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2,336,000 |
Frailty assessed by administrative tools and mortality in patients with pneumonia admitted to the hospital and ICU in Wales.
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The ideal method of identifying frailty is uncertain, and data on long-term outcomes is relatively limited. We examined frailty indices derived from population-scale linked data on Intensive Care Unit (ICU) and hospitalised non-ICU patients with pneumonia to elucidate the influence of frailty on mortality. Longitudinal cohort study between 2010-2018 using population-scale anonymised data linkage of healthcare records for adults admitted to hospital with pneumonia in Wales. Primary outcome was in-patient mortality. Odds Ratios (ORs [95% confidence interval]) for age, hospital frailty risk score (HFRS), electronic frailty index (eFI), Charlson comorbidity index (CCI), and social deprivation index were estimated using multivariate logistic regression models. The area under the receiver operating characteristic curve (AUC) was estimated to determine the best fitting models. Of the 107,188 patients, mean (SD) age was 72.6 (16.6) years, 50% were men. The models adjusted for the two frailty indices and the comorbidity index had an increased odds of in-patient mortality for individuals with an ICU admission (ORs for ICU admission in the eFI model 2.67 [2.55, 2.79], HFRS model 2.30 [2.20, 2.41], CCI model 2.62 [2.51, 2.75]). Models indicated advancing age, increased frailty and comorbidity were also associated with an increased odds of in-patient mortality (eFI, baseline fit, ORs: mild 1.09 [1.04, 1.13], moderate 1.13 [1.08, 1.18], severe 1.17 [1.10, 1.23]. HFRS, baseline low, ORs: intermediate 2.65 [2.55, 2.75], high 3.31 [3.17, 3.45]). CCI, baseline < 1, ORs: '1-10' 1.15 [1.11, 1.20], > 10 2.50 [2.41, 2.60]). For predicting inpatient deaths, the CCI and HFRS based models were similar, however for longer term outcomes the CCI based model was superior. Frailty and comorbidity are significant risk factors for patients admitted to hospital with pneumonia. Frailty and comorbidity scores based on administrative data have only moderate ability to predict outcome.
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2,336,001 |
Targeted smoking cessation for dual users of combustible and electronic cigarettes: a randomised controlled trial.
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Although many smokers use electronic cigarettes (e-cigarettes) to quit smoking, most continue to smoke while vaping. This dual use might delay cessation and increase toxicant exposure. We aimed to test the efficacy of a self-help intervention designed to help dual users to quit smoking.</AbstractText>In this three-arm randomised controlled trial we recruited individuals in the USA using Facebook and multimedia advertisements. Included participants were 18 years or older, smoked at least weekly in the preceding year, and vaped at least weekly in the preceding month. We used computer generated randomisation with balanced-permuted blocks (block size 10, with 2-4-4 ratio) to allocate participants to assessment only (ASSESS group), generic smoking cessation self-help booklets (GENERIC group), or booklets targeting dual users (eTARGET group). Individuals in the generic or targeted intervention groups received monthly cessation materials for 18 months, with assessments every 3 months for 24 months. The main outcome was self-reported 7-day point-prevalence smoking abstinence at each assessment point. All randomly allocated participants were included in primary analyses using generalised estimating equations for each of 20 datasets created by multiple imputation. Analysis of the χ2</sup>s produced an F test. The trial is registered with ClinicalTrials.gov, NCT02416011, and is now closed.</AbstractText>Between July 12, 2016, and June 30, 2017, we randomly assigned 2896 dual users (575 to assessment, 1154 to generic intervention, and 1167 to targeted self-help). 7-day point-prevalence smoking abstinence increased from 14% at 3 months to 42% at 24 months (F7,541·7</sub>=67·1, p<0·0001) in the overall sample. Targeted self-help resulted in higher smoking abstinence than did assessment alone throughout the treatment period (F1,973·8</sub>=10·20, p=0·0014 [α=0·017]). The generic intervention group had abstinence rates between those of the assessment and targeted groups, but did not significantly differ from either when adjusted for multiple comparisons (GENERIC vs eTARGET F1,1102·5</sub>=1·79, p=0·18 [α=0·05]; GENERIC vs ASSESS F1,676·7</sub>=4·29, p=0·039 [α=0·025]). Differences between study groups attenuated after the interventions ended.</AbstractText>A targeted self-help intervention with high potential for dissemination could be efficacious in promoting smoking cessation among dual users of combustible cigarettes and e-cigarettes.</AbstractText>National Institute on Drug Abuse, National Cancer Institute.</AbstractText>Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.</CopyrightInformation>
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2,336,002 |
Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish.
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The differentiation of hematopoietic stem cells (HSCs) is tightly controlled to ensure a proper balance between myeloid and lymphoid cell output. GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of HSCs. GATA2 is expressed throughout development, but because of early embryonic lethality in mice, its role during adult hematopoiesis is incompletely understood. Zebrafish contains 2 orthologs of GATA2: Gata2a and Gata2b, which are expressed in different cell types. We show that the mammalian functions of GATA2 are split between these orthologs. Gata2b-deficient zebrafish have a reduction in embryonic definitive hematopoietic stem and progenitor cell (HSPC) numbers, but are viable. This allows us to uniquely study the role of GATA2 in adult hematopoiesis. gata2b mutants have impaired myeloid lineage differentiation. Interestingly, this defect arises not in granulocyte-monocyte progenitors, but in HSPCs. Gata2b-deficient HSPCs showed impaired progression of the myeloid transcriptional program, concomitant with increased coexpression of lymphoid genes. This resulted in a decrease in myeloid-programmed progenitors and a relative increase in lymphoid-programmed progenitors. This shift in the lineage output could function as an escape mechanism to avoid a block in lineage differentiation. Our study helps to deconstruct the functions of GATA2 during hematopoiesis and shows that lineage differentiation flows toward a lymphoid lineage in the absence of Gata2b.
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2,336,003 |
32-Channel self-grounded bow-tie transceiver array for cardiac MR at 7.0T.
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Design, implementation, evaluation, and application of a 32-channel Self-Grounded Bow-Tie (SGBT) transceiver array for cardiac MR (CMR) at 7.0T.</AbstractText>The array consists of 32 compact SGBT building blocks. Transmission field ( <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>B</mml:mi><mml:mn>1</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:math> ) shimming and radiofrequency safety assessment were performed with numerical simulations and benchmarked against phantom experiments. In vivo <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>B</mml:mi><mml:mn>1</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:math> efficiency mapping was conducted with actual flip angle imaging. The array's applicability for accelerated high spatial resolution 2D FLASH CINE imaging of the heart was examined in a volunteer study (n = 7).</AbstractText><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>B</mml:mi><mml:mn>1</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:math> shimming provided a uniform field distribution suitable for female and male subjects. Phantom studies demonstrated an excellent agreement between simulated and measured <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msubsup><mml:mi>B</mml:mi><mml:mn>1</mml:mn><mml:mo>+</mml:mo></mml:msubsup></mml:math> efficiency maps (7% mean difference). The SGBT array afforded a spatial resolution of (0.8 × 0.8 × 2.5) mm3</sup> for 2D CINE FLASH which is by a factor of 12 superior to standardized cardiovascular MR (CMR) protocols. The density of the SGBT array supports 1D acceleration of up to R = 4 (mean signal-to-noise ratio (whole heart) ≥ 16.7, mean contrast-to-noise ratio ≥ 13.5) without impairing image quality significantly.</AbstractText>The compact SGBT building block facilitates a modular high-density array that supports accelerated and high spatial resolution CMR at 7.0T. The array provides a technological basis for future clinical assessment of parallel transmission techniques.</AbstractText>© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.</CopyrightInformation>
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2,336,004 |
Formoterol PLGA-PEG Nanoparticles Induce Mitochondrial Biogenesis in Renal Proximal Tubules.
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Formoterol is a long-acting β<sub>2</sub> agonist (LABA). Agonism of the β<sub>2</sub>-adrenergic receptor by formoterol is known to stimulate mitochondrial biogenesis (MB) in renal proximal tubules and recover kidney function. However, formoterol has a number of cardiovascular side effects that limits its usage. The goal of this study was to design and develop an intravenous biodegradable and biocompatible polymeric nanoparticle delivery system that targets formoterol to the kidney. Poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide) nanoparticles containing encapsulated formoterol were synthesized by a modified single-emulsion solvent evaporation technique resulting in nanoparticles with a median hydrodynamic diameter of 442 + 17 nm. Using primary cell cultures of rabbit renal proximal tubular cells (RPTCs), free formoterol, encapsulated formoterol polymeric nanoparticles, and drug-free polymeric nanoparticles were biocompatible and not cytotoxic over a wide concentration range. In healthy male mice, polymeric nanoparticles were shown to localize in tubules of the renal cortex and improved the renal localization of encapsulated formoterol compared to the free formoterol. At a lower total formoterol dose, the nanoparticle localization resulted in increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), the master regulator of MB, and increased electron transport chain proteins, markers of MB. This was confirmed by direct visual quantification of mitochondria and occurred with both free formoterol and the encapsulated formoterol polymeric nanoparticles. At the same time, localization of nanoparticles to the kidneys resulted in reduced induction of MB markers in the heart. These new nanoparticles effectively target formoterol to the kidney and successfully produce MB in the kidney.
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2,336,005 |
Analysis of Epidural Waveform to Determine Correct Epidural Catheter Placement After CSE Labor Analgesia.
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The epidural pressure is pulsatile and synchronized with arterial pulsations. Monitoring the epidural waveform has been suggested as a technique to reliably confirm the appropriate localization of the epidural catheter.</AbstractText>The aim of this study was to evaluate the sensitivity and specificity of the Computer Controlled Drug Delivery System with continuous pressure and waveform sensing technology (CCDDS) (CompuFlo®</sup> CathCheck™) as an instrument to assess the correct placement of the catheter in the epidural space in parturients who have received combined spinal-epidural technique (CSE) for labor analgesia.</AbstractText>We enrolled 40 consecutive healthy patients undergoing CSE labor analgesia with successful analgesia. All the cases in which pulsatile waveforms in synchrony with heart rate were detected were considered to be true positives; all the cases in which there was the absence of pulsatile waves were followed up. If these patients had to eventually relocate or manipulate the epidural catheter, they were considered to be true negative. If the absence of pulse waves was observed in the presence of successful analgesia during labor, the patients were considered to be false negatives.</AbstractText>Pulsatile waveforms synchronous with heart rate were observed in 33 cases associated with adequate analgesia. In 5 cases, the pulsatile waveforms were absent due to unilateral analgesia or catheter occlusion (true negatives). In 2 cases, the patients had effective analgesia but we were not able to observe a distinct pulsatile waveform. The pressure waveform analysis through the epidural catheter had a sensitivity of 95%, a positive predictive value of 100%, a specificity of 100% and a negative predictive value of 60%.</AbstractText>Pulsatile pressure waveform recording with CCDDS through the epidural catheter resulted in high sensitivity and positive predictive value which can help the proper placement of the epidural catheter.</AbstractText>© 2021 Coccoluto et al.</CopyrightInformation>
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2,336,006 |
A systematic review and meta-analysis of the effects of general anesthesia combined with continuous paravertebral block in breast cancer surgery and postoperative analgesia.
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This study aimed to compare the effects of general anesthesia (GA) combined with continuous paravertebral block (CPVB) in breast cancer surgery via systematic review and meta-analysis, in order to provide a theoretical basis for the clinical use of CPVB surgical analgesia.</AbstractText>A search of the PubMed, Embase, Medline, Ovid, Springer, and Web of Science databases was conducted to screen clinical trials on GA + CPVB for breast cancer surgery published before December 31, 2020. The Cochrane Handbook for Systematic Reviews of Intervention 5.0.2 was adopted for bias risk assessment, and Review Manager 5.3 software (RevMan, The Cochrane Collaboration, http://tech.cochrane.org/revman) was applied for meta-analysis of the literature.</AbstractText>A total of 15 studies that satisfied the requirements were included, involving a total of 1,435 research subjects. The results of our meta-analysis showed the following: the visual analogue scale (VAS) score of the observation group (group A) was significantly reduced [mean difference (MD) =-0.68; 95% confidential interval (CI): -1.04 - -0.33; Z=3.80; P=0.0001]; the level of monocyte chemoattractant protein -1 (MCP-1) was notably decreased (MD =-18.64; 95% CI: -29.68 - -7.61; Z=3.31; P=0.0009); the level of tumor necrosis factor-α (TNF-α) was markedly lower (MD =-1.89; 95% CI: -2.66 - -1.13; Z=4.87; P<0.00001); the interleukin-6 (IL-6) level was obviously reduced (MD =-12.10; 95% CI: -19.22 - -4.99; Z=3.33; P=0.0009); and the incidence of postoperative adverse reactions was substantially decreased (MD = 0.16; 95% CI: 0.07-0.36; Z=4.47; P<0.00001). Compared with group B, the differences of the above five indicators showed statistical significance. In addition, the heart rate (HR) (MD =-1.56; 95% CI: -6.20 - 3.08; Z=0.66; P=0.51), mean arterial pressure (MAP) (MD = 4.66; 95% CI: -0.12 -9.43; Z=1.91; P=0.06), Ramsay score (MD =0.44; 95% CI: -0.06-0.93; Z=1.73; P=0.08) of patients in group A showed no statistical differences compared to group B.</AbstractText>GA + CPVB applied to breast cancer surgery for analgesia can reduce the levels of MCP-1, TNF-α, and IL-6 in patients, thereby providing good postoperative analgesia. Therefore, GA + CPVB could effectively reduce the incidence of pain and adverse reactions in patients, and is effective for analgesia in breast cancer surgery.</AbstractText>2021 Gland Surgery. All rights reserved.</CopyrightInformation>
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2,336,007 |
Structure, Immunogenicity, and Conformation-Dependent Receptor Binding of the Postfusion Human Metapneumovirus F Protein.
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Human metapneumovirus (hMPV) is an important cause of acute viral respiratory infection. As the only target of neutralizing antibodies, the hMPV fusion (F) protein has been a major focus for vaccine development and targeting by drugs and monoclonal antibodies (MAbs). While X-ray structures of trimeric prefusion and postfusion hMPV F proteins from genotype A, and monomeric prefusion hMPV F protein from genotype B have been determined, structural data for the postfusion conformation for genotype B is lacking. We determined the crystal structure of this protein and compared the structural differences of postfusion hMPV F between hMPV A and B genotypes. We also assessed the receptor binding properties of the hMPV F protein to heparin and heparan sulfate (HS). A library of HS oligomers was used to verify the HS binding activity of hMPV F, and several compounds showed binding to predominantly prefusion hMPV F, but had limited binding to postfusion hMPV F. Furthermore, MAbs to antigenic sites III and the 66-87 intratrimeric epitope block heparin binding. In addition, we evaluated the efficacy of postfusion hMPV B2 F protein as a vaccine candidate in BALB/c mice. Mice immunized with hMPV B2 postfusion F protein showed a balanced Th1/Th2 immune response and generated neutralizing antibodies against both subgroup A2 and B2 hMPV strains, which protected the mice from hMPV challenge. Antibody competition analysis revealed the antibodies generated by immunization target two known antigenic sites (III and IV) on the hMPV F protein. Overall, this study provides new characteristics of the hMPV F protein, which may be informative for vaccine and therapy development. <b>IMPORTANCE</b> Human metapneumovirus (hMPV) is an important cause of viral respiratory disease. In this paper, we report the X-ray crystal structure of the hMPV fusion (F) protein in the postfusion conformation from genotype B. We also assessed binding of the hMPV F protein to heparin and heparan sulfate, a previously reported receptor for the hMPV F protein. Furthermore, we determined the immunogenicity and protective efficacy of postfusion hMPV B2 F protein, which is the first study using a homogenous conformation of the protein. Antibodies generated in response to vaccination give a balanced Th1/Th2 response and target two previously discovered neutralizing epitopes.
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2,336,008 |
Repeated greater occipital nerve injections with corticosteroids in medically intractable chronic cluster headache: a retrospective study.
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Current prophylactic drugs for cluster headache are associated with limited efficacy, serious side effects and poor tolerability. Greater occipital nerve injection (GON-injection) has been proven effective and safe as a single, one-time injection in episodic (ECH), and to a lesser extent, chronic cluster headache (CCH). We aim to analyse the effectiveness and safety of repeated GON-injections in medically intractable chronic cluster headache (MICCH).</AbstractText>Clinical data of all cluster headache patients who had received at least one GON-injection between 2014 and 2018 in our tertiary headache centre were retrieved from patients' medical records. Clinical history was taken as part of routine care shortly before and 6 weeks after GON-injection.</AbstractText>We identified 47 MICCH patients (79 injections), and compared results with 22 non-MI CCH patients (30 injections) and 50 ECH patients (63 injections). Nineteen MICCH patients received repeated injections (32 in total, range 2-8). Rates of clinical relevant improvement to a first injection were similar in all groups (MICCH: 60%, non-MICCH 73%, ECH 76%; attack freedom: MICCH: 30%, non-MICCH 32%, ECH 43%). Furthermore, no difference in response to the first and second injection was shown between groups (all p > 0.29). Median effect duration in MICCH was 6 weeks (IQR 2.8-12 weeks). Side effects were only mild and local.</AbstractText>In this retrospective analysis, first and repeated GON-injections were well-tolerated and equally effective in MICCH as in non-MICCH, and ECH.</AbstractText>© 2021. The Author(s).</CopyrightInformation>
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2,336,009 |
Combined spinal epidural anesthesia in obese parturients undergoing cesarean surgery : A single-blinded randomized comparison of lateral decubitus and sitting positions.
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There is a significant increase in number of obese pregnant women worldwide. Obese parturients undergoing cesarean section have a higher risk for hypotension and require higher doses of vasopressors following spinal anesthesia compared to nonobese parturients.</AbstractText>This study aimed to compare the maternal hemodynamic changes when combined spinal-epidural anesthesia (CSEA) is induced in the left lateral decubitus and sitting positions in obese pregnant women undergoing elective cesarean section.</AbstractText>In this study, pregnant women with full-term gestation diagnosed as obese undergoing elective cesarean section were included. Two groups were formed: the CSEA was performed in left lateral position in group I (n = 50) and in sitting position in group II (n = 50). At the end of the CSEA procedure, patients were placed in the supine position. When the sensory block reached at the upper level of T6 dermatome, surgery was initiated. Hemodynamic, anesthetic and neonatal parameters were recorded.</AbstractText>In all patients, CSEA was successful and sufficient anesthesia was provided for surgery. Time to reach T6 dermatome sensory level in group II was found to be longer than group I (P = 0.011). At 20 min after spinal injection, the maximum sensory block level was similar in both groups. There were no significant differences between groups in terms of sensory block time and the time to requiring postoperative supplemental analgesics. There were no significant differences in terms of the volume of intravenous fluid administered, ephedrine and atropine requirements between groups. Both groups had similar systolic blood pressure, heart rate and oxygen saturation values during surgery and postoperatively. While both groups had similar diastolic blood pressure (DBP) values during surgery and at the 1st postoperative hour, group II had lower DBP values at the 2nd postoperative hour compared with group I (P = 0.04).</AbstractText>Left lateral decubitus and sitting positions during performance of CSEA lead to similar maternal hemodynamic changes in obese pregnant women undergoing cesarean section.</AbstractText>© 2021. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.</CopyrightInformation>
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2,336,010 |
A prospective, randomized, single-blinded, crossover trial to investigate the effect of a wearable device in addition to a daily symptom diary for the remote early detection of SARS-CoV-2 infections (COVID-RED): a structured summary of a study protocol for a randomized controlled trial.
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It is currently thought that most-but not all-individuals infected with SARS-CoV-2 develop symptoms, but that the infectious period starts on average two days before the first overt symptoms appear. It is estimated that pre- and asymptomatic individuals are responsible for more than half of all transmissions. By detecting infected individuals before they have overt symptoms, wearable devices could potentially and significantly reduce the proportion of transmissions by pre-symptomatic individuals. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests [to determine if there are antibodies against the SARS-CoV-2 in the blood] or SARS-CoV-2 infection tests such as polymerase chain reaction [PCR] or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the following two algorithms to detect first time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava bracelet data when coupled with self-reported Daily Symptom Diary data (Wearable + Symptom Data Algo; experimental condition) the algorithm using self-reported Daily Symptom Diary data alone (Symptom Only Algo; control condition) In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing.</AbstractText>The trial is a randomized, single-blinded, two-period, two-sequence crossover trial. All subjects will participate in an initial Learning Phase (varying from 2 weeks to 3 months depending on enrolment date), followed by two contiguous 3-month test phases, Period 1 and Period 2. Each subject will undergo the experimental condition (the Wearable + Symptom Data Algo) in one of these periods and the control condition (Symptom Only Algo) in the other period. The order will be randomly assigned, resulting in subjects being allocated 1:1 to either Sequence 1 (experimental condition first) or Sequence 2 (control condition first). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence.</AbstractText>The trial will be conducted in the Netherlands. A target of 20,000 subjects will be enrolled. Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence. This results in approximately 6,500 normal-risk individuals and 3,500 high-risk individuals per sequence. Subjects will be recruited from previously studied cohorts as well as via public campaigns and social media. All data for this study will be collected remotely through the Ava COVID-RED app, the Ava bracelet, surveys in the COVID-RED web portal, and self-sampling serology and PCR kits. During recruitment, subjects will be invited to visit the COVID-RED web portal ( www.covid-red.eu ). After successfully completing the enrolment questionnaire, meeting eligibility criteria and indicating interest in joining the study, subjects will receive the subject information sheet and informed consent form. Subjects can enrol in COVID-RED if they comply with the following inclusion and exclusion criteria.</AbstractText>Resident of the Netherlands At least 18 years old Informed consent provided (electronic) Willing to adhere to the study procedures described in the protocol Must have a smartphone that runs at least Android 8.0 or iOS 13.0 operating systems and is active for the duration of the study (in the case of a change of mobile number, study team should be notified) Be able to read, understand and write Dutch Exclusion criteria: Previous positive SARS-CoV-2 test result (confirmed either through PCR/antigen or antibody tests; self-reported) Previously received a vaccine developed specifically for COVID-19 or in possession of an appointment for vaccination in the near future (self-reported) Current suspected (e.g., waiting for test result) COVID-19 infection or symptoms of a COVID-19 infection (self-reported) Participating in any other COVID-19 clinical drug, vaccine, or medical device trial (self-reported) Electronic implanted device (such as a pacemaker; self-reported) Pregnant at time of informed consent (self-reported) Suffering from cholinergic urticaria (per the Ava bracelet's User Manual; self-reported) Staff involved in the management or conduct of this study INTERVENTION AND COMPARATOR: All subjects will be instructed to complete the Daily Symptom Diary in the Ava COVID-RED app daily, wear their Ava bracelet each night and synchronise it with the app each day for the entire period of study participation. Provided with wearable sensor and/or self-reported symptom data within the last 24 hours, the Ava COVID-RED app's underlying algorithms will provide subjects with a real-time indicator of their overall health and well-being. Subjects will see one of three messages, notifying them that: no seeming deviations in symptoms and/or physiological parameters have been detected; some changes in symptoms and/or physiological parameters have been detected and they should self-isolate; or alerting them that deviations in their symptoms and/or physiological parameters could be suggestive of a potential COVID-19 infection and to seek additional testing. We will assess intraperson performance of the algorithms in the experimental condition (Wearable + Symptom Data Algo) and control conditions (Symptom Only Algo).</AbstractText>The trial will evaluate the use and performance of the Ava COVID-RED app and Ava bracelet, which uses sensors to measure breathing rate, pulse rate, skin temperature, and heart rate variability for the purpose of early and asymptomatic detection and monitoring of SARS-CoV-2 in general and high-risk populations. Using laboratory-confirmed SARS-CoV-2 infections (detected via serology tests, PCR tests and/or antigen tests) as the gold standard, we will determine the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for each of the following two algorithms to detect first-time SARS-CoV-2 infection including early or asymptomatic infection: the algorithm using Ava Bracelet data when coupled with the self-reported Daily Symptom Diary data, and the algorithm using self-reported Daily Symptom Diary data alone. In addition, we will determine which of the two algorithms has superior performance characteristics for detecting SARS-CoV-2 infection including early or asymptomatic infection as confirmed by SARS-CoV-2 virus testing. The protocol contains an additional seventeen secondary outcomes which address infection incidence rates, health resource utilization, symptoms reported by SARS-CoV-2 infected participants, and the rate of breakthrough and asymptomatic SARS-CoV-2 infections among individuals vaccinated against COVID-19. PCR or antigen testing will occur when the subject receives a notification from the algorithm to seek additional testing. Subjects will be advised to get tested via the national testing programme, and report the testing result in the Ava COVID-RED app and a survey. If they cannot obtain a test via the national testing programme, they will receive a nasal swab self-sampling kit at home, and the sample will be tested by PCR in a trial-affiliated laboratory. In addition, all subjects will be asked to take a capillary blood sample at home at baseline (Month 0), and at the end of the Learning Phase (Month 3), Period 1 (Month 6) and Period 2 (Month 9). These samples will be used for SARS-CoV-2-specific antibody testing in a trial-affiliated laboratory, differentiating between antibodies resulting from a natural infection and antibodies resulting from COVID-19 vaccination (as vaccination will gradually be rolled out during the trial period). Baseline samples will only be analysed if the sample collected at the end of the Learning Phase is positive, and samples collected at the end of Period 1 will only be analysed if the sample collected at the end of Period 2 is positive. When subjects obtain a positive PCR/antigen or serology test result during the study, they will continue to be in the study but will be moved into a so-called "COVID-positive" mode in the Ava COVID-RED app. This means that they will no longer receive recommendations from the algorithms but can still contribute and track symptom and bracelet data. The primary analysis of the main objective will be executed using data collected in Period 2 (Month 6 through 9). Within this period, serology tests (before and after Period 2) and PCR/antigen tests (taken based on recommendations by the algorithms) will be used to determine if a subject was infected with SARS-CoV-2 or not. Within this same time period, it will be determined if the algorithms gave any recommendations for testing. The agreement between these quantities will be used to evaluate the performance of the algorithms and how these compare between the study conditions.</AbstractText>All eligible subjects will be randomized using a stratified block randomization approach with an allocation ratio of 1:1 to one of two sequences (experimental condition followed by control condition or control condition followed by experimental condition). Based on demographics, medical history and/or profession, each subject will be stratified at baseline into a high-risk and normal-risk group within each sequence, resulting in equal numbers of high-risk and normal-risk individuals between the sequences.</AbstractText><AbstractText Label="BLINDING (MASKING)" NlmCategory="UNASSIGNED">In this study, subjects will be blinded as to study condition and randomization sequence. Relevant study staff and the device manufacturer will be aware of the assigned sequence. The subject will wear the Ava bracelet and complete the Daily Symptom Diary in the Ava COVID-RED app for the full duration of the study, and they will not know if the feedback they receive about their potential infection status will only be based on data they entered in the Daily Symptom Diary within the Ava COVID-RED app or based on both the data from the Daily Symptom Diary and the Ava bracelet.</AbstractText><AbstractText Label="NUMBERS TO BE RANDOMISED (SAMPLE SIZE)" NlmCategory="UNASSIGNED">20,000 subjects will be recruited and randomized 1:1 to either Sequence 1 (experimental condition followed by control condition) or Sequence 2 (control condition followed by experimental condition), taking into account their risk level. This results in approximately 6,500 normal-risk and 3,500 high-risk individuals per sequence.</AbstractText>Protocol version: 1.2, dated January 22nd</sup>, 2021 Start of recruitment: February 22nd</sup>, 2021 End of recruitment (estimated): April 2021 End of follow-up (estimated): December 2021 TRIAL REGISTRATION: The trial has been registered at the Netherlands Trial Register on the 18th</sup> of February, 2021 with number NL9320 ( https://www.trialregister.nl/trial/9320 ) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.</AbstractText>
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2,336,011 |
On the origin of germ cell neoplasia in situ: Dedifferentiation of human adult Sertoli cells in cross talk with seminoma cells in vitro.
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Germ cell neoplasia in situ (GCNIS) is the noninvasive precursor of testicular germ cell tumors type II, the most common cancer in young men, which originates from embryonic germ cells blocked in their maturation. GCNIS is associated with impaired Sertoli cells (SCs) that express fetal keratin 18 (KRT18) and the pluripotency factor SRY-Box transcription factor 2 (SOX2). According to the current theory concerning the origin of GCNIS, these SCs are prepubertal cells arrested in their maturation due to (epi)genetic anomalies and/or environmental antiandrogens. Thus, they are unable to support the development of germ cells, which leads to their maturational block and further progresses into GCNIS. Alternatively, these SCs are hypothesized to be adult cells dedifferentiating secondarily under the influence of GCNIS. To examine whether tumor cells can dedifferentiate SCs, we established a coculture model of adult human SCs (FS1) and a seminoma cell line similar to GCNIS (TCam-2). After 2 wk of coculture, FS1 cells showed progressive expression of KRT18 and SOX2, mimicking the in vivo changes. TCam-2 cells showed SOX2 expression and upregulation of further pluripotency- and reprogramming-associated genes, suggesting a seminoma to embryonal carcinoma transition. Thus, our FS1/TCam-2 coculture model is a valuable tool for investigating interactions between SCs and seminoma cells. Our immunohistochemical and ultrastructural studies of human testicular biopsies with varying degrees of GCNIS compared to biopsies from fetuses, patients with androgen insensitivity syndrome, and patients showing normal spermatogenesis further suggest that GCNIS-associated SCs represent adult cells undergoing progressive dedifferentiation.
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2,336,012 |
Rapid Repurposing of Novel Combination Drugs for the Treatment of Heart Failure via a Computationally Guided Network Screening Approach.
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Combination drugs, characterized by high efficacy and few side effects, have received extensive attention from pharmaceutical companies and researchers for the treatment of complex diseases such as heart failure (HF). Traditional combination drug discovery depends on large-scale high-throughput experimental approaches that are time-consuming and costly. Herein we developed a novel, rapid, and potentially universal computer-guided combination drug-network-screening approach based on a set of databases and web services that are easy for individuals to obtain and operate, and we discovered for the first time that the menthol-allethrin combination screened by this approach exhibited a significant synergistic cardioprotective effect <i>in vitro</i>. Further mechanistic studies indicated that allethrin and menthol could synergistically block calcium channels. Allethrin bound to the central cavity of the voltage-dependent L-type calcium channel subunit alpha-1S (CACNA1S) lead to a conformational change in an allosteric site of CACNA1S, thereby enhancing the binding of menthol to this allosteric site. In summary, we reported a potentially universal computational approach to combination drug screening that has been used to discover a new combination of menthol-allethrin against HF <i>in vitro</i>, providing a new synergistic mechanism and prospective agent for HF treatment.
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2,336,013 |
Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial.
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Occipital nerve stimulation (ONS) has shown promising results in small uncontrolled trials in patients with medically intractable chronic cluster headache (MICCH). We aimed to establish whether ONS could serve as an effective treatment for patients with MICCH.</AbstractText>The ONS in MICCH (ICON) study is an investigator-initiated, international, multicentre, randomised, double-blind, phase 3, electrical dose-controlled clinical trial. The study took place at four hospitals in the Netherlands, one hospital in Belgium, one in Germany, and one in Hungary. After 12 weeks' baseline observation, patients with MICCH, at least four attacks per week, and history of being non-responsive to at least three standard preventive drugs, were randomly allocated (at a 1:1 ratio using a computer-generated permuted block) to 24 weeks of occipital nerve stimulation at either 100% or 30% of the individually determined range between paraesthesia threshold and near-discomfort (double-blind study phase). Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy. In weeks 25-48, participants received individually optimised open-label ONS. The primary outcome was the weekly mean attack frequency in weeks 21-24 compared with baseline across all patients and, if a decrease was shown, to show a group-wise difference. The trial is closed to recruitment (ClinicalTrials.gov NCT01151631).</AbstractText>Patients were enrolled between Oct 12, 2010, and Dec 3, 2017. We enrolled 150 patients and randomly assigned 131 (87%) to treatment; 65 (50%) patients to 100% ONS and 66 (50%) to 30% ONS. One of the 66 patients assigned to 30% ONS was not implanted and was therefore excluded from the intention-to-treat analysis. Because the weekly mean attack frequencies at baseline were skewed (median 15·75; IQR 9·44 to 24·75) we used log transformation to analyse the data and medians to present the results. Median weekly mean attack frequencies in the total population decreased from baseline to 7·38 (2·50 to 18·50; p<0·0001) in weeks 21-24, a median change of -5·21 (-11·18 to -0·19; p<0·0001) attacks per week. In the 100% ONS stimulation group, mean attack frequency decreased from 17·58 (9·83 to 29·33) at baseline to 9·50 (3·00 to 21·25) at 21-24 weeks (median change from baseline -4·08, -11·92 to -0·25), and for the 30% ONS stimulation group, mean attack frequency decreased from 15·00 (9·25 to 22·33) to 6·75 (1·50 to 16·50; -6·50, -10·83 to -0·08). The difference in median weekly mean attack frequency between groups at the end of the masked phase in weeks 21-24 was -2·42 (95% CI -5·17 to 3·33). In the masked study phase, 129 adverse events occurred with 100% ONS and 95 occurred with 30% ONS. None of the adverse events was unexpected but 17 with 100% ONS and eight with 30% ONS were labelled as serious, given they required brief hospital admission for minor hardware-related issues. The most common adverse events were local pain, impaired wound healing, neck stiffness, and hardware damage.</AbstractText>In patients with MICCH, both 100% ONS intensity and 30% ONS intensity substantially reduced attack frequency and were safe and well tolerated. Future research should focus on optimising stimulation protocols and disentangling the underlying mechanism of action.</AbstractText>The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.</AbstractText>Copyright © 2021 Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,336,014 |
Analgesic effects of a retrobulbar block with 0.75% ropivacaine in dogs undergoing enucleation.
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To assess the analgesic effects of a retrobulbar block with ropivacaine in dogs undergoing enucleation.</AbstractText>Prospective, randomized, masked placebo-controlled trial.</AbstractText>A total of 23 client-owned dogs.</AbstractText>Dogs were randomized to be administered a preoperative inferior-temporal palpebral retrobulbar injection of either ropivacaine 0.75% (1 mL 10 kg-1</sup>; group RG) or equivalent volume of 0.9% saline (control; group CG). Intraoperative variables recorded to detect a response to noxious stimuli included heart rate (HR) and mean arterial pressure (MAP). Three observers assessed and recorded pain using a numerical rating pain scale and visual analog scale (VAS) before anesthesia (baseline) and postoperatively at 0, 0.5, 1, 2, 3, 4, 5, 6 and 24 hours after extubation. Rescue analgesia was administered if intraoperative HR or MAP increased by ≥ 20% from the previously recorded surgical time point, average postoperative pain scores totaled ≥ 9/20, scored ≥ 3/4 in any one category with VAS ≥ 35/100, or if VAS was ≥ 35/100 with a palpation score > 0/4.</AbstractText>Intraoperatively, there was no significant difference in HR or MAP between groups. Rescue analgesia was administered intraoperatively to four and one dogs and postoperatively to five and seven dogs in groups CG and RG, respectively, with no significant difference between groups. VAS scores were significantly lower in ropivacaine dogs at extubation (p = 0.02), but not at other postoperative time points. Adverse events were not observed in either group.</AbstractText>Preoperative retrobulbar 0.75% ropivacaine injection (1 mL 10 kg-1</sup>) provided analgesia in dogs following enucleation at extubation; however, intraoperative and postoperative pain control did not differ from a placebo injection with saline. Lack of differences between groups may have been influenced by sample size limitations.</AbstractText>Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,336,015 |
Mutagenesis of Human Cytomegalovirus Glycoprotein L Disproportionately Disrupts gH/gL/gO over gH/gL/pUL128-131.
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Cell-free and cell-to-cell spread of herpesviruses involves a core fusion apparatus comprised of the fusion protein glycoprotein B (gB) and the regulatory factor gH/gL. The human cytomegalovirus (HCMV) gH/gL/gO and gH/gL/pUL128-131 facilitate spread in different cell types. The gO and pUL128-131 components bind distinct receptors, but how the gH/gL portions of the complexes functionally compare is not understood. We previously characterized a panel of gL mutants by transient expression and showed that many were impaired for gH/gL-gB-dependent cell-cell fusion but were still able to form gH/gL/pUL128-131 and induce receptor interference. Here, the gL mutants were engineered into the HCMV BAC clones TB40/e-BAC4 (TB), TR, and Merlin (ME), which differ in their utilization of the two complexes for entry and spread. Several of the gL mutations disproportionately impacted gH/gL/gO-dependent entry and spread over gH/gL/pUL128-131 processes. The effects of some mutants could be explained by impaired gH/gL/gO assembly, but other mutants impacted gH/gL/gO function. Soluble gH/gL/gO containing the L201 mutant failed to block HCMV infection despite unimpaired binding to PDGFRα, indicating the existence of other important gH/gL/gO receptors. Another mutant (L139) enhanced the gH/gL/gO-dependent cell-free spread of TR, suggesting a "hyperactive" gH/gL/gO. Recently published crystallography and cryo-electron microscopy studies suggest structural conservation of the gH/gL underlying gH/gL/gO and gH/gL/pUL128-131. However, our data suggest important differences in the gH/gL of the two complexes and support a model in which gH/gL/gO can provide an activation signal for gB. <b>IMPORTANCE</b> The endemic betaherpesvirus HCMV circulates in human populations as a complex mixture of genetically distinct variants, establishes lifelong persistent infections, and causes significant disease in neonates and immunocompromised adults. This study capitalizes on our recent characterizations of three genetically distinct HCMV BAC clones to discern the functions of the envelope glycoprotein complexes gH/gL/gO and gH/gL/pUL128-13, which are promising vaccine targets that share the herpesvirus core fusion apparatus component, gH/gL. Mutations in the shared gL subunit disproportionally affected gH/gL/gO, demonstrating mechanistic differences between the two complexes, and may provide a basis for more refined evaluations of neutralizing antibodies.
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2,336,016 |
ENDOCRINE TUMOURS: Thyrotropin-secreting pituitary adenoma: a structured review of 535 adult cases.
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Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare entity, occurring in one per million people. We performed a systematic review of 535 adult cases summarizing the clinical, biochemical, hormonal and radiological characteristics of TSHoma. Furthermore, we discussed the current guidelines for diagnosis and treatment.</AbstractText>A structured research was conducted using Pubmed and Web of Science with the following MeSH terms: 'thyrotropin secreting pituitary adenoma' OR 'TSHoma' OR 'thyrotropinoma.'</AbstractText>Our analysis included 535 cases originating from 18 case series, 5 cohort studies and 91 case reports. The mean age at diagnosis was 46 years. At presentation, 75% had symptoms of hyperthyroidism, 55.5% presented with a goitre and 24.9% had visual field defects. The median TSH at diagnosis was 5.16 (3.20-7.43) mU/L with a mean FT4 of 41.5 ± 15.3 pmol/L. The majority (76.9%) of the TSHomas were macroadenoma. Plurihormonality was seen in 37.4% of the adenoma with a higher incidence in macroadenoma. Surgical resection of the adenoma was performed in 87.7% of patients of which 33.5% had residual pituitary adenoma. Post-operative treatment with a somatostatin analogue (SSA) led to a stable disease in 81.3% of the cases with residual tumour. We noticed a significant correlation between the diameter of the adenoma and residual pituitary adenoma (r = 0.490, P < 0.001). However, in patients preoperatively treated with an SSA, this correlation was absent.</AbstractText>TSHomas are a rare cause of hyperthyroidism and are frequently misdiagnosed. Based on our structured analysis of case series, cohort studies and case reports, we conclude that the majority of TSHomas are macroadenoma being diagnosed in the fifth to sixth decade of life and presenting with symptoms of hyperthyroidism. Plurihormonalitiy is observed in one-third of TSHomas. Treatment consists of neurosurgical resection and SSA in case of surgical failure.</AbstractText>
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2,336,017 |
Interpersonal physiological synchrony is associated with first person and third person subjective assessments of excitement during cooperative joint tasks.
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Interpersonal physiological synchrony has been shown to play important roles in social activities. While most studies have shed light on the effects of physiological synchrony on recognition of the group state, such as cohesion or togetherness, the effect of physiological synchrony on the recognition of emotional experience has not been adequately researched. In this study, we examined how physiological synchrony is associated with first- and third-person emotion recognition during a joint task. Two participants played a cooperative block-stacking game (Jenga), alternating their roles as player and adviser, while their heart rates were recorded. The participants evaluated their own emotional experience for each turn. Bystanders watched the game to evaluate the players' emotions. Results showed that the players' subjective excitement increased not only with their own heart rate, but also with increased heart rate synchrony with their adviser. Heart rate synchrony between player and adviser also related to increased intensity in perceived excitement from the bystanders. Given that both first- and third-person emotion recognition can have cumulative impacts on a group, the relationship between physiological synchrony and emotion recognition observed in the present study will help deepen understanding of the psychophysiological mechanisms underlying larger group phenomena such as crowd excitement.
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2,336,018 |
Complete Heart Block Secondary to COVID-19.
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In our everyday practice with COVID-19 patients, we noticed that they are not tachycardic even when critically ill and shocked on pressors they are bradycardic. Most of them are in sinus rhythm. However, some of them go into advanced degree heart block and had cardiac arrest related to complete heart block. A 72-year-old female with a history of hypertension and diabetes admitted with COVID-19 bronchopneumonia. The hospital course has been complicated by respiratory failure requiring mechanical ventilation and septic shock requiring norepinephrine. It was noted that she is bradycardic in the 50s in sinus rhythm, her heart rate dipped down to 30 for about six seconds, and her telemetry strip showed evidence of complete heart block, and then she was back in sinus rhythm. The decision was made to follow-up, given that it was for a short time and did not recur. The next day she had cardiac arrest related to a complete heart block, and a temporary trans-venous pacemaker was placed, Later when her condition improved, her heart rate started recovering gradually. At first, she was in junctional tachycardia, and one week later, she was back in sinus rhythm. The temporary pacemaker was removed, and she was discharged on a ZIO monitor for two weeks with no further evidence of bradycardia. Bradycardia in COVID-19 patients is frequently reported. It is not always benign and should be managed promptly when there is evidence of advanced heart block.
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2,336,019 |
Personalized tumor-specific DNA junctions to detect circulating tumor in patients with endometrial cancer.
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There are no reliable blood biomarkers for monitoring endometrial cancer patients in the current clinical practice. Circulating tumor DNA (ctDNA) is emerging as a promising non-invasive method to measure tumor burden, define prognosis and monitor disease status in many solid cancers. In this pilot study, we investigated if unique tumor-specific DNA junctions can be used to detect ctDNA levels in patients with endometrial cancer.</AbstractText>Chromosomal rearrangements in primary tumors of eleven patients with high-grade or advanced stage endometrial cancer were determined by whole-genome Mate-Pair sequencing. Identified unique tumor-specific junctions were evaluated in pre- and six-week post-surgery patient plasma using individualized quantitative polymerase chain reaction (qPCR) assays. The relationship between clinicopathological features and detection of ctDNA was investigated.</AbstractText>CtDNA was detected in 60% (6/10) of cases pre-surgery and in 27% (3/11) post-surgery. The detection of ctDNA pre-surgery was consistent with clinical indicators of aggressive disease such as advanced stage (80% - 4/5), lymphatic spread of disease (100% - 3/3), serous histology (80% - 4/5), deep myometrial invasion (100% - 3/3), lympho-vascular space invasion (75% - 3/4). All patients in which ctDNA was detected post-surgically had type II endometrial cancer.</AbstractText>This pilot study demonstrates the feasibility of using personalized tumor-specific junction panels for detecting ctDNA in the plasma of endometrial cancer patients. Larger studies and longer follow-up are needed to validate the potential association between pre-surgical ctDNA detection and the presence of cancers with aggressive pathologic tumor characteristics or advanced stage observed in this study.</AbstractText>
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2,336,020 |
Heart rate variability and haemodynamic factors associated with hypotension during spinal anaesthesia for caesarean delivery: A case-control study.
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Hypotension frequently occurs during spinal anaesthesia for caesarean delivery, with potential adverse effects.</AbstractText>To investigate heart rate variability and haemodynamic factors associated with spinal anaesthesia-induced hypotension.</AbstractText>Secondary case-control analysis of a randomised study.</AbstractText>Single obstetric centre.</AbstractText>Data were obtained from 230 healthy term singleton parturients who underwent elective caesarean delivery under spinal anaesthesia.</AbstractText>With parturients at rest, continuous haemodynamic measurements were recorded using a Nexfin cardiac monitor. Baseline pre-operative values were defined as the average of five minutes of continuous measurements. After initiation of standardised spinal anaesthesia, vasopressors were administered to maintain SBP within 10% of pre-operative values. Hypotension was defined as any 10 seconds average SBP less than 80% of pre-operative values from initiation of spinal anaesthesia to foetal delivery. Parturients were classified into cases (hypotensive) or controls (normotensive), and both univariate and multivariable logistic regression models were used to identify independent factors associated with hypotension.</AbstractText>Pre-operative standard deviation of the interbeat interval (SDNN), root mean square of successive interbeat difference, low-frequency to high-frequency ratio, SD1, SD2, approximate entropy, sample entropy, mean arterial pressure, SBP, stroke volume variation and systemic vascular resistance index were recorded, as were sensory block height, intravenous fluid volume and vasopressor use between spinal anaesthesia and foetal delivery.</AbstractText>Of 230 parturients, 113 (49.1%) experienced hypotension. Pre-operative lower SDNN [odds ratio (OR) 0.87, 95% confidence interval (CI) 0.78 to 0.97], higher SD2 (OR 25.06, 95% CI 2.41 to 261.06), and lower SBP (OR 0.98, 95% CI 0.97 to 1.00) were independently associated with hypotension. Between spinal anaesthesia to foetal delivery, lower sensory block height (OR 0.76, 95% CI 0.65 to 0.90) and higher intravenous fluid volume (OR 0.98, 95% CI 0.96 to 0.99 per 15 ml change) were associated with a lower incidence of hypotension. Area under the receiver operating characteristic curve was 0.701.</AbstractText>Pre-operative higher SD2, lower SDNN and lower SBP were associated with hypotension during spinal anaesthesia for caesarean delivery.</AbstractText>NCT02277730.</AbstractText>Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.</CopyrightInformation>
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2,336,021 |
Block-like and cast-like hyperdense areas in the right heart cavities on post-mortem CT strongly suggest the presence of intracardiac blood clots at autopsy.
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To classify the types of hyperdense areas in the heart cavities on post-mortem CT (PMCT) and compare them according to the presence of blood clots in the heart cavities at forensic autopsy.</AbstractText>One hundred and twelve cases with CT images taken before forensic autopsy were evaluated. The presence and shape of hyperdense areas in the right or left heart cavities were retrospectively evaluated on PMCT images and were classified into four types (block-like, cast-like, fluid level-like, and unclear). The presence of blood clots was confirmed when there were clots in the heart cavities at forensic autopsy.</AbstractText>Of the 112 cases, 57 exhibited blood clots in the heart cavities at forensic autopsy. The hyperdense areas in the right heart cavities on PMCT in 57 cases exhibiting blood clots at forensic autopsy were classified as follows: block-like, 32; fluid level-like, 4; cast-like, 17; and unclear, 4. The sensitivity of block-like and cast-like hyperdense areas in the right heart cavities on PMCT for the presence of clots in the heart cavities at forensic autopsy was 86% (95% confidence interval [CI]: 74-94%); the corresponding specificity, PPV, and NPV were 95% (95% CI: 85-99%), 94% (95% CI: 84-99%), and 87% (95% CI: 75-94%), respectively.</AbstractText>Block-like and cast-like hyperdense areas in the right heart cavities on PMCT predicted the presence of intracardiac blood clots at forensic autopsy.</AbstractText>• Clinical radiologists likely have no experience of interpreting findings of blood clots on post-mortem CT (PMCT). • The appearance of blood clots on PMCT provides important clues for diagnosing the cause and process of death. • The shapes of the hyperdense areas in the heart cavities were classified into four types, and two of these types could be used to predict the presence of blood clots in the heart cavities at forensic autopsy.</AbstractText>© 2021. European Society of Radiology.</CopyrightInformation>
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2,336,022 |
Hotspot and Frontier Analysis of Exercise Training Therapy for Heart Failure Complicated With Depression Based on Web of Science Database and Big Data Analysis.
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<b>Background:</b> Exercise training has been extensively studied in heart failure (HF) and psychological disorders, which has been shown to worsen each other. However, our understanding of how exercise simultaneously protect heart and brain of HF patients is still in its infancy. The purpose of this study was to take advantage of big data techniques to explore hotspots and frontiers of mechanisms that protect the heart and brain simultaneously through exercise training. <b>Methods:</b> We studied the scientific publications on related research between January 1, 2003 to December 31, 2020 from the WoS Core Collection. Research hotspots were assessed through open-source software, CiteSpace, Pajek, and VOSviewer. Big data analysis and visualization were carried out using R, Cytoscape and Origin. <b>Results:</b> From 2003 to 2020, the study on HF, depression, and exercise simultaneously was the lowest of all research sequences (two-way ANOVAs, <i>p</i> < 0.0001). Its linear regression coefficient <i>r</i> was 0.7641. The result of hotspot analysis of related keyword-driven research showed that inflammation and stress (including oxidative stress) were the common mechanisms. Through the further analyses, we noted that inflammation, stress, oxidative stress, apoptosis, reactive oxygen species, cell death, and the mechanisms related to mitochondrial biogenesis/homeostasis, could be regarded as the primary mechanism targets to study the simultaneous intervention of exercise on the heart and brain of HF patients with depression. <b>Conclusions:</b> Our findings demonstrate the potential mechanism targets by which exercise interferes with both the heart and brain for HF patients with depression. We hope that they can boost the attention of other researchers and clinicians, and open up new avenues for designing more novel potential drugs to block heart-brain axis vicious circle.
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2,336,023 |
Bone regeneration in ceramic scaffolds with variable concentrations of PDRN and rhBMP-2.
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This study evaluated the bone regeneration capacity and mechanical properties of block-type hydroxyapatite (HA)/tricalcium phosphate (TCP) scaffolds in response to different concentrations of polydeoxyribonucleotide (PDRN) and recombinant human bone morphogenic protein 2 (rhBMP-2). Thirty-two male white rabbits were used as a model of calvarial bone defect and classified into eight groups according to type and concentration of growth factor administered, viz., control group (only HA/TCP scaffold), scaffold + PDRN (0.1, 1, 5, and 10 mg/mL each) and scaffold + rhBMP-2 (0.01, 0.05, and 0.1 mg/mL each). The specimens were evaluated using histomorphometric and radiological analyses. Histomorphometric analyses indicated that the administration of PDRN did not increase bone formation. However, significant increases in bone formation were observed with the administration of rhBMP-2 at 0.05 and 0.10 mg/mL on week 8 compared to the control (p < 0.05). Radiological analyses revealed a significant increase in bone formation at week 8 with the administration of PDRN at 5 mg/mL and 10 mg/mL, and rhBMP-2 at 0.05 or 0.10 mg/mL compared to the control (p < 0.05). Our findings show that block-type HA/TCP scaffolds possess sufficient mechanical strength and bone regeneration capacity when used with optimal concentrations of growth factors.
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2,336,024 |
Cardiac myosin-binding protein C interaction with actin is inhibited by compounds identified in a high-throughput fluorescence lifetime screen.
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Cardiac myosin-binding protein C (cMyBP-C) interacts with actin and myosin to modulate cardiac muscle contractility. These interactions are disfavored by cMyBP-C phosphorylation. Heart failure patients often display decreased cMyBP-C phosphorylation, and phosphorylation in model systems has been shown to be cardioprotective against heart failure. Therefore, cMyBP-C is a potential target for heart failure drugs that mimic phosphorylation or perturb its interactions with actin/myosin. Here we have used a novel fluorescence lifetime-based assay to identify small-molecule inhibitors of actin-cMyBP-C binding. Actin was labeled with a fluorescent dye (Alexa Fluor 568, AF568) near its cMyBP-C binding sites; when combined with the cMyBP-C N-terminal fragment, C0-C2, the fluorescence lifetime of AF568-actin decreases. Using this reduction in lifetime as a readout of actin binding, a high-throughput screen of a 1280-compound library identified three reproducible hit compounds (suramin, NF023, and aurintricarboxylic acid) that reduced C0-C2 binding to actin in the micromolar range. Binding of phosphorylated C0-C2 was also blocked by these compounds. That they specifically block binding was confirmed by an actin-C0-C2 time-resolved FRET (TR-FRET) binding assay. Isothermal titration calorimetry (ITC) and transient phosphorescence anisotropy (TPA) confirmed that these compounds bind to cMyBP-C, but not to actin. TPA results were also consistent with these compounds inhibiting C0-C2 binding to actin. We conclude that the actin-cMyBP-C fluorescence lifetime assay permits detection of pharmacologically active compounds that affect cMyBP-C-actin binding. We now have, for the first time, a validated high-throughput screen focused on cMyBP-C, a regulator of cardiac muscle contractility and known key factor in heart failure.
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2,336,025 |
Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial.
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Evidence suggests a role for excessive inflammation in COVID-19 complications. Colchicine is an oral anti-inflammatory medication beneficial in gout, pericarditis, and coronary disease. We aimed to investigate the effect of colchicine on the composite of COVID-19-related death or hospital admission.</AbstractText>The present study is a phase 3, randomised, double-blind, adaptive, placebo-controlled, multicentre trial. The study was done in Brazil, Canada, Greece, South Africa, Spain, and the USA, and was led by the Montreal Heart Institute. Patients with COVID-19 diagnosed by PCR testing or clinical criteria who were not being treated in hospital were eligible if they were at least 40 years old and had at least one high-risk characteristic. The randomisation list was computer-generated by an unmasked biostatistician, and masked randomisation was centralised and done electronically through an automated interactive web-response system. The allocation sequence was unstratified and used a 1:1 ratio with a blocking schema and block sizes of six. Patients were randomly assigned to receive orally administered colchicine (0·5 mg twice per day for 3 days and then once per day for 27 days thereafter) or matching placebo. The primary efficacy endpoint was the composite of death or hospital admission for COVID-19. Vital status at the end of the study was available for 97·9% of patients. The analyses were done according to the intention-to-treat principle. The COLCORONA trial is registered with ClinicalTrials.gov (NCT04322682) and is now closed to new participants.</AbstractText>Trial enrolment began in March 23, 2020, and was completed in Dec 22, 2020. A total of 4488 patients (53·9% women; median age 54·0 years, IQR 47·0-61·0) were enrolled and 2235 patients were randomly assigned to colchicine and 2253 to placebo. The primary endpoint occurred in 104 (4·7%) of 2235 patients in the colchicine group and 131 (5·8%) of 2253 patients in the placebo group (odds ratio [OR] 0·79, 95·1% CI 0·61-1·03; p=0·081). Among the 4159 patients with PCR-confirmed COVID-19, the primary endpoint occurred in 96 (4·6%) of 2075 patients in the colchicine group and 126 (6·0%) of 2084 patients in the placebo group (OR 0·75, 0·57-0·99; p=0·042). Serious adverse events were reported in 108 (4·9%) of 2195 patients in the colchicine group and 139 (6·3%) of 2217 patients in the placebo group (p=0·051); pneumonia occurred in 63 (2·9%) of 2195 patients in the colchicine group and 92 (4·1%) of 2217 patients in the placebo group (p=0·021). Diarrhoea was reported in 300 (13·7%) of 2195 patients in the colchicine group and 161 (7·3%) of 2217 patients in the placebo group (p<0·0001).</AbstractText>In community-treated patients including those without a mandatory diagnostic test, the effect of colchicine on COVID-19-related clinical events was not statistically significant. Among patients with PCR-confirmed COVID-19, colchicine led to a lower rate of the composite of death or hospital admission than placebo. Given the absence of orally administered therapies to prevent COVID-19 complications in community-treated patients and the benefit of colchicine in patients with PCR-proven COVID-19, this safe and inexpensive anti-inflammatory agent could be considered for use in those at risk of complications. Notwithstanding these considerations, replication in other studies of PCR-positive community-treated patients is recommended.</AbstractText>The Government of Quebec, the Bill & Melinda Gates Foundation, the National Heart, Lung, and Blood Institute of the US National Institutes of Health, the Montreal Heart Institute Foundation, the NYU Grossman School of Medicine, the Rudin Family Foundation, and philanthropist Sophie Desmarais.</AbstractText>Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.</CopyrightInformation>
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2,336,026 |
Dosimetric comparison between different tangential field arrangements during left-sided breast cancer radiotherapy.
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This study aimed to evaluate variations in dose distribution within the target volume and dose received by the organs at risk (OARs) for different tangential field arrangements during three-dimensional (3D) conformal treatment planning for left-sided breast cancer. Computed tomography (CT) images of 25 breast cancer patients were included, and three different mono-isocentric half-block (MIHB) treatment plans-parallel central axis technique (PCAXT), posterior border parallel technique (PBPT), and parallel quadrant technique (PQUDT)-were considered for each patient. The dosimetric and geometric parameters related to each followed plan were then extracted for the planning target volume (PTV) and the OARs, and compared. The results showed no significant differences among the extracted dosimetric and geometric parameters of the OARs for the different plans, while the D<sub>max</sub>, V<sub>95%</sub>, homogeneity index (HI), and conformity index (CI) values related to the PTV were significantly different (P < 0.05). The lowest D<sub>max</sub> and V<sub>95%</sub> values inside the PTV were related to the PCAXT plan. The best HI was achieved with the PBPT plan, whereas the best CI was observed for the PCAXT plan. The best correlation between the geometric and dosimetric parameters of the OARs was between V<sub>5Gy</sub>-central lung distance for the ipsilateral lung and the V<sub>5Gy</sub>-maximum heart distance for the heart in all plans. These results demonstrate that variations in the tangential field arrangement at the posterior border for optimal coverage of the PTV may not considerably affect the dose received by the OARs.
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2,336,027 |
Clemizole and La<sup>3+</sup> salts ameliorate angiotensin II-induced glomerular hyperpermeability in vivo.
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Angiotensin II (Ang II) induces marked, dynamic increases in the permeability of the glomerular filtration barrier (GFB) in rats. After binding to its receptor, Ang II elicits Ca<sup>2+</sup> influx into cells, mediated by TRPC5 and TRPC6 (transient receptor potential canonical type 5 and 6). Clemizole and La<sup>3+</sup> salts have been shown to block TRPC channels in vitro, and we therefore tested their potential effect on Ang II-induced glomerular hyperpermeability. Anesthetized male Sprague-Dawley rats were infused with Ang II (80 ng kg<sup>-1 </sup> min<sup>-1</sup> ) alone, or together with clemizole or low-dose La<sup>3+</sup> (activates TRPC5, blocks TRPC6) or high-dose La<sup>3+</sup> (blocks both TRPC5 and TRPC6). Plasma and urine samples were taken during baseline and at 5 min after the start of the infusions and analyzed by high-performance size-exclusion chromatography for determination of glomerular sieving coefficients for Ficoll 10-80 Å (1-8 nm). Ang II infusion evoked glomerular hyperpermeability to large Ficolls (50-80 Å), which was ameliorated by clemizole, having no significant effect on glomerular filtration rate (GFR) or Ang II-mediated increase in mean arterial pressure (ΔMAP). In contrast, high- and low-dose La<sup>3+</sup> significantly lowered ΔMAP and reduced Ang II-induced hyperpermeability. Combined, clemizole and low-dose La<sup>3+</sup> were less effective at ameliorating Ang II-induced glomerular hyperpermeability than low-dose La<sup>3+</sup> alone. In conclusion, our data show that both clemizole and La3+ are effective against Ang II-induced glomerular hyperpermeability, with differential effects on blood pressure. Further research using more specific blockers of TRPC5 and TRPC6 should be performed to reveal the underlying mechanisms.
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2,336,028 |
Comparing topical administration of lidocaine alone and in combination with alfentanil in children undergoing bronchoscopy.
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Airway surgery and endoscopy in pediatric patients are always associated with challenges in anesthesia management. Deep anesthesia is required for preventing patient bucking during the procedure but patient breath should be maintained; in this regard, a combination of general and topical anesthesia can be beneficial. There is also evidence of the peripheral effects of opioids. The main objective of this study is to compare using lidocaine topically alone and combined with alfentanil opioids with respect to the central effects of opioids.</AbstractText>In this study, 40 ASA class I and II children, aged 1-6 years, who were candidates for flexible diagnostic bronchoscopy were divided into two groups through block randomization using the random number table after obtaining parents' consent in complete health conditions. In this clinical trial, for collecting the data a special data collection form was used at the bedside of patients undergoing bronchoscopy at Pediatric Medical Center in 2017. Data including demographic information (age, weight, gender), duration of anesthesia, blood pressure before and after drug administration, duration of bronchoscopy, and recovery time were recorded in a form.</AbstractText>In terms of demographic variables, there were not any significant differences between the two studied groups, indicating that the groups were matched and randomized appropriately. Although there were not any significant differences between the two groups of using lidocaine alone and in combination with alfentanil in other variables, in the recovery time a significant difference was observed between the two groups, with a mean of 13.05 min in the lidocaine group and 18.75 min in the lidocaine combined with alfentanil group.</AbstractText>Topical administration of opioid with lidocaine through bronchoscopy had no impact on blood pressure, heart rate, anesthesia duration, and the frequency of perioperative complications.</AbstractText>Copyright: © 2021 Journal of Family Medicine and Primary Care.</CopyrightInformation>
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2,336,029 |
The association of neighborhood walkability with health outcomes in older adults after acute myocardial infarction: The SILVER-AMI study.
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Physical activity and social support are associated with better outcomes after surviving acute myocardial infarction (AMI), and greater walkability has been associated with activity and support. We used data from the SILVER-AMI study (November 2014-June 2017), a longitudinal cohort of community-living adults ≥ 75 years hospitalized for AMI to assess associations of neighborhood walkability with health outcomes, and to assess whether physical activity and social support mediate this relationship, if it exists. We included data from 1345 participants who were not bedbound, were discharged home, and for whom we successfully linked walkability scores (from Walk Score®) for their home census block. Our primary outcome was hospital-free survival time (HFST) at six months after discharge; secondary outcomes included physical and mental health at six months, assessed using SF-12. Physical activity and social support were measured at baseline. Covariates included cognition, functioning, comorbidities, participation in rehabilitation or physical therapy, and demographics. We employed survival analysis to examine associations between walkability and HFST, before and after adjustment for covariates; we repeated analyses using linear regression with physical and mental health as outcomes. In adjusted models, walkability was not associated with physical health (ß = 0.010; 95% CI: -0.027, 0.047), mental health (ß = -0.08; 95% CI: -0.175, -0.013), or HFST (ß = 0.008; 95% CI: -0.023, 0.009). Social support was associated with mental health in adjusted models. Neighborhood walkability was not predictive of outcomes among older adults with existing coronary disease, suggesting that among older adults, mobility limitations may supercede neighborhood walkability.
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2,336,030 |
Addition of low-dose sufentanil to ropivacaine for reducing shivering and visceral traction pain during cesarean section.
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To investigate the efficacy of low-dose sufentanil for preventing shivering and visceral traction pain during cesarean section under spinal anesthesia.</AbstractText>This was a prospective, randomized, controlled study. A total of 112 full-term parturients who underwent elective caesarean delivery were randomly divided into two groups. Group R received 0.75% isobaric ropivacaine intrathecally and group RS received 0.75% isobaric ropivacaine plus 5 µg sufentanil intrathecally.</AbstractText>There were no significant differences in the maximum sensory block time, motor block time, duration of the surgery, and heart rate, mean arterial pressure, and blood oxygen saturation before and 1, 5, and 10 minutes after spinal anesthesia, and at the end of the surgery between the two groups. Shivering was significantly more common in group R (n = 30) than in group RS (n = 8). The incidence of visceral traction pain in group R (46.43%) was significantly higher than that in group RS (14.29%). There was no significant difference in the newborns' Apgar scores between the groups.</AbstractText>Adding low-dose sufentanil to ropivacaine can significantly reduce the incidence of shivering and visceral traction pain after spinal anesthesia.</AbstractText>
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2,336,031 |
A randomized study of yoga therapy for the prevention of recurrent reflex vasovagal syncope.
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Vasovagal syncope (VVS) is a common cardiovascular dysautonomic disorder that significantly impacts health and quality of life (QoL). Yoga has been shown to have a positive influence on cardiovascular autonomics. This study assessed the effectiveness of yoga therapy on the recurrence of VVS and QoL.</AbstractText>We randomized subjects with recurrent reflex VVS (>3 episodes in the past 1 year) and positive head-up tilt test to guideline-directed therapy (Group 1) or yoga therapy (Group 2). Patients in Group 1 were advised guideline-directed treatment and Group 2 was taught yoga by a certified instructor. The primary endpoint was VVS recurrences and QoL. Between June 2015 and February 2017, 97 highly symptomatic VVS patients were randomized (Group 1: 47 and Group 2: 50). The mean age was 33.1 ± 16.6 years, male:female of 40:57, symptom duration of 17.1 ± 20.7 months, with a mean of 6.4 ± 6.1 syncope episodes. Over a follow-up of 14.3 ± 2.1 months Group 2 had significantly lower syncope burden compared with Group 1 at 3 (0.8 ± 0.9 vs. 1.8 ± 1.4, P < 0.001), 6 (1.0 ± 1.2 vs. 3.4 ± 3.0, P < 0.001), and at 12 months (1.1 ± 0.8 vs. 3.8 ± 3.2, P < 0.001). The Syncope functional score questionnaire was significantly lower in Group 2 compared with Group 1 at 3 (31.4 ± 7.2 vs. 64.1 ± 11.5, P < 0.001), 6 (26.4 ± 6.3 vs. 61.4 ± 10.7, P < 0.001), and 12 months (22.2 ± 4.7 vs. 68.3 ± 11.4, P < 0.001).</AbstractText>For patients with recurrent VVS, guided yoga therapy is superior to conventional therapy in reducing symptom burden and improving QoL.</AbstractText>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected].</CopyrightInformation>
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2,336,032 |
Comparison of the Efficacy and Safety of Direct Oral Anticoagulants and Vitamin K Antagonists in Patients with Atrial Fibrillation and Concomitant Liver Cirrhosis: A Systematic Review and Meta-Analysis.
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Patients with atrial fibrillation (AF) have a higher risk of developing thromboembolic events. Current guidelines recommend the use of oral anticoagulants for stroke prevention in these patients. Several clinical trials demonstrated that direct oral anticoagulants (DOACs) have similar efficacy and are safer alternatives to traditional oral anticoagulants. However, patients with concomitant liver cirrhosis were excluded from these trials.</AbstractText>We aimed to systematically identify and review published clinical studies on the use of DOACs in patients with AF and liver cirrhosis and assess the efficacy and safety of DOACs in these patients.</AbstractText>A systematic review of clinical trials and retrospective studies was conducted by searching the PubMed, Cochrane Library, Embase, SCOPUS, and Web of Science databases up to September 2020.</AbstractText>Three retrospective studies were included, involving 4011 patients with AF and liver cirrhosis. The use of DOACs was associated with a significant reduction in ischemic stroke (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.42-0.90; p = 0.01), major bleeding events (HR 0.64; 95% CI 0.57-0.72; p < 0.001), and intracranial hemorrhage (HR 0.49; 95% CI 0.40-0.59; p < 0.001).</AbstractText>Compared with warfarin in patients with AF and liver cirrhosis, DOACs appear to be associated with improved efficacy and safety outcomes. Randomized controlled trials are warranted to confirm these findings.</AbstractText>© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.</CopyrightInformation>
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2,336,033 |
Feasibility, efficacy, and safety of ethanol infusion into the vein of Marshall for atrial fibrillation: A meta-analysis.
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Contemporary radiofrequency catheter ablation (RFCA) approaches for atrial fibrillation (AF) have reached an efficacy "ceiling". Ethanol infusion into the vein of Marshall (EI-VOM) has shown potential in preliminary studies. Data on EI-VOM are largely limited to small single-center reports, and clinical benefits and risks have not been systematically examined. Therefore, we performed a meta-analysis to assess the feasibility, efficacy, and safety of EI-VOM for AF.</AbstractText>All studies evaluating EI-VOM for AF were initially searched from four electronic search engines: PubMed, Web of Science, Cochrane Library, and SinoMed. We used RevMan5.4 to calculate pooled outcomes of randomized controlled trial and cohort studies. We also performed single-arm meta-analyses using Open Meta-Analyst.</AbstractText>We included a total of 10 studies with 1322 patients. Successful EI-VOM was performed in 86.7% (95% CI 81.9-91.4%) of patients. For persistent AF patients, the recurrence of AF and/or atrial tachycardia (AT) was significantly lower in the EI-VOM combined with RFCA group compared with RFCA alone group (RR 0.58, 95% CI 0.35 to 0.96, p = 0.04). EI-VOM combined with RFCA significantly increased the rate of bidirectional mitral isthmus block compared with RFCA alone in AF patients (RR 1.50, 95% CI 1.34 to 1.67, p < 0.001). There were nine cardiac tamponades observed in 644 patients (PR 0.8%, 95% CI 0.1-1.5%) who were performed EI-VOM combined with RFCA.</AbstractText>Our meta-analysis brings encouraging evidence that adjuvant EI-VOM reduces AF and/or AT recurrence rate in persistent AF patients and increases the success rate of bidirectional mitral isthmus block.</AbstractText>© 2021 Wiley Periodicals LLC.</CopyrightInformation>
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2,336,034 |
Radiobiological Comparison of Teardrop Technique for Breast Cancer Radiotherapy Treatment Planning on a Tomotherapy System.
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Breast cancer is one of the most common cancer worldwide with large morbidity. In Mexico, it is the first cause of death by cancer in women. Radiotherapy has proven to be a great tool to control such ailments and TomoTherapy is a relatively new technology to accomplish it. To obtain good clinical outcomes, tight dosimetric constraints are placed on organs at risk (OARs) to maximize tumor control and minimize normal tissue complication probabilities. The teardrop technique helps meeting these constraints by placing a virtual block over parts of the ipsilateral lung and the heart but it contributes to lengthen the treatment time. In this work, we present our experience in using this technique and compare its radiobiological estimations with similar plans without it. Ten patients diagnosed with breast cancer were planned twice, with and without the teardrop technique. Dose-volume histograms were obtained and analyzed to get uncomplicated tumor control probability (UTCP) and optimization estimator (fEUD) parameters. Classical dosimetrical parameters for planning target volumes (PTVs): conformity index, homogeneity index, and coverage were also recorded and statistically described. Several dosimetrical parameters for OARs were recorded and analyzed. The UTCP parameter had a mean value of 0.968 ± 0.023 when no block was used and 0.966 ± 0.022 with the teardrop. The fEUD parameter values were: 0.515 ± 0.049 without blocks and 0.541 ± 0.057 with the teardrop. Optimization of every plan was stopped only after all constraints were met, and it was easier to accomplish this goal with the teardrop technique. The teardrop technique permitted a 5% gain in fEUD. The teardrop technique was observed to have a net radiobiological benefit with little impact on patient scheduling.
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2,336,035 |
Quantitative Assessment of the Incidence of Persistent Orthostatic Hemodynamic Changes After Celiac Plexus Neurolysis: A Prospective Case Series.
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Celiac plexus neurolysis has been associated with orthostatic hypotension but has not been quantified prospectively or evaluated for persistence after the immediate postprocedural period. Our objective was to quantify persistent hemodynamic changes induced by celiac plexus neurolysis. In this case series of 16 patients with cancer, 8 (50%) had orthostatic hypotension alone, 3 (18.75%) developed an exaggerated postural heart rate increase (>30 beats per min), and 1 (6.25%) had both orthostatic hypotension and an increased heart rate. While the analgesic benefit of celiac plexus neurolysis is clear, the observed hemodynamic changes may be poorly tolerated in some individuals.
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2,336,036 |
ECMO and adult mediastinal masses.
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The role of extracorporeal membrane oxygenation (ECMO) is expanding as surgeons look at its utility beyond rescue treatment and have started adopting it for high-risk procedures to provide temporary airway and hemodynamic stabilization. ECMO needs to be deliberated in all patients with mediastinal masses who have compromised airways as well as in those with compression of heart and great vessels. There is a dearth of literature highlighting the definitive role of ECMO in patients with mediastinal masses. This article reviews the available adult literature and highlights the possible situations where the use of ECMO would be supportive in the management of patients with mediastinal masses.
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2,336,037 |
Effect of KBP-5074 on Blood Pressure in Advanced Chronic Kidney Disease: Results of the BLOCK-CKD Study.
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[Figure: see text].
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2,336,038 |
Aspirin and omega-3 fatty acid status interact in the prevention of cardiovascular diseases in Framingham Heart Study.
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The roles of omega-3 (n3) fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and low-dose aspirin in the primary prevention of ischemic cardiovascular disease (CVD) are controversial. Since omega-3 (n3) fatty acids and aspirin affect cyclooxygenase activity in platelets, there could be a clinically-relevant effect of aspirin combined with a particular n3 fatty acid level present in each individual.</AbstractText>RBC EPA+DHA, arachidonic acid (AA) and docosapentaenoic acid (DPA) were measured in 2500 participants without known CVD in the Framingham Heart Study. We then tested for interactions with reported aspirin use (1004 reported use and 1494 did not) on CVD outcomes. The median follow-up was 7.2 years.</AbstractText>Having RBC EPA+DHA in the second quintile (4.2-4.9% of total fatty acids) was associated with significantly reduced risk for future CVD events (relative to the first quintile, <4.2%) in those who did not take aspirin (HR 0.54 (0.30, 0.98)), but in those reporting aspirin use, risk was significantly increased (HR 2.16 (1.19, 3.92)) in this quintile. This interaction remained significant when adjusting for confounders. Significant interactions were also present for coronary heart disease and stroke outcomes using the same quintiles. Similar findings were present for EPA and DHA alone but not for DPA and AA.</AbstractText>There is a complex interaction between aspirin use and RBC EPA+DHA levels on CVD outcomes. This suggests that aspirin use may be beneficial in one omega-3 environment but harmful in another, implying that a personalized approach to both aspirin use and omega-3 supplementation may be needed.</AbstractText>Copyright © 2021. Published by Elsevier Ltd.</CopyrightInformation>
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2,336,039 |
Pretreatment with Pectoral Nerve Block II Is Effective for Reducing Pain in Patients Undergoing Thoracoscopic Lobectomy: A Randomized, Double-Blind, Placebo-Controlled Trial.
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Although video-assisted thoracoscopy has a smaller incision than traditional surgery, the postoperative pain is still severe. Ultrasound-guided pectoral nerve block (PECS) II is a new technique that can reduce pain in patients, and it had not been reported in the analgesia after thoracoscopic lobectomy.</AbstractText>40 patients scheduled for thoracoscopic lobectomy were randomly divided into two groups. Patients in the PECS II group received 0.5% ropivacaine 25 ml before the general anesthesia, while patients in the placebo group received 0.9% saline. Thirty minutes after the block was performed, a pin-prick test was used to analyze the sense of pain of T2-T6 segments. The primary endpoint was the total consumption of fentanyl. Data were collected in the postanesthesia care unit (PACU) and in the ward within 24 hours after operation.</AbstractText>The total consumption of fentanyl and the consumption of fentanyl in the intravenous analgesia pump within 24 hours after the operation were significantly lower in the PECS II group compared to the placebo group (p</i> < 0.05). The implementation rate of rescue analgesia during operation and in PACU in the PECS II group was significantly lower than that in the placebo group (p</i> < 0.05). The numerical rating scale (NRS) in 1 and 4 h after operation was lower in the PECS II group (p</i> < 0.05). Mean arterial pressure (MAP) and heart rate (HR) of the PECS II group at chest entering (T1) were significantly lower than those in the placebo group (p</i> < 0.05).</AbstractText>Preconditioning of PECS II can stabilize the intraoperative circulation and significantly reduce pain and the consumption of opioids after operation.</AbstractText>Copyright © 2021 Ge Luo et al.</CopyrightInformation>
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2,336,040 |
An investigation of the effects of dexmedetomidine and fentanyl as an adjuvant to ropivacaine on pain scores and hemodynamic changes following laparoscopic cholecystectomy.
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Postoperative pain control is recognized as a challenging surgical issue receiving high priority in the healthcare system, and opioids are routinely prescribed for anesthesia and pain relief. This study aimed to investigate the effects of ropivacaine administered intraperitoneally alone or combined with dexmedetomidine or fentanyl on postoperative pain control following laparoscopic cholecystectomy. This randomized double-blind clinical trial recruited three equal-size block-randomized groups of patients (n = 138) scheduled for elective laparoscopic cholecystectomy at Valiasr Hospital, Arak, Iran, in 2019-2020 who received ropivacaine (40 mL/0.5%), ropivacaine (40 mL/0.5%) + dexmedetomidine (1 μg/kg), and ropivacaine (40 mL/0.5%) + fentanyl (1 μg/kg). No significant differences were observed among the three groups according to the vital signs (mean arterial pressure/heart-rate/oxygen saturation) in the study period and during surgery (P > 0.05). Lower pain was revealed in the ropivacaine + dexmedetomidine group (P = 0.001), with the lowest opioid dose in postoperative 24 hours (P = 0.001). Moreover, no clinically significant differences were observed in complications among the three groups (P = 0.483), and no patient developed ileus. Intraperitoneal ropivacaine administered with dexmedetomidine could relieve pain and reduce opioid use in postoperative 24 hours, without any complication and ileus. Therefore, intraperitoneal ropivacaine administered with dexmedetomidine is recommended for postoperative pain control in patients undergoing laparoscopic cholecystectomy. This study was approved by the Ethical Committee of Arak University of Medical Sciences (approval No. IR.ARAKMU.REC.1397.267) on December 30, 2018 and was registered in the Iranian Registry of Clinical Trials (No. IRCT 20141209020258N117) on July 13, 2019.
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2,336,041 |
A drug-repositioning screen using splicing-sensitive fluorescent reporters identifies novel modulators of VEGF-A splicing with anti-angiogenic properties.
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Alternative splicing of the vascular endothelial growth factor A (VEGF-A) terminal exon generates two protein families with differing functions. Pro-angiogenic VEGF-A<sub>xxx</sub>a isoforms are produced via selection of the proximal 3' splice site of the terminal exon. Use of an alternative distal splice site generates the anti-angiogenic VEGF-A<sub>xxx</sub>b proteins. A bichromatic splicing-sensitive reporter was designed to mimic VEGF-A alternative splicing and was used as a molecular tool to further investigate this alternative splicing event. Part of VEGF-A's terminal exon and preceding intron were inserted into a minigene construct followed by the coding sequences for two fluorescent proteins. A different fluorescent protein is expressed depending on which 3' splice site of the exon is used during splicing (dsRED denotes VEGF-A<sub>xxx</sub>a and EGFP denotes VEGF-A<sub>xxx</sub>b). The fluorescent output can be used to follow splicing decisions in vitro and in vivo. Following successful reporter validation in different cell lines and altering splicing using known modulators, a screen was performed using the LOPAC library of small molecules. Alterations to reporter splicing were measured using a fluorescent plate reader to detect dsRED and EGFP expression. Compounds of interest were further validated using flow cytometry and assessed for effects on endogenous VEGF-A alternative splicing at the mRNA and protein level. Ex vivo and in vitro angiogenesis assays were used to demonstrate the anti-angiogenic effect of the compounds. Furthermore, anti-angiogenic activity was investigated in a Matrigel in vivo model. To conclude, we have identified a set of compounds that have anti-angiogenic activity through modulation of VEGF-A terminal exon splicing.
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2,336,042 |
Comparison of ropivacaine plasma concentration after posterior Quadratus Lumborum Block in Cesarean Section with ropivacaine with epinephrine vs. plane.
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The posterior quadratus lumborum block (pQLB) has been used in postoperative pain management after cesarean section (CS). However, clinicians have no data about pQLB safety in pregnants, at increased risk of local anesthetic systemic toxicity (LAST). The purpose of the present study was to explore the efficacy and the safety of adding epinephrine to ropivacaine for bilateral pQLB vs. bilateral pQLB performed with ropivacaine alone in CS.</AbstractText>In this prospective trial 52 pregnants, ASA 2 physiological status, were consecutively allocated to one of two groups, e-pQLB and pQLB; e-pQLB group received 0.375% ropivacaine+100 mcg epinephrine, 20 mL each side; pQLB received 0.375% ropivacaine alone, 20 mL each side. The primary and secondary outcomes were to evaluate if the adjunct of epinephrine to ropivacaine increases efficacy and safety of pQLB, respectively.</AbstractText>Authors found in e-pQLB group vs. p-QLB group: a total mean morphine consumption statistically lower during the first 24 postoperative hours (5.08±3.12, vs. 9.11±4.67 SD mg, P=0.0002); NRS values statistically lower at six hours from block, both at rest (1.73±1.88 SD vs. 2.88±2.53, P=0.03) and with movement (3.03±1.98 SD vs. 4.23±2.87, P=0.04); a longer time between block and the first opioid request (5.92±2.48 vs. 3.78±2.68 SD hrs, P<0.003); venous ropivacaine concentrations significantly lower at any time of samples but at 120 minutes.</AbstractText>Adding epinephrine to ropivacaine increases efficacy and duration of pQLB. Moreover it increases block safety, reducing peak and mean venous ropivacaine concentration.</AbstractText>
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2,336,043 |
Multifocus Thermal Strain Imaging Using a Curved Linear Array Transducer for Identification of Lipids in Deep Tissue.
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Thermal strain imaging (TSI) is an ultrasound-based imaging technique intended primarily for diseases in which lipid accumulation is the main biomarker. The goal of the research described here was to successfully implement TSI on a single, commercially available curved linear array transducer for heating and imaging of organs at a deeper depth. For an effective temperature rise of the tissue over a large area, which is key to TSI performance, an innovative multifocus beamforming approach was applied. This yielded a heating area from 32 to 96 mm in the axial direction and -7 to +7 mm in the lateral direction. The pressure fields generated from simulation were in agreement with pressure fields measured with the hydrophone. TSI with safe acoustic power identified with high contrast a rubber inclusion and liposuction fat tissue embedded in a gelatin block.
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2,336,044 |
The Effect of Dexmedetomidine in Combination with Bupivacaine on Sensory and Motor Block Time and Pain Score in Supraclavicular Block.
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Brachial plexus block is frequently recommended for upper limb surgeries. Many drugs have been used as adjuvants to prolong the duration of the block. This study aimed to assess the effect of dexmedetomidine with bupivacaine combination and only bupivacaine on sensory and motor block duration time, pain score, and hemodynamic variations in the supraclavicular block in upper extremity orthopedic surgery.</AbstractText>This prospective, double-blind clinical trial study was conducted on 60 patients, 20 to 60 years old. Patients were candidates for upper extremity orthopedic surgeries. The sensory and motor block were evaluated by using the pinprick method and the modified Bromage scale. The postoperative pain was assessed by utilizing a visual analog scale.</AbstractText>The mean onset time of sensory and motor block in patients receiving only bupivacaine was, respectively, 31.03 ± 9.65 min and 24.66 ± 9.2 min, and in the dexmedetomidine receiving group, it was about 21.36 ± 8.34 min and 15.93 ± 6.36 minutes. The changes in heart rate and mean arterial blood pressure were similar in both groups. The duration of sensory and motor block and the time of the first analgesia request in the intervention group were longer. Postoperative pain was lower in the intervention group for 24 hours (P</i> = 0.001).</AbstractText>Dexmedetomidine plus bupivacaine reduced the onset time of sense and motor blocks and increased numbness and immobility duration. Also, dexmedetomidine reduced postoperative pain significantly with the use of bupivacaine for supraclavicular blocks. Trial Registration</i>. IRCT, IRCT20160430027677N15. Registered 05/28/2019, https://www.irct.ir/trial/39463.</AbstractText>Copyright © 2021 Shahryar Sane et al.</CopyrightInformation>
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2,336,045 |
Combination of Cyclosporine A and Levosimendan Induces Cardioprotection under Acute Hyperglycemia.
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Prognosis of patients with myocardial infarction is detrimentally affected by comorbidities like diabetes mellitus. In the experimental setting, not only diabetes mellitus but also acute hyperglycemia is shown to hamper cardioprotective properties by multiple pharmacological agents. For Levosimendan-induced postconditioning, a strong infarct size reducing effect is demonstrated in healthy myocardium. However, acute hyperglycemia is suggested to block this protective effect. In the present study, we investigated whether (1) Levosimendan-induced postconditioning exerts a concentration-dependent effect under hyperglycemic conditions and (2) whether a combination with the mitochondrial permeability transition pore (mPTP) blocker cyclosporine A (CsA) restores the cardioprotective properties of Levosimendan under hyperglycemia. For this experimental investigation, hearts of male Wistar rats were randomized and mounted onto a Langendorff system, perfused with Krebs-Henseleit buffer with a constant pressure of 80 mmHg. All isolated hearts were subjected to 33 min of global ischemia and 60 min of reperfusion under hyperglycemic conditions. (1) Hearts were perfused with various concentrations of Levosimendan (Lev) (0.3-10 μM) for 10 min at the onset of reperfusion, in order to investigate a concentration-response relationship. In the second set of experiments (2), 0.3 μM Levosimendan was administered in combination with the mPTP blocker CsA, to elucidate the underlying mechanism of blocked cardioprotection under hyperglycemia. Infarct size was determined by tetrazolium chloride (TTC) staining. (1) Control (Con) hearts showed an infarct size of 52 ± 12%. None of the administered Levosimendan concentrations reduced the infarct size (Lev0.3: 49 ± 9%; Lev1: 57 ± 9%; Lev3: 47 ± 11%; Lev10: 50 ± 7%; all ns vs. Con). (2) Infarct size of Con and Lev0.3 hearts were 53 ± 4% and 56 ± 2%, respectively. CsA alone had no effect on infarct size (CsA: 50 ± 10%; ns vs. Con). The combination of Lev0.3 and CsA (Lev0.3 ± CsA) induced a significant infarct size reduction compared to Lev0.3 (Lev0.3+CsA: 35 ± 4%; <i>p</i> < 0.05 vs. Lev0.3). We demonstrated that (1) hyperglycemia blocks the infarct size reducing effects of Levosimendan-induced postconditioning and cannot be overcome by an increased concentration. (2) Furthermore, cardioprotection under hyperglycemia can be restored by combining Levosimendan and the mPTP blocker CsA.
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2,336,046 |
Multi-Organ Protective Effects of Sodium Glucose Cotransporter 2 Inhibitors.
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Sodium glucose cotransporter 2 inhibitors (SGLT2i) block the reabsorption of glucose by inhibiting SGLT2, thus improving glucose control by promoting the renal excretion of glucose, without requiring insulin secretion. This pharmacological property of SGLT2i reduces body weight and improves insulin resistance in diabetic patients. Such beneficial metabolic changes caused by SGLT2i are expected to be useful not only for glucose metabolism, but also for the protection for various organs. Recent randomized controlled trials (RCTs) on cardiovascular diseases (EMPA-REG OUTCOME trial and CANVAS program) showed that SGLT2i prevented cardiovascular death and the development of heart failure. RCTs on renal events (EMPA-REG OUTCOME trial, CANVAS program, and CREDENCE trial) showed that SGLT2i suppressed the progression of kidney disease. Furthermore, SGLT2i effectively lowered the liver fat content, and our study demonstrated that SGLT2i reduced the degree of hepatic fibrosis in patients at high-risk of hepatic fibrosis. Such promising properties of SGLT2i for cardiovascular, renal, and hepatic protection provide us the chance to think about the underlying mechanisms for SGLT2i-induced improvement of multiple organs. SGLT2i have various mechanisms for organ protection beyond glucose-lowering effects, such as an increase in fatty acids utilization for hepatic protection, osmotic diuresis for cardiac protection, an improvement of insulin resistance for anti-atherogenesis, and an improvement of tubuloglomerular feedback for renal protection.
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2,336,047 |
Myelodysplasia Syndrome, Clonal Hematopoiesis and Cardiovascular Disease.
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The development of myelodysplasia syndromes (MDS) is multiphasic and can be driven by a plethora of genetic mutations and/or abnormalities. MDS is characterized by a hematopoietic differentiation block, evidenced by increased immature hematopoietic cells, termed blast cells and decreased mature circulating leukocytes in at least one lineage (i.e., cytopenia). Clonal hematopoiesis of indeterminate potential (CHIP) is a recently described phenomenon preceding MDS development that is driven by somatic mutations in hemopoietic stem cells (HSCs). These mutant HSCs have a competitive advantage over healthy cells, resulting in an expansion of these clonal mutated leukocytes. In this review, we discuss the multiphasic development of MDS, the common mutations found in both MDS and CHIP, how a loss-of-function in these CHIP-related genes can alter HSC function and leukocyte development and the potential disease outcomes that can occur with dysfunctional HSCs. In particular, we discuss the novel connections between MDS development and cardiovascular disease.
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2,336,048 |
Safety and Efficacy of Vadadustat for Anemia in Patients Undergoing Dialysis.
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Vadadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, a class of compounds that stimulate endogenous erythropoietin production.</AbstractText>We conducted two randomized, open-label, noninferiority phase 3 trials to evaluate the safety and efficacy of vadadustat, as compared with darbepoetin alfa, in patients with anemia and incident or prevalent dialysis-dependent chronic kidney disease (DD-CKD). The primary safety end point, assessed in a time-to-event analysis, was the first occurrence of a major adverse cardiovascular event (MACE, a composite of death from any cause, a nonfatal myocardial infarction, or a nonfatal stroke), pooled across the trials (noninferiority margin, 1.25). A key secondary safety end point was the first occurrence of a MACE plus hospitalization for either heart failure or a thromboembolic event. The primary and key secondary efficacy end points were the mean change in hemoglobin from baseline to weeks 24 to 36 and from baseline to weeks 40 to 52, respectively, in each trial (noninferiority margin, -0.75 g per deciliter).</AbstractText>A total of 3923 patients were randomly assigned in a 1:1 ratio to receive vadadustat or darbepoetin alfa: 369 in the incident DD-CKD trial and 3554 in the prevalent DD-CKD trial. In the pooled analysis, a first MACE occurred in 355 patients (18.2%) in the vadadustat group and in 377 patients (19.3%) in the darbepoetin alfa group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.11). The mean differences between the groups in the change in hemoglobin concentration were -0.31 g per deciliter (95% CI, -0.53 to -0.10) at weeks 24 to 36 and -0.07 g per deciliter (95% CI, -0.34 to 0.19) at weeks 40 to 52 in the incident DD-CKD trial and -0.17 g per deciliter (95% CI, -0.23 to -0.10) and -0.18 g per deciliter (95% CI, -0.25 to -0.12), respectively, in the prevalent DD-CKD trial. The incidence of serious adverse events in the vadadustat group was 49.7% in the incident DD-CKD trial and 55.0% in the prevalent DD-CKD trial, and the incidences in the darbepoetin alfa group were 56.5% and 58.3%, respectively.</AbstractText>Among patients with anemia and CKD who were undergoing dialysis, vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and correction and maintenance of hemoglobin concentrations. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; INNO2</sub>VATE ClinicalTrials.gov numbers, NCT02865850 and NCT02892149.).</AbstractText>Copyright © 2021 Massachusetts Medical Society.</CopyrightInformation>
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2,336,049 |
Vadadustat in Patients with Anemia and Non-Dialysis-Dependent CKD.
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Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production.</AbstractText>In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52.</AbstractText>A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter.</AbstractText>Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2</sub>TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).</AbstractText>Copyright © 2021 Massachusetts Medical Society.</CopyrightInformation>
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2,336,050 |
Erector spinae plane block: An effective analgesic technique for pleurodesis after senning operation.
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Pain emanating from pleurodesis is significantly distressing and presents an important management concern. Despite encouraging evidence on the application of fascial plane blocks for cardiothoracic surgery, the literature on the use of erector spinae block for pleurodesis remains scarce. We describe a case of bilateral recurrent pleural effusion following congenital heart surgery where erector spinae block was employed as an analgesic technique for pleurodesis. Finally, we discuss its regional analgesic effects in comparison to the conventional intravenous/systemic analgesia in a cross over fashion.
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2,336,051 |
Effect of bilateral infraorbital nerve block on intraoperative anesthetic requirements, hemodynamics, glycemic levels, and extubation in infants undergoing cheiloplasty under general anesthesia.
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Inappropriate use of intravenous and inhaled anesthetics may be dangerous in infants undergoing facial cleft surgeries. This study primarily aimed to compare the effect of infraorbital nerve block on sevoflurane requirement in infants undergoing cheiloplasty. Intraoperative opioid consumption, hemodynamics, blood glucose levels, extubation time, and delirium were also compared.</AbstractText>This prospective, randomized, double-blinded study was conducted in 34 infants undergoing cheiloplasty under general anesthesia. After induction, group A received bilateral infraorbital nerve block with 0.5 mL of 0.5% bupivacaine and group B 0.5 mL saline. An increase in heart rate or blood pressure > 20% was managed by increasing sevoflurane by 2-2.5%, followed by fentanyl 0.5 µg/kg bolus. The chi-square test and independent-sample t-test were used where applicable.</AbstractText>Demographics, duration of surgery, and intravenous fluids used were comparable between the groups. Compared to group A, patients in group B had significantly higher consumption of fentanyl (14.2 ± 4.4 µg vs. 22.1 ± 6.2 µg) and sevoflurane (14.2 ± 4.8 mL vs. 26.8 ± 15.6 mL). Intraoperative hemodynamic parameters were significantly lower in group A, the number of times increases in hemodynamic parameters occurred, and fentanyl supplemental bolus was required remained significantly lower in group A than in group B. Intraoperative glycemic levels remained higher in group B, and the extubation time was significantly shorter in group A than in group B (4.40 ± 1.60 min vs. 9.2 ± 2.18 min). Group A had a lesser occurrence of postoperative delirium.</AbstractText>Supplemental infraorbital block in infants undergoing cheiloplasty under general anesthesia resulted in significantly decreased anesthetic requirements and optimal hemodynamic and glycemic levels with faster extubation and lesser delirium.</AbstractText>Copyright © 2021 Journal of Dental Anesthesia and Pain Medicine.</CopyrightInformation>
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2,336,052 |
Associations of the Neighborhood Built Environment With Physical Activity Across Pregnancy.
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Several features of the neighborhood built environment have been shown to promote leisure-time physical activity (PA) in the general population, but few studies have examined its impact on PA during pregnancy.</AbstractText>Data were extracted from 8362 Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be cohort participants (2010-2013). Residential address information was linked to 3 built environment characteristics: number of gyms and recreation areas within a 3-km radius of residence and census block level walkability. Self-reported leisure-time PA was measured in each trimester and dichotomized as meeting PA guidelines or not. Relative risks for cross-sectional associations between neighborhood characteristics and meeting PA guidelines were estimated using Poisson regression.</AbstractText>More gyms and recreation areas were each associated with a greater chance of meeting PA guidelines in models adjusted for sociodemographic characteristics and preexisting conditions. Associations were strongest in the third trimester where each doubling in counts of gyms and recreation areas was associated with 10% (95% confidence interval, 1.07-1.13) and 8% (95% confidence interval, 1.03-1.12), respectively, greater likelihood of meeting PA guidelines. Associations were similar though weaker for walkability.</AbstractText>Results from a large, multisite cohort suggest that these built environment characteristics have similar PA-promoting benefits in pregnant women as seen in more general populations.</AbstractText>
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2,336,053 |
HDAC1 and 2 regulate endothelial VCAM-1 expression and atherogenesis by suppressing methylation of the <i>GATA6</i> promoter.
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Increased expression of vascular cell adhesion molecule (VCAM)-1 on the activated arterial endothelial cell (EC) surface critically contributes to atherosclerosis which may in part be regulated by epigenetic mechanisms. This study investigated whether and how the clinically available histone deacetylases 1 and 2 (HDAC1/2) inhibitor drug Romidepsin epigenetically modulates VCAM-1 expression to suppress atherosclerosis. <b>Methods:</b> VCAM-1 expression was analyzed in primary human aortic EC (HAEC) treated with Romidepsin or transfected with HDAC1/2-targeting siRNA. Methylation of GATA6 promoter region was examined with methylation-specific PCR assay. Enrichment of STAT3 to GATA6 promoter was detected with chromatin immunoprecipitation. Lys685Arg mutation was constructed to block STAT3 acetylation. The potential therapeutic effect of Romidepsin on atherosclerosis was evaluated in <i>Apoe</i><sup>-/-</sup> mice fed with a high-fat diet. <b>Results:</b> Romidepsin significantly attenuated TNFα-induced VCAM-1 expression on HAEC surface and monocyte adhesion through simultaneous inhibition of HDAC1/2. This downregulation of VCAM-1 was attributable to reduced expression of transcription factor GATA6. Romidepsin enhanced STAT3 acetylation and its binding to DNA methyltransferase 1 (DNMT1), leading to hypermethylation of the <i>GATA6</i> promoter CpG-rich region at +140/+255. Blocking STAT3 acetylation at Lys685 disrupted DNMT1-STAT3 interaction, decreased <i>GATA6</i> promoter methylation, and reversed the suppressive effects of HDAC1/2 inhibition on GATA6 and VCAM-1 expression. Finally, intraperitoneal administration of Romidepsin reduced diet-induced atherosclerotic lesion development in <i>Apoe</i><sup>-/-</sup> mice, accompanied by a reduction in GATA6/VCAM-1 expression in the aorta. <b>Conclusions:</b> HDAC1/2 contributes to VCAM-1 expression and atherosclerosis by suppressing STAT3 acetylation-dependent <i>GATA6</i> promoter methylation. These findings may provide a rationale for HDAC1/2-targeting therapy in atherosclerotic heart disease.
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2,336,054 |
Neighborhood education status drives racial disparities in clinical outcomes in PPCM.
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Peripartum cardiomyopathy (PPCM) disproportionately affects women of African ancestry. Additionally, clinical outcomes are worse in this subpopulation compared to White women with PPCM.  The extent to which socioeconomic parameters contribute to these racial disparities is not known.</AbstractText>We aimed to quantify the association between area-based proxies of socioeconomic status (SES) and clinical outcomes in PPCM, and to determine the potential contribution of these factors to racial disparities in outcomes. A retrospective cohort study was performed at the University of Pennsylvania Health System, a tertiary referral center serving a population with a high proportion of Black individuals. The cohort included 220 women with PPCM, 55% of whom were Black or African American. Available data included clinical and demographic characteristics as well as residential address georeferenced to US Census-derived block group measures of SES. Rates of sustained cardiac dysfunction (defined as persistent LVEF <50%, LVAD placement, transplant, or death) were compared by race and block group-level measures of SES, and a composite neighborhood concentrated disadvantage index (NDI). The contributions of area-based socioeconomic parameters to the association between race and sustained cardiac dysfunction were quantified.</AbstractText>Black race and higher NDI were both independently associated with sustained cardiac dysfunction (relative risk [RR] 1.63, confidence interval [CI] 1.13-2.36; and RR 1.29, CI 1.08-1.53, respectively). Following multivariable adjustment, effect size for NDI remained statistically significant, but effect size for Black race did not. The impact of low neighborhood education on racial disparities in outcomes was stronger than that of low neighborhood income (explaining 45% and 0% of the association with black race, respectively). After multivariate adjustment, only low area-based education persisted as significantly correlating with sustained cardiac dysfunction (RR 1.49; CI 1.02-2.17).</AbstractText>Both Black race and NDI independently associate with adverse outcomes in women with PPCM in a single center study. Of the specific components of NDI, neighborhood low education was most strongly associated with clinical outcome and partially explained differences in race. These results suggest interventions targeting social determinants of health in disadvantaged communities may help to mitigate outcome disparities.</AbstractText>Copyright © 2021 Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,336,055 |
Xinmailong Attenuates Doxorubicin-Induced Lysosomal Dysfunction and Oxidative Stress in H9c2 Cells via HO-1.
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The clinical use of doxorubicin (DOX) is limited by its cardiotoxicity, which is closely associated with oxidative stress. Xinmailong (XML) is a bioactive peptide extracted from American cockroaches, which has been mainly applied to treat chronic heart failure in China. Our previous study showed that XML attenuates DOX-induced oxidative stress. However, the mechanism of XML in DOX-induced cardiotoxicity remains unclear. Heme oxygenase-1 (HO-1), an enzyme that is ubiquitously expressed in all cell types, has been found to take antioxidant effects in many cardiovascular diseases, and its expression is protectively upregulated under DOX treatment. Lysosome and autophagy are closely involved in oxidative stress as well. It is still unknown whether XML could attenuate doxorubicin-induced lysosomal dysfunction and oxidative stress in H9c2 cells via HO-1. Thus, this study was aimed at investigating the involvement of HO-1-mediated lysosomal function and autophagy flux in DOX-induced oxidative stress and cardiotoxicity in H9c2 cells. Our results showed that XML treatment markedly increased cell proliferation and SOD activity, improved lysosomal function, and ameliorated autophagy flux block in DOX-treated H9c2 cells. Furthermore, XML significantly increased HO-1 expression following DOX treatment. Importantly, HO-1-specific inhibitor (Znpp) or HO-1 siRNA could significantly attenuate the protective effects of XML against DOX-induced cell injury, oxidative stress, lysosomal dysfunction, and autophagy flux block. These results suggest that XML protects against DOX-induced cardiotoxicity through HO-1-mediated recovery of lysosomal function and autophagy flux and decreases oxidative stress, providing a novel mechanism responsible for the protection of XML against DOX-induced cardiomyopathy.
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2,336,056 |
Prazoles Targeting Tsg101 Inhibit Release of Epstein-Barr Virus following Reactivation from Latency.
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Epstein-Barr virus (EBV) is a ubiquitous herpesvirus responsible for several diseases, including cancers of lymphoid and epithelial cells. EBV cancers typically exhibit viral latency; however, the production and release of EBV through its lytic phase are essential for cancer development. Antiviral agents that specifically target EBV production do not currently exist. Previously, we reported that the proton pump inhibitor tenatoprazole, which blocks the interaction of ubiquitin with the ESCRT-1 factor Tsg101, inhibits production of several enveloped viruses, including EBV. Here, we show that three structurally distinct prazoles impair mature particle formation postreactivation and identify the impact on stages of replication. The prazoles did not impair expression of lytic genes representative of the different kinetic classes but interfered with capsid maturation in the nucleus as well as virion transport from the nucleus. Replacement of endogenous Tsg101 with a mutant Tsg101 refractory to prazole-mediated inhibition rescued EBV release. These findings directly implicate Tsg101 in EBV nuclear egress and identify prazoles as potential therapeutic candidates for conditions that rely on EBV replication, such as chronic active EBV infection and posttransplant lymphoproliferative disorders. <b>IMPORTANCE</b> Production of virions is necessary for the ubiquitous Epstein-Barr virus (EBV) to persist in humans and can set the stage for development of EBV cancers in at-risk individuals. In our attempts to identify inhibitors of the EBV lytic phase, we previously found that a prazole proton pump inhibitor, known to block the interaction of ubiquitin with the ESCRT-1 factor Tsg101, blocks production of EBV. We now find that three structurally distinct prazoles impair maturation of EBV capsids and virion transport from the nucleus and, by interfering with Tsg101, prevent EBV release from lytically active cells. Our findings not only implicate Tsg101 in EBV production but also identify widely used prazoles as candidates to prevent development of posttransplant EBV lymphomas.
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2,336,057 |
Direct conversion of adult human fibroblasts into functional endothelial cells using defined factors.
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We aimed to directly convert adult human dermal fibroblasts (aHDFs) into functional endothelial cells (ECs). Lentiviral vectors encoding endothelial transcription factors (TFs) were constructed. We examined whether five TFs (FOXO1, ER71, KLF2, TAL1, and LMO2) used for the generation of mouse induced ECs (iECs) could convert the aHDFs into human iECs. Twenty-eight days after transduction with lentiviral constructs, 32.1 ± 5.1% cells expressed vascular endothelial (VE)-cadherin. Factor screening revealed that only three factors (3F: ER71, KLF2, and TAL1) were necessary to induce VE-cadherin (+) cells (49.4 ± 3.5%). However, whole transcriptome sequencing showed that VE-cadherin (+) cells were not completely reprogrammed. Mature iECs double-positive for VE-cadherin/Pecam1 (DP cells) with a cobblestone appearance were obtained at a frequency of only 5.1 ± 0.6%. Using whole transcriptome analysis, the potential factors that could block the conversion were screened. Among candidates TWIST1-knockdown enhanced efficiency of conversion. Rosiglitazone, an inhibitor of epithelial-mesenchymal transition (EMT), also improved the conversion efficiency. Moreover, a 2nd second-stage conversion process, in which VE-cadherin (+) cells were incubated for additional two weeks, further enhanced the efficiency. The final protocol for 6 weeks yielded a conversion rate of 19.6 ± 3.0% iECs, defined by DP cells depicting the nature of mature ECs in various analyses. Further analyses revealed that the genetic and epigenetic profiles of iECs resembled those of functional ECs. Collectively, aHDFs can be converted into functional ECs through the transduction of ER71, KLF2, and TAL1, combined with two EMT inhibitors (siTWIST1 and rosiglitazone), followed by 2nd stage conversion.
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2,336,058 |
Comparison of efficacy between the genicular nerve block and the popliteal artery and the capsule of the posterior knee (IPACK) block for total knee replacement surgery: A prospective randomized controlled study.
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The aim of this study was to compare the efficacy of popliteal artery and the capsule of the posterior knee (IPACK) block and genicular nerve block on postoperative pain scores, the need for rescue analgesics, range of motion (ROM), walking distance, and perioperative monitorization variables in patients undergoing total knee replacement (TKR) surgery.</AbstractText>Sixty American Society of Anesthesiologists (ASA) physical status I-III patients were enrolled in this study and then were randomly assigned into three groups: the IPACK block group (17 female, 3 male; mean age=67.5±1.4 years), genicular nerve block (16 female, 4 male; mean age=68±1.76 years), and the control group (13 female, 7 male; mean age=63±1.67years). All the patients underwent TKR under spinal anesthesia. The visual analog scale (VAS) score, mobility, pre- and intra-operative monitorization of systolic and diastolic holding area, non-invasive blood pressure, heart rate, and SPO 2 were compared between the groups.</AbstractText>Patients in the IPACK and genicular block groups had a significantly lower visual analogous scale (VAS) at postoperative 4 hours (p<0.01), 8h (p<0.01), 12h (p<0.01), and 24h (p<0.05). VAS score was significantly lower in the genicular block group at the postoperative 4h (5.5±0.55) and 8h (5.0±0.53) in the mobile state compared to the IPACK (8.0±0.47 and 8.0±0.43, respectively) and the control group (9.5±0.20; 10±0.28, respectively) (p< 0.01). The use of patient-controlled-analgesia (PCA) devices and button push count for analgesics demand were significantly lower in the genicular block group on the immediate postoperative period (p<0.01 at the postoperative 0 to 4 h). The total consumption of morphine equivalents on the postoperative day 0 was significantly lower in the genicular block group (p<0.01, and p<0.001 for IPACK and control groups, respectively). The degree of flexion was significantly higher in the genicular block group at the postoperative 12h compared to the IPACK and the control group (p<0.001). The length of hospital stay was significantly lower in the genicular block group compared to the IPACK and the control group (p<0.05 for both variables).</AbstractText>IPACK and genicular blocks both are effective in improving patient comfort during and after TKR surgery and reducing the potential need for systemic analgesic and opioids. The genicular block seems to be a promising technique that can offer improved pain management in the immediate and early postoperative period without adverse effects on systemic and motor variables.</AbstractText>
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2,336,059 |
Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial.
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Multiple early reports of patients admitted to hospital with COVID-19 showed that patients with chronic respiratory disease were significantly under-represented in these cohorts. We hypothesised that the widespread use of inhaled glucocorticoids among these patients was responsible for this finding, and tested if inhaled glucocorticoids would be an effective treatment for early COVID-19.</AbstractText>We performed an open-label, parallel-group, phase 2, randomised controlled trial (Steroids in COVID-19; STOIC) of inhaled budesonide, compared with usual care, in adults within 7 days of the onset of mild COVID-19 symptoms. The trial was done in the community in Oxfordshire, UK. Participants were randomly assigned to inhaled budsonide or usual care stratified for age (≤40 years or >40 years), sex (male or female), and number of comorbidities (≤1 and ≥2). Randomisation was done using random sequence generation in block randomisation in a 1:1 ratio. Budesonide dry powder was delivered using a turbohaler at a dose of 400 μg per actuation. Participants were asked to take two inhalations twice a day until symptom resolution. The primary endpoint was COVID-19-related urgent care visit, including emergency department assessment or hospitalisation, analysed for both the per-protocol and intention-to-treat (ITT) populations. The secondary outcomes were self-reported clinical recovery (symptom resolution), viral symptoms measured using the Common Cold Questionnare (CCQ) and the InFLUenza Patient Reported Outcome Questionnaire (FLUPro), body temperature, blood oxygen saturations, and SARS-CoV-2 viral load. The trial was stopped early after independent statistical review concluded that study outcome would not change with further participant enrolment. This trial is registered with ClinicalTrials.gov, NCT04416399.</AbstractText>From July 16 to Dec 9, 2020, 167 participants were recruited and assessed for eligibility. 21 did not meet eligibility criteria and were excluded. 146 participants were randomly assigned-73 to usual care and 73 to budesonide. For the per-protocol population (n=139), the primary outcome occurred in ten (14%) of 70 participants in the usual care group and one (1%) of 69 participants in the budesonide group (difference in proportions 0·131, 95% CI 0·043 to 0·218; p=0·004). For the ITT population, the primary outcome occurred in 11 (15%) participants in the usual care group and two (3%) participants in the budesonide group (difference in proportions 0·123, 95% CI 0·033 to 0·213; p=0·009). The number needed to treat with inhaled budesonide to reduce COVID-19 deterioration was eight. Clinical recovery was 1 day shorter in the budesonide group compared with the usual care group (median 7 days [95% CI 6 to 9] in the budesonide group vs 8 days [7 to 11] in the usual care group; log-rank test p=0·007). The mean proportion of days with a fever in the first 14 days was lower in the budesonide group (2%, SD 6) than the usual care group (8%, SD 18; Wilcoxon test p=0·051) and the proportion of participants with at least 1 day of fever was lower in the budesonide group when compared with the usual care group. As-needed antipyretic medication was required for fewer proportion of days in the budesonide group compared with the usual care group (27% [IQR 0-50] vs 50% [15-71]; p=0·025) Fewer participants randomly assigned to budesonide had persistent symptoms at days 14 and 28 compared with participants receiving usual care (difference in proportions 0·204, 95% CI 0·075 to 0·334; p=0·003). The mean total score change in the CCQ and FLUPro over 14 days was significantly better in the budesonide group compared with the usual care group (CCQ mean difference -0·12, 95% CI -0·21 to -0·02 [p=0·016]; FLUPro mean difference -0·10, 95% CI -0·21 to -0·00 [p=0·044]). Blood oxygen saturations and SARS-CoV-2 load, measured by cycle threshold, were not different between the groups. Budesonide was safe, with only five (7%) participants reporting self-limiting adverse events.</AbstractText>Early administration of inhaled budesonide reduced the likelihood of needing urgent medical care and reduced time to recovery after early COVID-19.</AbstractText>National Institute for Health Research Biomedical Research Centre and AstraZeneca.</AbstractText>Copyright © 2021 Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,336,060 |
Evaluation of an opioid restrictive pain management initiative in adult kidney transplant recipients.
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Evidence to guide opioid utilization following kidney transplantation is lacking. The purpose of this study is to evaluate the implementation of an opioid restrictive post-operative pain management protocol in adult kidney transplant recipients.</AbstractText>We analyzed patients who underwent kidney transplant between 1/1/2017 to 8/15/2018. A standardized, opioid restrictive pain management protocol was implemented in February 2018. The primary outcome was quantity of opioid tablets prescribed at discharge. Secondary outcomes included amount of opioid prescribed within first 30 days, number of patient calls for pain, and opioid prescription in electronic medical record (EMR) at 90 days and 1 year.</AbstractText>After implementation, significantly fewer opioid tablets were prescribed at discharge (4 vs. 60 tablets, p < .001) and less oral morphine milligram equivalence (OME) were prescribed within 30 days of transplant (38 vs. 300, p < .001). In cohort 2, fewer patients received more than one opioid prescription, more patients received truncal block and only 5 patients received patient controlled analgesia compared to all in cohort 1.</AbstractText>A standardized, patient-centered pain management strategy after kidney transplantation reduced opioid prescribing without increasing readmissions or clinic calls. This data may be used to inform guidelines for appropriate OME prescribing at discharge after kidney transplantation.</AbstractText>© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.</CopyrightInformation>
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2,336,061 |
Evaluation of ropivacaine combined with dexmedetomidine versus ropivacaine alone for epidural anesthesia: A meta-analysis.
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Ropivacaine is considered the most commonly used for epidural anesthesia. We compared the efficiency and safety of ropivacaine alone (R group) and ropivacaine combined with dexmedetomidine (RD group).</AbstractText>PubMed, the Cochrane Library, Google Scholar, Ovid Medline, the Web of Science, Scopus, Embase, and ScienceDirect were searched. We considered sensory and motor block, duration of anesthesia, time to rescue, hemodynamics, and adverse effects as the primary endpoints.</AbstractText>Eleven randomized controlled trials were included with 337 patients in the R group and 336 patients in the RD group. The RD group had a shorter time to onset of sensory (mean difference [MD]: 3.97 [1.90-6.04] minutes; P = .0002) and motor (MD: 2.43 [0.70-4.16] minutes; P = .006) block and a longer duration of anesthesia (MD: -164.17 [-294.43 to -33.91]; P = .01) than the R group. Comparison of the time to rescue between the groups showed no significant difference (MD: -119.01[-254.47-16.46] minutes; P = 0.09). The R group showed more stable hemodynamics than the RD group in heart rate and arterial pressure at 10 minutes. The R group had a lower incidence of bradycardia and a higher incidence of shivering than the RD group.</AbstractText>RD may be a more suitable choice for epidural anesthesia with better anesthetic outcomes than R alone. However, the safety of the combination must be carefully assessed.</AbstractText>Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.</CopyrightInformation>
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2,336,062 |
Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia.
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COVID-19 is a disease with unique characteristics that include lung thrombosis<sup>1</sup>, frequent diarrhoea<sup>2</sup>, abnormal activation of the inflammatory response<sup>3</sup> and rapid deterioration of lung function consistent with alveolar oedema<sup>4</sup>. The pathological substrate for these findings remains unknown. Here we show that the lungs of patients with COVID-19 contain infected pneumocytes with abnormal morphology and frequent multinucleation. The generation of these syncytia results from activation of the SARS-CoV-2 spike protein at the cell plasma membrane level. On the basis of these observations, we performed two high-content microscopy-based screenings with more than 3,000 approved drugs to search for inhibitors of spike-driven syncytia. We converged on the identification of 83 drugs that inhibited spike-mediated cell fusion, several of which belonged to defined pharmacological classes. We focused our attention on effective drugs that also protected against virus replication and associated cytopathicity. One of the most effective molecules was the antihelminthic drug niclosamide, which markedly blunted calcium oscillations and membrane conductance in spike-expressing cells by suppressing the activity of TMEM16F (also known as anoctamin 6), a calcium-activated ion channel and scramblase that is responsible for exposure of phosphatidylserine on the cell surface. These findings suggest a potential mechanism for COVID-19 disease pathogenesis and support the repurposing of niclosamide for therapy.
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2,336,063 |
E-health StandingTall balance exercise for fall prevention in older people: results of a two year randomised controlled trial.
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To test whether StandingTall, a home based, e-health balance exercise programme delivered through an app, could provide an effective, self-managed fall prevention programme for community dwelling older people.</AbstractText>Assessor blinded, randomised controlled trial.</AbstractText>Older people living independently in the community in Sydney, Australia.</AbstractText>503 people aged 70 years and older who were independent in activities of daily living, without cognitive impairment, progressive neurological disease, or any other unstable or acute medical condition precluding exercise.</AbstractText>Participants were block randomised to an intervention group (two hours of StandingTall per week and health education; n=254) or a control group (health education; n=249) for two years.</AbstractText>The primary outcomes were the rate of falls (number of falls per person year) and the proportion of people who had a fall over 12 months. Secondary outcomes were the number of people who had a fall and the number who had an injurious fall (resulting in any injury or requiring medical care), adherence, mood, health related quality of life, and activity levels over 24 months; and balance and mobility outcomes over 12 months.</AbstractText>The fall rates were not statistically different in the two groups after the first 12 months (0.60 falls per year (standard deviation 1.05) in the intervention group; 0.76 (1.25) in the control group; incidence rate ratio 0.84, 95% confidence interval 0.62 to 1.13, P=0.071). Additionally, the proportion of people who fell was not statistically different at 12 months (34.6% in intervention group, 40.2% in control group; relative risk 0.90, 95% confidence interval 0.67 to 1.20, P=0.461). However, the intervention group had a 16% lower rate of falls over 24 months compared with the control group (incidence rate ratio 0.84, 95% confidence interval 0.72 to 0.98, P=0.027). Both groups had a similar proportion of people who fell over 24 months (relative risk 0.87, 95% confidence interval 0.68 to 1.10, P=0.239), but the proportion of people who had an injurious fall over 24 months was 20% lower in the intervention group compared with the control group (relative risk 0.80, 95% confidence interval 0.66 to 0.98, P=0.031). In the intervention group, 68.1% and 52.0% of participants exercised for a median of 114.0 min/week (interquartile range 53.5) after 12 months and 120.4 min/week (38.6) after 24 months, respectively. Groups remained similar in mood and activity levels. The intervention group had a 0.03 (95% confidence interval 0.01 to 0.06) improvement on the EQ-5D-5L (EuroQol five dimension five level) utility score at six months, and an improvement in standing balance of 11 s (95% confidence interval 2 to 19 s) at six months and 10 s (1 to 19 s) at 12 months. No serious training related adverse events occurred.</AbstractText>The StandingTall balance exercise programme did not significantly affect the primary outcomes of this study. However, the programme significantly reduced the rate of falls and the number of injurious falls over two years, with similar but not statistically significant effects at 12 months. E-health exercise programmes could provide promising scalable fall prevention strategies.</AbstractText>ACTRN12615000138583.</AbstractText>© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.</CopyrightInformation>
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2,336,064 |
Nonadditive genetic effects induce novel phenotypic distributions in male mating traits of F1 hybrids.
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Hybridization is a source of phenotypic novelty and variation because of increased additive genetic variation. Yet, the roles of nonadditive allelic interactions in shaping phenotypic mean and variance of hybrids have been underappreciated. Here, we examine the distributions of male-mating traits in F1 hybrids via a meta-analysis of 3208 effect sizes from 39 animal species pairs. Although additivity sets phenotypic distributions of F1s to be intermediate, F1s also showed recessivity and resemblance to maternal species. F1s expressed novel phenotypes (beyond the range of both parents) in 65% of species pairs, often associated with increased phenotypic variability. Overall, however, F1s expressed smaller variation than parents in 51% of traits. Although genetic divergence between parents did not impact phenotypic novelty, it increased phenotypic variability of F1s. By creating novel phenotypes with increased variability, nonadditivity of heterozygotic genome may play key roles in determining mating success of F1s, and their subsequent extinction or speciation.
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2,336,065 |
Effects of pomegranate juice (Punica Granatum) on inflammatory biomarkers and complete blood count in patients with COVID-19: a structured summary of a study protocol for a randomized clinical trial.
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This study is conducted to investigate efficacy of pomegranate juice on inflammatory biomarkers, C-reactive protein (CRP), interleukin 6(IL-6), erythrocyte sedimentation rate (ESR) and complete blood count (CBC) in hospitalized patients with mild to moderate coronavirus disease 2019 (COVID- 19).</AbstractText>This is a randomized, placebo-controlled, double-blind, parallel 2-arm (1:1 ratio) clinical trial.</AbstractText>Patients with COVID-19 admitted to hospitals in Yasuj City, Kohgiluyeh and Boyer-Ahmad Province, Iran.</AbstractText>Informed consent Patients 18 years of age or older Diagnosis of COVID-19 based on real-time polymerase chain reaction (RT-PCR) test EXCLUSION CRITERIA: Pregnancy or lactation Immunoglobulin A (IgA) level <61 mg/dl Disseminated intravascular coagulation or any other types of coagulopathy Severe congestive heart failure Participation in any clinical trial within 30 days prior to enrollment in this RCT Other contraindications determined by the specialist.</AbstractText>Intervention: 500 ml pomegranate juice and standard of care hospital treatment for COVID-19 Comparator: matching placebo containing 500 ml of red water and standard of care hospital treatment for COVID-19 Both intervention and comparator to be taken twice a day, after lunch and dinner, for 14 days.</AbstractText>Transfer of patients to intensive care unit (ICU) Death Unwillingness to continue participating in the study MAIN OUTCOMES: The main outcomes of this study are levels of inflammatory biomarkers, CRP, IL-6, ESR, and CBC after 14 days of treatment.</AbstractText>Eligible patients will be randomly assigned into the intervention or control group in a 1:1 ratio. Randomization will be performed based on 8 permuted blocks with block sizes of 6 and they will be stratified according to sex and age categories. Randomization sequences will be prepared by the trial's pharmacist using computer-generated random numbers.</AbstractText><AbstractText Label="BLINDING (MASKING)" NlmCategory="UNASSIGNED">This study is a double-blind clinical trial (participant, researcher). The pomegranate juice and placebo juice are packaged in identical bottles, and the researcher and all the patients will be unaware of the study assignment until the end of the study. To ensure blinding, the randomization sequences will be kept in identical, opaque, sealed, and sequentially numbered envelopes.</AbstractText><AbstractText Label="NUMBERS TO BE RANDOMIZED (SAMPLE SIZE)" NlmCategory="UNASSIGNED">The calculated total sample size is 48 patients, with 24 patients assigned into each group.</AbstractText>The protocol is Version 1.0, on March 3, 2021. Recruitment started on February 28, 2021, and is anticipated to be completed by May 21, 2021.</AbstractText>The Name of registering trial Effects of Pomegranate Juice (Punica Granatum) on Inflammatory Biomarkers and CBC in Patients with COVID-19: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Iranian registry of clinical trials (IRCT) Registration Number: IRCT20150711023153N2 Date of Trial Registration February 28, 2021, retrospectively registered FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials҆ website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.</AbstractText>
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2,336,066 |
MiR-92 Family Members Form a Cluster Required for Notochord Tubulogenesis in Urochordate <i>Ciona savignyi</i>.
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MicroRNAs are frequently clustered in the genome and polycistronically transcribed, regulating targeted genes in diverse signaling pathways. The miR-17-92 cluster is a typical miRNA cluster, playing crucial roles in the organogenesis and homeostasis of physiological processes in vertebrates. Here, we identified three miRNAs (csa-miR-92a, csa-miR-92b, and csa-miR-92c) that belonged to the miR-92 family and formed a miRNA cluster in the genome of a urochordate marine ascidian <i>Ciona savignyi</i>. Except for miR-92a and miR-92b, other homologs of the vertebrate miR-17-92 cluster members could not be identified in the <i>Ciona</i> genome. We further found that the mature sequences of urochordate miR-92 family members were highly conserved compared with the vertebrate species. The expression pattern revealed that three miR-92 family members had consistent expression levels in adult tissues and were predominantly expressed in heart and muscle tissue. We further showed that, at the embryonic and larval stages, csa-miR-92c was expressed in the notochord of embryos during 18-31 h post fertilization (hpf) by in situ hybridization. Knockout of csa-miR-92c resulted in the disorganization of notochord cells and the block of lumen coalescence in the notochord. Fibroblast growth factor (FGF), mitogen-activated protein kinase (MAPK), and wingless/integrated (Wnt)/planar cell polarity (PCP) signaling pathways might be involved in the regulatory processes, since a large number of core genes of these pathways were the predicted target genes of the miR-92 family. Taken together, we identified a miR-92 cluster in urochordate <i>Ciona</i> and revealed the expression patterns and the regulatory roles of its members in organogenesis. Our results provide expression and phylogenetic data on the understanding of the miR-92 miRNA cluster's function during evolution.
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2,336,067 |
Use of Spinal Anaesthesia with Anaesthetic Block of Intercostal Nerves Compared to a Continuous Infusion of Sufentanyl to Improve Analgesia in Cats Undergoing Unilateral Mastectomy.
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Unilateral mastectomy is a common surgical procedure in feline species and requires postoperative pain management. Our study aimed to evaluate the analgesic efficacy of subarachnoid anaesthesia combined with an intercostal nerve block, in comparison with the use of sufentanyl citrate administered as a constant-rate infusion (CRI). Twenty cats were randomly divided into two groups (<i>n</i> = 10/group) based on the analgesic protocol used: the first received loco-regional anaesthesia with levobupivacaine (LR group), and the second received a CRI of sufentanyl (SUF group). The evaluation criteria during surgery were the need for a bolus of fentanyl in the event of an increased heart rate or increased blood pressure. In the postoperative period, the levels of comfort/discomfort and pain were used to obtain a score according to the UNESP-Botucatu multimodal scale. Subjects who scored above seven received analgesic drug supplementation. Intraoperative analgesia was satisfactory, with good haemodynamic stability in both groups. Four patients in the LR group required an extra dose of methadone after they achieved the sternal decubitus position, whereas those in the SUF group required many more doses. The analgesia achieved in the LR group was more satisfactory than that in the SUF group.
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2,336,068 |
Endothelin B receptors impair baroreflex function and increase blood pressure variability during high salt diet.
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Baroreflex function is an integral component maintaining consistent blood pressure. Hypertension is often associated with baroreflex dysfunction, and environmental risk factors such as high salt diet exacerbate hypertension in subjects with baroreflex dysfunction. However, the interactions between high salt diet, baroreflex dysfunction, and hypertension are incompletely understood. The endothelin system is another potent mediator of blood pressure control especially in response to a high salt diet. We hypothesized that the endothelin B (ET<sub>B</sub>) receptor activation on adrenergic nerves decreases baroreflex sensitivity. We utilized male ET<sub>B</sub> receptor deficient (ET<sub>B</sub>-def) rats that express functional ET<sub>B</sub> receptors only on adrenergic nerves and transgenic (TG) controls to evaluate baroreflex function during normal (0.49% NaCl) and high (4.0% NaCl) salt diets. In conscious rats equipped with telemetry, ET<sub>B</sub>-def rats had an increased lability of systolic blood pressure (SBP) compared to TG controls as indicated by higher standard deviation (SD) of SBP under both normal (10.2 ± 0.6 vs. 12.4 ± 0.9 mmHg, respectively, p = 0.0001) and high (11.7 ± 0.6 vs. 16.1 ± 1.0 mmHg, p = 0.0001) salt diets. In anesthetized preparations, ET<sub>B</sub>-def rats displayed reduced heart rate (p genotype = 0.0167) and renal sympathetic nerve (p genotype = 0.0022) baroreflex sensitivity. We then gave male Sprague-Dawley rats the selective ET<sub>B</sub> receptor antagonist, A-192621 (10 mg/kg/day), to block ET<sub>B</sub> receptors. Following ET<sub>B</sub> receptor antagonism, even though SBP increased (131 ± 7 before vs. 152 ± 8 mmHg after, p < 0.0001), the lability (standard deviation) of SBP decreased (9.3 ± 2.0 vs. 7.1 ± 1.1 mmHg, p = 0.0155). These data support our hypothesis that ET<sub>B</sub> receptors on adrenergic nerves contribute to baroreflex dysfunction.
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2,336,069 |
Optimizing the Polymer Cloak for Upconverting Nanoparticles: An Evaluation of Bioactivity and Optical Performance.
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The ability of upconversion nanoparticles (UCNPs) to convert low-energy near-infrared (NIR) light into high-energy visible-ultraviolet light has resulted in their development as novel contrast agents for biomedical imaging. However, UCNPs often succumb to poor colloidal stability in aqueous media, which can be conquered by decorating the nanoparticle surface with polymers. The polymer cloak, therefore, plays an instrumental role in ensuring good stability in biological media. This study aims to understand the relationship between the length and grafting density of the polymer shell on the physicochemical and biological properties of these core-shell UCNPs. Poly(ethylene glycol) methyl ether methacrylate block ethylene glycol methacrylate phosphate (PPEGMEMA<i><sub>n</sub></i>-<i>b</i>-PEGMP<sub>3</sub>) with different numbers of PEGMEMA repeating units (26, 38, and 80) was prepared and attached to the UCNPs <i>via</i> the phosphate ligand of the poly(ethylene glycol methacrylate phosphate) (PEGMP) block at different polymer densities. The <i>in vitro</i> and <i>in vivo</i> protein corona, cellular uptake in two-dimensional (2D) monolayer and three-dimensional (3D) multicellular tumor spheroid (MCTS) models, and <i>in vivo</i> biodistribution in mice were evaluated. Furthermore, the photoluminescence of single-polymer-coated UCNPs was compared in solid state and cancer cells using laser scanning confocal microscopy (LSCM). Our results showed that the bioactivity and luminescence properties are chain length and grafting density dependent. The UCNPs coated with the longest PPEGMEMA chain, grafted at low brush density, were able to reduce the formation of the protein corona <i>in vitro</i> and <i>in vivo</i>, while these UCNPs also showed the brightest upconversion luminescence in the solid state. Moreover, these particular polymer-coated UCNPs showed enhanced cellular uptake, extended <i>in vivo</i> blood circulation time, and more accumulation in the liver, brain, and heart.
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2,336,070 |
Capillary Changes Precede Disordered Alveolarization in a Mouse Model of Bronchopulmonary Dysplasia.
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Bronchopulmonary dysplasia (BPD), the most common sequela of preterm birth, is a severe disorder of the lung that is often associated with long-lasting morbidity. A hallmark of BPD is the disruption of alveolarization, whose pathogenesis is incompletely understood. Here, we tested the vascular hypothesis that disordered vascular development precedes the decreased alveolarization associated with BPD. Neonatal mouse pups were exposed to 7, 14, or 21 days of normoxia (21% O<sub>2</sub>) or hyperoxia (85% O<sub>2</sub>) with <i>n</i> = 8-11 for each group. The right lungs were fixed by vascular perfusion and investigated by design-based stereology or three-dimensional reconstruction of data sets obtained by serial block-face scanning EM. The alveolar capillary network of hyperoxia-exposed mice was characterized by rarefaction, partially altered geometry, and widening of capillary segments as shown by three-dimensional reconstruction. Stereology revealed that the development of alveolar epithelium and capillary endothelium was decreased in hyperoxia-exposed mice; however, the time course of these effects was different. That the surface area of the alveolar epithelium was smaller in hyperoxia-exposed mice first became evident at Day 14. In contrast, the surface area of the endothelium was reduced in hyperoxia-exposed mouse pups at Day 7. The thickness of the air-blood barrier decreased during postnatal development in normoxic mice, whereas it increased in hyperoxic mice. The endothelium and the septal connective tissue made appreciable contributions to the thickened septa. In conclusion, the present study provides clear support for the idea that the stunted alveolarization follows the disordered microvascular development, thus supporting the vascular hypothesis of BPD.
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2,336,071 |
Chronotropic Index and Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Secondary Analysis of BLOCK COPD.
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<b>Rationale:</b> The chronotropic index quantifies the proportion of the expected heart rate increase that is attained during exercise. The relationship between the chronotropic index and acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) has not been evaluated. <b>Objectives:</b> To determine whether a higher chronotropic index during a 6-minute walk (CI-6MW) is associated with lower risk of AECOPD and whether the CI-6MW is a marker of susceptibility to adverse effects of metoprolol in chronic obstructive pulmonary disease (COPD). <b>Methods:</b> We analyzed data from the BLOCK COPD (Beta-Blockers for the Prevention of AECOPDs) trial. We used Cox proportional hazards models to investigate the relationship between the CI-6MW and the time to AECOPDs. We also tested for interactions between study group assignment (metoprolol vs. placebo) and the CI-6MW on the time to AECOPDs. <b>Results:</b> Four hundred seventy-seven participants with exacerbation-prone COPD (mean forced expiratory volume in 1 second, 41% of predicted) were included in this analysis. A higher CI-6MW was independently associated with a decreased risk of AECOPDs of any severity (adjusted hazard ratio per 0.1 increase in CI-6MW of 0.88; 95% confidence interval, 0.80-0.96) but was not independently associated with AECOPDs requiring hospitalization (adjusted hazard ratio, 0.94; 95% confidence interval, 0.81-1.05). There was a significant interaction by treatment assignment, and in a stratified analysis, the protective effects of a higher CI-6MW on AECOPDs were negated by metoprolol use. <b>Conclusions:</b> A higher CI-6MW is associated with a decreased risk of AECOPDs and may be an indicator of susceptibility to the adverse effects of metoprolol.
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2,336,072 |
Effect of ondansetron on spinal anesthesia-induced hypotension in non-obstetric surgeries: a randomised, double-blind and placebo-controlled trial.
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Spinal anesthesia is an effective technique for many surgical procedures, but it is often associated with an increased risk of potentially deleterious hemodynamic disturbances. The benefits of prophylactic ondansetron for preventing spinal anesthesia-induced hypotension are still uncertain. Therefore, this study aimed to compare the effect of ondansetron and placebo before spinal block on the incidence of hypotension in patients having non-obstetric surgeries.</AbstractText>Randomized, double-blind, parallel-group, superiority trial with a 1:1 allocation ratio. A total of 144 patients scheduled for non-obstetric surgeries with an indication for spinal anesthesia were randomized. Patients received intravenous ondansetron (8mg) or placebo before standard spinal anesthesia. The primary outcome was the rate of hypotension in the first 30 minutes after spinal anesthesia.</AbstractText>Hypotension occurred in 20 of 72 patients (27.8%) in the ondansetron group and in 36 of 72 patients (50%) in the placebo group (Odds Ratio-OR=0.38; 95% Confidence Interval-CI 0.19 to 0.77; p=0.007). Fewer patients in the ondansetron group required ephedrine compared to the placebo group (13.9% vs. 27.8%; OR=0.42; 95% CI 0.18 to 0.98; p=0.04). Exploratory analyses revealed that ondansetron may be more effective than placebo in patients aged 60 years or older (OR=0.12; 95% CI 0.03 to 0.48; p=0.03). No difference in heart rate variations was observed.</AbstractText>Our findings suggest that ondansetron can be a viable and effective strategy to reduce both the incidence of spinal anesthesia-induced hypotension and vasopressors usage in non-obstetric surgeries.</AbstractText>Copyright © 2021 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.</CopyrightInformation>
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2,336,073 |
Inducible fold-switching as a mechanism to fibrillate pro-apoptotic BCL-2 proteins.
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Neurodegenerative diseases often are associated with cellular dysregulation that results in premature cell death or apoptosis. A common example is the accumulation of amyloid plaques that promotes the excessive expression of p38 mitogen-activated protein kinase. The increased abundance of this enzyme leads to mass phosphorylation and activation of a protein from the B-cell lymphoma 2 (BCL-2) family, BAX. BAX is the central regulatory protein for mitochondrial outer membrane permeabilization (MOMP), a poration process that commits cells to apoptosis by releasing death-propagating factors from the mitochondria. Recent reports identify a naturally occurring peptide, Humanin (HN), that could block amyloid-beta-associated neuronal apoptosis by interacting with BCL-2 proteins. We recently showed humanin interaction leads to the amyloid-like fibrillation of BAX and a second BCL-2 family member, BID. We proposed this as a novel anti-apoptotic mechanism that inhibits pro-apoptotic BCL-2 proteins from initiating MOMP by sequestering them into fibrils, a heretofore unprecedented phenomenon that involves refolding globular BCL-2 proteins rapidly into fibrils where they undergo significant alpha-helix to beta-sheet fold-switching. Here we seek to further characterize the fibrillation and fold-switch in conditions that are known to induce amyloid fibrillation.
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2,336,074 |
Role of Mineralocorticoid and Angiotensin Type 1 Receptors in the Paraventricular Nucleus in Angiotensin-Induced Hypertension.
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The hypothalamic paraventricular nucleus (PVN) is an important site where an interaction between circulating angiotensin (Ang) and mineralocorticoid receptor (MR) activity may modify sympathetic nerve activity (SNA) to influence long-term elevation of blood pressure. We examined in conscious Ang II-treated rabbits, the effects on blood pressure and tonic and reflex renal SNA (RSNA) of microinjecting into the PVN either RU28318 to block MR, losartan to block Ang (AT<sub>1</sub>) receptors or muscimol to inhibit GABA <sub><i>A</i></sub> receptor agonist actions. Male rabbits received a moderate dose of Ang II (24 ng/kg/min subcutaneously) for 3 months (<i>n</i> = 13) or sham treatment (<i>n</i> = 13). At 3 months, blood pressure increased by +19% in the Ang II group compared to 10% in the sham (<i>P</i> = 0.022) but RSNA was similar. RU28318 lowered blood pressure in both Ang II and shams but had a greater effect on RSNA and heart rate in the Ang II-treated group (<i>P</i> < 0.05). Losartan also lowered RSNA, while muscimol produced sympatho-excitation in both groups. In Ang II-treated rabbits, RU28318 attenuated the blood pressure increase following chemoreceptor stimulation but did not affect responses to air jet stress. In contrast losartan and muscimol reduced blood pressure and RSNA responses to both hypoxia and air jet. While neither RU28318 nor losartan changed the RSNA baroreflex, RU28318 augmented the range of the heart rate baroreflex by 10% in Ang II-treated rabbits. Muscimol, however, augmented the RSNA baroreflex by 11% in sham animals and none of the treatments altered baroreflex sensitivity. In conclusion, 3 months of moderate Ang II treatment promotes activation of reflex RSNA principally via MR activation in the PVN, rather than via activation of AT<sub>1</sub> receptors. However, the onset of hypertension is independent of both. Interestingly, the sympatho-excitatory effects of muscimol in both groups suggest that overall, the PVN regulates a tonic sympatho-inhibitory influence on blood pressure control.
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2,336,075 |
Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.
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Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress.</AbstractText>In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC.</AbstractText>Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.</AbstractText>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected].</CopyrightInformation>
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2,336,076 |
Genome-first approach to rare EYA4 variants and cardio-auditory phenotypes in adults.
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While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.
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2,336,077 |
Significance of manifest localized staining during ethanol infusion into the vein of Marshall.
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Localized staining due to venule injury is attributable to ethanol infusion into the vein of Marshall (Et-VOM).</AbstractText>The purpose of this study was to investigate adverse outcomes of localized staining during Et-VOM in patients undergoing ablation for atrial fibrillation.</AbstractText>Two hundred four patients (age 64 ± 10 years; 153 male) were sorted based on the aspect of localized staining. Staining of atrial myocardium that spread uniformly along the VOM vascular tree following selective VOM venography was considered normal, in contrast to predominantly localized staining that spread concentrically from a focal point due to vascular injury. Outcomes between the 2 groups were compared.</AbstractText>Localized staining was observed in 27% of patients. No patients developed clinically significant pericardial effusions during Et-VOM; however, 7 patients developed pericardial effusions on the first postprocedural day (3.6% in patients with vs 3.4% in patients without localized staining). No significant difference was found in achievement of acute mitral isthmus (MI) block (96% vs 98%) and size of the endocardial low-voltage area (8.5 ± 4.1 cm2</sup> vs 9.3 ± 5.3 cm2</sup>) in patients with and without localized staining, respectively. Long-term follow-up was not impacted by localized staining. Freedom from recurrent atrial tachyarrhythmias (66% vs 76%) and durability of MI block (57% vs 54%) were not significantly different with and without localized staining. There were no cases of rehospitalization for pericarditis, chronic pericardial effusion, or heart failure.</AbstractText>In our study, localized staining was frequent but was not associated with clinically relevant impact or disadvantages.</AbstractText>Copyright © 2021 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.</CopyrightInformation>
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2,336,078 |
Effect of sealing strategy on the feeding value of corn silage for growing dairy heifers.
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Our objective was to compare the performance of dairy heifers fed diets based on whole-plant corn silage stored in bunker silos sealed with either standard polyethylene film (white-on-black, actual thickness 121 ± 3.1 µm) covering the top surface, held in place with rows of tires every 3 m (PE) or an oxygen barrier system comprised of an ethylene-vinyl alcohol film (actual thickness 46.7 ± 2.5 µm) lining side walls and covering the silage, protected with a woven anti-UV cover and gravel bags placed around the edges and every 3 m across the silo (OB). Whole-plant corn was mechanically harvested at 39% dry matter (DM), packed in bunker silos, and sealed with PE or OB covering methods. After 6 mo of storage, silos were opened and fed to 26 Holstein heifers (260 ± 89.1 kg of shrunk body weight) for 60 d. Heifers were blocked by initial weight (13 blocks with 2 heifers each block) and housed in individual pens. Diets contained (on a DM basis) 80% corn silage (PE or OB), 17.5% soybean meal, and 2.5% mineral mix. Dry matter intake was measured daily, whereas shrunk body weight, hip height, heart girth, and body condition score were measured at the beginning and end of the experiment. Feeding behavior was recorded on d 24 and 46, and total-tract digestibility was measured from d 26 to 30 and 48 to 52. Data of intake, feeding behavior, and digestibility were averaged by animal for the whole feeding period before the statistical analysis. Data of animal performance were analyzed as a randomized complete block design. Initial shrunk body weight was used as a covariate for analyses of intake and body measures. During feed-out, silage quality was also assessed at the top (15 cm depth from upper surface) and bottom layer (135 cm depth from upper surface) and analyzed as a split-plot design. Silage stored under the OB sealing system had less yeast, mold, and NH<sub>3</sub>-N, and more lactic acid and ethanol-soluble carbohydrates. An interaction between sealing strategy and silo layer showed that OB silage had lower values of temperature, pH, anaerobic spores, acetic acid, and DM loss, and greater in vitro DM digestibility and aerobic stability, especially in the top layer. The proportion of inedible silage was lower in OB than in PE treatment (0.82 vs. 4.00% DM). Total-tract digestibility was similar between treatments, but animals that received the OB diet had higher DM intake by approximately 9% (9.39 vs. 10.20 kg/d) due to a faster eating rate and a greater number of meals per day. Therefore, OB treatment increased the digestible energy intake by 8% (26.3 vs. 28.3 Mcal/d) and average daily gain by 12% (1.08 vs. 1.21 kg/d). Body condition score change was similar between treatments, but heifers fed OB had greater heart girth and tended to have higher hip height. In conclusion, replacing a standard PE film with an OB sealing system improved silage conservation and performance of growing dairy heifers.
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2,336,079 |
Dysfunctional Eating Behaviors and Dietary Intake in Puerto Rico.
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Dysfunctional eating behaviors (DEB: emotional eating (EE), uncontrolled eating (UE) and cognitive restraint (CR)) are prevalent in U.S. Latinos and may influence diet. However, this has not been studied in Puerto Rico (PR). This study documents DEB in PR, and explores associations with diet. Cross-sectional study of adults (n = 92) in Ponce, PR. DEB were measured with the TFEQ-R18-V2. The Block Fat and Fruits and Vegetables Screener measured dietary intake. Analysis included adjusted proportions, means and linear regressions. 76%, 88%, and 87% of participants experienced EE, UE and CR, respectively. EE was associated with calories from fats (β = 1.95, 95% CI 0.40, 3.51) and saturated fats (β = 3.26, 95% CI 0.67, 5.85), and CR with fruits and vegetables (β = 0.69, 95% CI 0.20, 1.19). A large percentage of the sample experienced DEB. EE and CR were associated with dietary intake. Studies are needed to understand associations between DEB, diet and health in PR.
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2,336,080 |
In-Hospital Outcomes of Female Patients With Inferior Wall Myocardial Infarction.
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Background The aim of this study was to determine the in-hospital outcome of female patients with inferior wall myocardial infarction (MI). Methodology This study was conducted from January to December 2017 at the Department of Cardiology, National Institute of Cardiovascular Disease, Karachi. A total of 59 women admitted with inferior wall MI were enrolled in the study. In all patients, in-hospital outcomes were observed. Descriptive statistics were applied. Stratification was done using chi-square test, and p-value of ≤0.05 was considered significant. Results The mean age of study participants was 58.80 ± 9.17 years, while 247 (79.7%) participants were above 50 years of age. The mean onset of duration of sign and symptoms of inferior wall MI was 3.48 ± 1.53 hours. There were 36 (61.0%) patients who had diabetes mellitus, 46 (78.0%) had hypertension, 17 (28.8%) were obese, nine (15.3%) had a family history of MI, and three (5.1%) were smokers. There were 43 (72.9%) patients who were illiterate. In our study, eight (13.6%) females were found to have sinus bradycardia, seven (11.9%) had sinus tachycardia, three (5.1%) had atrial fibrillation, and 24 (40.7%) had complete heart block. Mortality was noted in five (8.5%) patients. Conclusions Women with an acute inferior wall MI had a higher rate of complete heart block and adverse in-hospital outcomes. Female gender itself with inferior wall MI may be at risk for in-hospital adverse outcomes.
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2,336,081 |
Comparative Anesthesia Effect of Brachial Plexus Block Based on Smart Electronic Medical Ultrasound-Guided Positioning and Traditional Anatomical Positioning.
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With the intensification of population aging, the improvement of visualization technology, and the concept of accelerated rehabilitation surgery, the anesthesia method of upper extremity surgery is gradually changing. However, these methods are often caused by anatomical variations and often have low block success rates and patient satisfaction. The neuroanatomical position should be accurately located so that the puncture needle is right next to the nerve bundle or in the nerve sheath. This is very important for implementing accurate brachial plexus anesthesia. This article uses ultrasound-guided positioning technology and traditional anatomical positioning technology for brachial plexus block treatment, aiming to explore the anesthesia effect of brachial plexus block with different techniques. This article selects 120 patients undergoing brachial plexus block surgery for forearm or hand surgery and divides these 120 patients into 6 groups with 20 people in each group. The first 3 groups were treated with brachial plexus block using ultrasound-guided positioning technology. The latter 3 groups were treated with brachial plexus block using traditional anatomical positioning technology. Experiments proved that during anesthesia, compared with the ultrasound group, the heart rate of the traditional anatomy group was significantly decreased (<i>P</i> < 0.05), and the average arterial pressure of the six groups of patients at each time point had no statistical difference (<i>P</i> > 0.05). This shows that whether it is ultrasound-guided positioning technology or traditional anatomical positioning technology, it has no effect on the average arterial pressure of the patient at each time point. In addition to intuitive and accurate viewing of needle and nerve contact, ultrasound real-time guidance allows intuitive viewing of anesthesia. This is a special advantage of nerve block under ultrasound guidance.
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2,336,082 |
Human induced pluripotent stem cell-derived three-dimensional cardiomyocyte tissues ameliorate the rat ischemic myocardium by remodeling the extracellular matrix and cardiac protein phenotype.
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The extracellular matrix (ECM) plays a key role in the viability and survival of implanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We hypothesized that coating of three-dimensional (3D) cardiac tissue-derived hiPSC-CMs with the ECM protein fibronectin (FN) would improve the survival of transplanted cells in the heart and improve heart function in a rat model of ischemic heart failure. To test this hypothesis, we first explored the tolerance of FN-coated hiPSC-CMs to hypoxia in an in vitro study. For in vivo assessments, we constructed 3D-hiPSC cardiac tissues (3D-hiPSC-CTs) using a layer-by-layer technique, and then the cells were implanted in the hearts of a myocardial infarction rat model (3D-hiPSC-CTs, n = 10; sham surgery control group (without implant), n = 10). Heart function and histology were analyzed 4 weeks after transplantation. In the in vitro assessment, cell viability and lactate dehydrogenase assays showed that FN-coated hiPSC-CMs had improved tolerance to hypoxia compared with the control cells. In vivo, the left ventricular ejection fraction of hearts implanted with 3D-hiPSC-CT was significantly better than that of the sham control hearts. Histological analysis showed clear expression of collagen type IV and plasma membrane markers such as desmin and dystrophin in vivo after implantation of 3D-hiPSC-CT, which were not detected in 3D-hiPSC-CMs in vitro. Overall, these results indicated that FN-coated 3D-hiPSC-CT could improve distressed heart function in a rat myocardial infarction model with a well-expressed cytoskeletal or basement membrane matrix. Therefore, FN-coated 3D-hiPSC-CT may serve as a promising replacement for heart transplantation and left ventricular assist devices and has the potential to improve survivability and therapeutic efficacy in cases of ischemic heart disease.
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2,336,083 |
Comparison of anaesthetic efficacy of ropivacaine (0.75% & 0.5%) with 2% lignocaine with adrenaline (1:200000) in surgical extraction of bilateral mandibular 3<sup>rd</sup> molars using IANB:a prospective, randomized, single blind study.
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To evaluate and compare the anaesthetic efficacy of 0.75% ropivacaine and 0.5% ropivacaine with 2% lignocaine with 1:200000 Adrenaline (LWA) for surgical extraction of bilateral mandibular 3rd molars using Direct inferior alveolar nerve block (IANB).</AbstractText>Total of 60 outpatients of both sex,age group of 18-40 included in a prospective, randomized, single blind, split mouth clinical study after satisfying inclusion and exclusion criteria. Group I includes 30 patients and 0.75% ropivacaine as test drug, Group II includes 30 patients and 0.5% ropivacaine as test drug. In both group control drug was LWA.Parameters measured were onset of action, duration of action, systolic blood pressure, diastolic blood pressure, heart rate, visual analogue scale (VAS), faces pain scale (FPS).</AbstractText>Onset of action of 0.75%/0.5% ropivacaine (101.84 ​± ​16.92 ​secs/113.03 ​± ​12.77 ​sec) was faster than LWA (Group I-218 ​± ​21.51 ​secs, Group II-196.47 ​± ​26.27 ​secs). Duration of action of 0.75%/0.5% ropivacaine (343.55 ​± ​16.44 ​mins/319.03 ​± ​19.30 ​mins) was longer than 2% Lignocaine with 1:200000 adrenaline (Group I I-173 ​± ​16.86 ​mins, Group II-175.20 ​± ​18.02 ​mins). In Group I - VAS/FPS of 0.75% Ropivacaine (0.97 ​± ​0.54/1.32 ​± ​0.65) was significantly lower as compared to LWA (2.90 ​± ​0.83/3.29 ​± ​0.69). In group II-VAS/FPS of 0.5% ropivacaine (1.40 ​± ​0.72/1.47 ​± ​0.50) was lower as compared to LWA (3.40 ​± ​0.89/3.30 ​± ​0.87). Mean systolic blood pressure, diastolic blood pressure, heart rate was lower for ropivacaine (0.75%, 0.5%) than LWA except mean heart rate higher for 0.75% ropivacaine at 10 ​min after injection. Else mean heart rate lower in other time interval.</AbstractText>Ropivacaine (0.75%,0.5%) was more efficacious than 2% lignocaine with adrenaline (1:200000) it terms of all measured parameters in study.</AbstractText>© 2021 Craniofacial Research Foundation. Published by Elsevier B.V. All rights reserved.</CopyrightInformation>
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2,336,084 |
Anesthetic Impacts on the Oculocardiac Reflex: Evidence from a Large, Observational Study.
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The oculocardiac reflex (OCR) is a sudden vagal bradycardia that can be elicited by traction on an extraocular muscle. Bradycardia is highly variable from case to case necessitating a large sample size to observe small to moderate impact on OCR. While the surgeon's tissue manipulation has immediate impact on OCR and individual patients may have some proclivity to OCR, we sought to characterize the impact on OCR by the anesthesiologist.</AbstractText>From 1992 to 2019, during routine, community outpatient general anesthetic strabismus surgery, oculocardiac reflex was prospectively observed utilizing a uniform 10-second, 200 gram square wave tension on each extraocular muscle. Anesthetic parameters were recorded and analyzed with double-cohort design and non-parametric statistics and correlations. We define %OCR as the maximally tension-altered heart rate and a percent of stable pre-tension heart rate.</AbstractText>The median (IQR) confidence intervals OCR for 2527 initial cases was 89% (67% to 97%) without anticholinergic, and 99% (95% to 100%) in 165 patients with anticholinergic. OCR was 81% (62% to 96%) in 1034 with opioids and to 75% (60% to 95%) in 59 with dexmedetomidine and in 189 with IV dexamethasone to 72% (56% to 92%) There was a significant (p<0.01 Kruskal-Wallis) impact on OCR by various opioids, muscle relaxants and inhalational agents. Linear regression showed significant inhibitory impact on OCR by increased inhalational agent depth and by lower exhaled CO2</sub>.</AbstractText>The anesthesiologist can block OCR with sufficient anticholinergics, deeper inhalational agents and robust ventilation, and can augment OCR with opioids, dexmedetomidine and apparently also with dexamethasone.</AbstractText>NCT04353960.</AbstractText>© 2021 Arnold et al.</CopyrightInformation>
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2,336,085 |
Opioid requirements after locoregional anaesthesia in dogs undergoing tibial plateau levelling osteotomy: a pilot study.
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To determine the intraoperative and early postoperative opioid requirement after ultrasound-guided sciatic and/or femoral nerve block or epidural anaesthesia in dogs undergoing tibial plateau levelling osteotomy (TPLO).</AbstractText>Prospective, masked, pilot, randomized, clinical trial.</AbstractText>A total of 40 client-owned dogs undergoing TPLO.</AbstractText>Each dog was randomly assigned to group SF (combined sciatic and femoral nerve block), group S (sciatic nerve block), group F (femoral nerve block) or group E (epidural anaesthesia). A total of 0.3 mL kg-1</sup> of ropivacaine 0.5% was administered to each nerve or in the epidural space. Intraoperatively, fentanyl (2 μg kg-1</sup>) was administered intravenously when heart rate, mean arterial pressure or respiratory rate increased by >30% compared with baseline values. Postoperatively, a visual analogue scale (VAS) and a modified German version of the French pain scale (4AVet) were used to assess pain every 30 minutes for 150 minutes and again once the morning after surgery. Methadone (0.1 mg kg-1</sup>) was administered intravenously if the VAS was ≥ 4 cm [maximal value 10 cm; median (interquartile range)] or the composite pain score was ≥5 [maximal value 15; median (interquartile range)]. Significance was defined as p ≤ 0.05.</AbstractText>Groups SF and E required less total intraoperative and early postoperative opioid doses compared with groups S and F (p = 0.031). No dogs in group SF had a block failure or required postoperative methadone. A reduced methadone requirement was found in group SF compared with all the other groups up to 150 minutes after recovery (p = 0.041).</AbstractText>Combined sciatic and femoral nerve block and epidural anaesthesia lead to less cumulative consumption of perioperative opioids than single nerve blockade. Sciatic or femoral nerve block alone might be insufficient to control nociception and early postoperative pain in dogs undergoing TPLO.</AbstractText>Copyright © 2021 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.</CopyrightInformation>
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2,336,086 |
Evidence for discrete modes of YAP1 signaling via mRNA splice isoforms in development and diseases.
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Yes-associated protein 1 (YAP1) is a transcriptional co-activator downstream of Hippo pathway. The pathway exerts crucial roles in organogenesis and its dysregulation is associated with the spreading of different cancer types. YAP1 gene encodes for multiple protein isoforms, whose specific functions are not well defined. We demonstrate the splicing of isoform-specific mRNAs is controlled in a stage- and tissue-specific fashion. We designed expression vectors encoding for the most-represented isoforms of YAP1 with either one or two WW domains and studied their specific signaling activities in YAP1 knock-out cell lines. YAP1 isoforms display both common and unique functions and activate distinct transcriptional programs, as the result of their unique protein interactomes. By generating TEAD-based transcriptional reporter cell lines, we demonstrate individual YAP1 isoforms display unique effects on cell proliferation and differentiation. Finally, we illustrate the complexity of the regulation of Hippo-YAP1 effector in physiological and in pathological conditions of the heart.
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2,336,087 |
Mechanism of Inhibition of Cytochrome c Oxidase by Triton X-100.
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It is known that Triton X-100 (TX) reversibly inhibits activity of cytochrome c oxidase (CcO). The mechanism of inhibition is analyzed in this work. The action of TX is not directed to the reaction of CcO with cytochrome c, does not cause transition of the enzyme to the "slow" form, and is not associated with monomerization of the enzyme complex. TX completely suppresses oxygen reduction by CcO, but inhibition is prevented and partially reversed by dodecyl-β-D-maltoside (DDM), a detergent used to maintain CcO in solution. A 1/1 stoichiometry competition is shown between DDM and TX for binding to CcO, with K<sub>i</sub> = 0.3 mM and affinity of DDM for the enzyme of 1.2 mM. TX interaction with the oxidized enzyme induces spectral response with maximum at 421 nm and [TX]<sub>1/2</sub> = 0.28 mM, presumably associated with heme a<sub>3</sub>. When CcO interacts with excess of H2O2 TX affects equilibrium of the oxygen intermediates of the catalytic center accelerating the F<sub>I</sub>-607 → F<sub>II</sub>-580 transition, inhibits generation of O<sub>2</sub><sup>·-</sup> by the enzyme, and, to a lesser extent, suppresses the catalase partial activity. The observed effects can be explained by inhibition of the conversion of the intermediate F<sub>II</sub>-580 to the free oxidized state during the catalytic cycle. TX suppresses intraprotein electron transfer between hemes a and a<sub>3</sub> during enzyme turnover. Partial peroxidase activity of CcO remains relatively resistant to TX under conditions that block oxidase reaction effectively. These features indicate an impairment of the K proton channel conductivity. We suggest that TX interacts with CcO at the Bile Acid Binding Site (BABS) that is located on the subunit I at the K-channel mouth and contacts with amphipathic regulators of CcO [Buhrow et al. (2013) Biochemistry, 52, 6995-7006]. Apparently, TX mimics the physiological ligand of BABS, whereas the DDM molecule mimics an endogenous phospholipid bound at the edge of BABS that controls effective affinity for the ligand.
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2,336,088 |
Palliative Nerve Block for Penile Calciphylaxis: A Case Report on Ultrasound-Guided Phenol Neurolysis.
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A 78-year-old man with uncontrolled diabetes, heart failure, and hemodialysis-dependent end-stage renal disease presented with intractable penile pain secondary to calciphylaxis and necrosis of his glans penis. Given pain refractory to pharmacologic management and refusal of surgery, treatment entailed an ultrasound-guided dorsal penile nerve block with 5 mL of aqueous 4% phenol bilaterally. The patient reported immediate relief and died pain-free 3 months later. While phenol nerve blocks are increasingly uncommon due to local tissue toxicity, the precision of ultrasound leverages phenol's denaturing and axonal demyelinating properties to facilitate long-term targeted neurolysis to palliate chronic nonmalignant pain.
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2,336,089 |
Effects of Intravenous Flunixin Meglumine, Phenylbutazone, and Acupuncture on Ocular Pain Scores in the Horse: A Pilot Study.
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In this controlled, blinded, randomized block pilot study, the main objective was to evaluate the effectiveness of intravenous flunixin meglumine, phenylbutazone, and acupuncture on ocular pain relief using a multifactorial pain scale in the horse. Four experimental horses underwent corneal epithelial debridement in four sessions, when a randomly selected treatment or a control was used. All horses were pain scored before corneal wounding, then at 18 time points, when 11 parameters were allocated. Differences in the area under the curve of pain scores between the treatment groups were analyzed using a paired t-test. Corneal pain was significantly reduced by the third postoperative day (P = .03) when all 11 parameters were considered. Five ocular signs showed significant differences between treatments and proved to be good indicators of ocular pain. The other parameters (heart rate, corneal touch threshold, respond to palpation, and three behavioral parameters) were determined to be irrelevant when evaluating the degree of pain. When considering the five ocular signs, the lowest pain score was attributed to the flunixin meglumine group (1114), followed by the electroacupuncture group (1356), the phenylbutazone group (1397), and the control group (1580). There were significantly lower pain scores (P = .01) in the flunixin meglumine group when compared with those recorded in the control group during the first 46 hours. Flunixin meglumine was the most effective treatment at reducing ocular pain in the horse. In the future, a reduction in the number of pain score parameters and more precisely defined image evaluation criteria could be used.
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2,336,090 |
Combined analysis of gestational diabetes and maternal weight status from pre-pregnancy through post-delivery in future development of type 2 diabetes.
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We examined the associations of gestational diabetes mellitus (GDM) and women's weight status from pre-pregnancy through post-delivery with the risk of developing dysglycaemia [impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes (T2D)] 4-6 years post-delivery. Using Poisson regression with confounder adjustments, we assessed associations of standard categorisations of prospectively ascertained pre-pregnancy overweight and obesity (OWOB), gestational weight gain (GWG) and substantial post-delivery weight retention (PDWR) with post-delivery dysglycaemia (n = 692). Women with GDM had a higher risk of later T2D [relative risk (95% CI) 12.07 (4.55, 32.02)] and dysglycaemia [3.02 (2.19, 4.16)] compared with non-GDM women. Independent of GDM, women with pre-pregnancy OWOB also had a higher risk of post-delivery dysglycaemia. Women with GDM who were OWOB pre-pregnancy and had subsequent PDWR (≥ 5 kg) had 2.38 times (1.29, 4.41) the risk of post-delivery dysglycaemia compared with pre-pregnancy lean GDM women without PDWR. No consistent associations were observed between GWG and later dysglycaemia risk. In conclusion, women with GDM have a higher risk of T2D 4-6 years after the index pregnancy. Pre-pregnancy OWOB and PDWR exacerbate the risk of post-delivery dysglycaemia. Weight management during preconception and post-delivery represent early windows of opportunity for improving long-term health, especially in those with GDM.
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2,336,091 |
Enhanced cardiac vagal tone in mental fatigue: Analysis of heart rate variability in Time-on-Task, recovery, and reactivity.
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Heart Rate Variability (HRV) has been suggested as a useful tool to assess fatigue-sensitive psychological operations. The present study uses a between and within-subject design with a cognitively demanding task and a documentary viewing condition, to examine the temporal profile of HRV during reactivity, Time-on-Task (ToT), and recovery. In the cognitive task group, participants worked on a bimodal 2-back task with a game-like character (the Gatekeeper task) for about 1.5 hours, followed by a 12-minute break, and a post-break block of performance (about 18 min). In the other group, participants watched documentaries. We hypothesized an increasing vagal-mediated HRV as a function of Time spent on the Gatekeeper task and no HRV change in the documentary viewing group. We also analyzed the trial-based post-response cardiac activity as a physiological associate of task-related motivation. Relative to the documentary-viewing, ToT was associated with an elevated level of subjective fatigue, decreased heart rate, and increased HRV, particularly in the vagal-mediated components. Based on fatigued participants' post-error cardiac slowing, and post-error reaction time analyses, we found no evidence for motivation deficits. The present findings suggest that the parasympathetic branch of the autonomous nervous system functioning as a relaxation system tends to be activated under increasing mental fatigue. In addition, the study shows that many HRV indices also seem to change when individuals are engaged in a prolonged, less fatiguing activity (e.g. documentary viewing). This finding emphasizes the relevance of comparisons/control conditions in ToT experiments.
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2,336,092 |
Convallatoxin Promotes M2 Macrophage Polarization to Attenuate Atherosclerosis Through PPARγ-Integrin α<sub>v</sub>β<sub>5</sub> Signaling Pathway.
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As the primary immune cells, macrophages play a key role in atherosclerotic progression. M2 macrophage polarization has been reported to promote tissue repair and attenuate plaque formation upon the expression of anti-inflammatory factors. Convallatoxin (CNT) is a natural cardiac glycoside with anti-inflammatory pharmacological properties. However, whether CNT protects against atherosclerosis (AS) and underlying mechanisms is unknown. This work was designed to explore the potential effects of CNT on atherosclerosis.</AbstractText>In this study, Apolipoprotein E deficiency (ApoE-/-</sup>) mice fed with high-fat diet were established, and CNT (50 or 100 μg/kg) were intragastrically administrated for 12 weeks every day. In vitro, RAW264.7 macrophages stimulated with ox-LDL were treated with CNT (50 or 100 nM) for 24 h. The specific PPARγ antagonist, GW9662, was used to block the PPARγ signaling pathway in vitro. Then, the atherosclerotic lesions, macrophage polarization markers, inflammatory cytokines and PPARγ signaling pathway were examined in further examinations.</AbstractText>Our results showed that the atherosclerotic lesions were reduced by CNT, as demonstrated by the downregulation of serum lipid level and aortic plaque area in AS mice. Furthermore, we found that CNT treatment promoted the expression of M2 macrophage markers (Arg1, Mrc1, Retnla and Chi3l3), and decreased the levels of pro-inflammatory cytokines (IL-6 and TNF-α), accompanied by the increase of anti-inflammatory factor (IL-10) in aortic vessels of AS mice. In ox-LDL-induced RAW264.7 cells, CNT administration also facilitated macrophages polarizing towards M2 subtype and inhibited inflammatory responses. Furthermore, both the in vivo and in vitro experiments showed CNT could increase the expression of PPARγ, Integrin αv</sub> and Integrin β5</sub>, and GW9662 could block CNT-induced M2 macrophage polarization.</AbstractText>Taken together, these data suggest that CNT may promote M2 macrophage polarization to exert an anti-atherosclerotic effect, partially through activating PPARγ-Integrin αv</sub>β5</sub> signaling pathway.</AbstractText>© 2021 Zhang et al.</CopyrightInformation>
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2,336,093 |
The effects of reiki on heart rate, blood pressure, body temperature, and stress levels: A pilot randomized, double-blinded, and placebo-controlled study.
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Reiki is a biofield energy therapy that focuses on optimizing the body's natural healing abilities by balancing the life force energy or qi/chi. Reiki has been shown to reduce stress, pain levels, help with depression/anxiety, increase relaxation, improve fatigue, and quality of life. In this pilot randomized, double-blinded, and placebo-controlled study, the effects of Reiki on heart rate, diastolic and systolic blood pressure, body temperature, and stress levels were explored in an effort to gain objective outcome measures and to understand the underlying physiological mechanisms of how Reiki may be having these therapeutic effects on subjective measures of stress, pain, relaxation, and depression/anxiety. Forty eight (n = 48) subjects were block randomized into three groups (Reiki treatment, sham treatment, and no treatment). The changes in pre- and post-treatment measurements for each outcome measure was analyzed through analysis of variance (ANOVA) post hoc multiple comparison test, which found no statistically significant difference between any of the groups. The p-value for the comparison of Reiki and sham groups for heart rate was 0.053, which is very close to being significant and so, a definitive conclusion can not be made based on this pilot study alone. A second study with a larger sample size is warranted to investigate this finding further and perhaps with additional outcome measures to look at other possible physiological mechanisms that may underlie the therapeutic effects of Reiki.
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2,336,094 |
Neurologic complications of brady-arrhythmias.
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Brady-arrhythmias are responsible for both overt as well as subtle neurologic signs and symptoms, from the seemingly benign and nonspecific symptoms associated with presyncope, to sudden focal neurologic deficits. A brief background on nodal and infra-nodal brady-arrhythmias is provided, followed by extensive discussion regarding neurologic complications of brady-arrhythmias. The multiple mechanisms of and associations between Brady-arrhythmias and transient ischemic attacks and ischemic stroke are discussed. Controversial associations between brady-arrhythmias and neurologic disease are discussed as well, such as potential roles of brady-arrhythmias in cognitive impairment and sequelae of chronotropic incompetence; and the contribution of brady-arrhythmias to syncope and associated injuries to the nervous system. The chapter is written to stand on its own, with guidance toward other pertinent sections of this text where appropriate for further reading.
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2,336,095 |
Trifascicular Block and Ventricular Standstill: A Late Complication of Mediastinal Radiotherapy in a Cancer Survivor.
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Over the last half-century, radiation therapy has evolved to become one of the cornerstones of treatment for various types of cancers. It is estimated that more than 50% of patients with cancer are treated with radiotherapy. Patients with early stages of some cancers can even achieve a cure with radiotherapy alone. Radiation-induced heart disease is a well-recognized cause of mortality and morbidity in cancer survivors as a late complication of radiotherapy, often occurring more than a decade after radiotherapy. We describe a case of a middle-aged female who presented to the hospital with syncopal episodes. She was in remission from non-Hodgkin's lymphoma having received mediastinal radiotherapy 20 years, previously. Her initial workup such as laboratory investigations and 12 lead electrocardiogram were largely unremarkable. Cardiac monitoring over the course of the next few days was consistent with complete heart block with evidence of ventricular standstill. Her symptoms resolved following the implantation of a dual-chamber cardiac pacemaker. This case highlights the significance of clinical history taking and putting together all relevant facts to come to a differential diagnosis. In our case, this could have been easily overlooked as radiation therapy was given many years previously. We review and present an up-to-date albeit brief literature review on long-term cardiovascular complications of radiotherapy. Radiation-induced cardiac complications are an important cause of mortality and morbidity in cancer survivors. This article aims to raise awareness amongst clinicians of cardiac adverse effects occurring several years after the radiation therapy. This case also highlights the need for further research to better understand the pathophysiology of cardiovascular disease post-radiotherapy in order to develop effective prevention strategies and improve clinical outcomes.
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2,336,096 |
Evaluation of Light Physical Activity Measured by Accelerometry and Mobility Disability During a 6-Year Follow-up in Older Women.
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Almost 1 in 4 women older than 65 years is unable to walk 2 to 3 blocks, and mobility disability is a key factor associated with loss of independence. Lack of moderate to vigorous-intensity physical activity is associated with mobility disability, but whether lighter physical activity is associated with mobility disability is unknown.</AbstractText>To determine the association of light-intensity physical activity and incident mobility disability among older women.</AbstractText><AbstractText Label="DESIGN, SETTING, AND PARTICIPANTS">This prospective cohort study included women enrolled in the Objectively Measured Physical Activity and Cardiovascular Health study, an ancillary study of the Women's Health Initiative, between March 2012 and April 2014, with follow-up through March 31, 2018. The Women's Health Initiative was a population-based, multisite study that recruited from 40 clinical sites across the US. Participants in the present analysis included 5735 of 7058 ambulatory, community-dwelling women aged 63 years and older who returned an accelerometer with usable data, were free of mobility disability, and had follow-up data on mobility status. Data were analyzed from August 2018 to May 2019.</AbstractText>Light-intensity physical activity, defined as movement requiring energy expenditure between 1.6 and 2.9 metabolic equivalents, captured using an accelerometer over 7 days.</AbstractText>Incident mobility disability, defined as the first self-reported inability to walk 1 block or up a flight of stairs at annual follow-up, and persistent incident mobility disability, defined as incident mobility loss that persisted through the end of follow-up.</AbstractText>A total of 5735 participants were included for primary analysis of all incident mobility disability (mean [SD] age, 78.5 [6.6] years [range, 63-97 years]; 2811 [49.0%] White participants). Compared with women in the lowest quartile of light-intensity physical activity, lower risk of incident mobility disability was observed in quartile 2 (multivariable hazard ratio [HR], 0.78; 95% CI, 0.67-0.90), quartile 3 (HR, 0.60; 95% CI, 0.51-0.71), and quartile 4 (HR, 0.60; 95% CI, 0.51-0.71) (P < .001). This beneficial association was stronger for persistent mobility disability in quartile 2 (multivariable HR, 0.72; 95% CI, 0.60-0.85), quartile 3 (HR, 0.55; 95% CI, 0.46-0.67), and quartile 4 (HR, 0.52; 95% CI, 0.42-0.63) (P < .001). Stratified analyses showed the association was stronger among women with a body mass index of less than 30.0 (HR, 0.73; 95% CI, 0.66-0.82) compared with women with a body mass index of 30.0 or higher (HR, 0.91; 95% CI; 0.79-1.04; P = .04 for interaction).</AbstractText>In this cohort study, increased time spent in light-intensity physical activity was associated with reduced incident mobility disability. These findings support placing greater emphasis on promoting light-intensity physical activity for preserving mobility in later life.</AbstractText>
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2,336,097 |
The incidence of pulmonary thromboembolism in COVID-19 patients admitted to the intensive care unit: a meta-analysis and meta-regression of observational studies.
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Coronavirus disease 2019 (COVID-19) infection is associated with a prothrombotic state. We performed a meta-analysis of proportions to estimate the weighted average incidence of pulmonary thromboembolism (PTE) in COVID-19 patients who were admitted to the intensive care unit (ICU).</AbstractText>We searched various medical databases for relevant studies from 31 December 2019 till 30 September 2020. We included observational studies that reported the incidence of PTE in COVID-19 patients admitted to the ICU. We extracted data related to study characteristics, patient demographics, and the incidence of PTE. Risk of bias was assessed by using the ROBINS-I tool. Statistical analysis was performed with R 3.6.3.</AbstractText>We included 14 studies with a total of 1182 patients in this study. Almost all patients in this meta-analysis received at least prophylactic anticoagulation. The weighted average incidence of PTE was 11.1% (95% CI 7.7% to 15.7%, I2</sup> = 78%, Cochran's Q test P < 0.01). We performed univariate and multivariate meta-regression, which identified the proportion of males as a significant source of heterogeneity (P = 0.03, 95% CI 0.00 to - 0.09) CONCLUSION: The weighted average incidence of PTE remains high even after prophylactic anticoagulation. PTE is a significant complication of COVID-19 especially in critically ill patients in the ICU.</AbstractText>
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2,336,098 |
[Intellectual disorder and idiopathic sick sinus syndrome associated with GNB5 mutation: a case report].
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小儿特发性病态窦房结综合征是在儿童时期起病，表现为窦房结功能障碍的心律失常综合征，通常认为与遗传性因素有关。随着基因测序技术的发展，与特发性病态窦房结综合征相关的基因变异位点陆续被发现，人们对其发病机制的认识已深入到分子水平。本文报道1例智力障碍伴特发性病态窦房结综合征的病例，为GNB5基因移码变异c.136delG。该基因变异临床罕见，丰富了特发性窦房结综合征的基因和临床表型谱，为该病的精准诊断及遗传咨询提供依据。.
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2,336,099 |
A single educational intervention on heart failure self-care: Extended follow-up from a multisite randomized controlled trial.
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Heart failure outcomes remain poor, and little is known about the causes and predictors of these outcomes in Lebanon.</AbstractText>The purpose of this article is to report the causes and predictors of the 6- and 12-month readmission and mortality of previously recruited patients to the Family focused Approach to iMprove Heart Failure care In LebanonQualitY intervention (FAMILY) study.</AbstractText>A multi-site block randomized controlled trial in three tertiary medical centers in Beirut. Initially, participants were randomized to either the control or the intervention group. The latter group, with their family caregivers, received heart failure self-care resources and an educational intervention on self-care and symptom management during their index admission. Participants from the FAMILY study were followed up with through phone calls for readmission and mortality at 6 and 12 months following their hospital discharge.</AbstractText>A total of 218 (85%) patients were followed up with for this evaluation. There was a significant difference between the intervention group and the control group in terms of mortality at 6 months (n=18 (16%) versus n=36 (33%); p<0.05) and 12 months (n=29 (26%) versus n=45 (42%); p<0.05) post the index discharge. Mortality at 6 and 12 months was associated with aging, lower body mass index scores and readmission at 30 days post the index admission. Results of a logistic regression for mortality at 6 months showed hypertensive etiology of heart failure and 30-day readmission to be the only significant predictors.</AbstractText>A single session intervention was associated with lower mortality, even after an extended period of time, possibly mediated by other variables. Future studies should be powered for such outcomes while also addressing the cultural needs and literacy levels of the patients using multi-session trials and more frequent follow-ups.</AbstractText>© The European Society of Cardiology 2020.</CopyrightInformation>
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