, and 7 and 8) were applied to remove the vector multiple cloning site and create ABC (pOVC1), ACB (pOVC2) and BAC (pOVC3) cassettes. In the inverse PCR procedure, PCR products were digested with DpnI, digested with EcoRI, XmaI or AgeI (NEB), respectively, ligated for 3 h at room temperature (RT) or overnight at 4°C using T4 ligase (Promega), and propagated in E.coli XL10 Gold cells (Agilent). All cassettes contain Kozak sequences, start codons and stop codons (for backbone ABC, the stop codon was introduced using sitedirected mutagenesis in a separate reaction (oligonucleotides 9 and 10)). For linker insertion, backbone pOVC1 was digested using EcoRI and BamHI. Linker fragments were generated by inverse PCR (oligonucleotides 57 and 58) or by annealing and phosphorylating single stranded oligonucleotides (59 to 64). All vector sequences (Table S3) were verified by Sanger sequencing (Micromon, Monash University) and deposited at Addgene.org.
LSD amplification and vector library
LSDs were amplified using PCR and oligonucleotides with AgeI and/or XmaI restriction site overhangs (oligonucleotides 11 to 34 and 45 to 52). Templates were previously described vectors from our laboratory or obtained from Addgene.org (Table S1). In addition, gene fragments of AtCRY2-PHR, ScPH-1, AsLOV2-EcSsra, EcSSPB micro, AsLOV2-pep and HsPDZ1b were synthesized by a commercial supplier (Integrated DNA Technologies; Table S4). Restriction sites for AgeI and BamHI were removed from ScPH1-S and AtPHYB-S, respectively, as well as XmaI restriction sites from HsFKBP and AtCRY2-PHR using site directed mutagenesis (oligonucleotides 35 to 42). Site-directed mutagenesis was used to create EcSSPB nano (oligonucleotides 65 and 66). PCR products were digested with DpnI and with AgeI, XmaI or AgeI and XmaI depending on oligonucleotide overhangs. Backbone pOVC1 was digested with AgeI or XmaI for insertion into site A or C, respectively, and phosphatase treated.
Backbone and inserts were ligated either for 3 h at RT or overnight at 4°C using T4 ligase (Promega). All vector sequences (Table S5) were verified by Sanger sequencing (LGC Genomics) and deposited at Addgene.org. Note that for future subcloning of the generated genes, universal oligonucleotides can be designed that contain recognition sites for the enzymes AflII, ApaI, AscI, FseI, PacI, PspOMI or SbfI as these are not found in any of the genes.
Opto-casp9 constructs
The catalytic domain of casp9 (residues 135-416 of UniProt entry P55211) was synthesized (Integrated DNA Technologies; Table S4), amplified by PCR (oligonucleotides 43 and 44) and digested with XmaI. Vectors were digested with XmaI or AgeI, respectively, treated with phosphatase and gel purified. Backbone vectors and casp9 insert were ligated either for 3 h at RT or overnight at 4°C using T4 ligase.
Cell culture and transfection
HEK293 cells (Thermo Fisher Scientific; further authenticated by assessing cell morphology and growth rate) were cultured in mycoplasma-free Dulbecco's modified eagle medium (DMEM, Thermo Fisher Scientific) in a humidified incubator with 5% CO2 atmosphere at 37°C. Medium was supplemented with 10% FBS, 100 U/ml penicillin and 0.1 mg/ml streptomycin (Thermo Fisher Scientific). On the day after seeding, cells were transfected in DMEM supplemented with 5% FBS using polyethylenimine (Polysciences). Media was changed after 4 to 6 h and cells were stimulated with light starting 24 h after transfection for the durations specified below and at the intensities specified in the main text. Figure 2B, sample numbers are 14, except for mock (26), HsFKBP (15) and DMSO (13). In Figure 2C, sample numbers are 16, except for mock (25), HsFKBP (19) and DMSO (12). In Figure 2D, sample numbers are 14, except for HsFKBP (26 and 12, dark and light). In Figure 2E, sample numbers are 16, except for mock (28) and HsFKBP (28 and 12, dark and light) and DMSO (12).
Efficient genetic engineering strategy
A major challenge in the optical control of PPIs is to achieve functional coupling of LSD oligomerization state changes to activity of target proteins. For most target proteins, it is initially unclear if a suited LSD can be identified and in what orientation LSDs are best attached because steric compatibility and effects on protein folding are difficult to predict. In the majority of previous studies, LSD-target protein fusions were constructed by inserting several LSD genes into vectors that contain the target protein ( Figure S1A, top). This approach requires selecting candidate LSDs, obtaining the corresponding genes from collaborators or commercial sources, validating LSD sequences, delineating domain boundaries and preparing amplicons that adapt each LSD to the vector ( Figure S1A, bottom). Furthermore, generation of both N-and Cterminal fusion proteins may require additional modification of the vector and/or amplicons. We propose an inverted strategy in which the target protein is inserted into a series of vectors that already contain LSDs ( Figure 1D; see below for a comprehensive LSD vector library). The advantages of this strategy are that only a single amplicon of a familiar and available target gene is required and that multiple LSD-target protein fusions can be generated in a simple standardized reaction that is easily parallelized. As a consequence, multiple time-consuming steps that require analysis of sequences and reagents specific to each LSD are not required and the workflow is greatly simplified ( Figure S1B).
To achieve this strategy, we designed a modular cloning cassette termed ABC that harbours three insertion sites (A, B and C; Figure 1E). Importantly, sites A and C contain recognition sequences for restriction enzymes that produce compatible cohesive overhangs (in both cases a CCGG overhang after AgeI or XmaI digestion at site A and C, respectively; Figure 1E). Consequently, a target protein amplicon flanked by either of these restriction sites in any combination can be inserted into site A as well as C and thus N-and C-terminally of a LSD (start and stop codons are already contained in the cassette). Site B contains recognition sequences for restriction enzymes of different families (EcoRI and BamHI) for incorporation of additional domains (e.g., fluorescent proteins) or epitopes. In order to provide additional flexibility, we engineered ABC vectors to include four different flexible or stiff linkers ( Figure 1F). We also prepared compatible ACB and BAC cassettes that permit insertion of flanking targeting sequences or fluorescent proteins in terminal B sites.
LSD vector library
Employing above genetic engineering strategy, we generated 29 vectors that contain one of 11 LSDs or one of five LSD binding partners inserted into site A and C ( Figure 1G) thaliana (21,22)). The library also includes binding partners for the heterodimerizing LOV domains, CRY and PHY, which are the minimal proteins EcSspB of E.coli with different affinities, HsPDZ1b of H. sapiens, AtCIB and AtPIF6 of A. thaliana (20,22,(39)(40)(41); Figure 1G) (sequence information and protein database identifiers can be found in Table S1). Collectively, these vectors provide coverage of methods to induce homodimerization, homooligomerization, heterodimerization with binding partners, or monomerization in response to different wavelengths of light. Many of these domains have been previously utilized ex vivo and in vivo but the library also contains less frequently applied domains (e.g., CrPH-LOV or RsLP-LOV). Vectors are available with all proteins inserted into the site A and separately the site C (i.e. N-terminal and C-terminal of the target protein insertion site), except in cases where N-terminal attachment is incompatible with protein function (AsPT1-LOV2 and AtPHYB). In the future, the library is expected to grow as its modular design allows direct expansion with additional LSDs (23,42).
Light-activated caspase-9
We employed the engineering strategy and vector library to develop a light-induced variant of casp9, an initiator caspase in apoptosis induction. The function of casp9 is mediated by homomeric assembly through the N-terminal caspase recruitment domain (CARD) (43), and casp9 has been rendered inducible by substitution of CARD with orthogonal homodimerization domains (44,45). This work demonstrated that dimerization by an N-terminal domain is sufficient for casp9 activation and resulted in a chemically-induced casp9 (iCasp9) that is employed as a cellular safety and suicide switch (46). To generate casp9 activated by blue light (Opto-casp9), we inserted a casp9 amplicon N-terminally and C-terminally of four LOV domains and AtCRY2-PHR ( Figure 2A). We focused on these blue light-sensitive domains because they represent commonly applied optogenetic tools and because their flavin co-factors are ubiquitously available in cells of virtually all organisms. As a control, we employed casp9 fused to an engineered chemical dimerization domain derived from human FK506 binding protein (HsFKBP) analogous to iCasp9. We first tested if these proteins exhibit constitutive activity (i.e. dark activity) by metabolically assessing the viability of human embryonic kidney 293 (HEK293) cells using the fluorescent viability dye resazurin ( Figure 2B,C). As constitutive activity was not observed, we next tested if these proteins can be used to induce cell death. To analyse cell death while controlling for transfection efficiency, we co-transfected cells with Opto-casp9 and a genetic viability reporter (Renilla luciferase under the control of a constitutive promoter). We chose a luciferase over a fluorescent protein as the reporter gene because of the high signal-to-noise ratio in luminescence detection and to avoid undesired excitation of the reporter by stimulation light. Twenty-four h after transfection, cells were stimulated for 7 h with blue light (l » 470 nm, intensity (I) = 200 µW/cm 2 ) in a tissue culture incubator equipped with light emitting diodes, and luminescence signals were measured subsequently. We found strongly reduced viability for cells that were transfected with casp9 fused to VfAU1-LOV or AtCRY2-PHR domains but not the other domains ( Figure 2D,E). To confirm the specificity of the observed effect using VfAU1-LOV-casp9 as an example, we demonstrated that apoptosis increases with increasing light dose (the half maximal effective light dose was 5.5 µW/cm 2 ; Figure S2). We further verified that light stimulation resulted in apoptosis using flow cytometry analysis with propidium iodide (PI) and Annexin markers ( Figure 3A). For VfAU1-LOV-casp9 and AtCRY2-PHR-casp9 but not for mock transfected cells we observed robust induction of apoptosis ( Figure 3B,C). This result demonstrates that by linking a casp9 amplicon to multiple LSDs functional Opto-casp9 enzymes could be quickly designed.
Specificity in light-induced PPIs
The modularity of the genetic engineering strategy provides the possibility to perform additional experiments, such as negative controls and immunodetection, that complement the efficient fusion protein generation demonstrated above. In optogenetics, negative controls typically consist of the application of light to naïve cells or to cells that were transfected with inactivated optogenetic tools (e.g., through lossof-function mutations). The latter control is required to obtain baseline signals and to ensure that overexpression of LSDs or target proteins does not alter cellular sensitivity.
The most commonly applied loss-of-function mutations for inactivation either target photochemically-active LSD residues or residues involved in light-induced conformational changes. However, targeting LSD photochemistry can be incomplete with persistent LSD activation through alternative reaction mechanisms or generation of chemical photoreaction side products (47,48). In addition, because of the diversity in the structures and activation mechanisms of LSDs, generalizable loss-of-function mutations do not exist, and thus negative controls cannot be studied under identical conditions. To address these limitations, we developed a universal inactivation strategy for light-controlled PPIs, which is based on testing the function of constructs in which the LSD and target protein have been uncoupled (e.g., uncoupling of VfAU1-LOV and casp9 should result in a loss in light activation). We realized this strategy by taking advantage of the availability of site B in all generated vectors. Into this site, we inserted a self-cleaving peptide sequence of porcine teschovirus-1 2A (P2A) that will effectively dissociate the two domains resulting in a loss of light sensitivity ( Figure 4A).
As expected for a P2A-modified Opto-casp9, we observed that light-induction of cell death by was abolished completely with self-cleavage effectively producing the same experiment outcome as removal of the catalytic activity of casp9 ( Figure 4B, Figure S3). Immunoblotting against epitope tags that flanked the P2A sequence verified cleavage as we only detected the single LSD and casp9 domains but not the full protein ( Figure 4C). These results demonstrate a new control strategy that preserves target protein and LSD expression and LSD photochemistry taking advantage of linker and epitope incorporation into site B.
CONCLUSIONS
Optogenetics is one of few techniques that permits the regulation of cell behaviours with high precision in space and time. We developed a resource for the generation of light-induced PPIs and demonstrated its applicability by engineering Opto-casp9 enzymes. This resource will contribute to the broader use of optogenetics in cell and developmental biology and pave the way to novel optogenetics studies. For instance, experiments on the scale of entire families of LSDs or target proteins require efficient and modular genetic engineering approaches that are now within reach. Opto-casp9 enzymes may provide a test bed for optogenetic hardware development and testing, a process that entails optimization of light parameters (e.g. wavelength, intensity, duration) and culture conditions, because cell death can be assessed with different assays. Finally, the engineering strategy and empty cassettes may also be of use in areas other than optogenetics, such as for the rapid and modular design of fluorescent sensors and protein probes.
|
<?php
namespace Gugunso\LaravelUiViewComposer\Tests\Unit;
use Gugunso\CommonStructures\StackableArray;
use Gugunso\LaravelUiViewComposer\Contract\FormValueApplier;
use Gugunso\LaravelUiViewComposer\Contract\ViewComposerInterface;
use Gugunso\LaravelUiViewComposer\Contract\ViewParameterCreator;
use Gugunso\LaravelUiViewComposer\Exception\InvalidFormValuesApplierException;
use Gugunso\LaravelUiViewComposer\FormComposer;
use Illuminate\Http\Request;
use Illuminate\Support\Collection;
use Illuminate\View\View;
use Orchestra\Testbench\TestCase;
/**
* @coversDefaultClass \Gugunso\LaravelUiViewComposer\FormComposer
* Gugunso\LaravelUiViewComposer\Tests\Unit\FormComposerTest
*/
class FormComposerTest extends TestCase
{
/** @var $testClassName as test target class name */
protected $testClassName = FormComposer::class;
/**
* @covers ::setFormValuesAppliers
*/
public function test_setFormValuesAppliers_RaiseException()
{
$targetClass = \Mockery::mock($this->testClassName)->makePartial()->shouldAllowMockingProtectedMethods();
$argArray = new StackableArray();
$argArray->addValue([]);
$this->expectException(InvalidFormValuesApplierException::class);
$targetClass->setFormValuesAppliers($argArray);
}
/**
* @covers ::setFormValuesAppliers
*/
public function test_setFormValuesAppliers()
{
$argArray = new StackableArray();
$stubFormValueApplier = \Mockery::mock(FormValueApplier::class);
$argArray->addValue($stubFormValueApplier);
$targetClass = \Mockery::mock($this->testClassName)->makePartial()->shouldAllowMockingProtectedMethods();
$actual = $targetClass->setFormValuesAppliers($argArray);
$this->assertInstanceOf(FormComposer::class, $actual);
}
/**
* @covers ::addFormValuesApplier
*/
public function test_addFormValuesApplier()
{
$stubFormValueApplier = \Mockery::mock(FormValueApplier::class)->shouldIgnoreMissing();
$stubArray = \Mockery::mock(StackableArray::class)->shouldIgnoreMissing();
$stubArray->shouldReceive('addValue')->with($stubFormValueApplier)->once();
//テスト対象クラスのモック作成
$targetClass = \Mockery::mock($this->testClassName)->makePartial()->shouldAllowMockingProtectedMethods();
//準備：用意したスタブをセット
$targetClass->setFormValuesAppliers($stubArray);
//テスト対象メソッドを実行し、スタブのaddValue() が呼び出されることを検証
$actual = $targetClass->addFormValuesApplier($stubFormValueApplier);
$this->assertInstanceOf(FormComposer::class, $actual);
}
/**
* @covers ::setFormValueParameterName
*/
public function test_setFormValueParameterName()
{
/** @var mixed $targetClass */
$targetClass = $this->createEmptyInitConcreteObject(\Mockery::mock(Request::class));
//テスト対象メソッドの実行
$actual = $targetClass->setFormValueParameterName('any-parameter-name');
$this->assertInstanceOf(FormComposer::class, $actual);
\Closure::bind(
function () use ($targetClass) {
//assertions
$this->assertSame('any-parameter-name', $targetClass->formValueParameterName);
},
$this,
FormComposer::class
)->__invoke();
}
/**
* テスト用のインスタンス作成
*/
public function createEmptyInitConcreteObject($stubRequest)
{
return new class($stubRequest) extends FormComposer {
protected function init(Request $request, View $view): void
{
//do nothing
}
};
}
/**
* @covers ::setView
*/
public function test_setView()
{
$stubView = \Mockery::mock(View::class);
/** @var mixed $targetClass */
$targetClass = $this->createEmptyInitConcreteObject(\Mockery::mock(Request::class));
\Closure::bind(
function () use ($targetClass, $stubView) {
//テスト対象メソッドの実行
$targetClass->setView($stubView);
//assertions
$this->assertSame($stubView, $targetClass->view);
},
$this,
FormComposer::class
)->__invoke();
}
/**
* @covers ::getView
*/
public function test_getView()
{
$stubView = \Mockery::mock(View::class)->shouldIgnoreMissing();
$stubView->shouldReceive('getData')->andReturn([]);
/** @var mixed $targetClass */
$targetClass = $this->createEmptyInitConcreteObject(\Mockery::mock(Request::class));
\Closure::bind(
function () use ($targetClass, $stubView) {
//テスト対象メソッドの実行1.インスタンス作成直後はNULL
$actual1 = $targetClass->getView();
$this->assertNull($actual1);
//テスト対象メソッドの実行2.setView実行後は取得できる
//assertions
$targetClass->setView($stubView);
$actual2 = $targetClass->getView();
$this->assertSame($stubView, $actual2);
},
$this,
FormComposer::class
)->__invoke();
}
/**
* @covers ::getRequest
*/
public function test_getRequest()
{
$stubRequest = \Mockery::mock(Request::class);
/** @var mixed $targetClass */
$targetClass = $this->createEmptyInitConcreteObject($stubRequest);
//テスト対象メソッドの実行
\Closure::bind(
function () use ($targetClass, $stubRequest) {
$actual = $targetClass->getRequest();
//assertions
$this->assertSame($stubRequest, $actual);
},
$this,
$targetClass
)->__invoke();
}
/**
* ViewParameterCreatorインターフェースを実装していないクラスで実行した場合。
* 引数がそのまま返ってくる。
* @covers ::parameters
*/
public function test_parameters_NotViewParameterCreator()
{
$stubRequest = \Mockery::mock(Request::class);
$targetClass = $this->createEmptyInitConcreteObject($stubRequest);
//テスト対象メソッドの実行
\Closure::bind(
/** @var mixed $targetClass */
function () use ($targetClass) {
$actual = $targetClass->parameters(['result-of' => 'view->getData()']);
//assertions そのまま返ってくる
$this->assertSame(['result-of' => 'view->getData()'], $actual);
},
$this,
FormComposer::class
)->__invoke();
}
/**
* @covers ::parameters
*/
public function test_parameters_ImplementsViewParameterCreator()
{
$stubRequest = \Mockery::mock(Request::class);
$targetClass = new class($stubRequest) extends FormComposer implements ViewParameterCreator {
protected function init(Request $request, View $view): void
{
}
public function createParameter(): array
{
return ['parameters' => 'values', 'id' => 999];
}
};
//テスト対象メソッドの実行
\Closure::bind(
/** @var mixed $targetClass */
function () use ($targetClass) {
$actual = $targetClass->parameters(['result-of' => 'view->getData()', 'id' => null]);
//assertions View優先でマージされた結果が返ってくる
$this->assertIsArray($actual);
$this->assertArrayHasKey('id', $actual);
//assertions View優先でマージするので、idの値はNULLとなっているはず
$this->assertSame(null, $actual['id']);
$this->assertArrayHasKey('parameters', $actual);
$this->assertSame('values', $actual['parameters']);
$this->assertArrayHasKey('result-of', $actual);
$this->assertSame('view->getData()', $actual['result-of']);
},
$this,
FormComposer::class
)->__invoke();
}
/**
* @covers ::formValues
*/
public function test_formValues_EmptyCollection()
{
$stubRequest = \Mockery::mock(Request::class);
$targetClass = $this->createEmptyInitConcreteObject($stubRequest);
\Closure::bind(
/** @var mixed $targetClass */
function () use ($targetClass) {
//準備として、空の配列を渡す
$targetClass->setFormValuesAppliers(new StackableArray());
//assertions
$actual = $targetClass->formValues();
$this->assertInstanceOf(Collection::class, $actual);
$this->assertSame(0, $actual->count());
},
$this,
FormComposer::class
)->__invoke();
}
/**
* @covers ::formValues
*/
public function test_formValues_default()
{
$stubRequest = \Mockery::mock(Request::class);
$stubApplier = \Mockery::mock(FormValueApplier::class);
//shouldApply() はfalse,true,false の順に返すよう設定。2つめにtrueが呼ばれるので、結果2回しか呼びだされないはず。
$stubApplier->shouldReceive('shouldApply')->withNoArgs()->times(2)->andReturn(false, true, false);
//shouldApply() がtrueを返した場合のみgetBuilder->build() が呼び出される。
$stubApplier->shouldReceive('getBuilder->build')->withNoArgs()->once()->andReturn(collect(['result']));
$targetClass = $this->createEmptyInitConcreteObject($stubRequest);
\Closure::bind(
/** @var mixed $targetClass */
function () use ($targetClass, $stubApplier) {
//準備として、空の配列を渡す
$array = new StackableArray();
//applierを3つ登録
$array->addValue($stubApplier);
$array->addValue($stubApplier);
$array->addValue($stubApplier);
//set
$targetClass->setFormValuesAppliers($array);
//assertions
$actual = $targetClass->formValues();
$this->assertInstanceOf(Collection::class, $actual);
$this->assertSame(['result'], $actual->toArray());
},
$this,
FormComposer::class
)->__invoke();
}
/**
* @covers ::compose
*/
public function test_compose()
{
$stubRequest = \Mockery::mock(Request::class)->shouldIgnoreMissing();
$stubView = \Mockery::mock(View::class);
$stubView->shouldReceive('getData')->withNoArgs()->once()->andReturn([]);
$stubView->shouldReceive('with')->once();
$targetClass = \Mockery::mock($this->testClassName, [$stubRequest])
->makePartial()
->shouldAllowMockingProtectedMethods();
$targetClass->shouldReceive('init')->once()->with($stubRequest, $stubView);
//テスト対象メソッドの実行
$actual = $targetClass->compose($stubView);
$this->assertNull($actual);
}
/**
* @covers ::__construct
*/
public function test___construct()
{
$stubRequest = \Mockery::mock(Request::class)->shouldIgnoreMissing();
$targetClass = $this->createEmptyInitConcreteObject($stubRequest);
$this->assertInstanceOf(FormComposer::class, $targetClass);
$this->assertInstanceOf(ViewComposerInterface::class, $targetClass);
}
protected function tearDown(): void
{
parent::tearDown(); // TODO: Change the autogenerated stub
\Mockery::close();
}
}
|
Jikanko Eiyu
Basics:
Kanji Name: 時間子英雄
Romanji Name: Jikanko Eiyu
English Name: Eiyu Jikanko
Current Age: 15
Date of Birth: 23rd of May
Star Sign: Gemini
Birthplace: Somewhere in Sweden, in the sea
Hair Color: Teal
Eye Color: Purple
Blood Type: O
Voice Actor: Ogata Haruna
Family Members: Her mother is named Umi
Quote: "Everyone can be a hero whoever they are"
Appearance:
As Eiyu, she has long hair with short pigtails
Personality:
Etymology:
Jikanko: Jikan (時間) means time while Ko (子) means child
Eiyu: Eiyu (英雄) means hero
Cure Form:
Her pose is that she hands her left handed fist up while her right hand stays down.
But that doesn't stop her for making her dream come true. After hearing from Haruka that she's going to Vienna with her during the springtime, Eiyu was very excited. One day, she and Haruka bumped into a woman, who seems to be Honoka. Honoka told Eiyu that everyone's a hero, and Eiyu repeated those words when she saw Kowaii having the Melody of Sadness, and stopped her to fight with her.
Relationships:
Umi Jikanko:
Her mother, who she dearly loves.
Haruno Haruka:
Haruka is close friends with her.
Honoka Akaoto:
Her sensei. Honoka and Umi are close with each other.
The other cures in Eurovision Precure are friendly to her since joining the group.
Trivia:
|
Filtering and redirecting in a django view not performing as expected
I have a very simple view that checks to see if something exists and then redirects if it doesn't. For some reason it doesn't work. The exception keeps firing. I have verified that there are records in the DB that should be returning.
Any suggestions are welcome.
@login_required
def goal_display(request):
user = get_object_or_404(User, id=request.user.id)
if request.user != user:
return permission_denied(request)
try:
goal = Goal.objects.filter(user=user).latest('created')
return render_to_response('achieve/dashboard.html', {
"goal": goal
}, context_instance=RequestContext(request))
except:
return redirect('goal_add')
does Goal have created and user fields ?
What exception? A bare except is rarely a good idea, try to change it to except Goal.DoesNotExist and see if you get another error (please post full traceback if this is the case)
That's so weird. When I added you suggestion everything started working. That is really strange.
Funny :) If you change it back, is it broken again?
No, so now I'm really confused. One last question. Why Goal and not goal. How does the try know to look for the Goal?
The try block only knows it should catch exceptions of a specific kind, in this case, Goal.DoesNotExist. Every Django model has its own DoesNotExist exception class, so except Goal.DoesNotExist catches all DoesNotExist exceptions relating to Goal. The variable goal doesn't have anything to do with it; it is not even set yet when the exception is raised inside .latest()
The 'ghost' error might have something to do with your browser caching the redirect; you might want to limit/disable caching for views like that (for example using the decorator django.views.decorators.cache.never_cache)
Knowing when an apache restart is required and when it is not, is very subtle with Django. I make it a habit to restart Apache (or django server if that's what server you're using here) after almost any change, before testing (obviously in dev environment, hopefully you're not doing code changes in production). You can end up with old versions of code resurfacing oddly if you don't do this, in a way I find difficult to predict, and your ghost error might have been that.
Your call to get_object_or_404 for User is completely pointless. request.user is already the User object. You are querying again for no reason.
Are you try with a if statement and exists()? I think is easier.
def goal_display(request):
user = get_object_or_404(User, id=request.user.id)
if request.user != user:
return permission_denied(request)
if(Goal.objects.filter(user=user).lastest('created').exists()):
goal = Goal.objects.filter(user=user).latest('created')
return render_to_response('achieve/dashboard.html', {
"goal": goal
}, context_instance=RequestContext(request))
else:
return redirect('goal_add')
Maybe is not the prettiest way but i think it should work.
|
/* eslint @typescript-eslint/no-var-requires: "off" */
const codeceptjs = require('codeceptjs');
/**
* Custom Locators
*/
module.exports = function () {
codeceptjs.locator.addFilter((providedLocator, locatorObj) => {
// eslint-disable-next-line no-undef
if (typeof providedLocator === 'string' && process.env.DRIVER.toLowerCase() === 'webdriver') {
locatorObj.type = 'shadowDom';
}
});
};
|
key : on Azerty keyboard launches / to find
Hi,
Congratulations for this software and your work.
I use the latest version via a gentle git pull.
i meet this issue on every azerty keyboard (windows 10 or Ubuntu 18.04.02), when i type on the : key, Orca reacts as y type on the / character which is on a azerty keyboard the same key.
it's annoying to play just a little midi note.
An idea ?
Thanks
Just pushed an update that should fix that :)
Perfect ! Merci for french users !
|
Set cookie accessible by cross domain image api
I have a number of domains lorem.com, ipsum.com and dolor.com etc. They all access images through a central image API myapi.com. I need myapi.com to be able to know the screen size and width of the requesting client. I am thinking of using a solution similar to the one described here: https://css-tricks.com/server-side-mustard-cut/
TLDR: A small javascript function finds out the width and height of the screen and then saves that to a cookie. Requests to the image api should have that cookie included in the header so the server can figure out how large of an image to send back.
The problem is this is cross domain. lorem.com has an image tag as such <img src="http://www.myapi.com/image1" /> but the cookie won't be included in that request because it was set by a script running on a page from lorem.com
The solutions I am finding online involve iframes and fake image tags with display:none that actually call a php script from the 3rd party domain to set the cookie.
The problem is I need set the cookie client side with the proper height and width information. I can't use a php script to set that because the php script doesn't know the height and width.
Is there some non-hacky way to go about this that doesn't involve iframes or roundabout solutions? Thanks!
the solution will always be "roundabout" in some way - I've got the germination of three ideas. 1 - using redirects, 2 - loading the images dynamically using javascript, 3 - rather than img tags, use css background image (this one would best be if you have a set number of images for a set block of dimensions)
Thanks - I've already decided that I do need to load the images 'normally' and that somehow the server needs to be provided with the width and height of the client device along with that image request. Those requirements unfortunately can't be changed. As to how I can get that device resolution information sent along with the request - that's what I'm trying to figure out.
why don't you want to load img dynamic - i.e. using javascript?
I want to make my function able to work along side a lazy-loading library. If I decide to load the image dynamically then it'll make things more difficult for the function to co-exist because now there will be two functions trying to dynamically load an image. Also I just like the simplicity and streamlined-ness of not using any extra js to load an image.
well, cross site cookies are out - so I can only suggest what I've suggested
Here are two options:
1) use the JavaScript to update the img url with height and width information as query Params in the image url itself rather than relying on cookie e.g. ”/>
2) if you have to use cookies, than if you control myapi.com as well then you can spin an endpoint their which take the client width and height param and in response return set-cookie header. Since the call is made to myapi.com, browser will let it set cookie for myapi.com and it would passed to subsequent calls to that domain, though you would not able to access this cookie from JavaScript since you are not running under myapi.com
|
$(document).ready(function() {
var $alto= $( window ).height();
var $total=$alto-55;
$(".contenido-fijo").css({ height: $total+'px' })
});
|
#ifndef __RADGIGASTAR_USB_H_
#define __RADGIGASTAR_USB_H_
#ifdef __cplusplus
#include "icsneo/device/tree/radgigastar/radgigastar.h"
#include "icsneo/platform/ftdi3.h"
namespace icsneo {
class RADGigastarUSB : public RADGigastar {
public:
static constexpr const uint16_t PRODUCT_ID = 0x1204;
static std::vector<std::shared_ptr<Device>> Find() {
std::vector<std::shared_ptr<Device>> found;
for(auto neodevice : FTDI3::FindByProduct(PRODUCT_ID))
found.emplace_back(new RADGigastarUSB(neodevice)); // Creation of the shared_ptr
return found;
}
private:
RADGigastarUSB(neodevice_t neodevice) : RADGigastar(neodevice) {
initialize<FTDI3, RADGigastarSettings>();
productId = PRODUCT_ID;
}
};
}
#endif // __cplusplus
#endif
|
<?php
declare(strict_types=1);
/**
* This file is part of beotie/core_bundle
*
* As each files provides by the CSCFA, this file is licensed
* under the MIT license.
*
* PHP version 7.1
*
* @category Request
* @package Beotie_Core_Bundle
* @author matthieu vallance <[email protected]>
* @license MIT <https://opensource.org/licenses/MIT>
* @link http://cscfa.fr
*/
namespace Beotie\PSR7\Request\HttpComponent;
use Symfony\Component\HttpFoundation\Request;
use Beotie\PSR7\Request\HttpRequestServerAdapter;
/**
* Attribute component
*
* This trait is used to implement the PSR7 over symfony Request instance and manange attributes part
*
* @category Request
* @package Beotie_Core_Bundle
* @author matthieu vallance <[email protected]>
* @license MIT <https://opensource.org/licenses/MIT>
* @link http://cscfa.fr
*/
trait AttributeComponent
{
/**
* Http request
*
* The base symfony http request
*
* @var Request
*/
private $httpRequest;
/**
* Return an instance with the specified derived request attribute.
*
* This method allows setting a single derived request attribute as
* described in getAttributes().
*
* This method MUST be implemented in such a way as to retain the
* immutability of the message, and MUST return an instance that has the
* updated attribute.
*
* @param string $name The attribute name.
* @param mixed $value The value of the attribute.
*
* @see getAttributes()
* @return static
*/
public function withAttribute($name, $value)
{
return $this->duplicate(['attributes' => [$name => $value]]);
}
/**
* Retrieve a single derived request attribute.
*
* Retrieves a single derived request attribute as described in
* getAttributes(). If the attribute has not been previously set, returns
* the default value as provided.
*
* This method obviates the need for a hasAttribute() method, as it allows
* specifying a default value to return if the attribute is not found.
*
* @param string $name The attribute name.
* @param mixed $default Default value to return if the attribute does not exist.
*
* @see getAttributes()
* @return mixed
*/
public function getAttribute($name, $default = null)
{
return $this->httpRequest->get($name, $default);
}
/**
* Return an instance that removes the specified derived request attribute.
*
* This method allows removing a single derived request attribute as
* described in getAttributes().
*
* This method MUST be implemented in such a way as to retain the
* immutability of the message, and MUST return an instance that removes
* the attribute.
*
* @param string $name The attribute name.
*
* @see getAttributes()
* @return static
*/
public function withoutAttribute($name)
{
$httpRequest = clone $this->httpRequest;
$httpRequest->attributes->remove($name);
return new static($httpRequest);
}
/**
* Retrieve attributes derived from the request.
*
* The request "attributes" may be used to allow injection of any
* parameters derived from the request: e.g., the results of path
* match operations; the results of decrypting cookies; the results of
* deserializing non-form-encoded message bodies; etc. Attributes
* will be application and request specific, and CAN be mutable.
*
* @return array Attributes derived from the request.
*/
public function getAttributes()
{
return $this->httpRequest->attributes->all();
}
/**
* Duplicate
*
* This method duplicate the current request and override the specified parameters
*
* @param array $param The parameters to override
* @param bool $force Hard replace the parameter, act as replace completely
*
* @return HttpRequestServerAdapter
*/
protected abstract function duplicate(array $param = [], bool $force = false) : HttpRequestServerAdapter;
}
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Occurrence records map (0 records)
Datasets
datasets have provided data to the ALA for this species.
Browse the list of datasets and find organisations you can join if you are interested in participating in a survey for species like Eucalyptus perangusta Brooker
Names and sources
Accepted Name Source
Eucalyptus perangusta Brooker
According to:Brooker, M.I.H. (2000), A new classification of the genus Eucalyptus L'Her. (Myrtaceae). Australian Systematic Botany 13(1)
Published in:Brooker, M.I.H. (1988), Eucalyptus foecunda revisited and six related new species (Myrtaceae). Nuytsia 6(3)
Name Source
Eucalyptus perangusta Brooker accepted
Identifier Source
urn:lsid:biodiversity.org.au:apni.taxon:253097 Previous APNI ID replaced
http://id.biodiversity.org.au/node/apni/2900805 Taxon current
http://id.biodiversity.org.au/name/apni/104829 Scientific Name current
http://id.biodiversity.org.au/instance/apni/563459 Taxon Concept current
Classification
kingdom
Plantae
phylum
Charophyta
class
Equisetopsida
subclass
Magnoliidae
superorder
Rosanae
order
Myrtales
family
Myrtaceae
genus
Eucalyptus
species
Eucalyptus perangusta
Charts showing breakdown of occurrence records (0 records)
Genbank
Data sets Licence Records
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Rowntree
Etymology
Variant of.
Statistics
* According to the 2010 United States Census, Rowntree is the 96799th most common surname in the United States, belonging to 188 individuals. Rowntree is most common among White (97.34%) individuals.
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Hermetic sealing lid member and electronic component housing package
ABSTRACT
This hermetic sealing lid member ( 1 ) is made of a clad material ( 10 ) including a base material layer ( 11 ) made of an Fe alloy that contains 4 mass % or more of Cr and a silver brazing layer ( 13 ) bonded onto a surface of the base material layer on a side closer to an electronic component housing member through an intermediate layer ( 12 ).
TECHNICAL FIELD
The present invention relates to a hermetic sealing lid member and an electronic component housing package using the same.
BACKGROUND ART
A hermetic sealing lid member used for an electronic component housing package is known in general. Such a hermetic sealing lid member is disclosed in Japanese Patent No. 3850787, for example.
Japanese Patent No. 3850787 discloses a lid member directly braze-bonded to a case made of ceramics without using a seal ring. This lid member is made of a clad material in which a base material layer made of kovar (registered trademark), an intermediate metal layer directly made of Cu and directly bonded to a surface of the base material layer, and a brazing material layer made of a silver brazing alloy and directly bonded to a surface of the intermediate metal layer on a side opposite to the base material layer are bonded to each other. In the lid member, side surfaces of the intermediate metal layer and the base material layer and the silver brazing layer are exposed outward.
PRIOR ART DOCUMENT Patent Document
- Patent Document 1: Japanese Patent No. 3850787
SUMMARY OF THE INVENTION Problem to be Solved by the Invention
However, in the lid member disclosed in Japanese Patent No. 3850787, although there are no particular problems in the intermediate metal layer made of Cu and the brazing material layer made of the silver brazing alloy, the base material layer is made of kovar having a low corrosion resistance while side surfaces of the lid member are exposed outward, and hence there is such a problem that the base material layer may corrode in a harsh environment such as a location where the lid member comes in contact with salt water (seawater). In this case, the hermetic sealability of an electronic component housing package using the case and the lid member may be reduced.
The present invention has been proposed in order to solve the aforementioned problem, and an object of the present invention is to provide a hermetic sealing lid member capable of being directly braze-bonded to an electronic component housing member without using a seal ring, in which the corrosion of a base material layer can be suppressed, and an electronic component housing package using the hermetic sealing lid member.
Means for Solving the Problem
A hermetic sealing lid member according to a first aspect of the present invention is a hermetic sealing lid member used for an electronic component housing package including an electronic component housing member for housing an electronic component, and is made of a clad material including a base material layer made of an Fe alloy that contains 4 mass % or more of Cr and a silver brazing layer bonded onto one surface of the base material layer on a side closer to the electronic component housing member through an intermediate layer made of Cu or bonded in direct contact with the surface of the base material layer on the side closer to the electronic component housing member.
In the hermetic sealing lid member according to the first aspect of the present invention, as hereinabove described, the base material layer is made of the Fe alloy that contains 4 mass % or more of Cr such that the corrosion resistance of the base material layer can be reliably improved, and hence the corrosion of the base material layer can be suppressed even in a harsh environment. This has been confirmed by an experiment. Thus, the degradation of the hermetic sealing lid member caused by the corrosion can be suppressed, and hence a reduction in the hermetic sealability of the electronic component housing package using the hermetic sealing lid member can be suppressed. Furthermore, the hermetic sealing lid member can be directly braze-bonded to the electronic component housing member without using a seal ring by the silver brazing layer bonded onto one surface of the base material layer on the side closer to the electronic component housing member through the intermediate layer made of Cu or bonded in direct contact with one surface of the base material layer on the side closer to the electronic component housing member.
In the aforementioned hermetic sealing lid member according to the first aspect, the base material layer is preferably made of the Fe alloy that contains 4 mass % or more and 20 mass % or less of Cr. According to this structure, an increase in the thermal expansion coefficient of the base material layer caused by an increase in the content percentage of Cr over about 20 mass % can be suppressed. Thus, an increase in a difference in thermal expansion between the electronic component housing member made of a low thermal expansion material such as ceramics and the hermetic sealing lid member can be suppressed. Consequently, a thermal stress generated between the hermetic sealing lid member and the electronic component housing member can be reduced, and hence a reduction in the hermetic sealability of the electronic component housing package caused by the thermal stress can be suppressed.
In this case, the base material layer is preferably made of the Fe alloy that contains 6 mass % or more and 10 mass % or less of Cr. According to this structure, the corrosion resistance of the base material layer can be reliably improved by setting the content percentage of Cr of the base material layer to 6 mass % or more. Furthermore, an increase in the thermal expansion coefficient of the base material layer can be effectively suppressed by setting the content percentage of Cr of the base material layer to 10 mass % or less.
In the aforementioned hermetic sealing lid member according to the first aspect, the base material layer is preferably made of the Fe alloy that further contains Ni in addition to 4 mass % or more of Cr. According to this structure, an increase in the thermal expansion coefficient of the base material layer can be suppressed by containing Ni in the Fe alloy of the base material layer while the sufficient corrosion resistance of the base material layer is ensured by setting the content percentage of Cr of the base material layer to 4 mass % or more.
In this case, the base material layer is preferably made of the Fe alloy that further contains 36 mass % or more and 48 mass % or less of Ni in addition to 4 mass % or more of Cr. The base material layer is more preferably made of the Fe alloy that further contains 40 mass % or more and 48 mass % or less of Ni in addition to 4 mass % or more of Cr. According to this structure, an increase in the thermal expansion coefficient of the base material layer can be effectively suppressed by setting the content percentage of Ni of the base material layer to 36 mass % or more and 48 mass % or less (more preferably 40 mass % or more and 48 mass % or less) while the sufficient corrosion resistance of the base material layer is ensured by setting the content percentage of Cr of the base material layer to 4 mass % or more.
In the aforementioned structure in which the base material layer is made of the Fe alloy that contains Ni in addition to Cr, the base material layer is preferably made of the Fe alloy that further contains Co in addition to 4 mass % or more of Cr and Ni. According to this structure, an increase in the thermal expansion coefficient of the base material layer can be effectively suppressed by containing not only Ni but also Co in the Fe alloy of which the base material layer is made.
In this case, the base material layer is preferably made of the Fe alloy that further contains 6 mass % or more and 18 mass % or less of Co in addition to 4 mass % or more of Cr and 36 mass % or more and 48 mass % or less of Ni. According to this structure, an increase in the thermal expansion coefficient of the base material layer can be more effectively suppressed.
In the aforementioned hermetic sealing lid member according to the first aspect, the base material layer is preferably made of a Cr—Fe alloy that contains neither Ni nor Co and at least contains 16 mass % or more and 20 mass % or less of Cr. According to this structure, the corrosion resistance of the base material layer can be more reliably ensured, and the thermal expansion of the base material layer can be effectively suppressed when the hermetic sealing lid member is arranged in a high-temperature environment of 400° C. or more, for example.
In the aforementioned hermetic sealing lid member according to the first aspect, the silver brazing layer is preferably bonded to the base material layer through the intermediate layer made of pure Cu that contains 99.95 mass % or more of Cu. According to this structure, the intermediate layer can be sufficiently softened, and hence the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member and the electronic component housing member can be sufficiently relieved by the soft intermediate layer.
In the aforementioned hermetic sealing lid member according to the first aspect, a thickness of the intermediate layer is preferably 5 μm or more and 50 μm or less. The thickness of the intermediate layer is more preferably 10 μm or more and 30 μm or less. According to this structure, the thickness of the intermediate layer can be sufficiently ensured by setting the thickness of the intermediate layer to 5 μm or more (more preferably 10 μm or more), and hence the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member and the electronic component housing member can be sufficiently relieved. Furthermore, the thickness of the intermediate layer is about 50 μm or less (more preferably about 30 μm or less) such that the formation of an excessive amount of the intermediate layer can be suppressed, and hence an increase in the size of the hermetic sealing lid member in a thickness direction can be suppressed.
In the aforementioned hermetic sealing lid member according to the first aspect, the silver brazing layer preferably contains Ag and Cu. According to this structure, the melting point of the silver brazing layer can be reduced, and hence in a state where the temperature rising of the hermetic sealing lid member and the temperature rising of the electronic component housing member are suppressed at the time of braze bonding between the hermetic sealing lid member and the electronic component housing member, the hermetic sealing lid member and the electronic component housing member can be braze-bonded to each other by the melted silver brazing layer. Thus, the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member and the electronic component housing member can be sufficiently reduced.
In this case, the silver brazing layer preferably contains Sn in addition to Ag and Cu. According to this structure, the melting point of the silver brazing layer can be further reduced, and hence the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member and the electronic component housing member can be further reduced.
In the aforementioned hermetic sealing lid member according to the first aspect, the clad material preferably further includes a surface layer bonded to a surface of the base material layer on a side opposite to the electronic component housing member and made of Ni or a Ni alloy. According to this structure, the corrosion of the base material layer on the surface on the side opposite to the electronic component housing member can be more reliably suppressed by the surface layer made of Ni or the Ni alloy. Furthermore, when the hermetic sealing lid member and the electronic component housing member are braze-bonded to each other by seam welding, a contact resistance between the hermetic sealing lid member and a roller electrode can be reduced by the surface layer made of Ni or the Ni alloy, and hence occurrence of spark or the like between the hermetic sealing lid member and the roller electrode can be suppressed.
An electronic component housing package according to a second aspect of the present invention includes an electronic component housing member for housing an electronic component, and a hermetic sealing lid member made of a clad material including a base material layer made of an Fe alloy that contains 4 mass % or more of Cr, and a silver brazing layer bonded onto one surface of the base material layer on a side closer to the electronic component housing member through an intermediate layer made of Cu or bonded in direct contact with the surface of the base material layer on the side closer to the electronic component housing member, and bonded to the electronic component housing member through the silver brazing layer.
The electronic component housing package according to the second aspect of the present invention uses the hermetic sealing lid member according to the aforementioned first aspect in which the corrosion of the base material layer is suppressed such that the degradation of the hermetic sealing lid member caused by the corrosion can be suppressed, and hence a reduction in the hermetic sealability of the electronic component housing package using the hermetic sealing lid member can be suppressed. Furthermore, the hermetic sealing lid member is provided with the silver brazing layer bonded to one surface of the base material layer on the side closer to the electronic component housing member through the intermediate layer made of Cu or bonded in direct contact with one surface of the base material layer on the side closer to the electronic component housing member such that the electronic component housing package in which the hermetic sealing lid member is directly braze-bonded to the electronic component housing member without using a seal ring can be obtained.
In the aforementioned electronic component housing package according to the second aspect, the base material layer is preferably made of the Fe alloy that contains 4 mass % or more and 20 mass % or less of Cr. According to this structure, an increase in the thermal expansion coefficient of the base material layer caused by an increase in the content percentage of Cr over about 20 mass % can be suppressed. Thus, an increase in a difference in thermal expansion between the electronic component housing member made of a low thermal expansion material such as ceramics and the hermetic sealing lid member can be suppressed. Consequently, a thermal stress generated between the hermetic sealing lid member and the electronic component housing member can be reduced, and hence a reduction in the hermetic sealability of the electronic component housing package caused by the thermal stress can be suppressed.
In the aforementioned electronic component housing package according to the second aspect, the base material layer is preferably made of the Fe alloy that further contains Ni in addition to 4 mass % or more of Cr. According to this structure, an increase in the thermal expansion coefficient of the base material layer can be suppressed by containing Ni in the Fe alloy of the base material layer while the sufficient corrosion resistance of the base material layer is ensured by setting the content percentage of Cr of the base material layer to 4 mass % or more.
In this case, the base material layer is preferably made of the Fe alloy that further contains Co in addition to 4 mass % or more of Cr and Ni. According to this structure, an increase in the thermal expansion coefficient of the base material layer can be effectively suppressed by containing not only Ni but also Co in the Fe alloy of which the base material layer is made.
In the aforementioned electronic component housing package according to the second aspect, the clad material preferably further includes a surface layer bonded to a surface of the base material layer on a side opposite to the electronic component housing member and made of Ni or a Ni alloy. According to this structure, the corrosion of the base material layer on the surface on the side opposite to the electronic component housing member can be more reliably suppressed by the surface layer made of Ni or the Ni alloy. Furthermore, when the hermetic sealing lid member and the electronic component housing member are braze-bonded to each other by seam welding, a contact resistance between the hermetic sealing lid member and a roller electrode can be reduced by the surface layer made of Ni or the Ni alloy, and hence occurrence of spark or the like between the hermetic sealing lid member and the roller electrode can be suppressed.
Effect of the Invention
According to the present invention, as hereinabove described, the hermetic sealing lid member capable of being directly braze-bonded to the electronic component housing member without using the seal ring, in which the corrosion of the base material layer can be suppressed, and the electronic component housing package using the hermetic sealing lid member.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 A plan view showing the structure of a hermetic sealing lid member according to a first embodiment of the present invention.
FIG. 2 A sectional view taken along the line 300-300 in FIG. 1.
FIG. 3 A sectional view showing the structure of an electronic component housing package according to the first embodiment of the present invention.
FIG. 4 A sectional view showing the layer structure of a hermetic sealing lid member according to a modification of the first embodiment of the present invention.
FIG. 5 A sectional view showing the layer structure of a hermetic sealing lid member according to a second embodiment of the present invention.
FIG. 6 A table showing the results of a corrosion resistance test of a base material layer of a hermetic sealing lid member conducted in order to confirm the effect of the present invention.
FIG. 7 A table showing the average thermal expansion coefficient of a base material layer of a hermetic sealing lid member conducted in order to confirm the effect of the present invention.
MODES FOR CARRYING OUT THE INVENTION
Embodiments embodying the present invention are hereinafter described on the basis of the drawings.
First Embodiment (Structure of Hermetic Sealing Lid Member)
The structure of a hermetic sealing lid member 1 according to a first embodiment of the present invention is now described with reference to FIGS. 1 and 2.
The hermetic sealing lid member 1 according to the first embodiment of the present invention is used for an electronic component housing package 100 (see FIG. 3) that includes an electronic component housing member 30 for housing an electronic component 20 described later.
The hermetic sealing lid member 1 is made of a flat plate-shaped clad material 10, as shown in FIGS. 1 and 2. Specifically, the hermetic sealing lid member 1 is made of the four-layered clad material that includes a base material layer 11, an intermediate layer 12 bonded in direct contact with the lower surface 11 a (a surface on a Z2 side, a surface on a side closer to the electronic component housing member 30) of the base material layer 11, a silver brazing layer 13 bonded in direct contact with the lower surface 12 a of the intermediate layer 12, and a surface layer 14 bonded in direct contact with the upper surface 11 b (a surface on a Z1 side, a surface on a side opposite to the electronic component housing member 30) of the base material layer 11. No Ni plated layers or the like are provided on side surfaces of the clad material 10, and hence in the clad material 10, side surfaces 11 c of the base material layer 11, side surfaces 12 b of the intermediate layer 12, the silver brazing layer 13, and the surface layer 14 are exposed outward. The lower surface 11 a is an example of a “surface” in the present invention.
The base material layer 11 is a layer to mainly determine parameters such as the mechanical strength and thermal expansion rate of the clad material 10.
According to the first embodiment, the base material layer 11 is made of an Fe alloy that at least contains 4 mass % or more of Cr in order to sufficiently ensure the corrosion resistance. The base material layer 11 contains 4 mass % or more of Cr such that passive films that mainly contain Cr₂O₃ are formed on the exposed side surfaces 11 c, and hence the corrosion resistance of the side surfaces 11 c of the base material layer 11 is improved. The content percentage of Cr of the Fe alloy of which the base material layer 11 is made is preferably 4 mass % or more and about 20 mass % or less in order to further improve the corrosion resistance, and more preferably about 6 mass % or more and about 10 mass % or less. When the Fe alloy of which the base material layer 11 is made contains neither Ni nor Co described later, the content percentage of Cr of the Fe alloy is preferably about 16 mass % or more and about 20 mass % or less.
The base material layer 11 is preferably made of the Fe alloy that further contains Ni in addition to 4 mass % or more of Cr in order to improve the corrosion resistance and reduce the thermal expansion coefficient. At this time, the content percentage of Ni in the Fe alloy of the base material layer 11 is more preferably about 36 mass % or more and about 48 mass % or less, and still more preferably about 40 mass % or more and about 48 mass % or less. Furthermore, the base material layer 11 is more preferably made of the Fe alloy that further contains Co in addition to 4 mass % or more of Cr and Ni in order to further reduce the thermal expansion coefficient. At this time, the content percentage of Co in the Fe alloy of the base material layer 11 is more preferably about 6 mass % or more and about 18 mass % or less.
The intermediate layer 12 is made of pure Cu such as tough pitch copper or phosphorous-de oxidized copper that contains about 99.90% or more of Cu, or oxygen-free copper that contains about 99.95% or more of Cu. The intermediate layer 12 is preferably made of oxygen-free copper of higher purity. Thus, as compared with the case where the intermediate layer is made of Ni or a Ni alloy, the intermediate layer 12 can be sufficiently softened (low proof strength). Furthermore, the intermediate layer 12 is made of pure Cu, and hence the exposed side surfaces 12 b of the intermediate layer 12 each have a sufficient corrosion resistance. The thickness of the intermediate layer 12 in a direction Z is preferably a thickness of about 5 μm or more and about 50 μm or less, and more preferably a thickness of about 10 μm or more and about 30 μm or less in order to relieve a thermal stress described later. Furthermore, the thickness of the intermediate layer 12 is preferably about 30% of the thickness of the clad material 10 in the direction Z.
The silver brazing layer 13 is made of a silver brazing material made of a Ag—Cu alloy that contains Ag, inevitable impurities, and the balance Cu or a Ag—Sn—Cu alloy that contains Ag, Sn, inevitable impurities, and the balance Cu. For example, the silver brazing material is made of a 72Ag—Cu alloy that contains about 72 mass % of Ag, inevitable impurities, and the balance Cu, an 85Ag—Cu alloy that contains about 85 mass % of Ag, inevitable impurities, and the balance Cu, or the like. Furthermore, for example, the silver brazing material is made of a 67Ag-4Sn—Cu alloy that contains about 67 mass % of Ag, about 4 mass % of Sn, inevitable impurities, and the balance Cu and is excellent in workability. The silver brazing layer 13 is made of the Ag—Cu alloy or the Ag—Sn—Cu alloy, and hence the exposed silver brazing layer 13 has a sufficient corrosion resistance. The melting point of the silver brazing material is about 780° C. or less. The melting point of the silver brazing material made of the Ag—Sn—Cu alloy is lower than the melting point of the silver brazing material made of the Ag—Cu alloy.
The surface layer 14 is made of pure Ni or a Ni alloy. The surface layer 14 is made of pure Ni or the Ni alloy, and hence the exposed surface layer 14 has a sufficient corrosion resistance. This surface layer 14 has a function of suppressing occurrence of spark or the like between the hermetic sealing lid member 1 and a roller electrode (not shown) by reducing a contact resistance between the hermetic sealing lid member 1 and the roller electrode at the time of direct seam welding described later.
Consequently, any of the side surfaces 11 c of the base material layer 11, the side surfaces 12 b of the intermediate layer 12, the silver brazing layer 13, and the surface layer 14, all of which are exposed outward in the clad material 10, has a sufficient corrosion resistance, and hence the corrosion of the hermetic sealing lid member 1 is suppressed.
(Structure of Electronic Component Housing Package)
The structure of the electronic component housing package 100 using the hermetic sealing lid member 1 according to the first embodiment of the present invention is now described with reference to FIG. 3.
The electronic component housing package 100 according to the first embodiment includes the aforementioned hermetic sealing lid member 1 and the electronic component housing member 30 for housing the electronic component 20 such as a crystal unit or a SAW filter (surface acoustic wave filter). In the electronic component housing package 100, the hermetic sealing lid member 1 is arranged on the electronic component housing member 30 such that the silver brazing layer 13 of the hermetic sealing lid member 1 is on the side closer to the electronic component housing member 30 (a lower side, the Z2 side).
The electronic component housing member 30 is made of ceramics (Al₂O₃). Furthermore, the electronic component housing member 30 has a box shape including a recess portion 30 a with an opening on an upper side (Z1 side). In the recess portion 30 a, the electronic component 20 is fixed through a bump 40.
The hermetic sealing lid member 1 is braze-bonded to the electronic component housing member 30 by being welded (direct seam welded) by seam welding, which is a type of resistance welding, in a state where the hermetic sealing lid member 1 is arranged on the frame-shaped upper surface 30 b of the electronic component housing member 30. In other words, the silver brazing material of the silver brazing layer 13 of the hermetic sealing lid member 1 is melted by seam welding, and is bonded onto the upper surface 30 b of the electronic component housing member 30. At the time of seam welding, an electric current flows between the surface layer 14 made of Ni or the Ni alloy and the roller electrode (not shown) such that the silver brazing material of the silver brazing layer 13 is melted. Furthermore, the hermetic sealing lid member 1 and the electronic component housing member 30 are directly bonded to each other not through a seal ring.
In order to improve braze bonding between the hermetic sealing lid member 1 and the electronic component housing member 30, a metalization layer may be formed on the upper surface 30 b of the electronic component housing member 30. The metalization layer has a structure in which a W layer, a Ni layer, and a Au layer (not shown) are stacked in this order from the upper surface 30 b side of the electronic component housing member 30.
Heat for melting the silver brazing layer 13 of the hermetic sealing lid member 1 is applied to the hermetic sealing lid member 1 and the electronic component housing member 30, and both the hermetic sealing lid member 1 and the electronic component housing member 30 are thermally expanded. At this time, a thermal stress caused by a difference in thermal expansion between the hermetic sealing lid member 1 (base material layer 11) and the electronic component housing member 30 is generated. According to the first embodiment, as described above, the intermediate layer 12 made of pure Cu, which is sufficiently soft, is provided such that the intermediate layer 12 is easily plastic-deformed following the deformation of the base material layer 11, and hence the thermal stress generated in the hermetic sealing lid member 1 is relieved. Therefore, according to the aforementioned first embodiment, even when the difference in thermal expansion between the hermetic sealing lid member 1 (base material layer 11) and the electronic component housing member 30 somewhat exists, a reduction in the hermetic sealability of the electronic component housing package 100 can be sufficiently suppressed.
According to the first embodiment, the following effects can be obtained.
According to the first embodiment, as hereinabove described, the base material layer 11 is made of the Fe alloy that at least contains 4 mass % or more of Cr. Thus, the corrosion resistance of the base material layer 11 can be reliably improved, and hence the corrosion of the base material layer 11 can be suppressed even in a harsh environment. Thus, the degradation of the hermetic sealing lid member 1 caused by the corrosion can be suppressed, and hence a reduction in the hermetic sealability of the electronic component housing package 100 using the hermetic sealing lid member 1 can be suppressed. Furthermore, the hermetic sealing lid member 1 can be directly braze-bonded to the electronic component housing member 30 without using a seal ring by the silver brazing layer 13 bonded onto the lower surface 11 a of the base material layer 11 on the side closer to the electronic component housing member 30 through the intermediate layer 12 made of Cu.
According to the first embodiment, the base material layer 11 is made of the Fe alloy that contains 4 mass % or more and about 20 mass % or less of Cr such that an increase in the thermal expansion coefficient of the base material layer 11 caused by an increase in the content percentage of Cr over about 20 mass % can be suppressed. Thus, an increase in the difference in thermal expansion between the electronic component housing member 30 made of ceramics and the hermetic sealing lid member 1 can be suppressed. Consequently, the thermal stress generated between the hermetic sealing lid member 1 and the electronic component housing member 30 can be reduced, and hence a reduction in the hermetic sealability of the electronic component housing package 100 caused by the thermal stress can be suppressed.
According to the first embodiment, the base material layer 11 is made of the Fe alloy that contains about 6 mass % or more and about 10 mass % or less of Cr such that the corrosion resistance of the base material layer 11 can be reliably improved, and an increase in the thermal expansion coefficient of the base material layer 11 can be effectively suppressed.
According to the first embodiment, the base material layer 11 is made of the Fe alloy that further contains Ni in addition to 4 mass % or more of Cr such that an increase in the thermal expansion coefficient of the base material layer 11 can be suppressed by containing Ni in the Fe alloy of the base material layer 11 while the sufficient corrosion resistance of the base material layer 11 is ensured by setting the content percentage of Cr of the base material layer 11 to 4 mass % or more.
According to the first embodiment, the base material layer 11 is made of the Fe alloy that further contains about 36 mass % or more and about 48 mass % or less (more preferably about 40 mass % or more and about 48 mass % or less) of Ni in addition to 4 mass % or more of Cu such that an increase in the thermal expansion coefficient of the base material layer 11 can be effectively suppressed by setting the content percentage of Ni of the base material layer 11 to about 36 mass % or more and about 48 mass % or less (more preferably about 40 mass % or more and about 48 mass % or less) while the sufficient corrosion resistance of the base material layer 11 is ensured by setting the content percentage of Cr of the base material layer 11 to 4 mass % or more.
According to the first embodiment, the base material layer 11 is made of the Fe alloy that further contains Co in addition to 4 mass % or more of Cr and Ni such that an increase in the thermal expansion coefficient of the base material layer 11 can be effectively suppressed by containing not only Ni but also Co in the Fe alloy of which the base material layer 11 is made.
According to the first embodiment, the base material layer 11 is made of the Fe alloy that further contains about 6 mass % or more and about 18 mass % or less of Co in addition to 4 mass % or more of Cr and about 36 mass % or more and about 48 mass % or less of Ni such that an increase in the thermal expansion coefficient of the base material layer 11 can be more effectively suppressed.
According to the first embodiment, the base material layer 11 is made of the Cr—Fe alloy that contains neither Ni nor Co and at least contains about 16 mass % or more and about 20 mass % or less of Cr such that the corrosion resistance of the base material layer 11 can be more reliably ensured, and the thermal expansion of the base material layer 11 can be effectively suppressed when the hermetic sealing lid member 1 is arranged in a high-temperature environment of about 400° C. or more.
According to the first embodiment, the silver brazing layer 13 is bonded to the base material layer 11 through the intermediate layer 12 made of pure Cu that contains about 99.95 mass % or more of Cu such that the intermediate layer 12 can be sufficiently softened, and hence the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member 1 and the electronic component housing member 30 can be sufficiently relieved by the soft intermediate layer 12.
According to the first embodiment, the thickness of the intermediate layer 12 in the direction Z is about 5 μm or more (more preferably about 10 μm or more) such that the thickness of the intermediate layer 12 can be sufficiently ensured, and hence the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member 1 and the electronic component housing member 30 can be sufficiently relieved. Furthermore, the thickness of the intermediate layer 12 in the direction Z is about 50 μm or less (more preferably about 30 μm or less) such that the formation of an excessive amount of the intermediate layer 12 can be suppressed, and hence an increase in the size of the hermetic sealing lid member 1 in a thickness direction (direction Z) can be suppressed.
According to the first embodiment, the silver brazing layer 13 contains Ag and Cu such that the melting point of the silver brazing layer 13 can be reduced, and hence in a state where the temperature rising of the hermetic sealing lid member 1 and the temperature rising of the electronic component housing member 30 are suppressed at the time of braze bonding between the hermetic sealing lid member 1 and the electronic component housing member 30, the hermetic sealing lid member 1 and the electronic component housing member 30 can be braze-bonded to each other by the melted silver brazing layer 13. Thus, the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member 1 and the electronic component housing member 30 can be sufficiently reduced.
According to the first embodiment, the silver brazing layer 13 contains Sn in addition to Ag and Cu such that the melting point of the silver brazing layer 13 can be further reduced, and hence the thermal stress caused by the difference in thermal expansion between the hermetic sealing lid member 1 and the electronic component housing member 30 can be further reduced.
According to the first embodiment, the surface layer 14 bonded to the upper surface 11 b of the base material layer 11 on the side (Z1 side) opposite to the electronic component housing member 30 and made of Ni or the Ni alloy is provided in the clad material 10. Thus, the corrosion of the base material layer 11 on the upper surface 11 b can be more reliably suppressed by the surface layer 14 made of Ni or the Ni alloy. Furthermore, when the hermetic sealing lid member 1 and the electronic component housing member 30 are braze-bonded to each other by seam welding, the contact resistance between the hermetic sealing lid member 1 and the roller electrode can be reduced by the surface layer 14 made of Ni or the Ni alloy, and hence occurrence of spark or the like between the hermetic sealing lid member 1 and the roller electrode can be suppressed.
Modification of First Embodiment
A hermetic sealing lid member 101 according to a modification of the first embodiment of the present invention is now described with reference to FIG. 4. The same structures as those of the first embodiment are denoted by the same reference numerals, to omit the description.
This hermetic sealing lid member 101 according to the modification of the first embodiment is made of a three-layered clad material 110 that includes a base material layer 11 made of an Fe alloy that at least contains 4 mass % or more of Cr, an intermediate layer 12 bonded in direct contact with the lower surface 11 a of the base material layer 11, and a silver brazing layer 13 bonded in direct contact with the lower surface 12 a of the intermediate layer 12. In other words, no surface layer is formed in the hermetic sealing lid member 101 according to the modification of the first embodiment, unlike the hermetic sealing lid member 1 according to the aforementioned first embodiment.
The melting point of a silver brazing material of which the silver brazing layer 13 is made is about 780° C. or less, and hence an excessively high temperature such as about 1000° C. or more is not required to melt the silver brazing layer 13. Thus, even when a value of an electric current that flows into a roller electrode is relatively small at the time of seam welding, the silver brazing layer 13 can be melted. In other words, even when the base material layer 11 of the hermetic sealing lid member 101 and the roller electrode (not shown) are brought into direct contact with each other not through a surface layer made of Ni or a Ni alloy, a value of an electric current that flows through the hermetic sealing lid member 101 is reduced such that it is possible to make it unlikely that spark caused by a large contact resistance occurs. As the silver brazing material, a Ag—Sn—Cu alloy having a lower melting point is used such that occurrence of spark can be further suppressed.
Any of side surfaces 11 c of the base material layer 11, side surfaces 12 b of the intermediate layer 12, and the silver brazing layer 13, all of which are exposed outward in the clad material 110, has a sufficient corrosion resistance such that the corrosion of the hermetic sealing lid member 101 is suppressed.
The remaining structures of the hermetic sealing lid member 101 according to the aforementioned modification of the first embodiment and the structure of an electronic component housing package using the hermetic sealing lid member 101 are substantially similar to those of the aforementioned first embodiment.
According to the modification of the first embodiment, the following effects can be obtained.
According to the modification of the first embodiment, as hereinabove described, the base material layer 11 is made of the Fe alloy that at least contains 4 mass % or more of Cr such that the corrosion of the base material layer 11 can be suppressed similarly to the aforementioned first embodiment.
According to the modification of the first embodiment, no surface layer is formed in the hermetic sealing lid member 101 such that the structure of the clad material 110 can be simplified, and the cost for preparing the clad material 110 can be reduced by providing no surface layer. The effects of the modification of the first embodiment are substantially similar to those of the aforementioned first embodiment.
Second Embodiment
A hermetic sealing lid member 201 according to a second embodiment of the present invention is now described with reference to FIG. 5. The same structures as those of the first embodiment are denoted by the same reference numerals, to omit the description.
This hermetic sealing lid member 201 according to the second embodiment is made of a two-layered clad material 210 that includes a base material layer 11 made of an Fe alloy that at least contains 4 mass % or more of Cr and a silver brazing layer 13 bonded in direct contact with the lower surface 11 a of the base material layer 11 on a side closer to an electronic component housing member 30. In other words, neither an intermediate layer nor a surface layer is formed in the hermetic sealing lid member 201 according to the second embodiment, unlike the hermetic sealing lid member 1 according to the aforementioned first embodiment. In the hermetic sealing lid member 201 according to the second embodiment, no intermediate layer for relieving a thermal stress is provided, and hence the base material layer 11 having a small thermal expansion coefficient is preferably used such that a difference in thermal expansion between the hermetic sealing lid member 201 (base material layer 11) and the electronic component housing member (see FIG. 3) is reduced.
Any of side surfaces 11 c of the base material layer 11 and the silver brazing layer 13, all of which are exposed outward in the clad material 210, has a sufficient corrosion resistance such that the corrosion of the hermetic sealing lid member 201 is suppressed.
The remaining structures of the hermetic sealing lid member 201 according to the aforementioned second embodiment and the structure of an electronic component housing package using the hermetic sealing lid member 201 are substantially similar to those of the aforementioned first embodiment.
According to the second embodiment, the following effects can be obtained.
According to the second embodiment, as hereinabove described, the base material layer 11 is made of the Fe alloy that at least contains 4 mass % or more of Cr such that the corrosion of the base material layer 11 can be suppressed similarly to the aforementioned first embodiment. Furthermore, the hermetic sealing lid member 201 can be directly braze-bonded to the electronic component housing member not through a seal ring by the silver brazing layer 13 directly bonded onto the lower surface 11 a of the base material layer 11 on the side closer to the electronic component housing member.
According to the second embodiment, neither an intermediate layer nor a surface layer is formed in the hermetic sealing lid member 201 such that the structure of the clad material 210 can be further simplified. The remaining effects of the second embodiment are substantially similar to those of the aforementioned first embodiment.
EXAMPLES
A study of a base material layer used for a hermetic sealing lid member, conducted in order to confirm the effects of the aforementioned embodiments is now described with reference to FIGS. 2 and 4 to 7.
Compositions of Examples and Comparative Example
As test materials (metal plates) of which a base material layer 11 (see FIGS. 2, 4, and 5) of a hermetic sealing lid member 1 (101, 201) is made, each of which has a corrosion resistance, six types of Ni—Cr—Fe alloy, one type of Ni—Co—Cr—Fe alloy, and one type of Cr—Fe alloy were used.
As the Ni—Cr—Fe alloys, five types of Ni—Cr—Fe alloy that contain Ni, 6 mass % of Cr, inevitable impurities, and the balance Fe, in which the content percentages of Ni are different from each other, were used. Specifically, a 36Ni-6Cr—Fe alloy that contains 36 mass % of Ni, a 38Ni-6Cr—Fe alloy that contains 38 mass % of Ni, a 40Ni-6Cr—Fe alloy that contains 40 mass % of Ni, a 42Ni-6Cr—Fe alloy that contains 42 mass % of Ni, and a 47Ni-6Cr—Fe alloy that contains 47 mass % of Ni were used. Furthermore, as the Ni—Cr—Fe alloy, a 42Ni-4Cr—Fe alloy that contains 42 mass % of Ni, 4 mass % of Cr, inevitable impurities, and the balance Fe was further used.
As the Ni—Co—Cr—Fe alloy, a 29Ni-17Co-6Cr—Fe alloy that contains 29 mass % of Ni, 17 mass % of Co, 6 mass % of Cr, inevitable impurities, and the balance Fe was used. As the Cr—Fe alloy, an 18Cr—Fe alloy (so-called SUS430) that contains 18 mass % of Cr, inevitable impurities, and the balance Fe was used.
On the other hand, as a test material (metal plate) according to Comparative Example, a Ni—Co—Fe alloy that contains no Cr was used. Specifically, a 29Ni-17Co—Fe alloy (co-called kovar) that contains 29 mass % of Ni, 17 mass % of Co, inevitable impurities, and the balance Fe was used.
(Study of Base Material Layer Based on Corrosion Resistance)
First, as a corrosion resistance test, a salt spray test was conducted on each of the test materials for at least 48 hours at a temperature of 35±2° C., a salt concentration of 5±1 mass %, and a pH of 6.5 or more and 7.2 or less according to JIS C60068-2-11. Then, the degree of corrosion of each of the test materials was observed. The corrosion resistance was evaluated after a lapse of 24 hours and after a lapse of 48 hours. Furthermore, the corrosion resistance of the test material of the 42Ni-4Cr—Fe alloy after a lapse of 72 hours was also evaluated. Furthermore, the corrosion resistance of the test material of the 42Ni-6Cr—Fe alloy after a lapse of 72 hours and after a lapse of 144 hours was also evaluated.
As evaluations of the corrosion resistance, X marks (cross marks) were put on test materials on which significant corrosion was confirmed. On the other hand, Δ marks (triangle mark) were put on test materials on which slight corrosion was confirmed but did not cause a practical problem, and ◯ marks (circle marks) were put on test materials on which no corrosion was confirm able. Referring to the results, ⋆ marks (star marks) were put on materials for the base material layer that were evaluated to be particularly suitable in practice, ⊚ marks (double circle marks) were put on materials for the base material layer that were evaluated to be preferable in practice, ◯ marks (circle marks) were put on materials for the base material layer that were evaluated to be usable in practice, and X marks (cross marks) were put on materials for the base material layer that were evaluated to be unsuitable in practice.
The results of the salt spray test were that on any of the Fe alloys that contain 4 mass % or more of Cr, corrosion was hardly confirmed after a lapse of 24 hours regardless of whether or not Ni is contained, as shown in FIG. 6. On the other hand, on the Fe alloy (29Ni-17Co—Fe alloy) according to Comparative Example that contains no Cr, significant corrosion was confirmed after a lapse of 24 hours. From these, the Fe alloys that contain 4 mass % or more of Cr could be confirmed to have a sufficient corrosion resistance. Consequently, it has been confirm able that the corrosion of a hermetic sealing lid member made of a clad material can be suppressed by preparing the clad material with the base material layer made of the Fe alloy that contains 4 mass % or more of Cr and an intermediate layer, a surface layer, and a silver brazing layer, each of which has a sufficient corrosion resistance.
On the 36Ni-6Cr—Fe alloy and the 38Ni-6Cr—Fe alloy, slight corrosion was confirmed after a lapse of 48 hours. Thus, it has been proved that of the content percentages of Fe and Ni of the Fe alloy of which the base material layer is made, the content percentage of Ni is increased such that the corrosion of the Fe alloy can be more reliably suppressed, and the corrosion resistance is improved.
On the 42Ni-4Cr—Fe alloy, slight corrosion was confirmed after a lapse of 72 hours. On the other hand, on the 42Ni-6Cr—Fe alloy, corrosion was hardly confirmed even after a lapse of 144 hours. Thus, it has been proved that the content of Cr of the Fe alloy of which the base material layer is made is set to 6 mass % or more such that the corrosion can be still more reliably suppressed, and the corrosion resistance is improved.
Therefore, an Fe alloy in which the content of Cr is 6 mass % or more and the content of Ni is 40 mass % or more is conceivably particularly suitable as the Fe alloy of which the base material layer is made in terms of corrosion resistance. Although no salt spray test for at least 48 hours is conducted on the 40Ni-6Cr—Fe alloy and the 47Ni-6Cr—Fe alloy, the 40Ni-6Cr—Fe alloy and the 47Ni-6Cr—Fe alloy each conceivably have a corrosion resistance capable of sufficiently suppressing corrosion for a long time exceeding 48 hours.
On the 18Cr—Fe alloy that contains no Ni, corrosion was hardly confirmed even after a lapse of 48 hours. Thus, it has been proved that even when the Cr—Fe alloy that contains no Ni is used for the base material layer, the content of Cr of the Fe alloy of which the base material layer is made is increased such that the corrosion can be more reliably suppressed, and the corrosion resistance is improved. Also on a Cr—Fe alloy (SUS430J1L) that contains about 16 mass % or more and about 20 mass % or less of Cr and small amounts of Cu, Nb, etc., the result of the corrosion resistance similar to that of the 18Cr—Fe alloy (SUS430) is conceivably obtained.
(Study of Base Material Layer Based on Thermal Expansibility)
Next, metal suitable for the base material layer according to the present invention was studied based on the average thermal expansion coefficients of the above test materials. An Fe alloy having a thermal expansion coefficient close to the thermal expansion coefficient of alumina (Al₂O₃) of which an object to be braze-bonded (electronic component housing member 30 in FIG. 3) is made is conceivably more suitable for the base material layer.
Specifically, an average thermal expansion coefficient in a temperature range of 30° C. to 300° C., an average thermal expansion coefficient in a temperature range of 30° C. to 400° C., and an average thermal expansion coefficient in a temperature range of 30° C. to 500° C. were determined for each of the test materials. For the alumina of a reference example, only an average thermal expansion coefficient in a temperature range of 30° C. to 400° C. was determined.
It has been confirm able from a table shown in FIG. 7 that the thermal expansion coefficient of the Fe alloy that contains 4 mass % or more of Cr is 14×10⁻⁶/K or less and can be sufficiently reduced in all the temperature ranges of 30° C. to 300° C., 30° C. to 400° C., and 30° C. to 500° C.
Furthermore, it has been proved that the thermal expansion coefficient of the Ni—Co—Cr—Fe alloy (29Ni-17Co-6Cr—Fe alloy) that contains Co is larger than the thermal expansion coefficient of the 29Ni-17Co—Fe alloy that contains no Cr, but is 8.5×10⁶/K or less in all the temperature ranges and is smaller than the thermal expansion coefficients of the Ni—Cr—Fe alloys and the Cr—Fe alloy. In addition, the thermal expansion coefficient of the Ni—Co—Cr—Fe alloy became a thermal expansion coefficient closest to the thermal expansion coefficient of the alumina. From these, it has been proved that the Ni—Co—Cr—Fe alloy is most preferable as low thermal expansion metal of which the base material layer of the hermetic sealing lid member is made in terms of thermal expansibility. This Ni—Co—Cr—Fe alloy is conceivably particularly suitable for the base material layer 11 of the clad material 210 according to the aforementioned second embodiment in which no intermediate layer for relieving a thermal stress is provided.
The thermal expansion coefficients of the Ni—Cr—Fe alloys were relatively increased in the temperature range of 30° C. to 500° C., but were reduced to 11×10⁶/K or less in the temperature range of 30° C. to 300° C. Consequently, it has been proved that the Ni—Cr—Fe alloys are also preferable for the base material layer of the hermetic sealing lid member mainly arranged in a low temperature environment of about 300° C. or less. It has been proved that when the content percentages of Ni contained in the Ni—Cr—Fe alloys are 40 mass % or more and 47 mass % or less, the thermal expansion coefficients can be further reduced in all the temperature ranges such that the Ni—Cr—Fe alloys that contain 40 mass % or more and 47 mass % or less of Ni are more preferable, and when the content percentages of Ni are in the vicinity of 42 mass %, the thermal expansion coefficients can be still further reduced in all the temperature ranges such that the Ni—Cr—Fe alloys that contain about 42 mass % of Ni are still more preferable. Furthermore, it has been proved that when the content percentages of Cr contained in the Ni—Cr—Fe alloys are less than 6 mass %, the thermal expansion coefficients can be further reduced such that the Ni—Cr—Fe alloys that contain less than 6 mass % of Cr are more preferable.
The thermal expansion coefficient of the Cr—Fe alloy (18Cr—Fe alloy) was increased to some extent in all the temperature ranges, but variations in thermal expansion coefficient caused by temperature changes were small. Particularly in the temperature range of 30° C. to 500° C., the thermal expansion coefficient of the Cr—Fe alloy was 11.3×10⁻⁶/K, and became smaller than the thermal expansion coefficients of the (36 to 40 and 47)Ni-6Cr—Fe alloys. From this, it has been proved that the Cr—Fe alloy is also preferable for the base material layer of the hermetic sealing lid member arranged particularly in a high temperature environment of about 400° C. or more. The thermal expansion coefficient of SUS430J1L is similar to that of the 18Cr—Fe alloy (SUS430), and hence SUS430J1L is also conceivably preferable for the base material layer of the hermetic sealing lid member arranged particularly in the high temperature environment of about 400° C. or more.
Modifications
The embodiments and Examples disclosed this time must be considered as illustrative in all points and not restrictive. The range of the present invention is shown not by the above description of the embodiments and Examples but by the scope of claims for patent, and all modifications within the meaning and range equivalent to the scope of claims for patent are further included.
For example, while the examples in which the hermetic sealing lid members 1, 101, and 201 are made of the four-layered clad material 10, the three-layered clad material 110, and the two-layered clad material 210, respectively have been shown in the aforementioned first embodiment, the aforementioned modification of the first embodiment, and the aforementioned second embodiment, the present invention is not restricted to this. According to the present invention, the hermetic sealing lid member may be made of a five- or more-layered clad material by providing two or more intermediate layers, for example.
While the example in which the hermetic sealing lid member 1 and the electronic component housing member 30 are bonded to each other by seam welding, which is a type of resistance welding, has been shown in the aforementioned first embodiment, the present invention is not restricted to this. The hermetic sealing lid member and the electronic component housing member may be bonded to each other by resistance spot welding, which is a type of resistance welding, for example. Alternatively, the hermetic sealing lid member and the electronic component housing member may be bonded to each other by a bonding method other than resistance welding. The hermetic sealing lid member and the electronic component housing member may be bonded to each other by electron beam welding using an electron beam, for example.
DESCRIPTION OF REFERENCE NUMERALS
- 1, 101, 201: hermetic sealing lid member - 10, 110, 210: clad material - 11: base material layer - 11 a: lower surface (surface) - 12: intermediate layer - 13: silver brazing layer - 14: surface layer - 20: electronic component - 30: electronic component housing member - 100: electronic component housing package
1. A hermetic sealing lid member (1) used for an electronic component housing package (100) including an electronic component housing member (30) for housing an electronic component (20), the hermetic sealing lid member made of a clad material (10) comprising: a base material layer (11) made of an Fe alloy that contains 4 mass % or more of Cr; and a silver brazing layer (13) bonded onto a surface of the base material layer on a side closer to the electronic component housing member through an intermediate layer (12) or bonded in direct contact with the surface of the base material layer on the side closer to the electronic component housing member.
2. The hermetic sealing lid member according to claim 1, wherein the base material layer is made of the Fe alloy that contains 4 mass % or more and 20 mass % or less of Cr.
3. The hermetic sealing lid member according to claim 2, wherein the base material layer is made of the Fe alloy that contains 6 mass % or more and 10 mass % or less of Cr.
4. The hermetic sealing lid member according to claim 1, wherein the base material layer is made of the Fe alloy that further contains Ni in addition to 4 mass % or more of Cr.
5. The hermetic sealing lid member according to claim 4, wherein the base material layer is made of the Fe alloy that further contains 36 mass % or more and 48 mass % or less of Ni in addition to 4 mass % or more of Cr.
6. The hermetic sealing lid member according to claim 5, wherein the base material layer is made of the Fe alloy that further contains 40 mass % or more and 48 mass % or less of Ni in addition to 4 mass % or more of Cr.
7. The hermetic sealing lid member according to claim 4, wherein the base material layer is made of the Fe alloy that further contains Co in addition to 4 mass % or more of Cr and Ni.
8. The hermetic sealing lid member according to claim 7, wherein the base material layer is made of the Fe alloy that further contains 6 mass % or more and 18 mass % or less of Co in addition to 4 mass % or more of Cr and 36 mass % or more and 48 mass % or less of Ni.
9. The hermetic sealing lid member according to claim 1, wherein the base material layer is made of a Cr—Fe alloy that contains neither Ni nor Co and at least contains 16 mass % or more and 20 mass % or less of Cr.
10. The hermetic sealing lid member according to claim 1, wherein the silver brazing layer is bonded to the base material layer through the intermediate layer made of pure Cu that contains 99.95 mass % or more of Cu.
11. The hermetic sealing lid member according to claim 1, wherein a thickness of the intermediate layer is 5 μm or more and 50 μm or less.
12. The hermetic sealing lid member according to claim 11, wherein the thickness of the intermediate layer is 10 μm or more and 30 μm or less.
13. The hermetic sealing lid member according to claim 1, wherein the silver brazing layer contains Ag and Cu.
14. The hermetic sealing lid member according to claim 13, wherein the silver brazing layer contains Sn in addition to Ag and Cu.
15. The hermetic sealing lid member according to claim 1, wherein the clad material further comprises a surface layer (14) bonded to a surface of the base material layer on a side opposite to the electronic component housing member and made of Ni or a Ni alloy.
16. An electronic component housing package (100) comprising: an electronic component housing member (30) for housing an electronic component (20); and a hermetic sealing lid member (1) made of a clad material (10) comprising a base material layer (11) made of an Fe alloy that contains 4 mass % or more of Cr, and a silver brazing layer (13) bonded onto a surface of the base material layer on a side closer to the electronic component housing member through an intermediate layer (12) or bonded in direct contact with the surface of the base material layer on the side closer to the electronic component housing member, the hermetic sealing lid member bonded to the electronic component housing member through the silver brazing layer.
17. The electronic component housing package according to claim 16, wherein the base material layer is made of the Fe alloy that contains 4 mass % or more and 20 mass % or less of Cr.
18. The electronic component housing package according to claim 16, wherein the base material layer is made of the Fe alloy that further contains Ni in addition to 4 mass % or more of Cr.
19. The electronic component housing package according to claim 18, wherein the base material layer is made of the Fe alloy that further contains Co in addition to 4 mass % or more of Cr and Ni.
20. The electronic component housing package according to claim 16, wherein the clad material further comprises a surface layer (14) bonded to a surface of the base material layer on a side opposite to the electronic component housing member and made of Ni or a Ni alloy.
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hasanat
Etymology
From, plural of.
Noun
* 1) Credit for good deeds, which Allah weighs up against one's bad deeds at the final judgement after death.
* 2) * 2003, Abu Alwafa, A study of the word "love" in the Qur'an Group: alt.religion.islam
* The muhasneen or those who do good deeds (hasanats).
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Custom Tflite Model Usage
We have created a custom tflite model with Tensorflow 2 and are running into issues with utilizing it. We tried to use it with the existing tfod object detector and got an error stating that we're using a newer model than what tfod accepts. Can you confirm what version you are using and what are our options for using Tensorflow 2?
You might want to use a MobileNet model, if you are using a floating-point model, you need to specify isModelQuantized to false in the tfodParameters.
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//! Primitive command log, currently used for undo / redo.
//! This is a deliberately unoptimized representation, for simplicity. It is by no means final.
use std::mem;
/// Represents a modification of data.
pub enum Change {
///Character insertion.
Insert(usize, u8),
///Character removal.
Remove(usize, u8),
}
impl Change {
/// Reverses a change, consuming it in the process
pub fn reverse(self) -> Change {
match self {
Change::Insert(usize, u8) => Change::Remove(usize, u8),
Change::Remove(usize, u8) => Change::Insert(usize, u8),
}
}
}
/// Log entry
/// Entries may only be played linearly--they don't make sense out of order.
pub struct LogEntry {
/// The initial point position associated with this log entry.
///
/// The OLD point position.
init_point: usize,
/// The NEW point position.
pub end_point: usize,
/// The changes associated with this log entry, in order of occurence (an undo will replay
/// their inverses, backwards).
pub changes: Vec<Change>,
}
impl LogEntry {
/// Reverse a log entry, consuming it in the process.
pub fn reverse(mut self) -> LogEntry {
self.changes.reverse();
LogEntry {
init_point: self.end_point,
end_point: self.init_point,
changes: self.changes.into_iter().map( |change| change.reverse() ).collect(),
}
}
}
/// A set of `Change`s that should be treated atomically.
///
/// This transaction always has an associated entry log. When the transaction is dropped, the
/// entries are committed.
pub struct Transaction<'a> {
/// Currently, only one transaction may be open at a time.
entries: &'a mut Log,
/// The LogEntry under construction by the transaction. Every data modification should be
/// recorded with the open Transaction.
entry: LogEntry,
}
impl<'a> Transaction<'a> {
/// Log a change with this transaction.
///
/// The logging should occur after the change has been executed. This may eventually allow
/// rollback in case of failure.
pub fn log(&mut self, change: Change, idx: usize) {
self.entry.changes.push(change);
self.entry.end_point = idx;
}
}
impl<'a> Drop for Transaction<'a> {
fn drop(&mut self) {
// Check to see if there were any changes, and if not return early.
if self.entry.changes.is_empty() { return }
// Create the new log entry
let entry = LogEntry {
changes: mem::replace(&mut self.entry.changes, Vec::new()),
.. self.entry
};
// Commit the transaction.
self.entries.undo.push(entry);
// Clear the redo entries now that the transaction has been committed.
self.entries.redo.clear();
}
}
/// Log entries structure. Just two stacks.
pub struct Log {
/// Undo log entries--LIFO stack.
undo: Vec<LogEntry>,
/// Redo log entries--LIFO stack. Cleared after a new change (other than an undo or redo)
/// is committed.
redo: Vec<LogEntry>,
}
impl Log {
/// Set up log entries. They are initially empty.
pub fn new() -> Log {
Log {
undo: Vec::new(),
redo: Vec::new(),
}
}
/// Start a new transaction.
///
/// This returns a RAII guard that can be used to record edits during the transaction.
#[cfg_attr(feature="clippy", allow(needless_lifetimes))]
pub fn start(&mut self, idx: usize) -> Transaction {
Transaction {
entries: self,
entry: LogEntry {
init_point: idx,
end_point: idx,
changes: Vec::new(),
}
}
}
/// This reverses the most recent change on the undo stack, places the new change on the redo
/// stack, and then returns a reference to it. It is the caller's responsibility to actually
/// perform the change.
pub fn undo(&mut self) -> Option<&LogEntry> {
match self.undo.pop() {
Some(change) => {
let last = self.redo.len();
self.redo.push(change.reverse());
Some(&self.redo[last])
},
None => None
}
}
/// This reverses the most recent change on the redo stack, places the new change on the undo
/// stack, and then returns a reference to it. It is the caller's responsibility to actually
/// perform the change.
pub fn redo(&mut self) -> Option<&LogEntry> {
match self.redo.pop() {
Some(change) => {
let last = self.undo.len();
self.undo.push(change.reverse());
Some(&self.undo[last])
},
None => None
}
}
}
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AMARYLLIS
Giant Hippeastrum. Large flowering hybrids. Our strain has taken many Blue Ribbons all over the country. Giant flowers sometimes 10 inches across. Offered ina Mixture of colors only in which you will find rich reds, orange, salmon, white, etc. Large, sure to bloom bulbs, each 50c; postage 10c.
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Optionally specify a data directory for command-line
optionally specify a data directory, change a couple data dir things to prevent crashes on readonly filesystems
#1818
@rmillikin Thanks a lot for fixing this issue. We have a group of users on our HPC cluster waiting to use this software. If the PR will take a while, can we use your forked repo?
@rsdmse I think this should get merged quite soon, but if you want, you can pull the current smithchemwisc/metamorpheus:dev tag from dockerhub which includes this change. usually the dev tag is the current master branch, but I made an exception in this case and pushed this PR to the dev tag for testing in Singularity.
something like this (assuming you're using Singularity to pull from dockerhub):
but in case that doesn't suit your purposes, yes you can definitely build this PR and use it as you wish.
@rsdmse it's not from my forked repo though, it's from a branch in this repo. https://github.com/smith-chem-wisc/MetaMorpheus/tree/optionalDataDir
Thanks so much for your prompt reply!
I was unable to specify and output folder with quotations (either "" or '') which is need for file paths with spaces.
e.g. "C:\User\Bob The Builder\Metamorpheus"
@trishorts this might be a singularity issue but I can poke around for a solution.
https://github.com/hpcng/singularity/issues/5437
https://stackoverflow.com/questions/62963043/escaping-filename-spaces-with-singularity-files-directive
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import { Employee } from '../../test/models'
import { NullType } from './type/null.type'
import { UndefinedType } from './type/undefined.type'
import {
detectCollectionTypeFromValue,
detectType,
isCollection,
isHomogeneous,
isNode,
isSet,
typeName,
typeOf,
typeOfFromDb,
} from './util'
describe('Util', () => {
describe('is set', () => {
it('Set instance', () => {
const set: Set<string> = new Set(['foo', 'bar'])
expect(isSet(set)).toBeTruthy()
})
it('array (using literal)', () => {
const arr: string[] = ['foo', 'bar']
expect(isSet(arr)).toBeFalsy()
})
it('array (using constructor)', () => {
const arr: string[] = new Array()
arr.push('foo', 'bar')
expect(isSet(arr)).toBeFalsy()
})
})
describe('is collection', () => {
it('set is collection', () => {
const set: Set<string> = new Set(['foo', 'bar'])
expect(isCollection(set)).toBeTruthy()
})
it('array (using literal) is collection', () => {
const arr: string[] = ['foo', 'bar']
expect(isCollection(arr)).toBeTruthy()
})
it('array (using constructor) is collection', () => {
const arr: string[] = new Array()
arr.push('foo', 'bar')
expect(isCollection(arr)).toBeTruthy()
})
it('all falsey', () => {
expect(isCollection('doAddCondition')).toBeFalsy()
expect(isCollection(5)).toBeFalsy()
expect(isCollection(null)).toBeFalsy()
expect(isCollection(true)).toBeFalsy()
expect(isCollection({ foo: 'foo', bar: 5 })).toBeFalsy()
})
})
describe('detect collection type without property metadata', () => {
it('set (empty)', () => {
const collection: Set<string> = new Set()
expect(detectCollectionTypeFromValue(collection)).toBe('SS')
})
it('set with string values', () => {
const collection: Set<string> = new Set(['foo', 'bar'])
expect(detectCollectionTypeFromValue(collection)).toBe('SS')
})
it('set with number values', () => {
const collection: Set<number> = new Set([25, 65])
expect(detectCollectionTypeFromValue(collection)).toBe('NS')
})
it('set with no values', () => {
const collection: Set<any> = new Set()
expect(detectCollectionTypeFromValue(collection)).toBe('SS')
})
it('set with object values should throw', () => {
const collection: Set<any> = new Set([{ foo: 'foo' }, { bar: 'bar' }])
expect(() => detectCollectionTypeFromValue(collection)).toThrow()
})
it('set with values of different type should throw', () => {
const collection: Set<any> = new Set(['foo', 5])
expect(() => detectCollectionTypeFromValue(collection)).toThrow()
})
})
describe('detect type', () => {
it('detects string', () => {
expect(detectType('aString')).toBe('S')
expect(detectType(String('aString'))).toBe('S')
// tslint:disable-next-line:no-construct
expect(detectType(new String('aString'))).toBe('S')
})
it('detects number', () => {
expect(detectType(3)).toBe('N')
expect(detectType(Number(-5))).toBe('N')
// tslint:disable-next-line:no-construct
expect(detectType(new Number(83))).toBe('N')
})
it('detects binary', () => {
let buffer: any
if (isNode()) {
buffer = Buffer.alloc(5)
} else {
buffer = new ArrayBuffer(8)
}
expect(detectType(buffer)).toBe('B')
})
it('detects null', () => {
expect(detectType(null)).toBe('NULL')
})
it('detects bool', () => {
expect(detectType(true)).toBe('BOOL')
expect(detectType(false)).toBe('BOOL')
// tslint:disable-next-line:no-construct
expect(detectType(new Boolean(1))).toBe('BOOL')
})
it('detects collection', () => {
expect(detectType(new Set(['a']))).toBe('SS')
expect(detectType(new Set([2]))).toBe('NS')
expect(detectType([0, 1, 1, 2, 3, 5])).toBe('L')
})
it('detects object', () => {
expect(detectType({})).toBe('M')
expect(detectType({ foo: 'bar' })).toBe('M')
})
it('throws if not such a type', () => {
expect(() => detectType(undefined)).toThrow()
})
})
describe('type name', () => {
it('String', () => {
expect(typeName(String)).toBe('String')
})
it('Number', () => {
expect(typeName(Number)).toBe('Number')
})
it('NaN', () => {
expect(typeName(NaN)).toBe('NaN')
})
it('Boolean', () => {
expect(typeName(Boolean)).toBe('Boolean')
})
it('Set', () => {
expect(typeName(Set)).toBe('Set')
})
it('Map', () => {
expect(typeName(Map)).toBe('Map')
})
it('Object', () => {
expect(typeName({})).toBe('[object Object]')
})
it('Null', () => {
expect(typeName(NullType)).toBe('NullType')
})
it('Null', () => {
expect(typeName(null)).toBe('Null')
})
it('UndefinedType', () => {
expect(typeName(UndefinedType)).toBe('UndefinedType')
})
it('Undefined', () => {
expect(typeName(undefined)).toBe('Undefined')
})
})
describe('typeof', () => {
it('string', () => {
expect(typeOf('foo')).toBe(String)
})
it('number', () => {
expect(typeOf(253)).toBe(Number)
})
it('number', () => {
expect(typeOf(-521)).toBe(Number)
})
it('number (NaN)', () => {
expect(typeOf(NaN)).toBe(Number)
})
it('boolean', () => {
expect(typeOf(true)).toBe(Boolean)
})
it('array', () => {
expect(typeOf(['foo', 'bar'])).toBe(Array)
})
it('set', () => {
expect(typeOf(new Set(['foo', 'bar']))).toBe(Set)
})
it('map', () => {
expect(typeOf(new Map())).toBe(Map)
})
it('object', () => {
expect(typeOf({ foo: 'foo', bar: 45 })).toBe(Object)
})
it('null', () => {
expect(typeOf(null)).toBe(NullType)
})
it('undefined', () => {
// tslint:disable-next-line:prefer-const
let undfn: undefined
expect(typeOf(undfn)).toBe(UndefinedType)
})
// object with type casting to custom
it('object', () => {
expect(typeOf(<Employee>{ name: 'foo', age: 45 })).toBe(Object)
})
it('custom class (Employee)', () => {
expect(typeOf(new Employee('foo', 45, null, null))).toBe(Object)
})
})
describe('typeOfFromDb', () => {
it('string', () => {
expect(typeOfFromDb({ S: 'myStrig' })).toBe(String)
})
it('number', () => {
expect(typeOfFromDb({ N: '253' })).toBe(Number)
})
it('boolean', () => {
expect(typeOfFromDb({ BOOL: true })).toBe(Boolean)
})
it('array', () => {
expect(typeOfFromDb({ L: [{ S: 'foo' }, { S: 'bar' }] })).toBe(Array)
})
it('set', () => {
expect(typeOfFromDb({ SS: ['foo', 'bar'] })).toBe(Set)
})
it('object', () => {
expect(typeOfFromDb({ M: { foo: { S: 'foo' }, bar: { N: '45' } } })).toBe(Object)
})
it('null', () => {
expect(typeOfFromDb({ NULL: true })).toBe(NullType)
})
it('undefined', () => {
expect(() => {
typeOfFromDb(undefined)
}).toThrowError()
})
})
describe('isHomogeneous', () => {
describe('array', () => {
it('array (homo -> number)', () => {
const { homogeneous, type } = isHomogeneous([1, 2, 3])
expect(homogeneous).toBeTruthy()
expect(type).toBe('N')
})
it('array (homo -> string)', () => {
const { homogeneous, type } = isHomogeneous(['one', 'two', 'three'])
expect(homogeneous).toBeTruthy()
expect(type).toBe('S')
})
it('array (homo -> boolean)', () => {
const { homogeneous, type } = isHomogeneous([true, false, false])
expect(homogeneous).toBeTruthy()
expect(type).toBe('BOOL')
})
it('array (homo -> boolean)', () => {
const { homogeneous, type } = isHomogeneous(['one', 2, false])
expect(homogeneous).toBeFalsy()
expect(type).toBeUndefined()
})
})
describe('set', () => {
it('set (homo -> number)', () => {
const { homogeneous, type } = isHomogeneous(new Set([1, 2, 3]))
expect(homogeneous).toBeTruthy()
expect(type).toBe('N')
})
it('set (homo -> string)', () => {
const { homogeneous, type } = isHomogeneous(new Set(['one', 'two', 'three']))
expect(homogeneous).toBeTruthy()
expect(type).toBe('S')
})
it('set (homo -> boolean)', () => {
const { homogeneous, type } = isHomogeneous(new Set([true, false, false]))
expect(homogeneous).toBeTruthy()
expect(type).toBe('BOOL')
})
it('set (hetero)', () => {
const { homogeneous, type } = isHomogeneous(new Set(['one', 2, false]))
expect(homogeneous).toBeFalsy()
expect(type).toBeUndefined()
})
})
})
})
|
eLife appoints two new Deputy Editors in Medicine
Diane Harper and Mone Zaidi will join the leadership team overseeing eLife’s efforts to drive change in scientific and medical publishing.
Press Pack
• Views 1,190
• Annotations
eLife has appointed two new Deputy Editors to lead the journal’s expansion into medical research and explore fresh approaches to peer review and publishing.
Mone Zaidi is Professor of Medicine (Endocrinology, Diabetes and Bone Disease), of Pharmacological Sciences, and of Geriatrics and Palliative Medicine, and Founding Director of the Mount Sinai Bone Program at the Icahn School of Medicine at Mount Sinai, New York, US. Speaking about his appointment as eLife Deputy Editor, he says: “It is gratifying to be able to contribute to medical publishing and to open access to biomedical research. I look forward to helping make eLife’s medicine section a highly respected and popular platform for publishing interdisciplinary lines of investigation focused on improving human health.”
Diane Harper is a Professor in the Departments of Family Medicine and Obstetrics & Gynecology, Biomedical Engineering, and Women's and Gender Studies at the University of Michigan, US. Speaking about her new role, she says: “I will strive to encourage others’ ideas in all clinical areas and new science that will lead to better health for everyone.”
Harper and Zaidi will lead expert review of significant translational research and clinical studies that deal with the etiology, pathophysiology, diagnosis, genetics, prevention and treatments to improve human health. Formerly Reviewing Editors for eLife, they now work alongside Deputy Editors Detlef Weigel (Max Planck Institute for Developmental Biology, Germany), Anna Akhmanova (Utrecht University, the Netherlands), and Tim Behrens (Oxford University and University College London, UK), and in collaboration with Editor-in-Chief Michael Eisen (University of California at Berkeley, US) and the broader editorial team.
eLife is a non-profit backed by the Howard Hughes Medical Institute (US), Max Planck Society (Germany), Wellcome (UK), and the Knut and Alice Wallenberg Foundation (Sweden) to transform research communication. eLife is actively promoting a new vision for publishing in which journals review papers already published by authors as preprints, providing expert feedback to authors and an indication of the reliability and potential significance of the findings to readers.
eLife Editor-in-Chief Michael Eisen says: “We’re thrilled to have Diane and Mone on the leadership team, bringing their significant and complementary medical expertise to new research. They are both stellar physician-scientists, equally committed to eLife’s mission to transform scholarly communication, and to fostering a collaborative, diverse and open research culture. We all look forward to working with them to improve the process of medical publishing for everyone – for authors, researchers, clinicians and the broader community.”
Harper's research has evolved around human papillomavirus (HPV)-associated cancer prevention, early detection and treatment. Her work has been funded by federal and state organisations such as the National Institutes of Health (NIH), private foundations and industry. She has worked with the World Health Organization and Pan American Health Organization to implement the new knowledge gained from research into health policy for the US and globally. Her work has brought about advanced and evolved changes in the vaccination, treatment and testing for HPV that increases the accuracy of screening and maximises the woman's quality of life.
Harper adds that she is passionate about supporting women in STEAM – science, technology, engineering, arts and maths. “As Deputy Editor of eLife, I will have the opportunity to work with a team of accomplished professionals from all over the world who can change the research culture to bring in diverse perspectives in medicine and its continuing evolution of evidence,” she says.
Zaidi’s research over the past three decades has crossed disciplines and focused on common and rare diseases of the skeleton. This work has been funded by the NIH, U.S. Department of Veterans Affairs, Medical Research Council (UK) and other private and commercial agencies. He is widely recognised for his discovery of biological circuits of medical significance through which bone communicates with the pituitary gland, fat tissue and the brain. He has created a new antibody to a pituitary hormone for the future therapy of osteoporosis and obesity. Zaidi is also a passionate advocate for ensuring integrity and transparency in biomedical research.
Additionally, he says he is “deeply committed” to supporting physician-scientists across the world who are in the early stages of their career. He has initiated national efforts to sustain and promote the workforce, especially through his leadership of the Research Committee of the Alliance of Academic Internal Medicine.
For more information, and to access the latest research published in eLife’s medicine section, visit https://elifesciences.org/subjects/medicine.
Media contacts
1. Emily Packer
eLife
<EMAIL_ADDRESS> +441223855373
About
eLife is a non-profit organisation created by funders and led by researchers. Our mission is to accelerate discovery by operating a platform for research communication that encourages and recognises the most responsible behaviours. We work across three major areas: publishing, technology and research culture. We aim to publish work of the highest standards and importance in all areas of biology and medicine, while exploring creative new ways to improve how research is assessed and published. We also invest in open-source technology innovation to modernise the infrastructure for science publishing and improve online tools for sharing, using and interacting with new results. eLife receives financial support and strategic guidance from the Howard Hughes Medical Institute, the Knut and Alice Wallenberg Foundation, the Max Planck Society and Wellcome. Learn more at https://elifesciences.org/about.
|
Wild wood Minstrels 47
they are very careful never to permit the human observer to come too close. ^They are duly warned of danger by their ever-vigilant parents. Sometimes a youngster will sit on the same perch for a long time, preening his feathers and uttering a little call at intervals, just to keep in practice, as it were; while at other times he will ^ pursue his parents about in the woods, loudly demanding his dinner. One season I succeeded in finding at least five pairs of these warblers, in company with their clamorous broods. The nest is set on the ground in the bushes and grass of second -growth timber tracts. Lined with ten drils and fine strips of bark, it is "firmly wrapped with numerous leaves, whose stems point upward." Another haunter of the dusky depths of the woods is the ovenbird. His song is one of the most peculiar in warbler dom. Beginning in moderate tones, it grows louder and louder as it nears the end, and really seems like a voice moving toward you. This bird also walks about in the woods, and does not hop, as most of his relatives do. As he walks about on his leafy carpet, his head erect, he has quite a consequential air. He derives his name from the fact that his nest, set on the ground, is globular in form, with the entrance at one side, giving it the appearance of a small oven.
The gay redstarts, which seem to be so tame and con fiding in the early spring, turn into veritable eremites in the breeding season, seeking the most secluded por tions of the woods as their habitat. Their little nests are harder to find than one would suppose; yet I have
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FIG. 35 does not show the groups of 25 bit words for Y=102 hex through Y=1FE hex, but they are structured in similar manner to groups 343 and 344.
The last group 345 for frame 301 is shown in FIG. 35 and is similar in structure to the groups 343 and 344. All five words in group 345 have 1FF hex in their Y coordinate field.
The last 25 bit word in the group 339 of words defining the rectangle 311 in frame 301, has a 16 hex in its command field 342. No data is contained in the y coordinate field 341 or in the X coordinate field 340. This word is a control word indicating the end of the 25 bit words for the frame.
FIG. 36 shows the 25 bit words 339 output by Filler Module2 23B to Pix el Memory Module2 24B, describing rectangle 312 in frame 302. The structure of these 25 bit words is similar to those shown in FIG. 36. The only difference is that the words shown in FIG. 36 are for rows 120 ranging in Y coordinates from 000 hex to 0FF hex.
Pix el Memory Modules to High Speed Laser Interface Module
FIG. 37 shows the final bit-map 347 of the entire frame 301, including the pix el locations which are not to be illuminated by the laser beam as it raster scans the rows of the frame. The bit-map shown in FIG. 37 resides in the output memory of Pix el Memory Module1 24A, as a sequence of 64 bit words at memory addresses 346. The sequence of 64 bit words is output from the output memory to the High Speed- Laser Interface Module 27. Each 64 bit word is output in parallel on a 64 bit bus to Module 27. The ECL High Speed Laser Interface Module 28 receives the 64 bit words from Module 27, and produces a serial bit stream by using a shift register to do parallel to serial conversion of the 64 bit words. The serial bit stream is input by the Vendor Laser Scan Electronics 348, which is a part of the Electro-optical/Acousto-optical laser optical system 37. The serial bit stream is used by the Vendor Laser Scan Electronics 348, and specifically the electro-optical modulator 101, to modulate a laser beam to illuminate selectively pix els on target 103. The laser beam raster scans every pix el position on target 103, and if the electro-optical modulator 101 receives a bit equal to one when the beam is over a given pix el position, then that pix el will be illuminated by the laser beam. If the bit received by the electro-optical modulator 101 is a zero rather than a one, then the electro-optical modulator will turn the beam off when it is over the given pix el position.
The bit-map 347 has a bit corresponding one-to-one for each pix el on target 103 surface 121. A zero in a bit position of any of the 64 bit words of the bit-map means that the corresponding pix el on the surface 121 will not be illuminated by the laser. A one in a bit position of any of the 64 bit words of the bit-map means that the corresponding pix el on the surface 121 will be illuminated by the laser as it raster scans the pix el's position.
As seen in FIG. 37, Pix el Memory addresses 0000 hex through 0FFF hex all contain 64 bit words having a zero in every bit position. There are 1000 hex words in this portion of memory, and 40,000 hex bits. Each row 120 has 400 hex (1024 decimal) bits, therefore, 40,000/400 gives 100 hex rows represented by Pix el Memory addresses 0000-0FFF hex. Thus, the word at Pix el Memory address 1000 hex corresponds to the leftmost 64 pix els of row Y=100 hex, which is the first row in which pix els will be illuminated to construct rectangle 311 in frame 301. Since the turnpoint 303, FIG. 26, has X coordinate equal to 100 hex, the first 100 hex pix els in that row will not be illuminated by the laser. Thus, the four 64 bit words in Pix el Memory positions 1000 hex through 1003 hex will contain all zeros. The next pix el will correspond to turnpoint 303 at X=100 hex. There are 101 hex pix els from X=100 hex through turnpoint 304 at X=200 hex. Therefore, four 64 bit words plus one bit are required in which each bit position contains a one. The four 64 bit words with each bit equal to one are the words in Pix el Memory addresses 1004-1007 hex. The extra bit equal to one is found in bit 63 of the 64 bit word at Pix el Memory address 1008 hex. Since the strip 105 has X addresses from 000 through 3FF hex, There are 200 hex pix els in the range X=200 hex through 3FF hex. Thus eight 64 bit words are required to describe this portion of the row Y=100 hex. The word at 1008 hex has bit 63=1, as discussed above, with bits 0-62 being zeros. The 64 bit words at addresses 1009-100F hex have zeros in all their bit positions, completing the description of row X=100 hex.
The description of row Y=101 hex begins with the 64 bit word at Pix el Memory location 1010 hex, and continues in the same manner as for row X=100 hex.
The description of rows Y=102-1FF hex will be the same as for row Y=100 hex.
The bit map for frame 302 is not shown, however, it will be structured in a similar manner to frame 301 as shown in FIG. 37. The rectangle begins with row Y=000 hex and ends with row Y=0FF hex. Rows Y=100-1FF hex do not contain any pix els in or on a polygon, therefore, all the 64 bit words describing this area of the frame 302 have zeros in all their bit positions.
PATTERN INSPECTION Pattern Illumination and Detection
As seen in FIGS. 41-43, pattern inspection can be done on any target 103 having a pattern 422 on a background 426, wherein either, but not both, the pattern 422 or the background 426 specularly reflects incident laser light, and the other diffusely reflects incident laser light. Thus, optically, the pattern 422 and the background 426 differ from each other by the manner in which they reflect an incident laser beam. This means that the pattern 422 can be distinguished from the background 426 by detecting the presence or absence of laser light which has been reflected at an angle larger than would be the case with specular or nearly specular reflection. Inspection can be performed most accurately on those targets whose patterns and backgrounds differ the most with respect to specular versus diffuse reflectivity.
In the example illustrated in FIG. 43, the pattern 422 specularly reflects incident laser light and the background 426 diffusely reflects laser light. Incident laser beam 414 is normal to the surface of pattern 422 and reflects back upon itself as shown at 423. Thus, the surface of the pattern 422 is shown producing perfectly specular reflection. Incident laser beam 424 is normal to the surface of background 426 and is scattered at many angles as indicated by reflections 425. Thus, the surface of the background 426 produces diffuse reflection.
An example of a target 103 which would produce the reflections shown in FIG. 43 is a printed wiring or printed circuit board having copper circuit patterns produced by etching away unwanted copper from the face of an epoxy board which had been entirely covered with a thin layer of copper. Printed wiring boards have patterns 422 which are shiny, specularly reflective copper circuit patterns, while the background 426 is epoxy board having a diffusely reflective surface.
Another example of a target such as the one shown in FIG. 43 is an epoxy board having a thin layer of copper on its face, and photoresist patterns 422 on the surface of the copper. The photoresist had covered the copper surface entirely and was then etched away selectively to produce the photoresist pattern 422. The etching process also etches the surface of the background copper 426 sufficiently to cause the surface to reflect light diffusely. The photoresist pattern 422 has a relatively shiny surface which causes incident laser light to be reflected in a substantially specular manner.
FIGS. 41 and 42 show an arrangement of four fiber-optical detector heads 416 surrounding the objective lens 117, to detect scattered or diffusely reflected laser light. Objective lens 117 is shown in the context of the optical system in FIG. 5. The optical system shown in FIG. 5 is used in the pattern inspection system 400 as well as in the pattern writing system 50. FIG. 5 does not show the fiber-optical detector system 413.
The fiber-optical detector system 413 includes the four fiber-optical detector heads 416, the fiber-optical cables 420 which join together as cable 421, and photomultiplier tube 45. Each fiber-optical cable 420 is a circular arrangement of a plurality of individual fiber-optic fibers. Head 416 terminates cable 420 in a thin, wide, rectangular array of the individual fiber-optic fibers. The width 427 of a fiber-optic head 416 is indicated in FIG. 42. The optical aperture 428 of head 416 is the end of the thin, wide, rectangular array of the individual fiber-optic fibers, through which light is admitted to travel down a cable 420 into cable 421 and into the photomultiplier tube 45, where an analog electrical signal is generated whose amplitude indicates the intensity of the light. Fiber-optical cable 413 is a circular arrangement of the individual fiber-optic fibers from each of the cables 420. The light entering photomultiplier tube 45 is the sum of the light entering the optical apertures 428 of the four heads 416. In the example shown in FIG. 43, an electrical signal is generated by the photomultiplier tube 45 when laser beam 424 strikes background 426 and is diffusely reflected and intercepted by the apertures 428 of heads 416. When laser beam 414 strikes pattern 422, the reflected light beam 423 returns along the same path and is not intercepted by apertures 428 of heads 416, and no electrical signal is generated. The electrical signals may be inverted if desired so that the presence of a signal indicates the presence of pattern 422, and the absence of a signal indicates the absence of any pattern.
As seen in FIGS. 41 and 42, the four fiber-optical heads are radially disposed about the optical axis 417 of objective lens 117, and are located at the four vertices of a square centered upon and normal to the optical axis 417. Arrow 429 in FIG. 42 indicates the direction that a row 120 will be raster scanned by the laser beam passing through objective lens 117. A row is very short so that the angle subtended by the row will be close to zero. Thus, although the scanning laser beam will not always be quite normal to the surface of target 103, specular reflection will produce a reflected beam in which the angle of incidence plus the angle of reflection is sufficiently small to prevent the reflected beam from entering the optical aperture 428 of any of the heads 416. Each fiber-optical head 416 is aligned so that its optical aperture 428 points at the region where a laser beam will strike the surface of target 103. This can be accomplished by pointing the apertures at the point where optical axis 417 intersects the surface of target 103, as shown in FIG. 41. It is, however, not required that all the apertures point to a single point, but each may point to a distinct point somewhere along or near the row to be raster scanned.
Instead of being disposed at the vertices of a square, the four fiber-optical heads 416 may be disposed at the vertices of a rectangle.
Diagonally opposed pairs of fiber-optical heads 416 are disposed at the proper height above the surface of target 103 so that the angle 415 subtended by their distance apart is a right angle. This may be seen in FIG. 41, where reflected light beams 418 and 419 are reflected from a pix el 119 at right angles to one another, and enter the optical apertures of the two fiber-optical heads 416 shown. This angle allows the apertures 428 of the heads to be sufficiently far from optical axis 417 so that specularly reflected light will not enter the apertures 428. Also, an angle 415 of ninety degrees is small enough to optimize the interception of diffusely reflected light, if there is any. An angle of ninety degrees works well for light diffusely reflected from epoxy board or etched copper. This angle can be varied if required for optimum interception of diffusely reflected light from other types of surfaces.
The Electronics
FIG. 38 is a block diagram of a pattern inspector system 400, which also is capable of writing, as described previously. The pattern inspector system shares many of the functions of the pattern writer system 50, shown in FIG. 6. The pattern inspection system 400 is another embodiment of the invention and will be described in terms of the additions and differences with the writer.
For the most part, the blocks numbered 1--11 function as described in conjunction with FIG. 6. The host computer 3 functions to generate a command list to inspect when the system 400 is functioning as an inspector, as well as to generate a command list for writing when the system is functioning as a writer, as described in conjunction with FIG. 6. During inspection, the host computer 3 also does sorting of a received error list which identifies the X-Y coordinates of those areas of a detected pattern on the target 103 surface which are part of the detected pattern but should not be present, or those areas of the target 103 which should have patterning but in fact do not. The host computer 3 stores the X-Y coordinates of the sorted list in host memory 4.
The database resident on tape 17 for the inspection system 400 is the same as described for the writer system 50, or for the inspection system 400 when in the writer mode. At this point, the database has only reference polygons in each frame of the database. The reference polygons form the ideal patterns against which the actual patterns on the target 103 will be compared. The reference polygons also are the ideal patterns which are written on photosensitive surface 121 when in the writer mode of operation.
As with the writer system 50, DPC2 15 reads the database from tape 17 through tape drive controller 16, reformats it into turnpoint polygon representation, as before, and stores the turnpoint polygon representation of the database on data disk 13 through disk controller 12. As part of the inspection system 400, DPC2 15 also generates guardband turnpoint polygons for the reference polygons in each frame 106. The guardband polygons form a don't care zone around each reference polygon side. During inspection of an actual part, mismatches between the actual pattern on a target 103 and the ideal pattern described by the database are not flagged as errors if the mismatches occur in a don't care zone, i e., within a guardband polygon. The guardband around each reference polygon side will be narrow enough so that unsatisfactory patterns will not be passed as being good, and wide enough so that insignificant variances between the ideal pattern and the actual pattern, will not cause the pattern on the target to be rejected unnecessarily.
Each side of a polygon is a line segment completely contained within a single frame 106. Preferably, a guardband polygon is a rectangle surrounding the line segment, such that the perpendicular distance from any point on the line segment to the nearest point on the guardband rectangle, is a fixed, small distance epsilon. Typically, epsilon will be a distance equal to a small number of pix els. Thus, the guardband rectangle will have two sides parallel to and equidistant from the line segment. Preferably, the other two sides of the guardband rectangle will each be a distance epsilon, measured from their midpoints, from the nearest endpoint of the line segment.
A guardband polygon will not always be a rectangle, nor will it always be exactly as previously described. When the line segment is near or on one of the frame boundaries, the distance epsilon may be greater than the distance of all or some portions of the line segment from the frame boundary. As is the case with reference polygons, a guardband polygon must lie completely within, or on, a single frame 106. Thus, any portions of the guardband rectangle which otherwise would protrude into an adjacent frame, instead are truncated by the frame boundary, and the truncating portion of the frame boundary forms one of the sides of the guardband polygon. In those cases where the guardband is truncated on a frame boundary, a dummy polygon is inserted on the boundary or in the adjacent frame having a width epsilon to prevent generation of false errors. The dummy polygon has only a guardband associated with it and no plotted geometry. The dummy geometry may be a line on the boundary of the two adjacent frames.
FIG. 47 shows the guardbands surrounding the sides of the rectangle 300, the example pattern illustrated and discussed in connection with FIG. 26. The rectangle 300 requires six guardband polygons, i.e., six guardband rectangles. Since the rectangle 300 straddles the upper frame 301 and the lower frame 302, and since guardband polygons cannot cross frame boundaries, the left and right sides of the rectangle 300 will each have two guardband polygons (rectangles) instead of only one. That is, the left side of rectangle 300 will be surrounded by guardband rectangle 248 in frame 301, and by guardband rectangle 251 in frame 302. Similarly, the right side of rectangle 300 will be surrounded by guardband rectangle 249 in frame 301, and by guardband rectangle 253 in frame 302.
The top side of rectangle 300 is completely contained within frame 301, and so, will have only one surrounding guardband rectangle 250. Likewise, the bottom side of rectangle 300 will have only one surrounding guardband rectangle 252.
In frame 301, guardband rectangle 248 extends from X=0FD hex to X=103 hex, and from Y=0FD hex to Y=1FF hex. Guard band rectangle 249 extends from X=1FD hex to X=203 hex, and from Y=0FD hex to Y=1FF hex. Guard band rectangle 250 extends from X=0FD hex to X=203 hex, and from Y=0FD hex to Y=103 hex.
In frame 302, guardband rectangle 251 extends from X=0FD hex to X=103 hex, and from Y=00 hex to Y=102 hex. Guard band rectangle 252 extends from X=0FD hex to X=203 hex, and from Y=0FC hex to Y=102 hex. Guard band rectangle 253 extends from X=1FD hex to X=203 hex, and from Y=00 hex to Y™102 hex.
As can be seen, guardband rectangles 248 and 250 overlap in the upper left corner, and guardband rectangles 249 and 250 overlap in the upper right corner. Similarly, guardband rectangles 251 and 252 overlap in the lower left corner, and guardband rectangles 252 and 253 overlap in the lower right corner.
It is seen that each of the surrounded guardband rectangles has sides spaced a distance epsilon=3 pix els from the surrounded side of rectangle 300.
From FIG. 47, it can be seen that guardband rectangles 248 and 251, abut frame boundary 318. Together, guardband rectangles 248 and 251 completely surround the left side of rectangle 300. Guard band rectangle 248 end at Y=1FF hex in frame 301, and guardband rectangle 251 begins at Y=00 hex in frame 302. Between Y=1FF in frame 301 and Y=00 hex in frame 302, there is no gap or omitted pix el position, since Y=1FF hex is the last Y address in frame 301. A similar situation exists with respect to guardband rectangles 249 and 253.
FIG. 47a illustrates the case where a dummy reference polygon is inserted in a frame adjacent to a frame having a side of an actual reference polygon a distance less than epsilon away from the common frame boundary of the two adjacent frames. A reference polygon DA is in frame FR1 and is positioned near the frame interface between frame FR1 and FR2. Reference polygon DA has four guardband polygons GB1, GB2, GB3 and GB4 around it. Since a guardband polygon is not to extend into an adjacent frame as explained above with reference to FIG. 47, a dummy reference polygon is constructed at a distance at least as great as epsilon from the side of the actual reference polygon which is a distance less than epsilon away from the common frame boundary. In FIG. 47a, the distance E is the distance of the side of the reference polygon which is less than epsilon from the frame boundary.
As with the writer system 50, DPC3 14 reads the database from data disk 13, inserts Move To and Draw commands into the database, and outputs the modified database into the pipelines. Unlike the writer system 50, however, DPC3 14 sends all the guardband words, frame-at-a-time, down the bus out1 401 to pipeline buffer1 18A, and all the reference words, frame-at-a-time, down the bus out2 402 to pipeline buffer2 18B. As with the writer system 50, alternate frames of words are sent to preprocessor3 20C and preprocessor4 20D. Similarly, frames of guardband words are alternately sent to preprocessor1 20A and preprocessor2 20B. Window clipper 19 functions as with the writer system 50. The embodiment of the inspection system 400 shown, has four pipelines which begin with the four preprocessors 20A-20D.
Preprocessors 20A-20D, filler modules 23A-23D, pix el memory modules 24A-24D, and stage controller 25 function as described for writer system 50.
The pix el memory interface module 53 functions like the high speed laser interface module 27, except that a memory buffer for the guardband words is also included. The reference and the guardband words are output to the ECL comparator 40.
The ECL comparator 40 has a shift register which converts the 64 bit reference data words from the pix el memory interface module 53 into serial reference data. Likewise, the ECL comparator 40 has a shift register which converts the 64 bit guardband data words from the pix el memory interface module 53 into serial guardband data.
Photo tube 45 receives laser light reflected from the pix els on the surface of target 103 and the pattern thereon, and converts the reflected light into an analog scan signal which is proportional to the intensity of the light received by the tube 45. An unmodulated laser beam raster scans the surface of target in the same manner as for writing. The only difference is that the laser beam is unmodulated and of a constant, predetermined intensity during inspection. The analog scan signal is amplified by amplifier 44, and the output of the amplifier is received by the ECL comparator 40. The received analog scan signal is converted by an analog-to-digital-converter to a digital representation of the reflected light intensity at a pix el on the surface of the target 103. The digital scan signal is clocked into a scan latch at the precise intervals during raster scanning so that the latched digital scan words are the digital representations of the reflected light intensity at each scanned pix el location. The digital scan word is a gray scale representation of the reflected light intensity. The digital scan word is sent to a digital comparator which compares the digital value with a predetermined, stored threshold value. If the digital scan word is greater than or equal to the threshold value, the comparator outputs a single bit which has the value of one. If the digital scan word is less than the predetermined threshold value, then the comparator outputs a single bit which has the value of zero. As the laser beam raster scans the target 103, 1024 digital scan words are clocked into the scan latch for each row scanned. Each digital scan word represents the reflected light intensity at one of the pix els in the scanned row. Thus, the comparator generates scan data comprising a serial bit stream consisting of 1024 bits for each raster scanned row, where each bit is a binary representation of the reflected light intensity at one of the 1024 pix el positions in the scanned row.
An alternate embodiment for the pattern inspector system 400 is used for inspection of patterned, transparent targets, such as film or glass photomasks or reticles. With this embodiment, the mask is inspected by transmission of laser light rather than by reflection. The back of the mask (target 103) is illuminated with a collimated uniform light source that illuminates the imaged area of the target. Imaging can be done effectively by the use of a CCD line scanner, particularly, a segmented scanner with multiple output such as the EG&G Ret icon 1024 element scanner which is subdivided into eight contiguous line scanners each comprised of 128 elements. These 128 element sections are organized as even and odd serial pix el outputs. That is, during the first clock pulse, signals for the first and second pix els are output in parallel; during the second clock cycle, signals for the third and fourth pix els are output in parallel; and so on.
The scanner is driven by parallel clocks for each section, so that during the first clock cycle, pix els 1 and 2, 129 and 130, 257 and 258, 385 and 386, 513 and 514, 641 and 642, 769 and 770, and 897 and 898 are output at the same time over 16 output lines. This increases the effective data rate, or bandwidth, to more than 240 mega pix els per second, given sufficient illumination intensity. Each of these analog grayscale pix el outputs is sampled to convert the CCD current pulse output into a constant level which is proportional to the light intensity falling on the corresponding pix el.
The sixteen sampled and held parallel pix el outputs individually are compared with the threshold reference level. These latched parallel analog outputs have been trimmed individually to reduce or eliminate differences in the efficiency of the individual CCD output channels. After threshold comparison the resulting bit-per-pix el binary information is stored until a row 120 of 1024 pix els has been built. The parallel 1024 bit data is double buffered to permit overlayed data acquisition and readout. This is useful for continuous stage 35 motion and synchronization. The 1024 bits of data are read out serially in left-to-right order relative to the scanned row. This output is analogous to the output from the photo tube 45 of FIG. 38. Readout in the light transmission embodiment is synchronized with the stage 35 motion and is clocked synchronously with the reference and guardband clocks. Because these CCD row scanners are integrating detectors over the row scan time rather than a pix el time, the system requires better stage 35 velocity uniformity than the fixed pix el illumination time of the acouto-optically scanned laser system 400 used for reflected inspection.
For situations that require serial data rates for which adequately bright light sources are not available for imaging with an integration time of one scan row 120, a time integrating imaging system can be used. In one embodiment of this technique, a conventional area CCD imager is used rather than a row scanner detector. With this approach, the stored charge is moved from row to row of the scanner, broadside (in parallel) at the same speed as the inspected image moves over the sensitive area of the scanner.
The effect of the time integrated detection is to increase the effective integration time from one-row scan-time, to the scan time for all the rows in the scanner. Typically, a one thousand fold increase in effective sensitivity can be achieved with this technique. A CCD area sensor such as the TI MC780 can be used in this manner and can take advantage of the triple output, normally provided for use with color camera applications. The area sensors either directly (for single output imagers) or after interleaving for multiple output imagers, are output in buffered serial form for comparison in the safe manner as described for reflective or row scanner light transmission systems.
These same imaging techniques can be extended to other forms of database referenced inspection, such as two or three dimensional x-ray inspection. The area sensor approach combined with either a microchannel or conventional x-ray image intensifier is effective particularly as a detection system.
The serial bit stream of scan data is compared bit-by-bit with the serial reference data and the serial guardband data to detect errors, or defective areas of the actual pattern on target 103. Each bit position being compared corresponds to a single pix el on the target surface and corresponds to the same pix el in the reference data and in the guardband data. The compare is a logical operation done by Exclusively ORing (XO Ring) a bit from the serial scan data with the corresponding bit from the serial reference data, and then ANDing the result with the ones complement of the corresponding bit from the serial guardband data, to get the error bit. If the result (the error bit) of the logical operation is a one, then the scan bit's corresponding pix el's X-Y position is flagged as being an error location on the target 103. The error is flagged as being one of having a portion of pattern present at that pix el on target 103 when it should not be there, if the scan bit is a one. The error is flagged as being one of not having a portion of pattern present at that pix el on target 103 when it should be there, if the scan bit is a zero. If the error bit is a zero, then there is no error at the corresponding pix el position on the target 103 and there is no error in that bit's corresponding pix el on target 103. Thus, the pattern is correct at that pix el.
As error data is first detected, the corresponding starting X-Y coordinates and scan data bit are latched. The starting X-Y coordinates are the X-Y coordinates of the first pix el, on the target 103, of a sequence of pix els generating error bits equal to one. When the length, in number of pix els, i.e., number of incoming scan bits, of the error sequence has been determined to be at least as long as a predetermined minimum recordable error length, the starting X-Y coordinates, error length and starting scan bit are saved in a First-In-First-Out (FIFO) memory error buffer. The minimum error length which will be saved is a predetermined value and represents the minimum length, in number of pix els, i.e., number of incoming scan bits, of a detected inspection error in the pattern on the surface of target 103, in order for that error to be stored for operator analysis. Errors shorter in length than the predetermined minimum are ignored by the inspection system 400, and are not saved in the FIFO memory error buffer in the ECL Comparator 40. An error length counter begins once an error sequence has been detected. The counter continues to count incoming scan bits until the number of consecutive good scan bits with error bit equal to zero, also equals the number representing the minimum recordable error length. A good scan bit is one whose corresponding error bit is equal to zero.
The X-Y coordinates of the first bit in an error sequence long enough to be saved in the FIFO, are saved in the FIFO memory error buffer along with the polarity of the scan bit. The FIFO memory error buffer allows for a smooth transfer of error information to the Error Buffer module 41, seen in FIG. 38. Upon availability of the error information, the Error Buffer module performs asynchronous reads from the FIFO.
The FIFO memory error buffer is 41 bits wide and 256 locations deep. Each 41 bit location holds 10 bits of X coordinate, 20 bits of Y coordinate, 10 bits of error sequence length, and a scan bit. The scan bit denotes that a section of pattern is missing if the scan bit is zero, and denotes that the pattern has additional area if the scan bit is one.
The Error Buffer module 41 is a 4K by 48 bit FIFO which serves as an intermediate storage between the ECL Comparator 40 and bit-slice processors in the Error Consolidator module 42. The Error Buffer module 41 reads the error information from the ECL Comparator 40 and places it in the 4K by 48 bit FIFO so that the Error Consolidator 42 processors can retrieve the information as required. The Error Buffer module 41 operates asynchronously with respect to both the ECL Comparator 40 and the Error Consolidator module 42.
Error Consolidator 42
The Error Consolidator 42 includes a 24 bit bit-slice processor whose function includes the task of grouping associated sequences of errors detected in the pattern on target 103 by the ECL Comparator 40. The error data is organized into one or more consolidated error defect areas. The error data is the collection of saved data describing, or flagging, those pix els whose X-Y coordinates have been saved by the ECL Comparator as being locations of missing or additional areas of the pattern on target 103.
The Error Consolidator also eliminates classes of false errors generated by the laser beam and optical system, and by inaccuracies in converting the digital representation of the reflected light intensity into a binary, single-bit representation. Also, closely spaced sequences of defective pix els are united into single defect areas by comparing the separation of defective sequences of pix els with an error criterion allowance.
The error criterion allowance is the minimum number of adjacent pix els in the X or Y direction that must be mis compared between reference data and scan data and not lie within a guardband, before an error is reported to DPCl 56.
As discussed above, the error criterion allowance in the X direction is applied by the ECL Comparator 40 to test a sequence of adjacent defective pix els for the requisite minimum length.
The error criterion allowance in the Y direction can be applied, as in FIG. 39, by the Error Consolidator 42 to ensure that a predetermined minimum, the error criterion allowance, of contiguous rows of sequences of error-flagged pix els overlap in the X direction, before the sequences of error data are consolidated and reported to DPCl 56 as a single defect area.
FIG. 39 shows a section of a frame 106 on the surface of target 103. Also shown is an example of a defect area 404 comprising pix els 119 whose X-Y coordinates have been saved as sequences by the ECL Comparator 40 due to mis compares between the scan data from these pix els and the reference data. Also, these pix els do not lie within any of the guardbands around the sides of the reference data polygons. Notwithstanding the fact that the ECL Comparator 40 has saved the data describing these pix els as being in a defect area, the Error Consolidator 42 will not report these pix el locations as containing defects unless the number of adjacent rows of sequences of pix els overlapping in the X direction is greater than the predetermined error criterion allowance. Defect areas, such as at 404, having a delta Y 403 (number of overlapping rows of sequences) which is less than or equal to the error criterion allowance, are considered false errors and are not reported as defect areas to DPCl 56. In the example of FIG. 39, delta Y 403 equals 4. In order for the area 404 to be reported as a consolidated defect area to DPCl 56, the predetermined error criterion allowance must be the number three or less. Otherwise, the area 404 will be considered a false defect area, and will not be consolidated or reported.
Error data which is consolidated as a defect area and reported to DPCl 56, is described by six parameters, which are: a 10 bit X minimum, a 10 bit X maximum a 20 bit Y minimum a 20 bit Y maximum, a 23 bit area expressed as the number of defective pix els in the defect area, and a single scan data bit indicating whether the defect area represents added or missing parts of the pattern on target 103. X minimum is the X coordinate of the leftmost pix el in the defect area. X maximum is the X coordinate of the rightmost pix el in the defect area. Y minimum is the Y coordinate of the topmost pix el in the defect area. Y maximum is the Y coordinate of the bottom-most pix el in the defect area. These six parameters are sent to DPCl 56 for each consolidated, reportable defect area.
For the example shown if FIG. 39, X minimum=5, X maximum=13, Y minimum=1, Y maximum=4, and the area=22 pix els. The scan data bit is not indicated as to whether it is a one or a zero.
The error criterion allowance can also be applied to consolidate into a single defect area, non-contiguous sequences of defective pix els closely spaced in the X or Y direction.
For example, in FIG. 40, the leftmost defect area 405 and the rightmost defect area 406 consolidate into a single defect area provided that at least one of the sequence separation distances, 408, 409 or 410 is less than or equal to the error criterion allowance. Furthermore, defect area 405 and defect area 406 must each have a sufficient number of overlapping adjacent rows of error sequences to be consolidatable as a defect area. That is, the number of overlapping rows of error sequences must be greater than the error criterion allowance.
Similarly, the bottom-most defect area 407 consolidates with defect areas 405 and 406 if areas 405-407 are separately consolidatable as defect areas, and if the defect separation 411, measured by the number of intervening rows, is less than or equal to the error criterion allowance. The bottom-most defect area 407 must also have its error sequence in row Y=7 overlap in the X direction with the two error sequences in row Y=5.
DPCl 56
DPCl 56 includes a bit-slice processor to do fast sorting of the data describing the defect areas consolidated by the Error Consolidator 42. The defect areas are sorted by the area in pix els, in descending order and formed into a list which is sent to host memory 4 for use by the host computer 3.
Modules 30-36 are the same as described in conjunction with FIG. 6.
Operator Review of Defect Areas
The list of sorted errors sent to the host computer 3 by DPCl 56 is presented on the video display terminal 2 for review by the human operator. The list of errors, that is, defect areas, is presented in order of the most serious, i.e., those with the largest area first. The operator selects which defect area he desires to view on color display 29. The stage 35 then moves the selected target defect area into the correct X-Y position to be laser scanned in real-time during the operator review process, to generate a gray scale image of the defect area. Positioning of the stage 35, and thus the target 103, is computed from location information that is a portion of the defect data collected by the error consolidator 42. The stage is moved to a backoff location so that it is moving at a constant speed when the defect area to be reviewed is under the raster scanning laser beam.
At this point, the target 103 area, which includes the defect to be displayed, is raster scanned by the laser beam, and a gray scale image of the scanned area is displayed with the defect area centered upon the screen of the color display 29. The ECL comparator 40 has a six bit analog-to-digital converter which transforms the analog representation of the reflected light intensity for a single pix el into a six bit digital gray scale representation. Thus, rather than thresholding each pix el to a one or a zero, as is done during the inspection process, a six bit range of intensity is stored, and then displayed. One of the embodiments of the invention does, however, contemplate that the gray scale image be selectively threshold able, either between one and zero as during inspection, or by dividing the 64 possible values for the six bit combination into a lesser number of values. Each pix el to be displayed maps onto one and only one display 29 pix el. Each display 29 pix el individually varies in brightness according to the six bit gray scale, or thresholded, output from the ECL comparator 40.
During the inspection process, when defect areas, if any, are located, only the area in number of pix els, the X-Y extremes and the type of defect are saved for each consolidated defect area. Scan data bit-maps of the defect areas are not saved. This means that the large amounts of memory which would be necessary to store bit-mapped images of all the defect areas discovered during an inspection process, are not required. Also, real-time generation on the fly of a scan data image of a defect area is quicker and easier than would be the case if a large, bit-map, scan data base had to be accessed and managed.
Overlaying the gray scale image of the scanned area, is a computer generated reference image of the same area. The computer generated reference image is generated from the reference data stored on data disk 13 on a real-time basis during operator review. The frames to be displayed are read from data disk 13 by DPC3 14. The location of a desired frame is found by using a frame look-up table created by DPC2 when the database was read from data disk 13 during the inspection process. This table is a directory for finding the beginning of the frame to be read. The data contained in the frame is read by DPC3 and sent down the pipeline that goes to the window clipper 19. This is repeated for each frame needed to create the overlayed reference image. Usually four frames are required. If the de-zoom (discussed below) process is not used, from one to four frames of data are possible to view at a time on color display 29. Where de-zoom scale of two or greater is used, then more than four frames can be viewed on color display 29.
The reference image is created frame-by-frame, on the fly, during operator review of the defect area. The data for the displayed frames is read from data disk 13 and changed by DPC3 to the previously discussed move/draw turnpoint polygon representation of the portion of the pattern in the displayed frames. The data is then sent to window clipper 19 where only the portion of the data to be displayed by color display 29 is sent on to preprocessor1 20A. All frames to be displayed are sent down the same pipeline to the window clipper 19. Thus, the review process represents a departure from the writing or inspection processes where consecutive frames of data are sent down alternate or different pipelines. Also, during the review process only a limited number of frames of data will be read from data disk 13 and subsequently sent down the pipeline. During the review process, guardbands are not generated or used, so the database processing is done in a similar manner to the processing of the data during the pattern writing process, with the previously noted exception of sending all the frames to be displayed down the same pipeline.
Preprocessor1 20A creates a vector representation of the frame reference image data sent by window clipper 19. Preprocessor1 20A then sends the vector representation of the image data to pix el memory module1 24A, where it is transformed into a representation addressing the pix els on and between left and right vectors. Pix el memory module1 24A then transforms the image data into a 64 bit word bit-map of the reference data to be displayed on color display 29.
These reference data transformations are performed on the fly, that is, only the reference data for the defect area being reviewed is read from data disk 13 and sent down the window clipper pipeline and subsequently is processed and sent to the display 29 on a real-time basis during the operator review of the defect area. Only the area in pix els, the X-Y extremes and the type of defect are saved for each consolidated defect area in the scan data. A reference data bit-map of the defect area is not saved. This means that the large amounts of memory which would be necessary to store bit-mapped reference data images for all the defect areas discovered during an inspection process, are not required. Also, the compacted reference data base on data disk 13 is easier and quicker to access than would be the much larger expanded reference data bit-map of all the defect areas. Requiring even more memory would be a reference data bit-map of the entire target surface as produced from the reference database at some point prior to the operator review process.
The overlay produces a yellow color in those areas where the gray scale image of the actual pattern and the computer generated reference image overlap. Thus, the yellow area of the image on the color display 29 represents that portion of the actual pattern on target 103 which contains no defects.
The overlay produces a green color in those areas on the target 103 where there is pattern present that should not be there.
The overlay produces a red color in those areas on the target 103 where pattern is absent that should be there.
The color display 29 displays a portion of the target 103 that is 512 pix els 119 by 512 pix els 119. A frame 106 is 1024 pix els 119 by 512 pix els 119 (FIG. 3), so, at most, only half a frame at a time can be displayed on color display 29. Real patterns on a target's surface can cross frame 106 boundaries. However, a reference data representation of the same pattern uses contiguous, constituent polygons to represent the pattern. The constituent reference data polygons do not cross frame boundaries but instead, abut against one another at the frame boundaries if the pattern crosses the boundaries. The color display may include areas from as many as four frames. For instance, the contiguous corner areas of four frames will be displayed if a strip boundary runs vertically down the middle of the display, and if the horizontal boundaries between the two sets of contiguous frames on either side of the strip boundary, run horizontally through the middle of the display 29. The window clipper 19 deletes the reference polygons from the portions of the frames which will not be shown on display 29.
The gray scale image of the pattern on target 103 and the reference data image of the ideal pattern, can both be de-zoomed. That is, a larger area of the target and of the reference data can be shown on color display 29, with a corresponding shrinkage in the display size of the target and reference data pattern features. De-zoom scales are 1, 2, 4 and 8.
With de-zoom scale 1, display 29 shows each pix el 119 that is within the viewing area on target 103, and shows each pix el of the reference data that corresponds to the viewing area. That is, there is a one-to-one correspondence between the pix els of the target viewing area and the pix els of the display 29. Likewise, there is a one-to-one correspondence between the pix els of the reference data viewing area and the pix els of the display 29.
With de-zoom scale 2, display 29 shows every other pix el of the target in the X direction, so that the viewing area is now twice as wide as for de-zoom scale 1. Likewise, display 29 shows every other pix el of the target in the Y direction, so that the viewing area is now twice as high as for de-zoom scale 1. Therefore, the new viewing area is four times as large as for de-zoom scale 1. Similarly, the viewing area for de-zoom scales 4 and 8 are 16 times and 64 times, respectively, as large as for de-zoom scale 1.
Gray scale module 38 receives a 6 bit gray scale word for each pix el in the target viewing area from the analog-to-digital converter in the ECL comparator 40. When de-zoom scale 1 is in effect, each pix el word received by the gray scale module 38 is sent to the color display 29. When de-zoom scale 2 is in effect, every other pix el word received from ECL comparator 40 for the first row of the viewing area is sent to color display 29. None of the pix el words received for the second row of the viewing area are sent to the display 29. For the third row of the viewing area, again every other pix el word received is sent to display 29, and so on. i.e., every other pix el word from every other viewing area row of pix el words received from ECL comparator 40 are sent to color display 29. For de-zoom scale 4, every fourth pix el word from every fourth viewing area row of pix el words received from ECL comparator 40 are sent to color display 29. Likewise, for de-zoom scale 8, every eighth pix el word from every eighth viewing area row of pix el words received from ECL comparator 40 are sent to color display 29.
Window clipper 19 performs the same de-zoom scaling functions on the reference data in the same way as gray scale module 38 performs de-zoom scaling on the scan data input from ECL comparator module 40.
Auto alignment of the Target
Auto alignment provides three functions for an inspection system 400, or for a writer system 50 that also has inspection capability: 1. determines the exact location of the target 103; 2. adjusts the rotational alignment of a stage 35 and target 103 about the theta axis so that the Y direction stage motion follows a strip 105; and 3. determines if the target 103 has thermally expanded or contracted. Auto alignment is achieved by providing fiducial marks in predetermined locations on the surface of target 103, and using the inspect capability to locate these fiducials after the target has been placed on the stage 35.
FIG. 45 shows a target 103 which is a reticle 520 having a top fiducial mark 518 and a bottom fiducial mark 519, each in the center of the reticle with respect to X. The top fiducial mark 518 is shown as a cross and the bottom fiducial mark 519 as a bar, although, any predetermined identifiable shapes will work. Top 518 and bottom 519 fiducial marks are shown larger with respect to reticle 520 than would actually be the case. Normally, each fiducial mark is small enough to fit within a single frame 1024 pix els wide by 512 pix els high Preferably, top 518 and bottom 519 fiducial marks have centroids with the same X coordinates in the same center strip 105, so that the reticle 520 will be aligned when a line between the centroids of the top and bottom fiducial marks is parallel to the Y axis. It will be understood, however, that the invention may be practiced with a target having two or more fiducials, at predetermined orientations, that do not have centroids with the same X coordinates or lie in the same strip, or lie in the center strip. Preferably, each fiducial mark is sized so that it can fit completely within a single frame 106.
The alignment process begins by placing manually a target 103 on a stage 35. Preferably the stage 35 has an X stop 523 and a Y stop 524 against which the target may be placed to achieve preliminary X-Y-Theta alignment of the target, where the Theta axis is perpendicular to the X-Y plane. Preliminary alignment means that the X-Y position of the centroid of each of the top 518 and bottom 519 fiducial marks is known within three adjacent strips 105 and five adjacent frames 106.
The top fiducial mark 518 is located by the pattern inspector 400 in the inspection mode, by raster scanning the middle three strips of the target 10, for a Y distance of five frames 106 for each strip 105. During the normal inspection mode, a target 103 is raster scanned in strips which extend for the full, or nearly the full, length of the target In the auto alignment mode, preferably, each strip is only five frames long. Also, during the normal inspection mode, a target is raster scanned in strips which cover, or nearly cover, the entire width of target 103. In the auto alignment mode, preferably, only the three center strips 105 are raster scanned. Thus, preferably, only the upper five frames of each of the center three strips are raster scanned in the reticle of FIG. 45.
Similarly, the bottom fiducial mark 519 is located by the pattern inspector 400 in the inspection mode, by raster scanning the bottom five frames 106 of each of the the center three strips 105 of reticle 520.
Thus, for both top 518 and bottom 519 fiducial marks, only fifteen frames 106 are scanned for each mark. This saves a great amount of time over scanning the entire target 103, although, that certainly could be done.
The data flow for inspection to find the fiducial marks proceeds as previously described for inspection of the entire target 103, up through the error consolidator 42. However, the reference database does not describe an idealized fiducial mark pattern, but describes the areas of the target where the fiducials are expected, as being clear areas devoid of any pattern. Thus, when the reference data is compared with the scan data, the fiducial marks register as errors. The error consolidator 42 outputs the consolidated error description of the top fiducial mark 518 as before, i.e., the area in pix els, X maximum, X minimum, Y maximum, Y minimum and the type of error. The error consolidator treats the bottom fiducial mark 519 and any other pattern in the scanned areas, in the same manner as for the top fiducial mark 518. As before, DPCl 56 sorts the errors in descending order of pix el area, creates a list of the errors, and sends the list to host computer 3.
Host computer 3 compares each of the errors with the following test:
IF AREA<=MAX₁₃ FIDUCIAL₋₋ AREA AND
IF AREA>=MIN₋₋ FIDUCIAL₋₋ AREA AND
IF (X maximum-X minimum)<=FIDUCIAL₁₃ WIDTH+(2*TOLERANCE) AND
IF (X maximum-X minimum)>=FIDUCIAL₋₋ WIDTH-(2*TOLERANCE) AND
IF (Y maximum-Y minimum)<=FIDUCIAL₋₋ HEIGHT+(2*TOLERANCE) AND
IF (Y maximum-Y minimum)>=FIDUCIAL₋₋ HEIGHT-(2*TOLERANCE)
THEN a fiducial mark has been found and corresponds to the data tested. The parameters MAX₋₋ FIDUCIAL₋₋ AREA and MIN₁₃ FIDUCIAL₋₋ AREA are the maximum and minimum fiducial areas, respectively, and they describe the acceptable limits within which a fiducial mark must fall. Parameters FIDUCIAL₋₋ WIDTH and FIDUCIAL₋₋ HEIGHT are the nominal width and nominal height respectively, of an ideal fiducial mark. 2* TOLERANCE is a parameter setting the acceptable deviations from the ideal width and height for a valid fiducial mark. The parameters are unique for each fiducial mark. Preferably, Top 518 and bottom 519 fiducial marks have different shapes and the parameters for the two will not be the same, although the parameter TOLERANCE preferably is the same for both. The above test is performed on each of the errors, first with the parameters for the top 518 fiducial and then with the parameters for the bottom 519 fiducial.
If the two fiducial marks are within the scanned areas of the target, and if they fall within the parameters defining acceptable fiducial marks, then the host computer will identify which of the fiducial marks is the top fiducial mark 518 and which is the bottom fiducial mark 519.
If the top 518 and bottom 519 fiducial marks have been located successfully, then their centroids will be determined by the host computer 3. Since the shapes chosen for the fiducial marks are symmetrical about their centroids, the X-Y coordinates of the centroids are determined by host computer 3 by setting X equal to X minimum+((X maximum-X minimum)/2), and setting Y equal to Y minimum+((Y maximum-Y minimum)/2).
If the top 518 and bottom 519 fiducial marks have the same X coordinates, then the target is aligned already. If the X coordinate of the top fiducial mark 518 is less than the X coordinate of the bottom fiducial mark 519 then the stage 35 has to be rotated clockwise to align the target 103. If the X coordinate of the top fiducial mark 518 is greater than the X coordinate of the bottom fiducial mark 519, then the stage 35 has to be rotated counter-clockwise to align the target 103. The stage will be rotated about the center of the target by an amount equal to one-half the absolute value of the difference between the X values of the top 518 and bottom 519 fiducial marks, as measured at the top or bottom fiducial. Preferably, the centroids of the fiducials are equidistant from the center of the target 103, and are centered in the X direction on the target 103.
The inspection process then can be carried out again on the fiducial marks to see if the centroids are within half a pix el of each other in the X direction. If they are not, then again the stage can be rotated. This process can be carried out as many times as are necessary to achieve the desired accuracy of alignment.
The distance MD between the centroid of the top fiducial mark 518 and the centroid of the bottom fiducial mark 519 is computed by host computer 3 by finding the absolute value of the difference between the Y coordinates of the two centroids. The measured distance MD is compared against a predetermined value PD for the distance. There is a predetermined value PV of the distance between two successive Y addresses, that corresponds to the predetermined value PD of the distance between the two centroids. The actual distance AV between two successive Y addresses that corresponds to the measured distance MD between the two centroids, can be found by solving for AV in the following relationship: (PD/MD)=(PV/AV). The actual distance AV is the spacing to be used between two adjacent rows 120 for the then existing environmental conditions for the target 103. These environmental conditions include the ambient temperature for the target, which influences the value for the measured distance MD.
Semiconductor Wafer Bar-by-Bar Alignment
The invention comprehends direct laser writing and inspection of integrated circuit patterns on the individual chips 526, i.e., IC bars 526, of a semiconductor wafer 525, as seen in FIG. 46. The wafer writing process is carried out by laser exposure of photosensitive photoresist on the face of the wafer. The inspection process is carried out on patterns of etched photoresist or etched metal on the semiconductor wafer.
Typically, each semiconductor wafer 525 is comprised of a plurality of rectangular IC bars 526, usually arranged in a rectangular matrix format. The IC bars will be defined by a grid of scribe alleys 529. A single IC bar 526 is defined by the area of semiconductor material between two adjacent, parallel, horizontal scribe alleys and between two adjacent, parallel, vertical scribe alleys.
If only a single patterned layer is required for each IC bar, requiring only a single raster scanning of the areas of the IC bars, then wafer-level alignment marks may be sufficient to determine the X positions marking the beginning of the rows 120 of the various IC bars. Wafer level alignment marks are marks uniquely identifiable by the pattern inspector 400 when in the inspect mode, as described previously in connection with auto alignment. The alignment marks need only be two in number to establish X and theta offsets of the orientation of the wafer, with respect to the orientation required to produce scanned strips 105 that are parallel with the vertical scribe alleys.
For more demanding applications, where previous layers have been patterned using bar-level alignment of optical wafer steppers, bar-by-bar alignment is required in addition to the wafer-level alignment discussed previously under auto alignment. Bar-by-bar alignment is not required in those instances where the first or only patterning layer is patterned by the laser pattern inspection system 400 while in the write mode.
FIG. 46 shows a section of a target 103 which is a semiconductor wafer 525, having a plurality of IC bars 526 on which integrated circuits may be fabricated. The IC bars are separated by a rectangular gridwork of intersecting rows and columns of scribe alleys 529. Scribe alleys are the areas which will be cut away or otherwise destroyed during the process of separating the individual IC bars 526 after the integrated circuits have been fabricated on the IC bars. Each IC bar 526 has associated with it an upper bar-alignment-mark 527 and a lower bar-alignment-mark 528, which were patterned photolithographically in the vertical scribe alley 529 to the left of the IC bar. The bar-alignment-marks were patterned at the same time that the first circuit layer was patterned on the IC bars 526. The bar alignment marks are illustrated as crosses, however, any recognizable pattern would work. Two alignment marks per bar have been shown, but more than two can be used.
Each pair of upper 527 and lower 528 bar-alignment-marks is associated with the IC bar immediately to its right and is at a predetermined orientation and distance from the pair. Each pair of bar-alignment-marks defines the rotational and translational offsets of the X-Y coordinate system for the previous layer or layers of patterning for that IC bar 526, with respect to the wafer-level orientation.
The inspection system 400 identifies and locates the bar-alignment-marks by raster scanning only the vertical scribe alleys 529. The vertical scribe alleys are scanned in strips 105 extending the full length of the scribe alleys. By scanning only the scribe alleys, time is saved over scanning the entire wafer 525. The scan data from the bar-alignment-marks can be compared to a reference data representation of the bar-alignment-marks, or, as in the case of auto alignment, described previously, the list of data corresponding to the bar-alignment-marks is sent to host computer 3 where the offsets are determined and an IC bar location map is constructed. Each scribe alley requires only a low number of scanned strips to identify and locate all the bar-alignment-marks, further reducing the total wafer scan time. A stepping map created by the optical stepper while patterning the first layer, combined with the individual bar header information or stepping design information can be used to provide the locations for each of the bar level bar-alignment-marks. Instead of the bar-alignment-marks, isolated, prominent features of the first layer of pattern, providing recognizable orientation information can be used.
Either the wafer 525 must be rotated and/or translated, or the laser pattern inspection system 400, while in the writer mode, must compensate for the X-Y translation by timing the beginning of modulation of the scanning laser beam and/or by rotating the data from the pipelines. The preferred embodiment of the invention contemplates using the latter method. Likewise, during inspection of the wafer 525, the top 527 and bottom 528 bar-alignment-marks are used to determine the individual orientations of the IC bars 526 so that data from the photo tube 45 will be clocked into ECL comparator 40 at the correct timing offsets so that the scan data will correspond to the correct pix el reference data positions.
Since most of the IC bar 526 pattern offsets from the wafer-level orientation are translational and not rotational, it should be sufficient in the majority of instances to compensate for the offsets solely by timing when to begin raster scanning each row. That is, the X-Y position of the start of each row is determined in light of the Y stage motion and X sweep direction by timing when to begin a sweep and timing at what point in the sweep that modulated data should begin to be output.
The wafer 525 is written or inspected by scanning the wafer in strips extending nearly the full height of the wafer, rather than by scanning each IC bar, one-at-time, in strips extending only for the height of the IC bar 526. This saves turnaround time at the end of each strip by a division factor equal to the number of IC bars 526 on the wafer 525. Each strip has a height sufficient so that the aggregate of the strips cover all the areas on the wafer which require patterning.
Since each wafer 525 is raster scanned in strips extending for the height of the wafer, strip memory buffers can be used at the outputs of the pix el memory modules 24A-24D to store a strip's worth of translated and possibly also rotated data to be written or used as reference data during the inspection process.
AUTOFOCUS FOR WRITER AND INSPECTION SYSTEMS
The autofocus system allows for very fast laser writers 50 and inspectors 400 to be able to move across non-flat targets 103 at high speed and still keep the objective lens 117 in focus. A small, preferably solid-state, laser is used to direct a focused spot coinciding with the spot focus of the objective lens on the surface of target 103. That is, both the writing or inspection laser 100 and the autofocus laser direct laser beams to the same pix els location on target 103. The autofocus spot is picked up as a reflection separate from any reflections from the scanning laser beam, and relayed to a linear photodetector which determines the target 103 surface to lens height by the lateral distance apparent to the detector. This information is fed to a spiral or ring and magnet system to keep the planametric distance constant.
For one embodiment of the laser writer system 50, an objective lens 117 having a fixed reduction of 7.145 and working over a distance of 23 inches was required. The depth of focus of this lens was less than one mil, but target 103 surface variations can cause the objective-lens-117-to-target-surface distance to vary as much as several mils. The autofocus system corrects for this distance variation. The high speeds of stage 35 require that the autofocus system be able to compensate for focusing variations up to the rate of 100 hz. An electro-mechanical system moves just the lower portion of the multi-element objective lens 117, with external paralactic sensing of the focal error. The focusing variations required to follow the surface contour of the target 103 do not change the reduction ratio of the objective lens 117.
Referring to FIG. 44, it can be seen that the objective lens system 117 includes an infinity corrected high resolution objective lens 501 movable along the optical axis to follow the surface contour of the target 103 to maintain focus of the laser 100 on the surface of target 103. The objective lens 501 movement along the optical axis takes place in a region 502 in which the laser beam is collimated, as indicated by parallel light rays 500.
The intermediate, non-moving long focus lens system 503 sets the magnification and track length. The upper field lens 504 gives the laser reflection system telecentricity. The laser deflection system includes the chirp deflector 102.
A 2 mw, 820 nm, 5 mm diameter collimated beam, gallium arsenide, infra-red laser 505 is used to provide the autofocus spot laser light for tracking the objective-lens-117-to-target-surface distance. The 100 mm lens 506 is used to focus the collimated light from laser 505 and to set the focal point of laser 505 at the desired writing or inspection distance. This distance is the objective-lens-117-to-target-surface distance. Prism 507 directs the laser beam from autofocus laser 505 to strike the target 103 surface coincidentally with the same spot struck by writer/inspector laser 100 beam. The prism 507 directed laser beam 508 has an angle of incidence with respect to the target 103 surface, of 45 degrees, and is specularly reflected from the target surface at a reflected angle of 45 degrees into a second prism 509. The second prism 509 directs the reflected autofocus laser beam through a series of two lenses and into a photodetector 514. The directed, reflected laser beam directed by the second prism 509, is parallel to the optical axis of the objective lens 117 only if the objective-lens-117-to-target-surface distance is correct.
The first of the series of two lenses is the 100 mm collimation lens 510, which re-establishes collimation of the reflected autofocus laser beam. The recollimated beam which emerges from the collimation lens 510, is exactly parallel with the optical axis of the objective lens 117 only if the objective-lens-117-to-target-surface distance is the desired distance. If the distance is too large, then the recollimated beam is deflected to the right, as seen in FIG. 44. If the distance is too small, then the recollimated beam is deflected to the left, as seen in FIG. 44.
The second of the series of two lenses is the telescope objective lens 511, which focuses the recollimated beam into a small spot on the silicon photodetector 514. The distance 512 between the collimation lens 510 and the telescope objective lens 511 is chosen to be approximately equal to the focal length of the collimation lens 510. This makes all reflected beams pass centrally through the telescope objective lens 511, notwithstanding any aperture shearing at the collimation lens 510 due to main focal error.
In order to prevent stray or diffusely reflected laser light from the writing/inspection laser 100 from reaching the photodetector and interfering with its operation, an optical filter 513 is placed in front of silicon photodetector 514. Some embodiments of the invention utilize a writer/inspector laser 100 which emits blue-green light at a 488 nm wavelength. In that embodiment, the optical filter 513 will preferably be a red filter for filtering out light at a wavelength of 488 nm.
The silicon photodetector 514 is a split "Double-D" design, differentially connected to a servo-amplifier system for moving axially the high resolution objective lens 501 to keep the writing/inspection laser beam focused on the surface of the target 103. Any objective-lens-117-to-target-surface distance errors are translated into horizontal laser 505 spot motions across the photosensitive face of the silicon photodetector 514. The spot motions across the "crack", or split diode in the face of the photodetector 514, give a plus or minus output from the photodetector 514, that is approximately linear over a spot movement range large enough to cover any normal variations in the contour of the target 103. A screw 515 is for adjusting the horizontal position of the mechanical stage upon which the photodetector 514 is mounted. With the screw 515, the horizontal position of the photodetector can be adjusted to make zero electrical output from the photodetector correspond exactly to the desired writing/inspection focus. That is, the desired objective-lens-117-to-target-surface distance exactly corresponds to zero electrical output from the photodetector.
The objective-lens-117-to-target surface distance error discovery system is based on parallax. The autofocus system responds primarily to the vertical position of the target 103 surface, and is not responsive to small angular variations of the contour of the tested spot on the target surface. The autofocus system is configured to be tolerant of minor optical imperfections in its component parts.
A two-section differentially connected coil 516 of 520 turns of number 26 wire, and having a total electrical resistance of 12.5 ohms, is fed electrical currents of up to plus or minus 0.7 amps by the servo amplifier (not shown). A one inch long 60 gram cylindrical magnet 517 of moment 2500 cgs units, responds to the coil current to produce the required axial motions of the moving assembly. The moving assembly includes the high resolution objective lens 501, the cylindrical magnet 517 the prisms 507 and 509, the 100 mm focusing lens 506, and the collimator lens 510. This moving assembly is supported by 0.008 inch thick beryllium-copper spiral-cantilever springs 518. The moving assembly weighs 280 grams and resonates at 28 hz with the spiral cantilever springs. Besides this primary resonance, there are several secondary resonances, of which the most important is a very high-Q resonance at 900 hz. Motions with amplitudes up to plus and minus 0.010 inches are possible.
Pattern Inspector Data Flow
The data flow for the pattern inspection system 400 is illustrated in FIGS. 53A and 53B, and is very similar to the data flow for the pattern writer system 50, as discussed previously in connection with FIG. 9. FIGS. 53A and 53B differ from FIG. 38 in that FIGS. 53A, 53B only show two pipelines 322 and 323, whereas FIG. 38 shows an inspection system 400 having four pipelines. As has been indicated previously, the invention comprehends the use of two or more pipelines to accomplish parallel processing of the database to a bit-map final form. FIGS. 53A, 53B shows only two pipelines merely to simplify the diagram.
The tape 17 resident database representation of a pattern is the same for the inspection system 400 as for the writer system 50. Thus, for the example rectangle 300 pattern shown in FIG. 26, the database 313 shown in FIG. 27 is also the database for rectangle 300 during an inspection process carried out as shown in FIGS. 53A, 53B.
As with the writer system 50, DPC2 reads the database from tape 17, reformats it into a turnpoint polygon representation, and stores that representation on data disk 13. What is different from the writer system 50, however, is that with the inspection system 400, DPC2 also adds guardband polygon descriptions to the database. These guardband polygons are also described in turnpoint polygon representation. For purposes of simplicity, only the reference data and guardband polygon data for frame 301 is shown, since the data for frame 302 is constructed in just the same way.
The reference data for frame 301 is identical to the reference data shown in FIG. 29 for the writer system 50.
In FIG. 48A, the data indicated at 254 is the turnpoint description of guardband 249 shown in FIG. 47. Likewise, the data indicated at 255 is the turnpoint description of guardband 250, and the data indicated at 256 is the turnpoint description of guardband 248. As can be seen, reference polygons and guardband polygons are each described separately.
FIGS. 49A and 49B illustrate the guardband data only which is sent down pipeline B at 323. The reference polygon data processing in the pipelines will not be shown since it is just the same as was illustrated and discussed with reference to FIG. 9 and writer system 50. The 25 bit words for the guardband polygons are constructed in the same manner as for the reference polygons.
FIGS. 50A and 50B illustrate the guardband data as formatted by preprocessor2 20B of FIG. 53A. The guardband polygon data has been constructed in the same manner as for the reference data.
FIGS. 51A through 51C illustrate the guardband data as formatted by filler module2 23B of FIG. 53A.
The first 25 bit word of FIG. 51A has a 5 bit command field 342 equal to 1C hex, which indicates that in the pix el memory module, the guardband polygon data is to be logically ORed with the data already at that memory location. Since the pix el memory module starts with all its memory positions cleared to zero, this allows overlapping guardband information to be loaded into pix el memory. The second word begins with command field 342 which is equal to 07 hex. This indicates that the guard band polygon data bits 000007 hex will be loaded into memory and indicate three one's are to be set from X=1FD hex to X=1FF hex at Y=0FD hex. The following two 25 bit words set the four bits from X=200 to X=203 at Y=0FD hex. Thus, the seven bits which are on or in the interior of guardband polygon 249 at Y=0FD hex have been set by the first four 25 bit guardband data words. Similarly, the next four 25 bit guardband data words set the seven bit for guardband polygon 249 at Y=0FE hex, and so on down to the last Y address, Y=1FF hex for guardband polygon 249.
FIG. 51B illustrates the setting of the bits on or within guardband polygon 250. Here, eight 25 bit words are required since guardband polygon 250 extends from X=0FD hex to X=203 hex.
FIG. 51C illustrates the setting of the seven bits at each X address of guardband polygon 248, in a similar manner to what is illustrated in FIG. 51A for guardband 249, since they both have the same width in the X direction.
FIG. 52 illustrates the 64 bit word bit-map for the guardbands that are constructed by pix el memory module 24B, in a similar manner to that discussed in connection with FIG. 37 for the writer system 50.
As previously discussed, the guardband data from pix el memory module 24B is logically ANDed bit-at-a-time with the result of logically Exclusively ORing the corresponding bit from the scan data 257 with the corresponding bit from the reference data from pix el memory module 24A.
We claim: PG,103
1. A computerized method of reducing the incident of false error reporting for an optical pattern inspection system, comprising the steps of:identifying the pattern boundaries of a database representation of an ideal pattern, wherein the ideal pattern is comprised of one or more reference polygons, and the data description of each reference polygon is contained within a frame of data, and each side of a polygon is a line segment completely contained within a single frame; constructing data representations of guardbands around said boundaries and constructing a guardband polygon surrounding each line segment of each side of each reference polygon, wherein each guardband polygon is completely contained within the frame of data containing the polygon whose side it surrounds; constructing a dummy reference polygon in a frame adjacent to a frame having a side of an actual reference polygon a distance less than epsilon away from the common frame boundary of the two adjacent frames; constructing a guardband around the dummy reference polygon a distance at least as great as epsilon from the side of the actual reference polygon which is a distance less that epsilon away from the common frame boundary; comparing data generated from an optically detected pattern on a target with the database representations of the ideal pattern, to detect mis compares; and identifying as errors only those mis compares which do not occur within the guardbands.
2. The method of claim 1, wherein the database representation of the ideal pattern is a bit-mapped database representation.
3. The method of claim 1, wherein the data generated from the optically detected pattern, is pix el data corresponding to pix els on the target.
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module Sequel
module Access
module DatabaseMethods
# Access uses type :access as the database_type
def database_type
:access
end
def dataset(opts = nil)
ds = super
ds.extend(DatasetMethods)
ds
end
# Doesn't work, due to security restrictions on MSysObjects
def tables
from(:MSysObjects).filter(:Type=>1, :Flags=>0).select_map(:Name).map{|x| x.to_sym}
end
# Access uses type Counter for an autoincrementing keys
def serial_primary_key_options
{:primary_key => true, :type=>:Counter}
end
private
def identifier_input_method_default
nil
end
def identifier_output_method_default
nil
end
end
module DatasetMethods
SELECT_CLAUSE_METHODS = Dataset.clause_methods(:select, %w'limit distinct columns from join where group order having compounds')
# Access doesn't support INTERSECT or EXCEPT
def supports_intersect_except?
false
end
private
# Access uses TOP for limits
def select_limit_sql(sql)
sql << " TOP #{@opts[:limit]}" if @opts[:limit]
end
# Access uses [] for quoting identifiers
def quoted_identifier(v)
"[#{v}]"
end
# Access requires the limit clause come before other clauses
def select_clause_methods
SELECT_CLAUSE_METHODS
end
end
end
end
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Abralia Pfeffer 1912, p. 762.
Fins large, sagittate; more or less pointed posteriorly, and not exceeded by the tip of the pointed body. Arms with two rows of hooks throughout the greater part of their length, but with true suckers at their tips; extremities of ventral arms normal. Left ventral arm hectocotylized. Dorsal row of suckers on proximal portion of tentacle club suppressed in adult, leaving. one row of hooks and two rows of suckers which give way to four rows of suckers distally. Buccal membrane in preserved specimens pale and scattered over with reddish chromatophorcs.
Animal of small size. Mantle firm, fleshy, cylindrical in shape, little compressed; tapering at first gradually, then more abruptly to a bluntish point posteriorly. Anterior edge of mantle smooth, emarginate below the funnel, and with a very slight obtuse medio-dorsal angle. Fins moderately large and very wide in proportion to their length; about one-third as long as the mantle, and each one about as broad as long; subterminal, triangular; attached firmly along the inner -margin for most of their length; anterior lobes prominent, but posterior margins nearly straight and converging at a very obtuse angle.
Head rather large, but decidedly narrower than the body, squarish, flattened above and below; "olfactory crest" comprising a series of four oblique fleshy folds behind the eye on either side. Eyes large; the circular lid opening with a minute rounded sinus in front. Funnel large, subtriangular, very firm and thick-walled, its center rounded and conspicuously swollen ventrally. Funnel organ well developed, posterior in position; comprising a V-shaped median pad on the interior dorsal wall, and a small elongate-ovate pad placed ventro-laterally to it on either side. The tip of the funnel is furnished with a wide shallow flaplike valve. (PI. Li, fig. 8.)
On its inner surface the edge of the mantle articulates with the head in the nuchal region and with the base of the funnel on either side by cartilages of the form usual in the genus. The dorsal apparatus consists of a simple longitudinal ridge on the mantle and a corresponding plate on the neck. The funnel cartilages are elongate, slightly widest near the base, have a thickened, raised and reflexed margin, and their grooves are simple, narrow, deep, and elongate (pi. Li, fig. 7); they fit over a slender linear ridgeon either side of the inner surface of the mantle.
Sessile arms stout, little attenuate; nearly of a length, but the second arms slightly the longest and stoutest, and the dorsal pair a little shorter and more slender than the others, so that the formula of their relative length is in general 2, 4, 3, 1 ; outer edge of arms angled and furnished with a keel, membranous and poorly developed on the four dorsal arms, but increased to a fleshy carina on the arms of the third pair and more particularly along the outer aspect of the ventral arms, where it is so heavy and con spicuous as to cause these arms to appear almost twice their true diameter when viewed ventrally. For the greater part of their length all the arms are armed with two widely spaced alternating rows of small hooks which are replaced on the extreme distal portions by a double series of minute crowded suckers; the tips of the ventral arms bear suckers similar to those of the other arms and are indeed entirely normal in every particular; the number of pairs of hooks on the ventral arms is about eight.
Tentacles slender, over half as long again as the arms, cylindrical, little tapering. Club but little expanded, armed with four rows of acetabula; which respectively may be described as follows: ( 1 ) On the distal half of the club all four rows consist of small suckers of about equal size at any given transection
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ubuntu on mac-mini: shell script to fix my screen-resolution?
I have Ubuntu installed in two machines: a laptop and a Mac Mini. While in the Laptop the screen is fine, on Mac Mini the resolutions option showing are only two and neither match perfectly well. Currently it shows the option: 1024x768 or 800x600.
It is a LED monitor Philips 24" (61cm) model 244EL2. I have never got such similar problem when running Ubuntu on PC. Is it a problem of drivers, related with Apple Mac Mini?
I wonder if some bash script could get this thing fixed? Or if someone could suggest a recipe on this?
Have you tried xrandr?
I got with a similar problem some time ago. The only thing that got it fixed for me was to replace the grub with rEFInd. Basically, after having started your Ubuntu, download the rEFInd for linux, and install it. Then reboot and when you login again, the screen resolution should got automatically fixed to the optimal possible match for your monitor.
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Process of fabricating a bipolar transistor having lightly doped epitaxial collector region constant in dopant impurity
ABSTRACT
A bipolar transistor has a lightly doped n-type single crystal silicon layer epitaxially grown in a recess formed in a heavily doped n-type impurity region after a selective growth of a thick field oxide layer, a base region, an emitter region and a collector contact region are formed in surface portions of the lightly doped n-type single crystal silicon layer, and the single crystal silicon layer is not affected by the heat during the growth of the thick field oxide layer, and has a flat zone constant in dopant concentration regardless of the thickness thereof.
This Application is a Divisional of Ser. No. 08/807,326 filed Feb. 27, 1997 which is a Continuation-in-Part of Ser. No. 08/802,313 filed Feb. 28, 1997 now ABN.
FIELD OF THE INVENTION
This invention relates to a semiconductor device and, more particularly, to a structure of a bipolar transistor and a process of fabrication thereof.
DESCRIPTION OF THE RELATED ART
A bipolar transistor is an important circuit component of a semiconductor integrated circuit device used for a communication network in the giga-he lz band. The switching speed of the bipolar transistor is mainly dominated by the thickness of the base region where the carrier passes through. The thinner the base region is, the faster the switching action is. The resistance of the emitter, base and collector regions and the parasitic capacitances coupled to the emitter/base and collector regions affect the switching speed of the bipolar transistor. These factors strongly relate to the miniaturization and the accuracy of patterning technologies used in the fabrication process of the bipolar transistor. However, a self-aligning technology between the emitter region and the base contact region makes the improvement in switching speed free from the accuracy of patterning technologies. The self-aligning technology is disclosed by Tak H. Ning et al. in “Self-Aligned Bipolar Transistors for High-Performance and Low-Power Delay VLSI”, IEEE Transactions on Electron Devices”, vol. ED-28, No. 9, September 1981, pages 1010 to 1013.
FIGS. 1A to 1G illustrate a typical example of the process of fabricating the self-aligned bipolar transistor of the n-p-n type. The prior art process starts with preparation of a p-type silicon substrate 1. A photo-resist ion-implantation mask (not shown) is prepared on the major surface of the p-type silicon substrate 1 by using lithographic techniques, and an area is uncovered with the photo-resist ion-implantation mask. Arsenic is ion implanted into the area, and the photo-resist ion-implantation mask is stripped off. The ion-implanted arsenic is activated in nitrogen ambience at 1000 degrees to 1200 degrees in centigrade for 2 to 4 hours, and forms a heavily doped n-type buried layer 1 b.
A photo-resist ion-implantation mask (not shown) is patterned on the major surface of the p-type silicon layer 1 a by using the lithographic techniques, and another area around the heavily doped n-type buried region 1 b is uncovered with the photo-resist ion-implantation mask. Boron is ion implanted into the exposed area, and the photo-resist ion-implantation mask is stripped off. The ion-implanted boron is activated in the nitrogen ambience at 900 degrees to 1100 degrees in centigrade for 30 minutes to an hour, and forms a heavily doped p-type buried region 1 c as shown in FIG. 1A. The heavily doped p-type buried region 1 c electrically isolates the self-aligned bipolar transistor from another circuit component.
N-type silicon is epitaxially grown to 2 microns thick on the major surface of the p-type silicon substrate la, and the p-type silicon substrate 1 a is overlain by an n-type epitaxial silicon layer 2 a. A p-type channel stopper region 2 b is formed in the n-type epitaxial silicon layer 2 a, and is merged with the heavily doped p-type buried layer 1 c as shown in FIG. 1B.
A thick field oxide layer 3 is selectively grown to 600 nanometers thick by using the LOCOS (local oxidation of silicon) technology. The growth of the thick filed oxide layer 3 is carried out at 1000 degrees in centigrade, and consumes long time. While the heat is growing the thick field oxide layer 3, the boron and the arsenic are diffused from the heavily-doped p-type buried layer/p-type channel stopper region 1 c/ 2 b and the heavily doped n-type buried layer 1 b, respectively, and the n-type buried layer 1 b expands as shown in FIG. 1C. As a result, the expansion of the n-type buried layer 1 b decreases the thickness of the n-type epitaxial layer 2 a inside of the thick field oxide layer 3.
Subsequently, phosphorous is thermally diffused into a narrow area of the n-type epitaxial layer 2 a, and reaches the heavily doped n-type buried layer 1 b. The phosphorous forms an n-type collector contact region 4 a merged into the heavily doped n-type buried layer 1 b.
Silicon oxide is deposited over the entire surface of the resultant semiconductor structure by using a chemical vapor deposition, and forms a silicon oxide layer. A photo-resist etching mask is patterned on the silicon oxide layer through the lithography, and the silicon oxide layer is selectively etched away. The silicon oxide layer is patterned into a silicon oxide mask 5 a. The n-type collector contact region 4 a is covered with the silicon oxide mask 5 a; however, the n-type epitaxial silicon layer 2 a is exposed to an opening of the silicon oxide mask 5 a as shown in FIG. 1D.
Subsequently, polysilicon is deposited over the entire surface of the resultant semiconductor structure by using a chemical vapor deposition, and p-type dopant impurity is introduced into the polysilicon layer. In this instance, boron is introduced into the polysilicon through an in-situ doping technique, or boron is ion implanted into the amorphous silicon layer. The boron-doped polysilicon layer is used for a base electrode as described herein later.
In order to isolate the base electrode from an emitter electrode, silicon nitride is deposited over the boron-doped polysilicon layer, and the boron-doped polysilicon layer is overlain by a silicon nitride layer. A photo-resist etching mask (not shown) is patterned on the silicon nitride layer, and the silicon nitride layer and the boron-doped polysilicon layer are selectively etched away so as to form a base electrode 4 b covered with an inter-level insulating layer 5 b as shown in FIG. 1E.
A photo-resist etching mask (not shown) is patterned on the inter-level insulating layer 5 b, and has an opening over a central area of the n-type epitaxial silicon layer 2 a. Using the photo-resist etching mask, the inter-level insulating layer 5 b and the base electrode 4 b are selectively etched away so as to form an opening 5 c over the central area of the n-type epitaxial layer 2 a.
The resultant semiconductor structure is treated with heat, and the boron is diffused from the base electrode 4 b into the central area of the n-type epitaxial layer 2 a. The boron forms a graft base region 4 c beneath the base electrode 4 b. Boron or boron difluoride (BF₂) is ion implanted into the central area of the n-type epitaxial silicon layer 2 a, and forms an intrinsic base region 4 d as shown in FIG. 1F.
Silicon oxide is deposited over the entire surface of the resultant semiconductor structure, and forms a silicon oxide layer topographically extending over the resultant semiconductor structure. The silicon oxide layer is anisotropically etched away without a photo-resist etching mask, and side wall spacers 5 d/ 5 e are left on the inner and outer side surfaces of the base electrode 4 b. The side wall spacer 5 d on the inner side surface covers a peripheral area of the intrinsic base region 4 d, and an central area of the intrinsic base region 4 d is still exposed.
Heavily arsenic-doped polysilicon is grown on the entire surface of the resultant semiconductor structure, and a heavily arsenic-doped polysilicon layer is held in contact with the central area of the intrinsic base region 4 d. A photo-resist etching mask (not shown) is patterned on the heavily arsenic-doped polysilicon layer, and the heavily arsenic-doped polysilicon layer is patterned into an emitter electrode 4 e.
The arsenic is thermally diffused from the emitter electrode 4 e into the central area of the intrinsic base region 4 d by using a lamp annealing, and forms an emitter region 4 f.
Finally, a collector contact hole is formed in the silicon oxide layer 5 a, and a collector electrode 4 g is held in contact with the corrector contact region 4 a through the collector contact hole as shown in FIG. 1G.
Thus, the side wall spacer 5 d causes the emitter region 4 f to be exactly nested into the intrinsic base region 4 c, and the emitter region 4 f never enters into the graft base region 4 c. However, the n-type epitaxial silicon layer 2 a is too thick to improve the switching speed. In detail, it is important to reduce the collector resistance for a high speed switching action, and the reduction of the collector resistance is achieved by a thin n-type epitaxial layer 2 a. However, if the n-type epitaxial layer 2 a is thin, the n-type dopant impurity is diffused from the heavily doped n-type buried layer 1 b into the thin epitaxial layer 2 a during the heat treatment for the thick field oxide layer 3, and increases the dopant concentration of the n-type epitaxial layer 2 a. A lightly doped n-type region called as “flat zone” is necessary for the collector region, and the n-type dopant impurity diffused from the heavily doped n-type buried layer 1 b damages the flat zone. This results in deterioration of the bipolar transistor. Thus, the diffusion from the heavily doped n-type buried layer 1 b does not allow the manufacturer to make the n-type epitaxial layer 2 a thin, and the thick n-type epitaxial layer 2 a sets a limit on the switching speed of the prior art bipolar transistor.
A problem of the prior art process is the lithographic step repeated twice for the heavily doped n-type buried layer 1 b and the heavily doped p-type buried layer 1 c. The prior art process is complex, and increases the production cost of the prior art bipolar transistor.
SUMMARY OF THE INVENTION
It is therefore an important object of the present invention to provide a bipolar transistor which is improved in switching speed.
It is also an important object of the present invention to provide a simple process of fabricating the bipolar transistor.
To accomplish the object, the present invention proposes to grow a lightly doped epitaxial silicon layer in a recess formed after a growth of a field oxide layer.
In accordance with one aspect of the present invention, there is provided a bipolar transistor fabricated on a silicon substrate of a first conductivity type, comprising: a heavily doped impurity region formed in a surface portion of the silicon substrate and having a second conductivity type opposite to the first conductivity type, a recess being formed in a surface portion of the heavily doped impurity region; a lightly doped epitaxial silicon layer of the second conductivity type filling the recess and having a flat zone substantially constant in dopant concentration below a first surface portion thereof; a base region of the first conductivity type formed in the first surface portion of the lightly doped epitaxial silicon layer; a heavily doped collector contact region of the second conductivity type formed in a second surface portion of the lightly doped epitaxial silicon layer contiguous to the flat zone; and an emitter region of the second conductivity type formed in a surface portion of the base region.
In accordance with another aspect of the present invention, there is provided a process of fabricating a bipolar transistor, comprising the steps of: a) preparing a silicon substrate of a first conductivity type; b) introducing a first dopant impurity into a surface portion of the silicon substrate so as to form a heavily doped impurity region of a second conductivity type opposite to the first conductivity type; c) thermally growing a field insulating layer occupying at least an outer peripheral area of the heavily doped impurity region; d) selectively removing a central portion of the heavily doped impurity region for forming a recess therein; e) epitaxially growing a single crystal silicon in the recess so as to form a lightly doped epitaxial silicon layer of the second conductivity type; and f) forming a base region in a surface portion of the lightly doped epitaxial silicon layer and an emitter region in a surface portion of the base region.
BRIEF DESCRIPTION OF THE DRAWINGS
The features and advantages of the bipolar transistor and the process according to the present invention will be more clearly understood from the following description taken in conjunction with the accompanying drawings in which:
FIGS. 1A to 1G are cross sectional views showing the prior art process of fabricating the self-aligned bipolar transistor;
FIGS. 2A to 2H are cross sectional views showing a process of fabricating a bipolar transistor according to the present invention;
FIG. 3 is a graph showing an impurity profile of a collector region of the bipolar transistor;
FIG. 4 is a plan view showing the layout of another bipolar transistor according to the present invention; and
FIGS. 5A to 5H are cross sectional views taken along line A—A of FIG. 4 and showing a process of fabricating the bipolar transistor.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
First Embodiment
FIGS. 2A to 2H illustrate a process of fabricating a bipolar transistor embodying the present invention. The bipolar transistor described hereinbelow is assumed to be an n-p-n type. However, a p-n-p type bipolar transistor is fabricated on an n-type silicon substrate by exchanging the conductivity types of dopant impurities.
The process starts with preparation of a p-type silicon substrate 11. The p-type silicon substrate 11 has an major surface 11 a with crystal plane (100). Boron is ion implanted through the major surface 11 a into the p-type silicon substrate 11 at dose of 1×10¹³ to 3×10¹³ ion per cm² under acceleration energy of 250 KeV to 350 KeV. The ion-implanted boron forms a heavily doped p-type impurity layer 11 b of 0.4 micron to 1.0 micron in depth. Although the ion-implantation is carried out, no heat treatment follows the ion-implantation. The resultant semiconductor structure is illustrated in FIG. 2A.
A photo-resist solution is spread over the upper surface of the heavily-doped p-type impurity layer 11 b, and is baked so as to form a photo-resist layer on the heavily doped p-type impurity layer. A pattern image is optically transferred from a photo-mask to the photo-resist layer by using a lithography, and forms a latent image in the heavily doped p-type impurity layer 11 b. The latent image is developed, and the photo-resist layer is patterned into a photo-resist ion-implantation mask 12. Using the photo-resist ion-implantation mask 12, phosphorous is ion implanted into the heavily doped p-type impurity layer 11 b at dose of 4×10¹⁴ ions per cm² to 6×10¹⁴ ions per cm² under acceleration energy of 550 KeV to 650 KeV, and forms a heavily doped n-type impurity region 11 c as shown in FIG. 2B. The heavily doped n-type impurity region 11 c is as deep as the heavily doped p-type impurity region 11 b, and is corresponding to the heavily doped n-type buried layer 1 b and the heavily doped n-type impurity region 4 a.
The photo-resist ion-implantation mask 12 is stripped off. A thick field oxide layer 13 a is selectively grown to 300 to 400 nanometers thick on the major surface 11 a by using the LOCOS technology. While the thick field oxide layer is being grown, the heat activates the n-type dopant impurity of the heavily doped n-type impurity region 11 c and the p-type dopant impurity of the heavily doped p-type impurity layer 11 b.
Subsequently, silicon oxide is deposited over the resultant semiconductor structure, and a silicon oxide layer topographically extends over the entire surface of the resultant semiconductor structure. A photo-resist etching mask (not shown) is provided on the silicon oxide layer by using the lithographic techniques, and the silicon oxide layer is patterned into a mask layer 13 b.
The resultant semiconductor structure is dipped into an etchant containing hydrazine or potassium hydroxide. The mask layer serves as an etching mask, and a recess 14 a is formed in the heavily doped n-type impurity region 11 c. {100} crystal plane defines the bottom of the recess 14 a. The etchant causes (111) crystal plane of single crystal silicon or the equivalent crystal plane, which are hereinbefore referred to as {111} crystal plane, to form the inner surface 11 d defining the recess 14 a. The recess 14 a ranges 0.2 micron to 0.8 micron in depth, and is shallower than the heavily doped n-type impurity region 11 c. The outer periphery of the recess 14 a is terminated at the lower surface of the thick field oxide layer 13 a. The resultant semiconductor structure is illustrated in FIG. 2D.
Lightly doped n-type single crystal silicon is grown in the recess 14 a by using a selective epitaxial growing technique, and forms a lightly doped n-type single crystal silicon layer 11 e as shown in FIG. 2E. In this instance, the selective epitaxial growing technique is a chemical vapor deposition, and the lightly doped n-type single crystal silicon is grown from gaseous mixture containing SiH₂Cl₂ and HCL at 700 degrees to 800 degrees in centigrade. Water vapor or oxygen in the gaseous mixture is minimized, and is less than 10⁻⁷ torr. For this reason, the deposition temperature is lowered. The lightly doped n-type single crystal silicon is grown on (100) crystal plane forming the bottom surface of the recess 14 a, and is hardly grown on {111} crystal plane. For this reason, the lightly doped n-type single crystal silicon is flat and good in crystal. The dopant concentration of the lightly doped n-type single crystal silicon layer 11 e is of the order of 1×10¹⁵ atoms per cm³.
Polysilicon is grown on the resultant semiconductor structure to 150 nanometers to 300 nanometers thick by using the chemical vapor deposition, and p-type dopant impurity is introduced into the polysilicon layer at 10¹⁸ atoms per cm³. Insulating material is further deposited to 100 nanometers to 200 nanometers thick over the p-type polysilicon layer, and the p-type polysilicon layer is overlain by an insulating layer. A photo-resist etching mask (not shown) is provided on the insulating layer, and the insulating layer and the p-type polysilicon layer are patterned into a base electrode 15 a and an inter-level insulating layer 13 c.
Subsequently, a photo-resist etching mask (not shown) is formed on the inter-level insulating layer 13 c, and the inter-level insulating layer 13 c and the base electrode 15 a are selectively etched away so as to form a primary emitter contact hole 14 b in the lamination of the inter-level insulating layer 13 c and the base electrode 15 a.
Heat is applied to the base electrode 15 a, and the p-type dopant impurity is diffused from the base electrode 15 a into an outer peripheral area of the lightly doped n-type single crystal silicon layer 11 e. The p-type dopant impurity forms a graft base region 11 f.
P-type dopant impurity such as boron or boron difluoride is ion implanted into the central area of the lightly doped n-type single crystal silicon layer 11 e exposed to the primary emitter contact hole 14 b, and forms an intrinsic base region 11 g inside of the graft base region 11 f. The resultant semiconductor structure is illustrated in FIG. 2F.
Silicon oxide is deposited over the resultant semiconductor structure, and a silicon oxide layer topographically extends over the entire surface of the resultant semiconductor structure. The silicon oxide layer is anisotropically etched without a photo-resist etching mask, and a side wall spacer 15 c is formed on the inner side surfaces of the base electrode/inter-level insulating layer 15 a/ 13 c. The side wall spacer 15 c defines a secondary emitter contact hole 14 c, and only a central area of the intrinsic base region 11 g is exposed to the secondary emitter contact hole 14 c.
Heavily arsenic-doped polysilicon is grown to 100 nanometers to 200 nanometers thick over the resultant semiconductor structure, and the arsenic concentration is of the order of 10¹⁹ to 10²¹ atoms per cm³. The heavily arsenic-doped polysilicon fills the secondary emitter contact hole, and swells into a heavily doped arsenic-doped polysilicon layer. The heavily doped arsenic-doped polysilicon layer is held in contact with the central area of the intrinsic base region 11 g exposed to the secondary emitter contact hole 14 c.
A photo-resist etching mask (not shown) is formed on the heavily arsenic-doped polysilicon layer, and the heavily arsenic-doped polysilicon layer is patterned into an emitter electrode 15 b. The arsenic is thermally diffused into the central area of the intrinsic base region 11 g by using a lamp annealing, and forms an emitter region 11 h as shown in FIG. 2G.
The base electrode 15 a is further patterned by using the lithographic techniques, and becomes small. A photo-resist etching mask (not shown) is provided on the resultant semiconductor structure, and has an opening over the heavily doped n-type impurity region 11 c on the right side of the lightly doped n-type single crystal silicon layer 11 e. The silicon oxide layer 13 b is selectively etched away, and a collector contact hole 14 d is formed in the silicon oxide layer 13 b. The heavily doped n-type impurity region 11 c is partially exposed to the collector contact hole 14 d.
Doped polysilicon is deposited over the entire surface of the resultant semiconductor structure. The doped polysilicon fills the collector contact hole, and swells into a doped polysilicon layer. The doped polysilicon layer is patterned into a collector electrode 15 c held in contact with the heavily doped n-type impurity region 11 c as shown in FIG. 2H.
Thus, the graft base region 11 f and the intrinsic base region 11 g are formed in the lightly doped n-type single crystal silicon layer 11 e which was grown in the heavily doped n-type impurity region 11 c. The lightly doped n-type single crystal silicon layer 11 e and the heavily doped n-type impurity region 11 c serve as a collector region of the bipolar transistor.
The lightly doped n-type single crystal silicon layer 11 e is completed during the growth of the thick field oxide layer 13 a, and is free from undesirable out-diffusion inherent in the prior art bipolar transistor. For this reason, the impurity profile in the collector region is stable, and the collector region has a clear flat zone.
The present inventor confirmed the flat zone formed in the collector region. The present inventor measured the dopant concentration in the collector region of the bipolar transistor according to the present invention and in the collector region of the prior art bipolar transistor, and plotted the impurity profiles in FIG. 3. The lightly doped n-type single crystal silicon layer 11 e and the n-type epitaxial silicon layer 2 a were corresponding to “lightly doped layer”, and were 0.5 micron thick. The heavily doped n-type impurity region 11 c and the heavily doped n-type buried layer 1 b were represented by “heavily doped layer”.
The impurity profile of the prior art bipolar transistor was represented by plots PL1, and a flat zone was not observed. On the other hand, plots PL2 represented the impurity profile of the present invention, and a flat zone was clearly formed in the lightly doped layer around 10¹⁵ atoms per cm³. Thus, even if the lightly doped n-type single crystal silicon layer 11 e was only 0.5 micron thick, the flat zone was clearly observed, and the extremely thin lightly doped n-type single crystal silicon layer 11 e drastically decreased the collector resistance without sacrifice of the transistor characteristics.
Moreover, the p-type impurity region 11 b is formed through the ion-implantation of the p-type dopant impurity without the lithography, and the fabrication process becomes simple.
Second Embodiment
FIG. 4 illustrates the layout of another bipolar transistor embodying the present invention, and FIGS. 5A to 5H show a process of fabricating the bipolar transistor. A thick field oxide layer 21 a is selectively grown on a p-type silicon substrate 21, and has an inner edge 21 a′ defining a recess 22 a filled with a lightly doped n-type single crystal silicon layer 21 b (not shown in FIG. 4).
A heavily doped collector contact region 23 a is formed in the peripheral area of the lightly doped n-type single crystal silicon layer 21 b along the inner edge 21 a′, and a collector electrode 24 a is held in contact with the collector contact region 22 a.
A graft base region 23 b is formed inside of the heavily doped collector contact region 23 a, and a base electrode 24 b is held in contact with the graft base region 23 b. The base electrode 24 b is electrically isolated from the collector electrode 24 a by means of an inter-level insulating layer 25 a (not shown in FIG. 4).
An emitter region 23 c is formed inside of the graft base region 23 b, and an emitter electrode 24 c is held in contact with the emitter region 23 c. An inter-level insulating layer 25 b (not shown in FIG. 4) electrically isolates the emitter electrode 24 c from the base electrode 24 b. The collector electrode 24 a, the base electrode 24 b and the emitter electrode 24 c are self-aligned with the thick field oxide layer 21 a, the collector electrode 24 a and the base electrode 24 b, respectively.
The bipolar transistor shown in FIG. 4 is fabricated as follows. The p-type silicon substrate 21 is firstly prepared, and (100) crystal plane forms the major surface 21 b of the p-type silicon substrate 21.
Boron is ion implanted through the major surface 21 b into the p-type silicon substrate 21, and forms a heavily doped p-type impurity layer 21 c. The heavily doped p-type impurity layer 21 c is 0.4 micron to 1.0 micron in thickness. The ion-implantation of the boron is carried out under the same conditions as the first embodiment.
Subsequently, phosphorous is ion implanted into the heavily doped p-type impurity layer 21 c, and forms a heavily doped n-type impurity region 21 d as deep as the heavily doped p-type impurity layer 21 c. The ion-implantation of the phosphorous is carried out under the same conditions as-the first embodiment.
The thick field oxide layer 21 a is selectively grown to 300 nanometers to 400 nanometers thick by using the LOCOS technology, and the ion-implanted boron and the ion-implanted phosphorous are activated with heat during the growth of the thick field oxide layer 21 a. The resultant semiconductor structure is shown in FIG. 5A.
Using the thick field oxide layer 21 a as an etching mask, the heavily doped n-type impurity region 21 d is selectively etched away by using an anisotropic dry etching technique, and forms a recess 22 a in the heavily doped n-type impurity region 21 d. The anisotropic dry etching does not control the crystal plane of the inner surface 21 e of the heavily doped n-type impurity region 21 d. The recess 22 a is shallower than the heavily doped n-type impurity region 21 d by 0.2 micron to 0.8 micron, and the resultant semiconductor structure is shown in FIG. 5B.
The lightly doped n-type single crystal silicon is epitaxially grown in the recess 22 a, and the dopant concentration of the lightly doped n-type single crystal silicon is of the order of 1×10¹⁶ atoms per cm³. The selective epitaxial growth is carried out by using the chemical vapor deposition as similar to the first embodiment. However, the lightly doped single crystal silicon is grown on not only the bottom surface but also the inner surface 21 e, and the lightly doped single crystal silicon layer 21 b has a convex portion 21 f along the inner edge of the thick field oxide layer 21 a as shown in FIG. 5C. However, the height of the convex portion 21 f is not greater than 0.1 micron.
Phosphorous-doped polysilicon is deposited to 100 nanometers to 200 nanometers thick over the resultant semiconductor structure by using a chemical vapor deposition, and the phosphorous concentration is of the order of 10¹⁹ atoms per cm³. The phosphorous-doped polysilicon is patterned into the collector electrode 24 a, and the inter-level insulating layer 25 a of 200 nanometers thick is deposited over the resultant structure. Subsequently, the collector electrode 24 a is heated, and the phosphorous is thermally diffused from the collector electrode 24 a into the peripheral area of the lightly doped n-type single crystal silicon layer 21 b. The phosphorous forms the collector contact region 23 a as shown in FIG. 5D.
Subsequently, a part of the inter-level insulating layer 25 a is etched away, and forms a base contact hole 22 b to which the lightly doped n-type single crystal silicon layer 21 b is exposed. P-type doped polysilicon is deposited to 150 nanometers to 300 nanometers thick over the resultant semiconductor structure, and the dopant concentration of the p-type doped polysilicon contains the p-type dopant impurity of the order of 10¹⁸ atoms per cm³. The p-type doped polysilicon layer 26 a is held on contact with the lightly doped n-type single crystal silicon layer 21 b through the base contact hole 22 b. The resultant semiconductor structure is covered with an insulating layer 26 b of 100 nanometers to 200 nanometers thick as shown in FIG. 5E.
The insulating layer 26 b and the p-type doped polysilicon layer 26 a are patterned into the inter-level insulating layer 25 b and the base electrode 24 b, and a primary emitter contact hole 22 c is formed in the lamination of the base electrode 24 b and the inter-level insulating layer 25 b.
Heat is applied to the base electrode 24 b, and the p-type dopant impurity is diffused from the base electrode 24 b into the lightly doped n-type single crystal silicon layer 21 b, and forms the graft base region 23 b.
Boron or boron difluoride is ion implanted through the primary emitter contact hole 22 c into the lightly doped n-type single crystal silicon layer 21 b, and is activated through a heat treatment. As a result, an intrinsic base region 23 d is formed inside of the graft base region 23 b as shown in FIG. 5F.
Silicon oxide is deposited over the resultant semiconductor structure, and a side wall spacer 25 c is formed from the silicon oxide layer on the inner surface of the lamination of the base electrode 24 b and the inter-level insulating layer 25 b by using an etch-back technique. The side wall spacer 25 c defines a secondary emitter contact hole 22 d. Heavily arsenic-doped polysilicon is deposited to 100 nanometer to 200 nanometers thick, and arsenic concentration is of the order of 10¹⁹ to 10²¹ atoms per cm³. The heavily arsenic-doped polysilicon layer is patterned into the emitter electrode 24 c, and the arsenic is thermally diffused from the emitter electrode 24 c into the central area of the intrinsic base region 23 d through a lamp annealing. The arsenic forms the emitter region 23 c as shown in FIG. 5G.
Finally, the base electrode 24 b and the inter-level insulating layer 25 b are partially etched away, and becomes small.
Thus, the collector contact region 23 a, the graft base region 23 b and the intrinsic base region 23 d are formed in the lightly doped single crystal silicon layer 21 b, and the lightly doped n-type single crystal silicon layer 21 b is formed after the growth of the thick field oxide layer 21 a, and the n-type dopant impurity is less diffused from the heavily doped n-type impurity region 21 d into the lightly doped n-type single crystal silicon layer 21 b. As a result, a flat zone takes place in the lightly doped n-type single crystal silicon layer 21 b, and collector resistance is decreased without sacrifice of the transistor characteristics.
The collector electrode 24 a, the base electrode 24 b and the emitter electrode 24 c are respectively self-aligned with the thick- field oxide layer 2 a, the collector electrode 24 a and the base electrode 24 b. For this reason, the bipolar transistor implementing the second embodiment is suitable for an ultra large scale integration.
If the edge of the recess is directed to [110], a facet takes place in the periphery of the lightly doped n-type single crystal silicon layer, and cancels the convex portion. Therefore, a flat surface is created in the second embodiment.
Although particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present invention.
For example, if the recess 14 a is formed in the heavily doped n-type impurity region 11 c through a dry etching, (110) crystal plane or the equivalent crystal plane forms the inner surface 11 d, and the single crystal silicon layer 11 e is similarly grown.
The heavily doped n-type impurity region 21 c may be formed after the growth of the thick field oxide layer 21 a.
The heavily doped n-type impurity regions 11 c/ 21 d may be thicker than the heavily doped p-type impurity layer 11 b/ 21 c.
A p-n-p type bipolar transistor may be formed through one of the processes described hereinbefore.
What is claimed is:
1. A process of fabricating a bipolar transistor, comprising the steps of: a) preparing a silicon substrate of a first conductivity type; b) introducing a first dopant impurity into a surface portion of said silicon substrate so as to form a heavily doped impurity region of a second conductivity type opposite to said first conductivity type; c) thermally growing a field insulating layer occupying at least an outer peripheral area of said heavily doped impurity region; d) selectively removing a central portion of said heavily doped impurity region for forming a recess therein; e) epitaxially growing a single crystal silicon in said recess so as to form a lightly doped epitaxial silicon layer of said second conductivity type; and f) forming a base region in a surface portion of said lightly doped epitaxial silicon layer and an emitter region in a surface portion of said base region.
2. The process as set forth in claim 1, in which said surface portion of said silicon substrate is formed by (100) crystal plane or a crystal plane equivalent to said (100) crystal plane, and said heavily doped impurity region has a first surface defining a bottom of said recess and formed by said (100) crystal plane or said crystal plane equivalent to said (100) crystal plane.
3. The process as set forth in claim 2, in which said heavily doped impurity region further has a second surface defining a side of said recess and formed by (111) crystal plane, (110) crystal plane or a crystal plane equivalent to said (111) crystal plane or said (110) crystal plane.
4. The process as set forth in claim 3, further comprising the step of introducing a second dopant impurity into said silicon substrate so as to form another heavily doped impurity region of said first conductivity type between said step a) and said step b), and said heavily doped impurity region of said second conductivity type is nested into said another heavily doped impurity region.
|
Thread:Hatebunny/@comment-24006535-20160913162454/@comment-3361105-20160913163624
This would help to narrow down the things that actually should be in the history section.
|
function equalDeep(obj1, obj2) {
if (typeof obj1 !== typeof obj2)
return false
if (typeof obj1 === 'number' && obj1 !== obj1)//NaN
return obj2 !== obj2
if (typeof obj1 !== 'object')
return obj1 === obj2
if (Array.isArray(obj1) || Array.isArray(obj2)) {
if (Array.isArray(obj1) && Array.isArray(obj2)) {
if (obj1.length !== obj2.length)
return false
for (let i = 0; i < obj1.length; i++)
if (!equalDeep(obj1[i], obj2[i]))
return false
return true
} else {
return false
}
}
if (!obj1 || !obj2)//null
return obj1 === obj2
const ent1 = Object.entries(obj1)
const ent2 = Object.entries(obj2)
if (ent1.length !== ent2.length)
return false
for (let i1 = 0; i1 < ent1.length; i1++) {
let found = false
for (let i2 = 0; i2 < ent2.length; i2++) {
if (ent1[i1][0] !== ent2[i2][0])
continue
found = true
if (!equalDeep(ent1[i1][1], ent2[i2][1]))
return false
ent2.splice(i2, 1)
break
}
if (!found)
return false
}
return true
}
module.exports = equalDeep
|
Vesperngo Kuhlii, Blasius, Wirbelth. Deutschl.
Description-. — Teeth 32 in number. The muzzle fur nished with scattered, dark hairs, blackish, swollen, rather short, the space from the ears to the top of the nose is little greater than that between the ears, the nose, as it were, sunk between the swollen nostrils; ears three-fourths of the length of the head, oval-triangular, with rounded tips, not notched, but with a conspicuous fold on the out side at base, expanded, with whitish hairs inside ; tragus as long as the feet, slender, long-oval ; wings very thin, Avhen folded to the body reaching a little beyond the tip • of the nose, furnished near the body with scattered whitish hairs ; general colour blackish, with white transverse veins, edged with white for the whole extent of the hinder mar gin, which edging increases in size between the last finger and the foot, forming a whitish curved space inside the wing, about a quarter of an inch broad ; the interfemoral membrane is of a lighter colour than the wings, slightly curved on the margin, which is edged with white ; the feet free, claws white. Fur of the head and back dull cinna mon-grey, becoming pale towards the tail, the bases of the hairs blackish ; body beneath ashy white with a yellowish tinge, lightest near the tail ; bases of the hairs always black for a large portion of their length; tail and membrane clothed with scattered yellowish hairs on both sides.
Length (in a veiy young specimen) of head and body, 1 inch 2 lines ; of the tail, 1 inch 5 lines ; of the fore-arm, 1 inch 4 lines ; extent of mngs, 7 inches 4 lines.
|
package org.shimomoto.yakety.csv.field;
import org.jetbrains.annotations.NotNull;
import org.jetbrains.annotations.Nullable;
import org.shimomoto.yakety.csv.api.HasDisplayName;
import org.shimomoto.yakety.csv.field.api.MapFieldParser;
import java.util.EnumSet;
import java.util.Map;
public class BaseDomainMapParser<C, D extends Enum<D> & HasDisplayName>
implements MapFieldParser<C, D> {
private final C col;
private final Class<D> enumType;
public BaseDomainMapParser(final C col, final Class<D> enumType) {
this.col = col;
this.enumType = enumType;
}
@Override
public @Nullable D parse(@NotNull final Map<C, String> map) {
final @Nullable String value = map.get(col);
return EnumSet.allOf(enumType).stream()
.filter(e -> e.getDisplayName().equals(value))
.findFirst()
.orElse(null);
}
}
|
Command Line PHP Scripts
========================
This file describes how I am attempting to write the command line utility
scripts that will be used in the PHP CCM project.
Script utilities for the PHP CCM project will *generally* be written in PHP
except where PHP really does not make sense to do what needs to be done.
PHP Version
-----------
All scripts should work with all versions of PHP from 5.3.3 through the current
version of PHP (7.2.x as of 2018-02-22).
RHEL/CentOS 6 will continue to receive vendor support through
[November 30, 2020](https://wiki.centos.org/FAQ/General#head-fe8a0be91ee3e7dea812e8694491e1dde5b75e6d)
and CentOS 6 ships with PHP 5.3.3.
While I *highly* encourage system administrators of CentOS 6/7 to update to PHP
7.x, a frequent method of updating is to install the newer version of PHP
either within `/opt` or within `/usr/local` while leaving the operating system
provided version of PHP intact.
This means the update version of the `php` binary may not be available to
command line scripts, depending upon the `PATH` variable of the user calling
the script. Even when a CentOS 6 system administrator has installed a newer
version of PHP, the updated `php` binary used for command line scripts may not
be in the `PATH` used by the `rpm` utility or by the `cron` utility.
Script Shebang
--------------
All command line utility scripts must start with the shebang `#!/usr/bin/php`
as the very first line.
It was tempting to use `#!/usr/bin/env php` as that could bring in a newer
version of the PHP binary if a newer version is earlier in the defined `PATH`
when the script is invoked, however that makes it more difficult to use the
facilities of RPM to guarantee a suitable binary is available when the
scriptlets actually run.
Script Naming Scheme
--------------------
Executable command line scripts should __NOT__ end in `.php`. They should not
have any extension at all.
In the [CCM Github repository](https://github.com/AliceWonderMiscreations/CCM)
they should end in `.php` to make it obvious to users viewing the git tree that
they are PHP scripts, but when installed on the system they need to be without
the `.php` extension.
Binary PHP Extensions
---------------------
Unless absolutely necessary, PHP binary modules that are not part of a
‘standard’ PHP install should be avoided.
If the extension is part of a ‘standard’ PHP 7.x install but requires a PECL
extension for earlier PHP, as long as the extension exists then it is okay
to require it.
Non-Binary PHP Classes
----------------------
When a PHP CLI script requires a particular non-binary class, it must be a
class that works with PHP 5.3.3 and should be required full path. As many of
the PHP CLI scripts will be run by a user with administrative privileges, it is
dangerous to use an autoloader or the `phpinclude` path to find the needed file
to load.
PEAR
====
The CCM scripts related to managing PEAR will require PHP 5.4.0 or newer rather
that following the previously mentioned 5.3.3 version.
The PEAR management is completely optional. System administrators can continue
using whatever they currently use to manage PEAR packages and they will still
work with the PHP CCM project as long as the directory that contains their PEAR
modules is within the `phpinclude` path.
The current version of PEAR requires PHP 5.4.0 or newer. With that requirement
combined with nothing that needs to be run in an RPM post scriptlet or cron
job that will not also require PHP 5.4.0 or newer, there is no point at all
in requiring scripts related to PEAR management work with versions of PHP that
predate PHP 5.4.0.
|
How easy/difficult it is to create app to send text field to sql for Android?
I have basic knowledge of Java but have never developed for Android.
A friend asked me for an app that seems easy enough to develop but I would need some help for Android.
All the app needs to do is send a text field (for example license plate number) to a predetermined SQL Server database.
Is this easy in Android as it sounds?
Thanks in advance. Cheers.
Darko.
I'm not sure how we can help you here. Yes, it's perfectly doable and not terribly complicated. I'd say jump in and try to do it, and if you run into specific problems in the process, then that's when to ask those questions here.
That should be easy, but does it need to be a full-blown Android application for that?
Sounds like a simple webpage with an input-field and a submit button would do the job as well.
Thanks guys. My first thought was also that a full app is not needed at all, but maybe there is a reason behind it. It will be for a parking lot and maybe they want to avoid having a PC with paid windows license just for running few apps. Or maybe to avoid having a PC on-site at all. That is the only case where mobile app would be worth it that I can think of.
If you're familiar with using databases from Java the task is very simple. Just write the code that sends a string to a database. The exact same code you would use on a desktop Java application will do.
The rest is a matter of defining your user interface and obtaining the string. There is a good basic tutorial you can use on the Android developers web site: http://developer.android.com/guide/tutorials/notepad/index.html.
The number of code lines in the whole application will be in the range of a couple of dozens.
It sounds like you want the license plate information stored in a separate server, but if you also wanted to store some information on the device itself there is a simple Notepad tutorial provided by the Android Developers site that explains how to setup and utilize an SQLite database on the device. This by no means would replace the functionality of a server, but is another Android feature that is at your disposal.
|
The Palace of the Evil Shee
* Address: www.shee.demon.co.uk (offline, see archive)
* Webmaster: Lis Morris
* Ran from/to: 1999 - 2004
Summary Of Content
* Creatures 1 - Terra Nornia downloads, the Grorns, the Hippy Norns, and a C1 Shee creature
* Creatures 3 - Gaia, the Peace Grendels, and a few tools
|
With no explanation, label the following with either "negative", "neutral" or "positive".
I had previously gone to an Aveda salon, but was so disappointed that I had spent over $200 at one appointment only to have the color drastically fade within three weeks.
negative.
|
# frozen_string_literal: true
# rubocop:disable Style/BarePercentLiterals, Style/RescueModifier, Layout/SpaceInsideStringInterpolation, Style/UnneededPercentQ
module ActiveRecord
module ConnectionAdapters
class OracleEnhancedAdapter
# This method is near-verbatim from https://github.com/rsim/oracle-enhanced/tree/v1.6.7
# The only difference is under the value.acts_like?(:time) condition to
# patch a bug where it assumed that no fractional seconds meant the value
# was a Date, not a Time.
#
# Without the patch:
#
# [1] pry(main)> ActiveRecord::Base.connection.quote(Time.current.change(usec: 0))
# => "TO_DATE('2017-01-04 19:40:56','YYYY-MM-DD HH24:MI:SS')"
# [2] pry(main)> ActiveRecord::Base.connection.quote(Time.current.change(usec: 1))
# => "TO_TIMESTAMP('2017-01-04 19:40:58:000001','YYYY-MM-DD HH24:MI:SS:FF6')"
#
# With the patch:
#
# [1] pry(main)> ActiveRecord::Base.connection.quote(Time.current.change(usec: 0))
# => "TO_TIMESTAMP('2017-01-04 19:41:51:000000','YYYY-MM-DD HH24:MI:SS:FF6')"
# [2] pry(main)> ActiveRecord::Base.connection.quote(Time.current.change(usec: 1))
# => "TO_TIMESTAMP('2017-01-04 19:41:53:000001','YYYY-MM-DD HH24:MI:SS:FF6')"
#
# This patch should be disabled in config/environment.rb and removed after
# upgrading activerecord-oracle_enhanced-adapter to 1.7, which should
# coincide with an upgrade to Rails 5.
def quote(value, column = nil) #:nodoc:
if value && column
case column.type
when :text, :binary
%Q{empty_#{ type_to_sql(column.type.to_sym).downcase rescue 'blob' }()}
# NLS_DATE_FORMAT independent TIMESTAMP support
when :timestamp
quote_timestamp_with_to_timestamp(value)
# NLS_DATE_FORMAT independent DATE support
when :date, :time, :datetime
quote_date_with_to_date(value)
when :raw
quote_raw(value)
when :string
# NCHAR and NVARCHAR2 literals should be quoted with N'...'.
# Read directly instance variable as otherwise migrations with table column default values are failing
# as migrations pass ColumnDefinition object to this method.
# Check if instance variable is defined to avoid warnings about accessing undefined instance variable.
column.instance_variable_defined?("@nchar") && column.instance_variable_get("@nchar") ? "N" << super : super
else
super
end
elsif value.acts_like?(:date)
quote_date_with_to_date(value)
elsif value.acts_like?(:time)
quote_timestamp_with_to_timestamp(value)
else
super
end
end
end
end
end
# rubocop:enable Style/BarePercentLiterals, Style/RescueModifier, Layout/SpaceInsideStringInterpolation, Style/UnneededPercentQ
|
Xesta citrina, Linn.
Two varieties, one with lemon-colourel ground with a dark brown band on periphery of last whorl, the other dark brown above with a still darker band at periphery of last whorl, which is sharply contrasted by a white band below, the remainder of underside being of a glassy white colour.
Shell subcircular, with deep umbilicus about 2 mm. wide at upper part, white, smooth and polished, subtransparent, with a very narrow reddish-brown band at suture of upper whorls descending to edge of peristome and situate on last whorl just a little above the periphery (where it is about 1 mm. in width) ; spire almost flat, apex being slightly depressed ; whorls 4£, last descending about 2 mm. ; peri stome white, moderately expanded, margins joined by thin callus ; aperture snbovate, very oblique; constriction at rear of peristome very slight.
with smaller aperture and different coloration.
Thinner and more circular in form than cormcu\im } H. & J. ; the aperture is smaller and the peristome not so widely expanded. Compared with papuana, Mlldff., and semirasa, Marts., it is larger, not so flat, and not nearly so strongly constricted at rear of aperture.
|
import ConfigFactory from '../../context/factories/ConfigFactory';
import { ILogger } from '../../context/Logger/interfaces';
import { SignInResponse } from './enums';
import { IIAMService, IIAMServiceConfig, ILoginCreds } from './interfaces';
import { APP_ENV } from '../../context/Config/enums';
export default class PingId implements IIAMService {
protected cookieName: string | undefined;
protected logger: ILogger;
constructor(config: IIAMServiceConfig, logger: ILogger) {
this.cookieName = config.cookieName;
this.logger = logger;
}
public async getToken(): Promise<string> {
let token: string = '';
const config = ConfigFactory.getInstance();
try {
/**
* if env is not dev then
* getToken()
* @returns {String} token or empty string
*/
if (config.env !== APP_ENV.dev) {
if (this.cookieName) {
token = this.getCookieValue();
}
}
}
catch (err) {
this.logger.log('warn', `getToken: ${err.toString()}`);
}
return token;
}
public signIn = async (loginObj: ILoginCreds) => {
return SignInResponse.Ok;
}
public signOut = async () => {
return;
}
protected getCookieValue = () => {
let key: string;
let val: string;
let cookie: string = '';
document.cookie.split(';').forEach((cke) => {
key = cke.split('=')[0];
val = cke.split('=')[1];
if (key.trim() === this.cookieName) {
cookie = val;
}
});
return cookie;
}
}
|
Interpolation polynomials for $n$-tuples.
I apologise if this is a duplicate in any way or is off topic.
Given a (finite) set $S$ of $n$-tuples of real numbers, is there an interpolation polynomial that goes through each $s\in S$?
Motivation.
A common type of problem found on social media is to infer a pattern from a list of triples, usually in the form of a few evaluations of a binary operation, then apply that pattern to a couple. For instance,
If
$2+3=10,$
$7+2=63,$
$6+5=66,$
then what is $11+12$?
The intended answer is presumably $253$; the pattern you're supposed to infer is "$a+b=a(a+b)$".
It is my suspicion that the answer could be anything with enough imagination or, indeed, something akin to an interpolation polynomial.
You're intending that the last entry of the tuple is the output of a polynomial in the preceding $n - 1$ entries?
Yes, @Mr.Chip. ${}$
For each $s = (s_1, \dots, s_{n-1}, s_n) \in S$, define the following polynomial:
$$f_s = (x_1 - s_1)^2 + \dots + (x_{n-1} - s_{n-1})^2.$$
Then let
$$f = \sum_{s \in S} s_n \prod_{s' \ne s} \frac{f_{s'}}{f_{s'}(s_1, \dots, s_{n-1})}.$$
You'll now have $f(s_1, \dots, s_{n-1}) = s_n$. The idea is simply to generalise the factors $x - s$ in usual Lagrange interpolation to these functions $f_s$, which are chosen to be zero precisely at the point $s$.
|
Avoid live dependency on fonts.googleapis.com
Hello,
We have an application that should be able to run without internet access.
This is not compatible with the fact that some css on this project are importing font from fonts.googleapis.com.
I think that google fonts should be fully imported in the messenger project at build time. Deployed applications should not have to rely on any unmanaged provider to run correctly.
Perhaps, https://www.npmjs.com/package/google-fonts-offline could be used here.
|
Character and crew
Character stats and progression
Whenever a crew member gains a level they are allocated 5 STAT points to assign to various stats.
Skills and perks
* Additional damage
* Applying status effect bonuses
* Modifying resistances
* The ability to heal status effects.
* Finding better equipment in hacked lockers and chests.
* And more...
Inventory and equipped items
Every crew member has multiple equipment slots:
* Helmet - Base AC and up to three additional STAT bonuses depending on the quality
* Armor - Base AC and up to three additional STAT bonuses depending on the quality
* Gloves - Base AC and up to three additional STAT bonuses depending on the quality
* Boots - Base AC and up to three additional STAT bonuses depending on the quality
Weapons
* Primary weapon slot
* Rifles
* Beam rifles (various beam types)
* Shotguns
* Heavy weapons: Mini-gun, Plasma streamer, Rocket launcher, and Flame thrower
* Two hand pierce
* Two hand slash
* Two hand blunt
* Secondary weapon slot
* Pistols
* Beam pistols (various beam types)
* Sub-machine guns
* One hand pierce
* One hand slash
* One hand blunt
* Ranged weapon mods
* Scopes
* Grips
* Trigger groups
* Magazine expansions
* Nano augments
* Barrels
* Melee weapon mods
* Hafts
* Vibro mods
* Nano augments
Weapon Mods
* Just drag any mod for that weapon type to one of the slots
* Some mods are weapon specific
* Pistols and SMG's share mods so you can equip pistol mods on SMG's
* You cannot equip more than one mod type in any one weapon.
Weapon damage
* 1) Stats (DEX, STR, AGI etc)
* 2) Equipped mod bonuses
* 3) Equipped armor stat bonuses
* 4) Perk selection
Finding crew members
The crew manager
* You must have at least one crew member assigned to your space crew roster.
|
Add tauri version of examples/counter app
This is a working version of the counter example app, using Tauri 2.0.0 alpha with React. I'm opening this PR mainly to show that this combination works, and seems as clean as any of the other examples. This is all possible because of @charypar 's recent changes in #87. I'm not sure if we want to add this example to the repo. I realize that every example is a maintenance commitment, and we can't include everything.
Anyway, some notes:
much of the code is lifted from other counter examples (e.g. cli), so it should be pretty familiar
the UI is vanilla React, but the React component is copied from examples/web-nextjs
so far I've only built this in the desktop dev environment
I haven't packaged the app yet
I've tried building iOS unsuccessfully. Tauri mobile is still in alpha, and it's pretty unstable at the moment. I just haven't had time to slog through the errors. This should be easy to update once the Tauri dependency settles down.
Getting started
cd examples/counter
cargo build --package shared
cargo build --package shared_types
cd tauri
pnpm install
pnpm dev
@charypar cool, I'll fix this up today!
@charypar thanks for the review. I've updated the PR and fixed those issues. And now that the build command in the instructions is correct, you should actually be able to run this example 😄
Apologies for all the CI failures on this PR, I think we should be back in business now!
@wasnotrice no worries at all, thanks for figuring that stuff out!
|
Custom Permalinks issue with YOAST - Showing category.php before page-template.php
I have a problem with YOAST on my site. When it´s deactivated everything is fine, but if I activate YOAST the permalink to my template-pages stop working. Instead of going to the page-template.php file, they go straight to category.php instead.
Anyone know how to fix this issue?
After activating, try saving your premalinks in the settings. If that doesn't help check every setting in Yoast, is there a setting that uses the same slug as that page?
Iv´e tryied that. It work's if I choose any other permalink structure, it´s only a problem with custom permalink. The pages that dont work aren't a cpt, they only list cpt:s and work with a page-template.php file. The odd thing is that one page works, then it´s 6 or 7 who dont work...
|
Abstract
Clopidogrel is a commonly prescribed antiplatelet agent that carries a rare risk of hepatotoxicity. We describe a case of severe clopidogrel-induced hepatitis with liver biopsy assessment. Prompt recognition and withdrawal of the offending agent are imperative to prevent progression and potentially fatal liver injury.
1. Introduction
Clopidogrel is a commonly used antiplatelet agent, yet only several cases of hepatotoxicity have been described [116]. Liver biopsies were not performed in many of these cases. We report a rare case of severe clopidogrel-induced hepatitis with histological assessment.
2. Case Description
A 34-year-old male with a history of coronary artery disease and remote coronary artery stent was placed on aspirin plus clopidogrel. His baseline liver biochemistries were normal. He had been on clopidogrel for 2 months 12 years ago without adverse effects but discontinued the medication on his own at that time due to nonadherence. Four and a half months after restarting clopidogrel, he presented with jaundice and fatigue. He denied fever, rash, arthralgias, or abdominal pain. His only other medications were aspirin and metoprolol, which he had been on for many years with normal liver biochemistries.
The patient was not on a statin. He denied recent alcohol or herbal medications. Physical examination was significant only for icterus. There was no hepatosplenomegaly, clubbing, rash, asterixis, or other stigmata of chronic liver disease.
Initial bilirubin was 5.7 mg/dL (normal 0.2–1.2 mg/dL), ALT 1,393 U/L (normal 7–48 U/L), AST 1,418 U/L (normal 7–48 U/L), alkaline phosphatase 130 U/L (normal 35–115 U/L), INR 1.5, and partial prothrombin time 37 seconds (normal 15–37 seconds). Extensive serologies were negative to hepatitis A, hepatitis B, hepatitis C (including hepatitis C RNA), hepatitis E, IgM to cytomegalovirus and Epstein-Barr virus, anti-nuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, anti-liver kidney microsomal antibody, and ceruloplasmin.
Imaging studies were negative, and bile ducts were not dilated, including by ultrasound, computed tomography, and endoscopic retrograde cholangiopancreatography. No gallstones were present on any imaging modality. Liver biopsy revealed severe acute hepatitis with mixed inflammatory portal tract infiltrates including plasma cells, neutrophils and eosinophils, bile ductular reaction, patchy hepatocyte ballooning degeneration, and extensive periportal hepatocyte dropout, without fibrosis (Figure 1).
The patient was diagnosed with clopidogrel-induced severe hepatitis. Despite discontinuing clopidogrel, AST increased to 2,107 U/L, ALT to 1,567 U/L, and bilirubin to 37 mg/dL (predominately direct bilirubin). INR had increased to 2.1 despite empiric administration of vitamin K. A brief course of prednisone and ursodiol was initiated, with subsequent normalization of liver biochemistries.
3. Discussion
We describe a rare case of severe clopidogrel-induced hepatitis, with histological assessment. Our patient’s drug-induced hepatitis was particularly severe with jaundice (peak bilirubin 37 mg/dL), marked elevation of transaminases (peak ALT of 1,567 U/L), and coagulopathy (INR 2.1). This degree of hepatic injury portends an increased mortality and underscores the importance of early recognition and discontinuation of the offending agent.
Clopidogrel-induced hepatitis has been described [116]. Table 1 lists reported cases in reverse chronological order. The degree of liver injury has ranged from reversible liver injury and recovery [19, 1116] to acute hepatic failure and death [10]. Onset of liver injury in these cases ranges between 3 and 180 days [116]. Rechallenge confirmed clopidogrel-induced hepatitis in some of these cases [25]. Our patient’s Naranjo scale and RUCAM (Roussel Uclaf Causality Assessment Method) scores were both 8, indicating probable drug-induced hepatitis [17, 18].
Our patients liver biopsy revealed severe hepatocellular injury. This adds to the histological findings in clopidogrel-induced hepatitis, as liver biopsy was only performed in 3 of the previously reported cases [1, 2, 11]. Clopidogrel-induced liver injury can be cholestatic, hepatocellular [11], or mixed hepatocellular plus cholestatic [1, 2].
The exact mechanism of clopidogrel-induced hepatitis is unclear. The delayed onset of 4.5 months in our case suggests a toxic-metabolic etiology, whereas the inflammatory infiltrate and response to corticosteroids raise the possibility of a superimposed immune mediated mechanism of injury. Clopidogrel is a prodrug which is metabolized to inactive clopidogrel carboxylate (90%) and an active metabolite containing a mercapto group (10%) by cytochrome P450 3A4 and 2C19. In vitro studies suggest that the active metabolite is responsible for the hepatotoxicity and that high cytochrome 3A4 activities coupled with cellular glutathione depletion are potential risk factors [19]. Interestingly, an earlier antiplatelet agent, ticlopidine, has also been reported to cause drug-induced cholestatic hepatitis [20, 21].
Clopidogrel-induced hepatitis is a rare but potentially serious adverse effect. A high degree of clinical suspicion is required in patients presenting with abnormal liver biochemistries within a few months after starting clopidogrel. Prompt recognition and discontinuation of the offending agent are necessary, as progressive liver injury and even death can occur.
Competing Interests
The authors declare that they have no competing interests.
|
import matplotlib.pyplot as plt
#plt.style.use('ggplot')
import ipywidgets as widgets
import sys, os, io, string, shutil, math
import numpy as np
import re
import time
import threading
from threading import Thread
from io import StringIO
from ipywidgets import Layout, Box, Label, Output
from IPython.display import display,HTML
#sys.path.append('../python/')
#import train as nn
import random
import datetime
#from IPython.core.display import display, HTML
style = {'description_width': 'initial'}
# % is single line magic
# %% is magic cell
#!pip install jupyter_dashboards
#!jupyter dashboards quick-setup --sys-prefix
import glob, json
from codes.SSH import SSH
from codes.BagOfJobs import BagOfJobs
from ipyupload import FileUpload
class SSHAttributes:
def __init__(self, hostname = 'bigred3.uits.iu.edu', username = 'kadu', server_password = None, ssh_private_key = None, port = 22 ):
self.ssh = None
self.hostname = widgets.Text(
value=hostname,
description='Hostname: ',
style=style,
)
self.username = widgets.Text(
value=username,
description='Username: ',
style=style,
)
self.server_password = widgets.Password(
value=server_password,
description='Password: ',
placeholder='********',
style=style,
)
self.ssh_private_key = widgets.Dropdown(
options=['None'],
value='None',
description='ssh key: ',
style=style,
)
self.port = widgets.BoundedIntText(
value=port,
description='Port: ',
style=style,
)
self.connect_btn = widgets.Button(description='Connect')
self.connect_btn.on_click(self.onclick_coonect_btn)
self.attribute_widget = widgets.HBox([ self.hostname, self.username, self.server_password, self.ssh_private_key, self.port, self.connect_btn])
self.command_line = widgets.Text(
value='',
description='Enter Command: ',
style=style,
layout=Layout(flex='0 1 auto', width='100%')
)
self.execute_btn = widgets.Button(description='Execute')
self.execute_btn.on_click(self.onclick_execute_btn)
self.clear_btn = widgets.Button(description='Clear')
self.clear_btn.on_click(self.onclick_clear_btn)
self.command_exe_widget = widgets.HBox([ self.command_line, self.execute_btn, self.clear_btn ])
self.ssh_log = widgets.Textarea(
value='',
placeholder='',
disabled=True,
layout=Layout(flex='0 1 auto', height='100px', min_height='100px', width='100%')
)
group_area_layout=Layout(
display='flex',
border='solid 1px',
align_items='stretch',
padding='5px',
width='100%'
)
self.textlog_widget = widgets.HBox([ self.ssh_log])
self.wigetbox = widgets.VBox([self.attribute_widget, self.command_exe_widget, self.textlog_widget], layout=group_area_layout)
self.populate_ssh_key_drop()
def populate_ssh_key_drop(self):
file_path = os.path.join('ssh-config', '*')
self.all_keys = glob.glob(file_path)
self.ssh_private_key.options = ['None'] + [ item.replace("\\", "/").split('/')[-1] for item in self.all_keys]
if len(self.ssh_private_key.options) > 1:
self.ssh_private_key.value = self.ssh_private_key.options[1]
def onclick_coonect_btn(self, change):
try:
if self.connect_btn.description != 'Disconnect':
if self.username.value != '' and self.hostname.value != '' and self.port:
key_file = self.ssh_private_key.value
key_path = os.path.join('ssh-config', key_file)
if key_file != 'None':
self.ssh_log.value += "Connecting to %s with username=%s with ssh key...\n" %(self.hostname.value, self.username.value)
self.ssh = SSH(username = self.username.value, hostname = self.hostname.value, port = self.port.value, ssh_private_key = key_path)
elif self.server_password.value !='':
self.ssh_log.value += "Connecting to %s with username=%s with password...\n" %(self.hostname.value, self.username.value)
self.ssh = SSH(username = self.username.value, hostname = self.hostname.value, port = self.port.value, server_password = self.server_password.value)
else:
self.ssh_log.value += 'Please provide either ssh_private_key or server_password.\n'
if(self.ssh and self.ssh.sshclient):
self.connect_btn.description = 'Disconnect'
self.ssh_log.value += 'Connected...\n'
else:
self.connect_btn.description = 'Retry'
else:
self.ssh_log.value += 'Check username, hostname and port.\n'
else:
self.ssh.close_ssh()
self.ssh = None
self.connect_btn.description = 'Connect'
self.ssh_log.value += 'Connection colsed...\n'
except Exception as e: print(e)
def onclick_execute_btn(self, change):
try:
if(self.ssh and self.ssh.sshclient and self.command_line.value != ''):
(std_out_st, std_error_st) = self.ssh.execute_command(self.command_line.value)
self.ssh_log.value += std_out_st
self.command_line.value = ''
except Exception as e: print(e)
def onclick_clear_btn(self, change):
try:
self.command_line.value = ''
self.ssh_log.value = ''
except Exception as e: print(e)
class SSH_Manager:
def __init__(self):
self.num_of_ssh_connections = widgets.BoundedIntText(
value=1,
min=0,
max=100,
step=1,
description='How many SSH connections: ',
style=style,
)
self.ssh_description = widgets.HTML(
value="Upload a ssh key<b></b>",
placeholder='',
description=' ',
)
self.sshkey_upload = FileUpload(
# https://developer.mozilla.org/en-US/docs/Web/HTML/Element/input#attr-accept
# eg. '.txt', '.pdf', 'image/*', 'image/*,.pdf'
accept='', # default
# True to accept multiple files upload else False
multiple=False, # default
# True to disable the button else False to enable it
disabled=False, # default
# CSS transparently passed to button (a button element overlays the input[type=file] element for better styling)
# e.g. 'color: darkblue; background-color: lightsalmon; width: 180px;'
style_button='', # default
# to compress data from browser to kernel
# compress level from 1 to 9 incl. - 0 for no compression
compress_level=0 # default
)
self.save_btn = widgets.Button(description='Save the key')
self.save_btn.on_click(self.save_ssh_key)
self.connnect_all = widgets.Button(description='Connect all')
self.connnect_all.on_click(self.connnect_all_clicked)
self.check_queue_info = widgets.Button(description='Check queue info')
self.check_queue_info.on_click(self.check_queu_info_click)
self.header_wigetbox = widgets.HBox([self.num_of_ssh_connections, self.connnect_all, self.check_queue_info, self.ssh_description, self.sshkey_upload, self.save_btn])
#self.ssh_connections = [SSHAttributes()]
#self.ssh_connections = [SSHAttributes(), SSHAttributes(username = 'nhewagam'), SSHAttributes(username = 'vjadhao'), SSHAttributes(username = 'huanshen'), SSHAttributes(username = 'knilsson'), SSHAttributes(username = 'nbrunk'), SSHAttributes(username = 'lm44')]
self.ssh_connections = [SSHAttributes(), SSHAttributes(username = 'nhewagam'), SSHAttributes(username = 'vjadhao')]
#self.attributes_widgets = widgets.VBox([self.ssh_connections[0].wigetbox])
self.attributes_widgets = widgets.VBox([item.wigetbox for item in self.ssh_connections])
self.num_of_ssh_connections.value = len(self.ssh_connections)
#self.footer_wigetbox = widgets.HBox([self.gen_config_btn])
self.text_area_for_ssh = widgets.Textarea(
value='',
placeholder='',
disabled=True,
layout=Layout(flex='0 1 auto', height='100px', min_height='100px', width='100%')
)
self.textlog_widget = widgets.HBox([ self.text_area_for_ssh])
group_area_layout=Layout(
display='flex',
border='solid 1px',
align_items='stretch',
padding='5px',
width='100%'
)
self.wigetbox = widgets.VBox([self.header_wigetbox, self.attributes_widgets, self.textlog_widget], layout = group_area_layout)
self.num_of_ssh_connections.observe(self.onChange_num_of_ssh_connection,'value')
def onChange_num_of_ssh_connection(self, change):
try:
if int(change.new) > int(change.old):
for i in range(int(change.new) - int(change.old)):
self.ssh_connections.append(SSHAttributes())
self.attributes_widgets.children += (self.ssh_connections[-1].wigetbox,)
elif int(change.new) < int(change.old):
self.attributes_widgets.children = self.attributes_widgets.children[:change.new]
self.ssh_connections = self.ssh_connections[:change.new]
except Exception as e: print(e)
def save_ssh_key(self, change):
try:
if self.sshkey_upload.value:
for filename, data in self.sshkey_upload.value.items():
self.text_area_for_ssh.value += 'File is being uploaded.\n'
file_path = os.path.join('ssh-config', filename)
with open(file_path, "bw") as file:
file.write(data['content'])
self.refresh_drop_key()
self.text_area_for_ssh.value += 'key file: {} should be available to select.\n'.format(filename)
else:
self.text_area_for_ssh.value += 'Please select a private key file to save.\n'
except Exception as e: print(e)
def refresh_drop_key(self):
try:
for con in self.ssh_connections:
con.populate_ssh_key_drop()
except Exception as e: print(e)
def check_queu_info_click(self, change):
try:
for connection_ in self.ssh_connections:
command_str = 'qstat -u ' + connection_.username.value
if(connection_.ssh and connection_.ssh.sshclient):
(std_out_st, std_error_st) = connection_.ssh.execute_command(command_str)
connection_.ssh_log.value += std_out_st
except Exception as e: print(e)
def connnect_all_clicked(self, change):
try:
if self.connnect_all.description == 'Connect all':
self.connnect_all.description = 'Disconnect all'
elif self.connnect_all.description == 'Disconnect all':
self.connnect_all.description = 'Connect all'
self.text_area_for_ssh.value += 'Clicking all connect/disconnect buttons...\n'
for connection_ in self.ssh_connections:
connection_.onclick_coonect_btn({})
#connection_.wigetbox
self.text_area_for_ssh.value += 'Clicking Done.\n'
except Exception as e: print(e)
|
User:MShefa
About me
I am proud of my Afghan heritage! I have been on Wikipedia since November 21st, 2006.
|
# terraform-shell-resource
[](https://travis-ci.org/matti/terraform-shell-resource)
This module runs a command as a `null_resource` and makes the stdout, stderr and exit status available as outputs (with temporary files stored in the module). See an external data source version with more features at https://github.com/matti/terraform-shell-outputs (that runs on every apply, this one only runs once when the resource is created).
*warning* there is a support for `trigger` to re-run the module, but while it runs the command it does not update the outputs! There is nothing we can do before related issues (see below) are fixed.
```
module "files" {
source = "matti/resource/shell"
command = "ls -l"
}
output "my_files" {
value = "${module.files.stdout}
}
```
## Additional examples
See [tests](tests)
## Related issues:
- https://github.com/hashicorp/terraform/issues/17337
- https://github.com/hashicorp/terraform/issues/6830
- https://github.com/hashicorp/terraform/issues/17034
- https://github.com/hashicorp/terraform/issues/10878
- https://github.com/hashicorp/terraform/issues/8136
- https://github.com/hashicorp/terraform/issues/18197
- https://github.com/hashicorp/terraform/issues/17862
|
LINK+SHEET+PROJECT
=Resources for "Create your own Link Sheet Project"=
[|LINK SHEET PROJECT DIRECTIONS AND RUBRIC.doc]
[|LINK SHEET PROJECT TEMPLATE (A) GRAPH.doc]
[|LINK SHEET PROJECT TEMPLATE (B) TABLE.doc]
[|LINK SHEET PROJECT TEMPLATE (C) EQUATION.doc]
|
COVID-19 Pandemic, Physical Distancing Policies, and the Non-Profit Sector Volunteer Force
Although COVID-19-related physical distancing has had large economic consequences, the impact on volunteerism is unclear. Using volunteer position postings data from Canada’s largest volunteer center (Volunteer Toronto) from February 3, 2020, to January 4, 2021, we evaluated the impact of different levels of physical distancing on average views, total views, and total number of posts. There was about a 50% decrease in the total number of posts that was sustained throughout the pandemic. Although a more restrictive physical distancing policy was generally associated with fewer views, there was an initial increase in views during the first lockdown where total views were elevated for the first 4 months of the pandemic. This was driven by interest in COVID-19-related and remote work postings. This highlights the community of volunteers may be quite flexible in terms of adapting to new ways of volunteering, but substantial challenges remain for the continued operations of many non-profit organizations.
Introduction
Despite the impacts of COVID-19 on paid labor being widely reported (Bell & Blanchflower, 2020), the effects of physical distancing policies on the provision of volunteer labor have received relatively little attention.Research has discussed the number of individuals recruited for COVID-19-related volunteer drives, COVID-19-related volunteering activities, and the characteristics of volunteers (Mak & Fancourt, 2022;Mao et al., 2021;Mo et al., 2022;Sin et al., 2021), with most studies being qualitative analyses of the experiences of volunteers during the COVID-19 pandemic (Cooney & McCashin, 2022;Seddighi et al., 2020;Sengupta & Al-Khalifa, 2022).The impacts of lockdowns on COVID-19 caseloads, employment, and healthrelated outcomes have been studied extensively (Brodeur et al., 2021), yet few studies have examined the effect of initiating and loosening of COVID-19 restrictions on demand for or interest to volunteer.One study highlighted increased contributions to Wikipedia during lockdowns (Ruprechter et al., 2021), and another reported on the proportion of volunteers increasing, decreasing, or maintaining the same level of volunteering during a lockdown (Mak & Fancourt, 2022).However, the overall advertised demand for volunteers and interest to volunteer over time during the COVID-19 pandemic and impacts of lockdowns have not been studied.We address this by examining the evolution in the interest in and amount and nature of formal job postings by non-profit organizations (NPOs) through the most popular coordination platform in Canada's largest city.Unlike most prior crises, which tend to be localized and to last for a short term (Rotolo et al., 2015), COVID-19 is a more drawn-out and widespread affair.Therefore, we also contribute to the crisis volunteering literature where there has been relatively limited quantification of changes in overall levels of volunteering (Lim & Laurence, 2015;Penner et al., 2005;Rotolo et al., 2015), and little is known about the demand for or interest by volunteers in long-running crises (Twigg & Mosel, 2017).This article is structured as follows: Section 2 presents a review of the literature on volunteering during times of crisis and how the COVID-19 pandemic may have influenced volunteering.Section 3 discusses the study setting and data, study variables, and statistical analyses.Section 4 presents the primary and secondary analyses.Finally, Section 5 provides a summary and discussion of the study implications.
Literature Review
Individuals typically respond in crisis times by helping those affected through greater levels of informal and formal volunteering.Penner et al. (2005) found a very large increase in individuals contacting organizations to volunteer after the 9/11 terrorist attacks in the United States, which was primarily driven by crisis-related activities.This response lasted 3 weeks, after which volunteering returned to pre-9/11 levels for the next 3 months (Penner et al., 2005).Rotolo et al. (2015) examined the American home foreclosure crisis and found that greater metropolitan area-level foreclosures had a positive effect on the overall rates of self-reported volunteering (Rotolo et al., 2015).
Volunteer responses to natural disasters such as earthquakes and hurricanes are common and frequently consist of both formal organizations such as the Red Cross and informal volunteering such as spontaneous volunteers (Hustinx & Lammertyn, 2004;Strandh & Eklund, 2018;Twigg & Mosel, 2017).These spontaneous volunteers often include family, friends, or neighbors who typically assist at the neighborhood level through a variety of activities (Strandh & Eklund, 2018;Twigg & Mosel, 2017).These responses can be large with upward of 60% to 70% of the population responding and volunteers numbering in the millions (Twigg & Mosel, 2017).Prior studies on crisis volunteerism have tended to examine the nature of the response (Simsa et al., 2019), motivations (Hustinx & Lammertyn, 2004;Marjanovic et al., 2009), or characteristics of participants (Twigg & Mosel, 2017).However, there has been relatively limited quantification of changes in overall levels of volunteering (Lim & Laurence, 2015;Penner et al., 2005;Rotolo et al., 2015), and little is known about responses to longrunning crises (Twigg & Mosel, 2017).
The rich literature on crisis volunteerism suggests that there may be an increase in volunteering in response to the COVID-19 pandemic driven by positions that respond directly to the pandemic's effects.However, the COVID-19 crisis is more widespread and long-lasting than many prior-studied crises.Due to the high risk of transmission, morbidity, and death, COVID-19 likely places greater risks on volunteers than past social-economic crises such as recessions, foreclosure, and refugee crises (Lim & Laurence, 2015;Rotolo et al., 2015;Simsa et al., 2019).However, COVID-19 risks may be comparable to risks in spontaneous volunteering during natural disasters, which are associated with physical injuries and poor mental health (Sauer et al., 2014).These health risks are particularly important for older individuals who volunteer more hours on average (Hahmann et al., 2020).Meanwhile, in contrast to prior crises, physical distancing policies and health risks restrict many of the most common volunteer activities and settings such as hospitals (Pickell et al., 2020), in-person services (e.g., friendly visiting), and events and fundraisers (Hahmann et al., 2020).Economic models of volunteering examine both investment and consumption motives and would predict reduced interest in volunteering due to greater costs caused by health risks and decreased benefits given there may be less enjoyment and gains in human and social capital among a much more restricted selection of volunteer activities and settings (Govekar P. L. & Govekar M. A., 2002).In contrast to other crises, Lim and Laurence (2015) demonstrated that both formal and informal volunteerism decreased during the 2008 to 2009 recession in the United Kingdom, suggesting the recession caused by COVID-19 may have a similar negative influence.COVID-19 and the subsequent recession have been particularly challenging for NPOs who have seen revenues decrease (Lasby, 2021), program cuts (Kim & Mason, 2020), and layoffs of half the number of volunteer managers (Kurek, 2020).There have also been greater costs with the transition to virtual programming and the need to create new programs (Lasby, 2020).These changes in combination with restrictions in the types of feasible volunteer activities and settings would suggest a decrease in demand for volunteers by non-profits (Govekar P. L. & Govekar M. A., 2002).
Setting and Data
Although Canada at the federal level had modest success in enlisting volunteers (i.e., ~35,000-54,000 volunteers), the volunteers from one program (~54,000) were never used (Miller, 2020), and another program was canceled (Press, 2020).There have also been no successful large-scale recruitment initiatives by the provincial government (Ontario) or city (Toronto).Eight months into the pandemic, roughly 60% of Canadian non-profit leaders reported reduced volunteer numbers and hours (Lasby, 2021).
Toronto is Canada's largest city with over 2.9 million residents (2018), and Volunteer Toronto is Canada's largest volunteer center.We used Volunteer Toronto's repository of volunteer position postings advertised online using the YourMembership volunteer system.Non-profit organizations who post positions include registered charities, volunteer-run organizations, public agencies/organizations, and associations/ groups (e.g., religious, community, sport clubs, etc.).
Volunteer postings are active for 90 days, after which they can be renewed.Given that the time over which postings accumulated views was not recorded, starting on February 3, 2020, the data on postings were collected (i.e., downloaded) from the online system every 1 to 4 days (mean 1.3 days) to enable calculation of views and the time between subsequent days when the data were collected.The sample included postings that were active (i.e., searchable on the website) for at least 2 days between February 3, 2020, and January 4, 2021.Postings were only included in the sample on active days as inactive posts do not accumulate views.
Study Variables
Dependent Variables.We defined the demand for volunteers as the total number of active postings each day.The number of views between subsequent collections reflects the interest of people in volunteering.The daily number of views was converted into a daily rate by adjusting the number of views for the variable number of hours between data collections (i.e., daily rate = number of views/hours*24).The data are limited as they only measure interest in formal volunteer positions rather than actual volunteer behavior such as the number of recruited volunteers or volunteer hours worked.
Primary Independent Variables.The primary independent variables were the initiation and relaxing of physical distancing measures by the provincial government.Following the World Health Organization declaration of COVID-19 as a pandemic on March 11, 2020, a widely publicized lockdown was initiated across Ontario and included the cancelation of in-person classes, closure of city services and non-essential businesses, and restrictions on gatherings to five people (all instituted during March 11-28, 2020) (Patton, 2020; Rocca & Shah, 2020).Subsequently, Toronto went through multiple other stages with different levels of restrictions including Stage 2 (June 24), (least restrictive) Stage 3 (July 31), Modified Stage 2 (October 10), and a second lockdown (November 23).Description of these policies is included in the Supplemental Appendix Table A1.
Covariates/Characteristics.On March 19, 2020, Volunteer Toronto implemented a COVID-19-related response to promote remote and COVID-19-related volunteer positions.A category for COVID-19 positions was added in the search function to make COVID-19 positions highly visible.A "COVID-19 Volunteer Response Team" was formed, and members were sent emails every 3 to 7 days with COVID-19 positions.Volunteer Toronto staff also promoted remote volunteer positions in one-on-one phone calls with prospective volunteers.To explore the potential influence of this programmatic response to the pandemic and the response by citizens to engage in COVID-19 volunteerism, we classified positions as COVID-19 or remote.We identified a position as COVID-19 where the primary category was "COVID-19 response" or if the position included "COVID" or "Corona" in the job title.We identified remote posts as positions classified as "Volunteer from home" or if the position included the words "remote" or "from home" in the job title.Weekly COVID-19 hospitalization numbers (City of Toronto, 2021) and 3-month average of unemployment rates (Statistics Canada, 2021) were also included given these factors represent community needs (i.e., perceived problems) (Ziemek, 2006) that can motivate individuals to volunteer for altruistic purposes and to isolate the influence of physical distancing policies from COVID-19 case loads and economic impacts.
We also examined position type categories, which are the category for the position chosen by the individual who created the volunteer posting.Given there were categories with few (i.e., 3% or less) observations, we combined similar categories together as follows (original and revised categories shown in Supplemental Appendix Table A2).Given that COVID-19 positions did not have a separate category listed to further distinguish the type of position, this may have resulted in artificial decreases in views and post numbers across the original (i.e., pre-COVID-19) set of position types.Therefore, we also characterized positions as event assistance, food related, support with errands, non-food-related drivers or movers, social/mental health, and technology positions by using a combination of position type categories and position title keyword searches (Supplemental Appendix Table A3).We also used organization lists to categorize positions as hospital, rehabilitation hospital, or long-term care (LTC) positions (Toronto Central Healthline, 2021;City of Toronto, 2020).
Analysis.The number of active postings, average rate of views, and total of the daily rate of views were graphed.The number of active posts and total of the daily rate of views were also graphed and by type of position.Given there was a large day-to-day variability in views and in active posts by type of position, weekly averages were graphed.
Segmented regressions were used (Wagner et al., 2002), which model the number of views a volunteer posting receives as function of changes in level (i.e., assessing immediate changes) and changes in the time trend/slope (i.e., assessing gradual changes) following each of the five physical distancing periods, while controlling for the pre-existing time trend prior to physical distancing being introduced.Models also controlled for the weekly number of COVID-19 cases, monthly unemployment, and day of the week.
Given views are a count, we used Poisson regressions with robust variance estimation clustering on the posting to estimate the segmented regression models.The offset was set to the natural log of the hours between data collections.To model the data longitudinally, we used random-effects Poisson regression and generalized estimating equations (GEEs) with a Poisson specification and autoregressive of Order 2 correlation matrix, with both types of models estimated with robust standard errors.To account for repeated observations on each posting, GEE models adjust the variance with a covariance structure while random-effects models use posting-specific intercepts (Gardiner et al., 2009) providing complementary approaches given their alternative assumptions and interpretations (GEE: effect on average views across all postings; random effects: effect on average views holding the posting random effect fixed) (Gardiner et al., 2009).In a secondary analysis, a separate Poisson GEE model examined the effect of a volunteer posting being a COVID-19 or remote volunteer position controlling for days of the week, unemployment rate, and weekly COVID-19 cases.All analyses were conducted using Stata version 16.1.
There was a large decrease in active postings with the onset of physical distancing policies, which was consistently ~50% lower throughout the observation period (Figure 2A).After an initial dip lasting most of March, the daily rates of views and total views increased during the pandemic, and by the end of June, total views returned to and were maintained at pre-physical-distancing levels throughout the rest of the year (Figure 2B/C).The daily rate of views remained elevated throughout the year.The initial increase was largely driven by views of COVID-19 and remote positions, which were highly elevated until late July.There was a large initial decrease in the number of postings (Supplemental Appendix Figure 1A) and total views (Supplemental Appendix Figure 1B) for hospital/LTC and event assistance positions, which continued throughout the rest of the year (Supplemental Appendix Figure 1A).There were large increases in total views for food, driver-movers, social services, and support positions, especially during the first 4 months of the pandemic.
Only the first lockdown period had a change in level that was consistently significant and negative across models, suggesting a large immediate decrease during the first lockdown (Incident Rate Ratio [IRR] range = 0.51-0.73;p < .001)(Table 1, Supplemental Appendix Table 4).However, the first lockdown had a significantly positive change in slope, suggesting a gradual increase in views during this period (IRR range = 1.06-1.14;p < .001).Overall, periods with more restrictive physical distancing including Stage 2 and Modified Stage 2 were associated with negative changes in slope (IRR range = 0.82-0.93;p ≤ .01).The least restrictive physical distancing period, Stage 3, was associated with a positive change in slope in random-effects models only (IRR = 1.07; p = .045).There was an approximately 2.66-fold (p < .001)increase in views among COVID-19-related positions and 1.8-fold (p < .001)increase in remote positions.
Discussion
Our findings demonstrate that the COVID-19 pandemic and associated physical distancing has had large impacts on volunteerism in Toronto, Canada.This study found a large (~50%) initial decrease in the number of postings starting with the first lockdown, which remained low throughout the duration of this phase of the pandemic.Although more restrictive physical distancing was generally associated with declining interest in volunteering, during the first lockdown, there were greater total views and a gradual increase in views.Total views remained elevated during the first 4 months of physical distancing restrictions and were driven primarily by large interest in COVID-19-related and remote volunteering positions.Our results highlight the short-and longer-term impacts of COVID-19 and COVID-19-related restrictions, such as lockdowns, on aggregate measures of volunteerism.Furthermore, our results demonstrate that crises can fundamentally change the nature of volunteerism, from in-person to remote, as well as the mix of volunteer organizations and positions available.Finally, they demonstrate, that although long-term demand for volunteers remained similar throughout the year, similar to other crises such as 9/11 (Penner et al., 2005), the volunteer response was relatively short-lived in comparison.
The large shift to COVID-19-related and remote volunteering provides evidence that volunteers are flexible in terms of adapting to new ways of volunteering.The increase in views for COVID-19 positions and COVID-19-related positions such as food distribution, social and mental health roles, and support for errands is similar to that during past natural disasters (Twigg & Mosel, 2017) and past pandemics such as the AIDS pandemic (Omoto & Snyder, 1993).However, this response only lasted approximately 4 months after which total views returned to baseline levels and COVID-19 and remote position views were only slightly elevated relative to other posts.Average views remained elevated throughout the pandemic, but this may be in part because there were approximately half as many posts.Long-term analysis of crises is understudied (Twigg & Mosel, 2017), and our results and a prior study on the 9/11 terrorist attack (Penner et al., 2005) suggest that the volunteer response to some crises might be relatively short-lived.It is not possible to identify the reasons for this short-lived response, but similar experiences with COVID-19-related volunteerism have been described elsewhere (Mao et al., 2021).It is possible that community needs became less apparent when lockdowns were loosened or that these needs may have been addressed to a greater extent by governments (Ziemek, 2006), especially given the large benefits administered by the Canadian government during the pandemic.Alternatively, over time, individuals may have become tired of this emergency, and volunteer efforts may be hard to sustain (Mao et al., 2021).Future, qualitative, and survey-based research should investigate the reasons for these findings.
The introduction of physical distancing measures was accompanied by a large decrease in active positions which points to a significant decrease (~50%) in demand for volunteers by the non-profit sector.This was sustained even with efforts to promote COVID-19/remote positions, additional assistance provided by Volunteer Toronto to NPOs, and with lessening of COVID-19 physical distancing restrictions (i.e., Stage 3), suggesting that the demand may not return to pre-COVID-19 levels until the end of the pandemic.Large decreases in total views and posts for hospitals/ LTC institutions suggest that COVID-19 health risks to volunteers and clients likely impeded the ability of non-profits to continue volunteer recruitment.The strict limits on the size of indoor gatherings (5-10 people) throughout much of the pandemic are also likely responsible for decreases in volunteer recruitment given the large and sustained decrease in event assistance volunteering views and posts.These results may also highlight operational challenges that NPOs face, which restrict recruitment of volunteers, such as reduced donations, program cuts, and layoffs of approximately half the number of volunteer managers (Kurek, 2020).Operational challenges have been reported by non-profits in Canada (Lasby, 2020), the United States (Kim & Mason, 2020), and globally (CAF America, 2020), suggesting our results are generalizable beyond Toronto or Canada.
The decreases in demand for volunteers likely resulted in further negative effects of physical distancing for the most vulnerable members of society such as hospital/LTC patients who disproportionately receive services from NPOs.The decrease in opportunities to volunteer may have contributed to unintended negative consequences for individuals who want to volunteer such as lower well-being (Jenkinson et al., 2013).Further policies may be needed to stimulate the demand for volunteers to continue engaging the labor expertise of volunteers, similar to what occurred in the paid employment sector where payments to small businesses by the government were implemented (The Canadian Press, 2020).
Nonetheless, this study is not without limitations.First, the study relied on administrative databases that measure metrics for a large number of units (i.e., thousands of posts among hundreds of organizations) repetitively over time, which is rare among the volunteerism literature and enabled a detailed examination of the influence of different lockdowns, including immediate (i.e., level changes) and delayed (i.e., slope changes).However, the data lacked many variables included in theoretical models of organizational demand for volunteer labor (e.g., volunteer management practices and instruments, organizational attitudes and values, etc.; Studer & von Schnurbein, 2013), which future research should investigate.There was also a lack of qualitative data, which could further explain the findings or provide a deeper understanding of the actions of different NPOs, volunteers, governments, and Volunteer Toronto during different phases of COVID-19 and physical distancing.Collection of qualitative data by future studies such as interviews, analysis of field notes, and document analysis is recommended and will likely help clarify which specific elements of the pandemic, government policies, and programmatic response by the non-profit sector were most impactful and why.Second, volunteer postings were only for formal volunteer positions recruited by non-profits and do not reflect spontaneous volunteering, which has been a common response to past crises such as natural disasters (Twigg & Mosel, 2017) and COVID-19 in some other countries (Monbiot, 2020).Third, the database did not measure the number of people who applied for volunteer positions or completed volunteer hours.However, there is likely a significant relationship between viewing volunteer postings and applying to volunteer positions given 8,000 individuals signed up for the COVID-19 Response team email list, and prior studies examining online volunteer posting data have also been limited by a lack of data on actual volunteer commitments (Penner et al., 2005).Therefore, further research is needed that quantifies the amount of formal and informal volunteering in response to COVID-19.Fourth, given that individuals do not register to visit a post website, a single individual may have contributed to multiple views across posts.
Conclusions
Large increases in COVID-19-related, remote, and food distribution roles demonstrate volunteers were responsive to the needs of the community.However, decreases in the demand for volunteers highlight decreased opportunities for individuals to volunteer, which may contribute to unintended negative impacts on individuals, and operational challenges faced by NPOs which may limit their ability to provide services to those in need.Our findings demonstrate that crises can have long-lasting impacts on the mix of volunteer positions and organizations' recruitment and that while demand for crisisrelated volunteers may remain high over longer periods of time, sustaining interest in volunteers may be challenging.
France Gagnon is a professor of epidemiology and the associate dean of research at the Dalla Lana School of Public Health, University of Toronto.Her research focuses on identifying genetic and epigenetic determinants of cardiovascular diseases and risk factors and the application of polygenic risk scores.
Audrey Laporte is a professor of health economics, the Director of the Canadian Centre for Health Economics, and the Director of the Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto.Her research focuses on the development of micro-economic theory and the application of micro-econometric methods to address questions of policy interest to health and health care.
Figure 1 .
Figure 1.Breakdown of Categories for Remote and Non-Remote Positions.
Figure 2 .
Figure 2. (A) Daily Number of Active Postings.(B) Weekly Average of the Rate Of Posting Views.(C) Weekly Average of Daily Total Rate of Posting Views.*One week had a rate of 149.2.
Table 1 .
Segmented Regression Analysis of the Effect of Physical Distancing Policies on the Mean Rate of Daily Views.aGEEPoissonregression w/ robust SEAlso controlled for days of the week, unemployment rate, and weekly COVID-19 cases.b Modeled continuously as weeks since the start of the period (and coded 0 prior to that day). a
|
Thread:BoltBlizard/@comment-26187158-20150708203013/@comment-26187158-20150709194332
Yeah, Ender's blocked now, So I'mma just take them back.
|
Warriors Wiki talk:Characters
Willowbreeze - kittypet
I agree with you, but let's see what others think. 23:05, March 8, 2015 (UTC)
Graystripe nevet stayed willingly. He got the KP image because of how long he stayed, I think.
how on earth is being stuffed into a cage being treated as a kittypet? 06:37, March 11, 2015 (UTC)
Exactly. Neither Tall or Willow should get it, imho. 07:45, March 11, 2015 (UTC)
Agreeing with Burnt. 00:23, March 26, 2015 (UTC)
Is it agreed or not? 04:54, April 16, 2015 (UTC)
Is it agreed that they both don't get kittypet ranks or something? 07:57, April 22, 2015 (UTC)
No it isn't, we ned more opinions. 11:56, April 22, 2015 (UTC)
Is there anymore comments? I don't think this is resolved. 23:07, June 15, 2015 (UTC)
A cat stuffed in a cage is not a kittypet. 06:31, June 20, 2015 (UTC)
Alright, lets review the book a little, as I am certain she did more than sit in a cage.
* Hailstar: Did they hurt her?
* Crookedjaw: They just carried her to their den.
* Hailstar: They didn’t harm her at all? Did they seem angry? Pg 299
Even Hailstar figures out the Twolegs will not and never did hurt Willowbreeze.
* Crookedjaw: I can see her! They’ve got her in some sort of trap and they’re teasing her. It later described the box den close enought to a cardboard box.
* Twolegs were bursting out of the dens all over the meadow, flashing lights and howling. Pg 309
Spoiler Tag
I'd say go for it, do you want me to start now? 07:38, April 16, 2015 (UTC)
Maybe let's wait a bit longer for other people to comment. 23:49, April 17, 2015 (UTC)
Alright let's do it. 06:02, May 5, 2015 (UTC)
-nudges conversation- Storm ♫ 17:09, June 5, 2015 (UTC)
What exactly do you mean Storm? This is sounds interesting. 01:41, June 17, 2015 (UTC)
She means exactly what I suggested above. It's a show/hide thing that reduces clutter.
Maybe we could edit that and bumble it around a little bit to fit on every page. Like I know how Firestar's page is ridiculously long, and I mean really long. It would help reduce the size of the page if we put those kinds of drop down menus for every book/novella/whatever that they've been in. But in books that they're only in the allegiances and not seen in the book, we can keep those there, but still have them in the show/hide thing. I think we should make the spoiler tag thing more visible as well. Storm ♫ 02:00, June 17, 2015 (UTC)
Descriptions alongside toggles
hi can we get some input on this 03:03, March 29, 2015 (UTC)
Is anyone else going to comment on this?
I guess it'd be safe to go ahead and do that 00:47, April 27, 2015 (UTC)
Not a bad idea, maybe right under the formal description? 00:27, May 16, 2015 (UTC)
Anymore comments? 23:07, June 15, 2015 (UTC)
Suggestion
Demote them. I think that would bring them to attention. 11:41, May 14, 2015 (UTC)
That sounds fair enough to me 11:58, May 14, 2015 (UTC)
Descriptions / Synonyms
Anymore comments? 21:51, June 22, 2015 (UTC)
Yep - i mean some one made Hollyleaf's description to much like... well... holly.
Page Numbers Idea-ish
Toggle to Tabbers
Hmm, if the coding will make everything easier than sure. 21:51, June 22, 2015 (UTC)
Ivypool ~ mentor
Bumblestripe ~ name
I agree. He is named once Bumbleflight and every single other time Bumblestripe. It makes sense to.
Yo, speaking of FAs...
Patchkit sounds perfect! His page is very well-written ^^ 22:45, June 13, 2015 (UTC)
It looks like everyone likes Patchkit. Any other comments? 21:51, June 22, 2015 (UTC)
Content Drive
Alternate Descriptions
Snowbird and Mosspelt
Kinfolk
I like that idea, renaming Family to kin. Makes it more warriors like. 21:51, June 22, 2015 (UTC)
Owlstar
I support as well. Storm ♫ 14:49, June 17, 2015 (UTC)
We can certainly seperate them now. 21:46, June 18, 2015 (UTC)
Request to Join?
May I join? YOU'VE MET WITH A TERRIBLE FATE, HAVEN'T YOU? 18:28, June 16, 2015 (UTC)
Thanks for that Atelda. I'll add you Stealthheart. 23:08, June 22, 2015 (UTC)
Could use some editing...
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William Heisten, Respondent, v. Beech-Nut Packing Company, Appellant.
— Order unanimously modified by eliminating the provision for examination through Bartlett Arkell, and by striking from the last paragraph of the order the words “ with leave to plaintiff to inspect and make copies or photostats thereof,” and by providing that there may be a limited inspection and use of papers and documents under the rule laid down in Zeltner v. Fidelity & Deposit Co. (220 App. Div. 21), and as so modified affirmed, without costs. The date for the examination to proceed to be fixed in the order. Settle order on notice. Present — Martin, P. J., McAvoy, O’Malley, Townley and Dore, JJ.
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Android's Firestore's snapshot listener on query takes too long (1 min) to update from the network when returning from being in the background
I'm seeing terrible update frequency when resuming the app after it had been in the background for a while. If I kill and re-launch the app from scratch it'll usually query the most recent data fine. Similarly, when I first start listening for snapshots it works as expected, receiving data as soon as the firestore data is updated.
It is only after the app has been in the background for too long (say 1-2 hours) and I reopen it that I see the query return cached data but not receive an update from the network for 30-90 seconds.
Here's my query:
firestore.collection(GAMES_COLLECTION)
.whereGreaterThanOrEqualTo("time_utc", start)
.whereLessThanOrEqualTo("time_utc", end)
.orderBy("time_utc")
.addSnapshotListener { snapshot, e ->
val games = snapshot.map { doc -> doc.toObject(GameEntity::class.java) }
}
The "Game" document is not too complex either (19 primitive fields and 1 array field that has 0-3 elements)
The "time_utc" field is an int that has one of the automatic indexes enabled (ascending/descending)
I've tried subscribing in a couple of different ways to see if that's the problem but I really doubt that's the problem given that it's not a problem of the subscription being lost or something, if I stay for long enough (1 minute) I'll eventually get an update. I'm subscribing on jetpack's ViewModel's init and unsubscribing in onCleared() (i.e. fragment's onCreate/ onDestroy).
I also tried having a single "global" subscription (started in the Application class' onCreate()) in case it was a "cold start" issue but that doesn't work either.
Also tried using .get().addOnSuccessListener() on that same query through a manual refresh when I know the data is stale and I'm not getting network updates but it immediately returns the same cached data.
Offline persistence is enabled, I have not setup any caching limits.
Using firestore 21.5.0
EDIT: Found more folks dealing with the same exact problem but in the flutter SDK:
https://github.com/FirebaseExtended/flutterfire/issues/4305
My Flutter app with Firestore experiences very slow queries when it is resumed from the background on Android
I don't know how firestore work internally, what happen with the connection in few hours in background, maybe there are connectivity manager or other constructs and the connection may terminated, but I think that for sure you shouldn't keep snapshotListener in the background for hours/days (when you click home button viewmodel's onClear() not called).
I think it's wrong way to add snapshotListener in viewmodel's init block and unsubscribe in onClear, you should subscribe/unsubscribe at least at onStart()/onStop().
This way you subscribing again in onStart() and the initial problem with delay disappear, and also you don't leak resources(connection) when the app in background.
I'll have to test this out, but wouldn't onClear() get called when the fragment is detached? E.g. when navigating between fragments in a bottom navigation view.
When you navigate between fragments via replace() method, onClear is called(if it not a shared view model that attached to activity), but you said "It is only after the app has been in the background for too long" so I guess the app is not terminated and you clicked home button.
Sorry it was a bit misleading. You're right that going home won't clear it, but after returning to the foreground and even navigating between tabs (that I verified do trigger onCleared and recreation of the VM) it'll take up to a minute to callback with network data.
In fact, every single screen (bottom tab) that is using a firestore snapshot will be blank until that minute passes and all of a sudden all data in all screens will load.
I suspect it has more to do the with the retry backoff strategy that firestore uses for the entire instance (not just a single query/snapshot). It seems to go into a bad state and no new snapshots will come in until this retry timer (of 60s) expires and all of a sudden ALL snapshots start working again
The snapshot have delay with 1 minute and even not returns old data when attached listener? whereGreaterThanOrEqualTo("time_utc", start).whereLessThanOrEqualTo("time_utc", end) you sure don't have here issue with your time interval, that may contain no items that match the query, and match the query only after 1 min?
Is does return cached data immediately, but "fresh" (i.e. network) data doesn't show up until after a minute even though new data has been in the backend for 30-60minutes before opening the app again.
It's surely not an issue with the query - the documents returned by that query are the exact same during the whole day, only a few fields of the documents change every minute. I've also tried with a clean project with only 1 document (no where clause) that contains a "now" field with the current timestamp. I see the same behavior.
Looks like other people have this issue with the Flutter SDK which leads me to believe that it's on the SDK or server side.
https://github.com/FirebaseExtended/flutterfire/issues/4305
https://stackoverflow.com/questions/63434654/my-flutter-app-with-firestore-experiences-very-slow-queries-when-it-is-resumed-f#comment116410663_63434654
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