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PMC11277730_p19
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[0]
|
2.1.4. Actinic Keratoses
| 3.949219 |
biomedical
|
Study
|
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Concerning the use of TPHs on AKs, the recruited participants were mostly middle-aged and elderly Caucasian males (40–100%, 28–92 years) with FFII-III . Interestingly, some of the studies even included high-risk individuals such as patients with XP and those with a personal history of non-melanoma skin cancer (NMSC) or immunosuppression . As these commonly show severe cancerization fields and accumulate great amounts of UV-induced DNA mutations, they could benefit significantly from the use of TPHs . The scalp and face were the most commonly involved sites .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277730_p20
|
PMC11277730
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sec[1]/sec[0]/sec[3]/p[1]
|
2.1.4. Actinic Keratoses
| 3.916016 |
biomedical
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Assessing therapeutic efficacy for AK is extremely challenging, both in clinical trials and in the real-life setting . Efficacy is assessed in most studies based on the count of macroscopic lesions by the investigators, with clear inter-observer variation. Additionally, results are usually presented using clearance rates, which vary across studies. These may include the reduction in AK count, percentage of patients achieving clerance greater than 50%, complete clearance, and incidence of new AK lesions… Comparison of the efficacy of a treatment between studies can thus be extremely difficult.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p21
|
PMC11277730
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sec[1]/sec[0]/sec[3]/p[2]
|
2.1.4. Actinic Keratoses
| 3.998047 |
biomedical
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Following this strategy is suboptimal, as it does not take into account important factors such as the severity of mutations, epithelial dysplasia, erythema, and roughness in the “normal” skin (field cancerization) surrounding the clinical lesions . Several authors have tried to overcome these limitations by assessing the efficacy of treatments in biopsies and using histological and genetic parameters . However, samples are either taken from randomly selected lesions or from those considered to be the most severe . The latter is an inappropriate method, as Schmitz et al. reported that physician-perceived severity (i.e., Olsen score) does not accurately match histological findings and the risk of transformation into squamous cell carcinoma (SCC).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p22
|
PMC11277730
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sec[1]/sec[0]/sec[3]/p[3]
|
2.1.4. Actinic Keratoses
| 3.974609 |
biomedical
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|
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The natural evolution of macroscopic lesions indeed shows extreme inter- and intraindividual variability . On the one hand, the spontaneous resolution of AK lesions is a well-known phenomenon, with an estimated annual rate of 25% . On the other hand, the risk of malignant transformation into invasive SCC is not negligible. Lee et al. recently estimated the hazard ratio in AK patients 80 years or older for developing SCC at 5.69. For these reasons, different clinical (i.e., AKASI) and histological scores (i.e., PRO) were designed to better predict the risk of malignant transformation . However, these tools are not exempt from limitations that hinder their widespread use in the real-life setting.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p23
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[4]
|
2.1.4. Actinic Keratoses
| 3.984375 |
biomedical
|
Study
|
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The previously mentioned limitations hindered comparisons between studies and the calculation of a global clearance rate encompassing all TPH trials. Despite this, TPHs have been shown to be an excellent active treatment, reducing the count of AK lesions . Clearance rates 50% or greater were present in 20 –100% of the treated patients, while 29 –42.86% of the individuals exposed to TPHs achieved complete resolution of the lesions. Assessing the available results as a whole, most participants managed with TPHs achieved at least some degree of improvement greater than the rate of spontaneous resolution of AK lesions . Reduced incidence of new lesions has also been reported in three studies .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p24
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[5]
|
2.1.4. Actinic Keratoses
| 3.673828 |
biomedical
|
Study
|
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Improvement in other clinical parameters beyond the clearance of AK lesions has also been observed. After TPH exposure, field cancerization and AK lesions showed less erythema , scaling , and pigmentation , assessed both clinically and by dermoscopy.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p25
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[6]
|
2.1.4. Actinic Keratoses
| 4.164063 |
biomedical
|
Study
|
[
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TPHs maintain a proper long-term clearance of AK lesions after previous photodynamic therapy (PDT) with methyl aminolevulinic acid (MAL-PDT) (λ = 630 nm, 37 J/cm 2 ) . A total of 30 patients with face or scalp AKs were randomly assigned to receive Eryfotona AK-NMSC fluid ® ( Anacystis nidulans encapsulated in liposomes) or standard SC (1:1), twice daily for 9 months ( Table 2 ) . The basal AK count was relatively low (2 ± 2 vs. 0.6 ± 0.5, p > 0.05), as the last MAL-PDT treatment was administered 2 weeks before the administration of Eryfotona ® . At the final visit, the TPH-exposed patients showed lower AK counts (1 ± 1.1 vs. 3.6 ± 3.8, p < 0.01) and a reduced need of new PDT sessions (0 vs. 10, p = 0.01) . Most (87%) SC-treated patients developed at least one new AK lesion during the trial . The application of these findings in real-life practice is crucial, as this research clearly indicates TPHs achieve an excellent long-term clearance of AK lesions .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p26
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[7]
|
2.1.4. Actinic Keratoses
| 4.171875 |
biomedical
|
Study
|
[
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Recently, a double-blinded RCT assessed the efficacy of TPHs in AK sited on the forearms ( Table 2 ) . Although previous studies had included patients with AKs in this anatomical region , none had specifically addressed this location . A total of 40 AK patients were randomly assigned to treatment courses of TPH + SC SPF99 vs. SPF99 alone (1:1) twice daily for 2 months . The recruited participants were mostly women (60%) with FFII-III . The baseline field-cancerization severity was at least moderate, with a baseline lesion count on each forearm of 7 (6–9), a forearm AK severity score (AKSS) of 72 (51–95) and forearm photoaging scale (FPS) of 107 (91–116) . AK count reduction was similar in both groups after completion of the treatment (5 vs. 5, −38.7%) . Clearance rates were modest, as few patients managed to achieve a reduction in the number of AK lesions greater than 50% (25% vs. 20%) . The final AKSS (38 vs. 32) and FPS (78 vs. 85) scores were inferior to baseline levels, although no statistically significant differences were found between groups . One patient in each group developed one NMSC during the trial . The TPHs failed, thus, to add any benefit to standard SC in the treatment of AKs located on the forearms, which is precisely one of the sites most challenging to manage .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p27
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[8]
|
2.1.4. Actinic Keratoses
| 3.091797 |
biomedical
|
Study
|
[
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Non-invasive diagnostic techniques have shed light on the effects on tissular and cellular structure after the topical application of photolyases ( Table 3 ).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p28
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[9]
|
2.1.4. Actinic Keratoses
| 4.210938 |
biomedical
|
Study
|
[
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Puig et al. directed the first controlled interventional clinical study which robustly assessed the efficacy of TPHs in AK management using dermoscopy and RCM ( Table 3 ) . Eryfotona AK-NMSC fluid ® and SPF50+ SC were independently used twice daily for 1 month in 11 low-phototype patients (3:1) with AKs on the head, scalp, and forearms . Most participants were at high risk: eight (61.54%) had a personal history of NMSC, two were affected by XP (15.38%), and one was under immunosuppression (7.69%) . Only patients treated with TPH achieved complete (44.44%) or partial (33.33%) clearance of AK lesions at the end of the study . Dermoscopic evaluation showed improvement in erythema ( p = 0.03) and scaling ( p = 0.028), without changes in pigmentation or follicular plugs ( Table 3 ) . After TPH treatment, RCM improved in several items compared to the baseline, with significantly less scaling (−78.81%, p = 0.004), fewer round cells at the stratum granulosum (−57.14%, p = 0.019), and less atypical honeycomb pattern , as well as a decreased coherence of corneocytes (+72%, p = 0.018). No changes were detected in the density of nucleated cells in the stratum corneum ( p = 0.221), disarray of epidermal pattern ( p = 0.095), vascularization ( p = 0.413), and inflammation ( p = 0.221) . Interestingly, no improvement in dermoscopy or RCM was detected in the three SC-treated individuals ( Table 3 ) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p29
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[10]
|
2.1.4. Actinic Keratoses
| 4.160156 |
biomedical
|
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|
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These RCM findings were not later replicated by Moscarella et al. , as no statistically significant difference was detected between TPH and SPF50+ SC after 6 months of treatment ( Table 3 ). This study had a larger sample size (n = 50 vs. n = 13), a longer follow-up period (6 months vs. 1 month) and the second-highest AK basal count (13 ± 6.8) of all of the published works . Most cases were severe, as 60% (n = 30) of the participants had more than 10 AK clinical lesions within the target area . At the end of the treatment, the AK count (−3.8 vs. −3.3) and investigator-assessed severity (−0.2 vs. −0.2) dropped in both groups, although no statistical analysis of the results was shown . No differences (1.2 vs. 1) were found in the investigator global improvement index (range: −2 vs. +7) . TPH-treated patients had higher baseline AK counts (13 ± 6.8 vs. 10.9 ± 0.5), which could explain why photolyases only proved to be superior after the subgroup analysis, specifically preventing the appearance of new AK lesions in mild cancerization fields (0.1 vs. 1.5, p = 0.04) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p30
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[11]
|
2.1.4. Actinic Keratoses
| 4.148438 |
biomedical
|
Study
|
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Rstom et al. confirmed the positive evolution of facial AKs on dermoscopy after TPH treatment ( Table 3 ) . Fourteen grade I and three grade II AK lesions were treated with Eryfotona AK-NMSC fluid ® , once daily for 3 months . After completing their administration, 64.29% of the grade I lesions experienced at least some degree of improvement in both erythema and scaling, with a partial normalization of the atypical honeycomb pattern with RCM . However, dermoscopy and RCM failed to detect any improvement in grade II lesions ( Table 3 ) . Increased thickness of the epidermis may reduce the percutaneous absorption of TPHs in vivo and thus minimize their concentration in the cell nuclei.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p31
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[12]
|
2.1.4. Actinic Keratoses
| 4.210938 |
biomedical
|
Study
|
[
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As previously mentioned, different groups of investigators have evaluated the effect of TPHs on human skin through different optical devices such as fluorescence, spectrophotometry, or telethermography ( Table 3 ) . In 2015, Laino et al. published the results of a prospective cohort of 30 low-phototype AK scalp patients treated with TPH, twice daily for 9 months . Efficacy was assessed through active teletermography (ATT) . ATT analyzes the vascular pattern of tumors by detecting the infrared radiation emitted from a lesion before and after the rapid removal of a thermal stimulus . Results were expressed in the form of thermal recovery time (TRT) and subdivided into three categories: rapid (R: <10 s), slow (S: 10 s–2 min), and normal (N: >2 min) . Before the onset of the TPHs, all AK lesions had a rapid TRT (100%) . At the 9th month of treatment, TPHs managed to increase the TRT; most lesions showed a slow TRT (n = 19, 70.37%) and even in 3 AK (11.11%) was completely normalised . On the other hand, at baseline evaluation, all AK lesions (100%) displayed a surrounding hyperthermic halo (HH), whose overall size considerably diminished after treatment (0.61 cm 2 vs. 3.45 cm 2 , −82.37%) . These outcomes suggested TPHs could reduce the hypervascularization associated with skin carcinogenesis . Puviani et al. reached a similar conclusion in the same year. Target areas from 11 AK patients with low phototypes (II-III) were treated with Eryfotona AK-NMSC fluid ® twice daily for 3 months . Anatomical location was not detailed, although most lesions were sited on the face and the scalp . Colorimetry was chosen to evaluate the clinical response . This procedure is based on a scanning device that assesses changes over time in melanin, hemoglobin, and skin profiles . Content of hemoglobin partially diminished in the lesions where TPHs were applied . Additionally, the size of the target lesions dramatically decreased after TPH treatment (−75%, p < 0.01) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p32
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[13]
|
2.1.4. Actinic Keratoses
| 4.148438 |
biomedical
|
Study
|
[
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Overall improvement in field cancerization has been demonstrated in an RCT ( Table 3 ) . Caucasian patients (n = 28) with thin (grade I and II) facial and scalp AKs were randomly assigned to receive treatment with a combination of photolyases (1%, A. nidulans ), endonucleases (1%, M. luteus ), and SPF50+ SC vs. SC alone . The products were applied twice daily for 6 months . The photodamage was moderate, as the AK count at onset ranged from 4 to 10 in each target area . Topical application of methyl aminolevulinate acid (MAL) was used to assess the fluorescence of field cancerization . An incubation period of 3 h was followed . At the 6th month visit, the combination was superior to SC alone ( Table 3 ) in reducing the field cancerization fluorescence (−29.09% vs. −10.19%, p < 0.001) and CPD levels (−61.76% vs. −34.48%, p < 0.001).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277730_p33
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[14]
|
2.1.4. Actinic Keratoses
| 4.222656 |
biomedical
|
Study
|
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Puig-Batillé et al. conducted the first and only clinical trial to this date which assessed the effects of photolyases on the expression of different genes in human skin in vivo . Eleven AK patients were treated with Eryfotona AK-NMSC fluid ® twice daily for 1 month. Biopsies were taken before (T0) and after (T1) the completion of the treatment . Complete responders showed a significantly lower final expression of TNF ( p = 0.012) and upregulated levels of WDR72 ( p = 0.04) and CPI-17 ( p = 0.039) . CPI-17 expression was higher than in the partial responders . The authors concluded that increased expression of CPI-17 controlled MYPT1-PPδ activity, regulating the dephosphorylation of the retinoblastoma protein and subsequently improving cell cycle control and adhesion . However, the final sample size was low, as 4 out of 11 patients (36.36%) refused to take a second biopsy due to personal issues, or the RNA extraction failed . Puig et al. later confirmed that TPHs regulate the cell cycle, as keratinocyte expression of p21 decreased after 1 month of treatment (−38.71%, p = 0.042).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p34
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[15]
|
2.1.4. Actinic Keratoses
| 4.175781 |
biomedical
|
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0.0003020763397216797
] |
Giustini et al. particularly evaluated the use of TPH as a photoprotective agent in the real-life management of eight patients with XP ( Table 2 ). XP-affected individuals suffer from different genetic defects in the DNA repair system, making them extremely vulnerable to UV-induced skin carcinogenesis . Apart from their preventive properties, TPHs could serve as an excellent therapy in this disease, actively reducing the accumulation of CPD dimers and the risk of malignant transformation . The recruited patients were middle-aged (55) with previous long exposure to solar UV radiation (sUVR) . During the last year before TPH application, a mean of 6.8 basal cell carcinomas (BCC) and 3 SCC had been diagnosed . Eryfotona AK-NMSC fluid ® was prescribed twice daily for a year . The product achieved a significant reduction in the appearance of new AK lesions compared to the year before (5, −64.29%) . Remarkably, this has been the only research that hinted at the possibility that TPH reduces practice the development of BCC (n = 3, −56%) and SCC (0, −100%) in real life . As a result, the use of TPHs and SCs must be thoroughly encouraged in XP patients . Further studies are warranted to confirm the potential benefits of long-term administration of TPHs in the quality of life and long-term survival of XP patients .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p35
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[16]
|
2.1.4. Actinic Keratoses
| 2.728516 |
biomedical
|
Study
|
[
0.998046875,
0.0009298324584960938,
0.0010766983032226562
] |
[
0.98388671875,
0.006603240966796875,
0.00891876220703125,
0.0005164146423339844
] |
Beyond clinical trial data, three observational studies have confirmed the benefits of TPH in real-life AK patients ( Table 4 ) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p36
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[17]
|
2.1.4. Actinic Keratoses
| 4.226563 |
biomedical
|
Study
|
[
0.9970703125,
0.002681732177734375,
0.00028824806213378906
] |
[
0.99755859375,
0.0013408660888671875,
0.0006012916564941406,
0.00028634071350097656
] |
Vañó Galván et al. published in 2016 the largest open-label longitudinal prospective study (n = 41). A total of 41 patients with ≥4 AKs, all treatable with cryotherapy, were included ( Table 4 ) . Participants were excluded if they had received field-cancerization-targeted treatments in the previous 3–6 months . Most were male (n = 37, 90.24%), with a mean age of 75.3 years (58–85) and FFII . AK lesions were mainly located on the scalp (n = 33, 80%). Eryfotona AK-NMSC fluid ® was started 1 day after cryotherapy and continued twice daily for 6 months . Nonetheless, this work has some biases that limit the validity of its outcomes and conclusions. Firstly, a specific definition of AKs treatable with cryotherapy was lacking . Since the global baseline number of AK lesions was high (9.56), this indicates that patients with even higher basal counts were nevertheless included . Furthermore, no details were given of why the investigators prioritised destructive therapies over field cancerization therapies precisely in this subset of severely photodamaged participants . Secondly, efficacy was assessed strictly by clinical means, with the obvious limitations previously mentioned . As there was a lack of a comparator, the final outcomes cannot be fully attributed to the use of Eryfotona AK-NMSC fluid ® , as several patients were continuously and discretionally exposed to adjuvant cryotherapy while receiving treatment . In this respect, the percentage of patients that required this therapy while on TPHs is not detailed . Therefore, the percentage of participants that achieved partial or complete clearance (100% and 29%) is thus overestimated, as lesions refractory to TPHs could have been precisely destroyed by cryotherapy . Consequently, three groups of patients (TPH vs. cryotherapy alone vs. cryotherapy + TBP) would have been necessary to correctly discern the overall efficacy, tolerability, and safety of TPH .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p37
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[18]
|
2.1.4. Actinic Keratoses
| 4.0625 |
biomedical
|
Study
|
[
0.9765625,
0.0231781005859375,
0.00043392181396484375
] |
[
0.97607421875,
0.0168609619140625,
0.004749298095703125,
0.0024242401123046875
] |
Smaller clinical series (n = 6–9) were published by Puviani et al. and Navarrete-Dechent et al. . AK patients mainly on the face and scalp were treated with Eryfotona AK-NMSC fluid ® twice daily for 1.5 to 3 months . Almost all of the patients were middle-aged to elderly males . Participants with a personal history of NMSC and immunosuppression were also recruited . All patients in both series achieved a clearance of AK lesions ≥50% after completing the treatment ( Table 4 ) . No remarkable side effects were identified .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p38
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[19]
|
2.1.4. Actinic Keratoses
| 4.035156 |
biomedical
|
Study
|
[
0.99951171875,
0.0004897117614746094,
0.0001728534698486328
] |
[
0.9970703125,
0.00048279762268066406,
0.00255584716796875,
0.00010603666305541992
] |
Self-perceived local tolerability and sense of improvement are important factors for achieving therapeutic success in chronic disorders such as AK . Both were highly rated by patients in the study conducted by Vañó Galván et al. , with mean scores of 2.71 and 2.85, respectively (range: 0–4). After 6 months of treatment, patients’ mean adherence was remarkably high, with a score of 3.21 (range: 0–4) . In the trial conducted by Moscarella et al. , patients’ satisfaction with treatment (5, range of the score 0–7) and assessment of local tolerability (5.1, range of the score 0–7) were remarkably good. These outcomes underline the ease of use of TPH and could indicate proper compliance in the real-life setting.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p39
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[20]
|
2.1.4. Actinic Keratoses
| 2.513672 |
biomedical
|
Study
|
[
0.96240234375,
0.035858154296875,
0.0016489028930664062
] |
[
0.6591796875,
0.326171875,
0.006679534912109375,
0.0080108642578125
] |
Overall tolerance of TPH is considered excellent, which is an important aspect of chronically prescribing a twice-daily topical product . The rate of adverse reactions was low (0 –7.5% ). No severe side effects warranting discontinuation of the treatment were detected .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p40
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[21]
|
2.1.4. Actinic Keratoses
| 3.996094 |
biomedical
|
Study
|
[
0.99951171875,
0.0003445148468017578,
0.00024056434631347656
] |
[
0.96923828125,
0.0006184577941894531,
0.0298919677734375,
0.00015842914581298828
] |
Despite the previously mentioned benefits, the outcomes are not exempt from biases and limitations that partially limit their validity. Firstly, the sample size was modest (n < 50) in all of the experimental trials and observational studies . Mean baseline AK count considerably varied between studies, which hampers a proper comparison and extrapolation of the results . On the other hand, most authors did not specify further details crucial to infer the field cancerization severity, such as the personal history of on-site NMSC, previously prescribed treatments, or affected surface area . Additionally, only in five studies were patients excluded if they had received field-cancerization-targeted treatments 3–6 months before the use of TPHs . Persisting benefits of recently prescribed therapies, such as imiquimod, may increase the clearance of AK lesions up to 6 months after completion, masking any potential differences of TPH compared to the placebo or standard SC .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p41
|
PMC11277730
|
sec[1]/sec[0]/sec[3]/p[22]
|
2.1.4. Actinic Keratoses
| 4.003906 |
biomedical
|
Review
|
[
0.9931640625,
0.0038967132568359375,
0.0029125213623046875
] |
[
0.00606536865234375,
0.001575469970703125,
0.99169921875,
0.0004265308380126953
] |
In addition to the latter, one of the greatest limitations of these studies is the still unknown effect of TPHs on skin carcinogenesis. Until the date of publication of this review, no work has specifically addressed the incidence of skin tumors in patients chronically treated with TPH. This is obviously crucial in the clinical setting, as the main aim of treating AKs is precisely reducing the risk of malignant transformation. Proper well-designed RCTs with larger sample sizes and longer follow-up periods are thus necessary for assessing this hypothesis. Future research warrants the development of clinical and histological scores with high inter- and intraindividual correlation for accurately assessing the efficacy of TPHs in AK patients and enabling an adequate comparison between studies.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p42
|
PMC11277730
|
sec[1]/sec[0]/sec[4]/p[0]
|
2.1.5. Polymorphic Light Eruption
| 4.265625 |
biomedical
|
Study
|
[
0.99755859375,
0.0020542144775390625,
0.000232696533203125
] |
[
0.9892578125,
0.005092620849609375,
0.005126953125,
0.0005121231079101562
] |
Although most research on the use of TPHs has been centred on the management of AKs, photolyases could prove beneficial in photosensitive disorders such as PoLE . In a randomized double-blinded placebo-controlled intra-individual half body trial, topical combined photolyases and endonucleases (without filters) were compared to SPF30 SC and a placebo in 14 patients with PoLE and FFII-III . This RCT is interesting in different aspects, but especially in its recruitment of individuals with photosensitive disorders, which were excluded in the remaining studies (except XP patients) . Two pairs of symmetrically distributed test fields (5 × 5 cm) in PoLE-predilection sites were selected for photoprovocation, which was performed once daily for 4 consecutive days. Sites were allocated to receive no treatment, SPF 30 SC (20 min before each UVR), TPHs (5 min after photoprovocation), and a placebo (5 min after provocation) . Authors employed a new clinical tool for evaluating the response (range: 0–12), assessing items such as percentage of site area affected, infiltration, and pruritus . SPF30 SC proved to be superior to TPHs, with a lower PLE score , erythema, and pigmentation measured through reflectance spectroscopy . Lesions were nearly absent in sites pretreated with SPF30 SC . Compared to the placebo, TPHs only managed to be superior in terms of pruritus . Avoiding or filtering UV photons are thus the best methods for preventing the elicitation of PoLE lesions. However, it should not be forgotten that the mechanism of action of TPHs consists mainly in the breakdown of photoproducts, which accumulate precisely after the UV non-filtered radiation has taken place. For these reasons, we consider that it could be interesting to discern whether the use of TPHs might have a synergistic effect in the management of PoLE when combined with SC, as they could reduce the formation of neoantigens and thus break the initial trigger of the pathogenic chain.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p43
|
PMC11277730
|
sec[1]/sec[1]/sec[0]/p[0]
|
2.2.1. Biological Origin
| 4.269531 |
biomedical
|
Study
|
[
0.99951171875,
0.00020182132720947266,
0.0002429485321044922
] |
[
0.98681640625,
0.0005822181701660156,
0.0126495361328125,
0.00014293193817138672
] |
Tanaka and his team discovered in 1975 that bacteriophage T4 endonuclease V (T4N5)- a 16,500-Da polypeptide from Escherichia coli infected with bacteriophage T4-, could enhance nucleotide excision repair in human cells and initiate the removal of CPD . T4N5 production is regulated by the v+ gene of T4. For this reason, extracts from uninfected Escherichia coli showed minimal function. Interestingly, T4 mutants with a higher sensitivity to UVR did not display any enhanced enzymatic activity . Later, in the 1980s, it was found that this enzyme could be delivered to cells using liposomes, which are microscopic spheres made up of lipid bilayers that form spontaneously in water, stabilizing the compound, slowing its transit through the skin, and improving percutaneous absorption . T4N5 liposomes have proven effective in delivering repair enzymes to cultured cells .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p44
|
PMC11277730
|
sec[1]/sec[1]/sec[1]/p[0]
|
2.2.2. Mechanism of Action
| 4.53125 |
biomedical
|
Study
|
[
0.99951171875,
0.00046634674072265625,
0.00021064281463623047
] |
[
0.9873046875,
0.0006823539733886719,
0.01157379150390625,
0.0003032684326171875
] |
T4 endonuclease plays a crucial role in initiating DNA repair at sites of UV-induced CPDs, which, if left unrepaired, can lead to mutations causing non-melanoma skin cancer . The enzyme binds to non-target DNA in a salt-dependent manner and utilizes facilitated diffusion to locate its target site . Upon detecting UV-damaged DNA, cleavage occurs through two combined activities, the pyrimidine dimer–DNA glycosylase activity and the apurinic–apyrimidinic endonuclease activity . This enzyme enhances the natural DNA repair process approximately fourfold . Additionally, T4 endonuclease V promotes skin regeneration and reconstruction, preventing the breakdown of extracellular matrix components and thereby helping to combat photoaging . For example, treatment with T4N5 reduces MMP-1 induction in human skin cells similarly to photolyase treatment, resulting in decreased collagen degradation . The single polypeptide of T4N5 can substitute for the human multi-enzyme complex to initiate excision repair, effectively repairing CPDs . Clinical trials have shown that topical application of T4N5 liposomes can prevent the development of new actinic keratoses and basal cell carcinomas in patients with XP; in addition, six-month follow-ups after the discontinuation of the medication showed that, unlike retinoids, there was no rebound increase in the rate of AKs and BCCs . Nevertheless, this study was underpowered to analyze the rate of melanomas and SCCs . Additionally, a murine model indicated that T4N5 application could serve as a useful adjunct to SC, reducing the harmful local effects of UVR such as sunburn cell formation .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p45
|
PMC11277730
|
sec[1]/sec[2]/p[0]
|
2.3. 8-Oxoguanine Glycosylase
| 4.292969 |
biomedical
|
Study
|
[
0.99951171875,
0.00035953521728515625,
0.0003204345703125
] |
[
0.9287109375,
0.06695556640625,
0.003780364990234375,
0.0006380081176757812
] |
Oxidative stress resulting from the accumulation of ROS induces nucleotide oxidation and mutated forms, the most frequent being 8-oxo-7,8-dihydroguanine (8-oxoG) . Guanine is a particularly susceptible base due to its relatively low oxidation threshold, and it is estimated that up to 3000 such mutations occur in each cell daily . If 8-oxoG is not removed, it can result in the substitution of cytosine (C)-complementary to 8-oxoG-with adenine (A) during transcription, causing a G-C → A-T mutation .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277730_p46
|
PMC11277730
|
sec[1]/sec[2]/p[1]
|
2.3. 8-Oxoguanine Glycosylase
| 4.261719 |
biomedical
|
Study
|
[
0.99951171875,
0.00019872188568115234,
0.0002065896987915039
] |
[
0.990234375,
0.0003590583801269531,
0.009490966796875,
0.00011748075485229492
] |
To prevent this, evolutionarily conserved mechanisms have been extensively studied in bacterial models . These are based on the NER pathway and are collectively referred to as the “guanine oxidation” (GO) system . The three fundamental enzymes of this process (mutT, mutM, and mutY) were first described in bacterial models in 1992 , and their human equivalents have since been identified as Nudix hydrolase (NUDT1, also known as MutT human homolog 1, also named MTH1), 8-oxoG glycosylase (OGG1), and the adenine glycosylase MutY homolog (MUTYH) . This oxidative damage repair system could play a crucial role in preventing skin cancer . A reduction in OGG1 expression has been observed in basal cell carcinoma cells . Another study found that while topical administration of OGG1 did not affect UVB-induced tumor multiplicity, it did reduce tumor size and significantly decrease tumor progression .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p47
|
PMC11277730
|
sec[1]/sec[2]/p[2]
|
2.3. 8-Oxoguanine Glycosylase
| 4.070313 |
biomedical
|
Study
|
[
0.99951171875,
0.00019407272338867188,
0.0002123117446899414
] |
[
0.9990234375,
0.0001583099365234375,
0.0006380081176757812,
0.00005131959915161133
] |
To our knowledge, no study has evaluated the isolated supplementation of OGG1. However, in 2015, Emanuele et al. demonstrated the efficacy of a combination of traditional SPF50 SC with a liposome-encapsulated DNA repair enzyme complex (photolyase, endonuclease, and OGG1), and a potent antioxidant complex (carnosine, arazine, and ergothioneine). This study showed that the triple combination was more effective in reducing CPD, protein carbonylation, and the formation of 8-oxoG compared to SPF50 alone . Notably, among the three markers, the formation of 8-oxoG exhibited the most modest changes, likely due to the high specificity of both the mutation and its repair process . Similar results have been described in other publications where photolyase, endonuclease, and OGG1 have been combined .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p48
|
PMC11277730
|
sec[2]/p[0]
|
3. Antioxidants
| 3.832031 |
biomedical
|
Review
|
[
0.99755859375,
0.0014734268188476562,
0.00115203857421875
] |
[
0.013153076171875,
0.03857421875,
0.947265625,
0.001064300537109375
] |
Antioxidant agents have become a major focus of interest in dermatology, not only in the field of photoprotection but also in inflammatory and immune-mediated dermatoses. Multiple substances have been studied for their antioxidant potential, both synthetic and natural. The latter have garnered significant interest, and an increasing number of plant-derived substances have been identified as potential antioxidants applicable in dermatology .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p49
|
PMC11277730
|
sec[2]/p[1]
|
3. Antioxidants
| 3.707031 |
biomedical
|
Study
|
[
0.9990234375,
0.00010925531387329102,
0.0007452964782714844
] |
[
0.81298828125,
0.09765625,
0.08868408203125,
0.00044798851013183594
] |
More than 50 plant species contain antioxidant substances, including well-known substances like flavonoids (found in species such as Ginkgo biloba and Camellia sinensis ), vanillic acid, protocatechuic acid, caffeic acid, p-coumaric acid, ferulic acid, phenolic acids, tannins, stilbenes, carotenes, lycopene, lutein squalene, pycnogenol, and Polypodium leucotomos extract, among others ( Table 5 ) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p50
|
PMC11277730
|
sec[2]/sec[0]/p[0]
|
3.1. Vitamins C and E
| 3.988281 |
biomedical
|
Study
|
[
0.99951171875,
0.00014400482177734375,
0.0001990795135498047
] |
[
0.97265625,
0.0011434555053710938,
0.0260162353515625,
0.000164031982421875
] |
Vitamin E (α-tocopherol) and its derivatives (including γ- and δ-tocopherol) have demonstrated potent antioxidant effects at the cutaneous level by neutralizing ROS and potentially reducing UVR-induced damage . These effects have been studied in vitro and in murine models . Their capacity to reduce UVA-induced immunosuppression in murine skin models has also been described .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277730_p51
|
PMC11277730
|
sec[2]/sec[0]/p[1]
|
3.1. Vitamins C and E
| 3.919922 |
biomedical
|
Study
|
[
0.99951171875,
0.00023686885833740234,
0.0003333091735839844
] |
[
0.76171875,
0.0028228759765625,
0.235107421875,
0.00035834312438964844
] |
Since the ability of vitamin E to scavenge ROS is based on its own oxidation, its combination with other antioxidant and stabilizing agents like vitamin C and ferulic acid may reduce the oxidation of vitamin E, thereby helping to preserve its antioxidant properties . Some studies have compared the combination of vitamin E with vitamin C and ferulic acid to vitamin E and a placebo, demonstrating a greater ability of the combination to prevent skin carcinogenesis . However, it is important to consider that application of vitamin E ester derivatives without stabilizing compounds has been associated with a possible increased risk of skin cancer, although these findings have not been confirmed .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p52
|
PMC11277730
|
sec[2]/sec[0]/p[2]
|
3.1. Vitamins C and E
| 3.955078 |
biomedical
|
Study
|
[
0.99951171875,
0.00022554397583007812,
0.0002918243408203125
] |
[
0.88916015625,
0.0010309219360351562,
0.10955810546875,
0.00024008750915527344
] |
Some population studies have shown a link between the consumption of vitamins E and C and a lower incidence of skin cancer; however, given the characteristics of the studies and the their limited sample size, these results should be interpreted with caution . In human skin, the topical application of vitamins C and E has been shown to increase the MED in healthy subjects . Similarly, other studies have confirmed this increase in the MED, as well as a decrease in sunburn cells, thymine dimers, and p53 expression . A lower expression of pro-inflammatory cytokine RNA has also been confirmed .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p53
|
PMC11277730
|
sec[2]/sec[1]/sec[0]/p[0]
|
3.2.1. Biological Origin and Mechanism of Action
| 2.8125 |
biomedical
|
Other
|
[
0.99365234375,
0.0004646778106689453,
0.005901336669921875
] |
[
0.189697265625,
0.80615234375,
0.002948760986328125,
0.00104522705078125
] |
Polypodium leucotomos (PL) is a tropical fern belonging to the family Polypodiaceae . PL hydrophilic extract (PLE), obtained from the aerial parts of the plant, is rich in phenolic compounds endowed with strong antioxidant and photoprotective properties . Caffeic and ferulic acid are the most relevant .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p54
|
PMC11277730
|
sec[2]/sec[1]/sec[0]/p[1]
|
3.2.1. Biological Origin and Mechanism of Action
| 4.027344 |
biomedical
|
Study
|
[
0.99951171875,
0.0002930164337158203,
0.0003299713134765625
] |
[
0.77197265625,
0.0099639892578125,
0.217529296875,
0.0005211830139160156
] |
The effects of these phenolic constituents on cellular homeostasis have been demonstrated both in vivo and in vitro, and they include the following : Direct absorption of UV photons, preventing the formation of photoproducts; Scavenging of reactive oxygen (ROS) and nitrogen species, mitigating photo-oxidative stress; Prevention of lipid and glutathione peroxidation; Reduction of cellular proliferation; Prevention of Langerhans cell (LC) abrogation; Preservation of skin immune surveillance.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p55
|
PMC11277730
|
sec[2]/sec[1]/sec[0]/p[2]
|
3.2.1. Biological Origin and Mechanism of Action
| 3.503906 |
biomedical
|
Other
|
[
0.99853515625,
0.0004525184631347656,
0.0011310577392578125
] |
[
0.25537109375,
0.465576171875,
0.27734375,
0.0017261505126953125
] |
All of these combined limit UV-induced erythema, skin aging, and carcinogenesis . For these reasons, PLE was the first systemic photoprotective agent (SPA) with well-documented effects in humans . SPAs offer several advantages compared to classical topical SCs: ease of use, better real-life adherence, and uniform photoprotection on the total body surface .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p56
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[0]
|
3.2.2. Experimental and Clinical Evidence
| 2.820313 |
biomedical
|
Review
|
[
0.99609375,
0.0013246536254882812,
0.0025272369384765625
] |
[
0.05389404296875,
0.0301971435546875,
0.91455078125,
0.00142669677734375
] |
Prior to its widespread commercial marketing, PLE had been used for centuries in Central American folklore medicine to relieve different skin conditions . Due to its immunomodulatory properties, PLE has been tried in the management of inflammatory dermatoses, including vitiligo, psoriasis, and atopic dermatitis, with varying results . Since these are out of reach of our work, we only reviewed clinical and experimental trials on the use of PLE as an SPA ( Table 6 ).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p57
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[1]
|
3.2.2. Experimental and Clinical Evidence
| 3.984375 |
biomedical
|
Study
|
[
0.9990234375,
0.0005335807800292969,
0.0002224445343017578
] |
[
0.96044921875,
0.000652313232421875,
0.03863525390625,
0.00026035308837890625
] |
Five out of six studies were RCTs with proper sample sizes . Follow-up periods were highly variable and ranged from 2 days to 12 months . Clinical indications significantly differed between studies, from young healthy individuals (n = 3) to patients with AK (n = 2) and melasma (n = 1) . Most subjects were phototypes II or III . Both topical and systemic administrations of PLE were investigated. Oral doses fluctuated, ranging from 240 mg/day to 960 mg/day . The selected anatomical sites varied according to the characteristics of the recruited population: non-exposed (healthy individuals) or sun-exposed sites (melasma and AK) . The types of assessment were considerably diverse, including biopsies and non-invasive imaging techniques such as spectrophotometry and dermoscopy of RCM .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p58
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[2]
|
3.2.2. Experimental and Clinical Evidence
| 4.171875 |
biomedical
|
Study
|
[
0.9892578125,
0.01035308837890625,
0.0005512237548828125
] |
[
0.96875,
0.02911376953125,
0.001071929931640625,
0.0013074874877929688
] |
Gonzalez et al. conducted the first clinical trial of PLE as an SPA in humans ( Table 6 ). They assessed whether PLE could protect the human skin from UV-induced erythema in vivo. Individuals were instructed to expose the tested areas to natural solar radiation in Malaga (Andalucia, Spain, 36°45′ N, 4°25′ O) for up to 120 min in August between 11:00 a.m. and 2:00 p.m. . An increment in the mean time for eliciting erythema was detected in both non-photosensitized individuals (80 min in the topical PLE group and 90 min in the oral PLE group, p < 0.05) . Photosensitized individuals with either 5-methoxypsoralen (5-MOP) or 8-methoxypsoralen (8-MOP) and who were treated with oral PLE had increased MPDs (the minimal erythema dose required to induce a phototoxic reaction 72 h after UVA radiation): 45 vs. 18 ± 4.1 and 57.5 ± 11.2 vs. 7.5, respectively . Interestingly, MPDs could not be measured in skin sites pretreated with SPF15 SC and a 10% PLE solution, as no phototoxic reaction was elicited due to complete protection (CP). Despite their astounding outcomes and the confirmation of the antioxidant properties of PLE in vivo, their interpretation of their findings was limited because the erythematous and tanning reactions were only clinically assessed by two investigators and not by means of objective instruments such as chromatography.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277730_p59
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[3]
|
3.2.2. Experimental and Clinical Evidence
| 4.160156 |
biomedical
|
Study
|
[
0.9931640625,
0.006549835205078125,
0.00035953521728515625
] |
[
0.98974609375,
0.008819580078125,
0.0007014274597167969,
0.0005898475646972656
] |
Nevertheless, these outcomes were later confirmed in an open-label prospective trial conducted by Middelkamp et al. ( Table 6 ) . Twelve healthy young subjects with low phototypes (I–II) were recruited . Seven back sites were selected and twice exposed to 1 MED (n = 5) and 2–3 MED radiations (n = 2) . Only before the second exposure, patients were pretreated with oral PLE (7.5 mg/kg) 30, 60, 90, 120, and 180 min before UVR . Erythema was assessed 24 h later . Patients treated with PLE showed statistically significant less erythema ( p < 0.01), although the difference was lost after 3 h . This indicates that oral PLE should be readministered at least once more per day to achieve adequate sun protection during the hours with the highest UV index .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p60
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[4]
|
3.2.2. Experimental and Clinical Evidence
| 4.085938 |
biomedical
|
Study
|
[
0.99951171875,
0.0002646446228027344,
0.0001780986785888672
] |
[
0.9990234375,
0.00021266937255859375,
0.0004858970642089844,
0.00006139278411865234
] |
PLE has also been confirmed to limit UV-induced cutaneous hyperpigmentation . Gonzalez et al. reported that non-photosensitized subjects showed increased IPD (the minimal UV dose required to induce darkening pigment reaction 30–45 min after exposure) if treated with 10% PLE lotion (56 ± 16.73) and oral PLE (75 ± 17.32) when compared to the placebo (25.9 ± 10.62) and this was similar to the IPD present in SPF15 SC-treated sites (80 ± 14.14) . IPD could not be calculated in areas exposed to 25–50% PLE lotions, as they offered complete protection .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p61
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[5]
|
3.2.2. Experimental and Clinical Evidence
| 4.113281 |
biomedical
|
Study
|
[
0.99951171875,
0.0003063678741455078,
0.0003211498260498047
] |
[
0.99951171875,
0.00025463104248046875,
0.00023818016052246094,
0.00004869699478149414
] |
The delayed tanning reaction was also assessed as the MMD (minimal melanogenic dose required for a delayed hyperpigmentation 5 days after exposure) . The MMD could not be measured in areas treated with SPF15 SC or 25–50% PLE lotions, since they achieved complete protection . In non-photosensitized individuals, no statistically significant differences ( p > 0.05) were found between 10% PLE lotion (88 ± 10.95) and oral PLE (82.5 ± 25.9) when compared to the placebo (72 ± 22.8) . The authors considered that these outcomes confirmed that PLE could not appropriately filter UVR .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p62
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[6]
|
3.2.2. Experimental and Clinical Evidence
| 4.160156 |
biomedical
|
Study
|
[
0.99169921875,
0.00799560546875,
0.00039958953857421875
] |
[
0.98681640625,
0.01079559326171875,
0.00147247314453125,
0.0007176399230957031
] |
These outcomes were remarkable, as PLE could have served as an excellent photoprotective agent in the prevention of post-inflammatory hyperpigmentation in high-phototype patients. Sixteen years later, Ahmed et al. conducted the first RCT on the efficacy of oral PLE in the management of moderate-to-severe facial melasma in non-pregnant and non-lactating Hispanic women with a melanin index ≥30 ( Table 6 ) . A regimen of 240 mg/8 h for 3 months was chosen. Patients in both groups were instructed to use standard broad-spectrum SC once daily . At the 3-month follow-up visit, the melanin index measured by narrowband spectrophotometry improved in both groups (−28.8% vs. −13.8%) compared to their baseline scores, although no statistically significant differences were found between them either in severity scores (MASI, p = 0.62) or in improvement of quality of life (MELASQoL) after treatment .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p63
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[7]
|
3.2.2. Experimental and Clinical Evidence
| 4.175781 |
biomedical
|
Study
|
[
0.98828125,
0.01117706298828125,
0.0005369186401367188
] |
[
0.9775390625,
0.0183563232421875,
0.003238677978515625,
0.000980377197265625
] |
One RCT showed that PLE can reduce the incidence of new scalp AKs after two sessions of MAL-PDT (3-h incubation, λ = 635 nm, 37 J/cm 2 , 8 min, 1 week apart) . AK severity was at least moderate, since recruited patients in both groups still displayed a higher basal count (7–8), even with sizes larger than 1 cm (n = 16, 47.06%) in spite of the field cancerization treatment received 1 week before the onset of PLE exposure . Subjects were randomized to receive oral PLE (960 mg/24 h in the first month, 480 mg/24 h from the second to the six month) or a placebo . All were instructed to use SPF50+ SC twice a day during sun exposure ( Table 6 ). At the 6-month follow-up visit, those treated with oral PLE showed a similar final AK count (1 vs. 2, p = 0.409) but experienced a greater long-term clearance of AK lesions (−8 vs. −3, p = 0.04) . Apart from MAL-PDT, the authors did not specify if patients had been previously managed with field cancerization treatments .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p64
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[8]
|
3.2.2. Experimental and Clinical Evidence
| 4.195313 |
biomedical
|
Study
|
[
0.998046875,
0.0017070770263671875,
0.000255584716796875
] |
[
0.99755859375,
0.001270294189453125,
0.0011758804321289062,
0.00019824504852294922
] |
The most recent study on the use of PLE as an SPA has been published in 2023 by Pellacani et al. . This trial has several advantages that guarantee the excellent validity and extrapolation of the results . Firstly, they compared the use of PLE with SPF100 SC ad libitum, as in the real-life setting . The study had a considerably long follow-up period (12 months) and a large sample size (n = 131), which is notable compared to previous clinical trials involving AK patients . To the best of our knowledge, it is the only trial with PLE that recruited patients with a personal history of NMSC (n = 47, 35.9%) . They also counted lesions in non-head and -neck areas, which are excluded from most AK trials . Patients were randomly assigned to three groups: placebo, topical PLE gel, and topical PLE gel + oral PLE (240 mg/24 h). At the 6-month follow-up visit, subjects treated with topical PLE alone or topical + oral PLE showed a lower incidence of new AKs (1 vs. 0 vs. 10, p = 0.008) and a lower need of field-cancerization-targeted treatments (10.3% vs. 2.9% vs. 23.1%, p = 0.027) as compared to the placebo ( Table 6 ) . However, no statistically significant differences were detected in both parameters at the 12-month follow-up visit (0 vs. 0 vs. 4, p = 0.054/9.1% vs. 0% vs. 13.3%, p = 0.112). At this point, treatment with PLE only showed significant benefits consisting of less clinical hyperkeratosis (5.9% vs. 3% vs. 30%, p = 0.002) and partial normalization of honeycomb pattern with RCM (45% vs. 50% vs. 26%, p = 0.04), without improvement of the involved surface area ( p = 0.614) and the AKASI (3.3 ± 1.2 vs. 3.1 ± 1.1 vs. 3.5 ± 1.3, p = 0.427) and IGA ( p = 0.105) scores.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277730_p65
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[9]
|
3.2.2. Experimental and Clinical Evidence
| 3.78125 |
biomedical
|
Study
|
[
0.998046875,
0.001590728759765625,
0.0002808570861816406
] |
[
0.66943359375,
0.2366943359375,
0.09185791015625,
0.00188446044921875
] |
These two trials highlight the efficacy of topical and oral PLE in preventing the long-term appearance of new AK lesions, reducing the need for field-cancerization-targeted treatments . This is of the utmost importance in the clinical setting, as severely photodamaged individuals may be hesitant to undergo these therapies due to concerns about potential side effects .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p66
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[10]
|
3.2.2. Experimental and Clinical Evidence
| 4.132813 |
biomedical
|
Study
|
[
0.99951171875,
0.00027751922607421875,
0.00017702579498291016
] |
[
0.9990234375,
0.0001932382583618164,
0.0006680488586425781,
0.00006878376007080078
] |
Apart from the previously mentioned clinical findings, histological data in vivo sup-port the use of PLE as a photoprotective agent in humans . Following the UVR equivalent to 2–3 MEDs, oral PLE has been shown to significantly reduce the sunburn reaction, decrease the density of papillary mastocytes (126.4/mm 2 vs. 173.76/mm 2 , p ≤ 0.05) and sunburn cells (16.3/mm 2 vs. 22.4/mm 2 , p = 0.03), reduce the formation of CPD (CPD positive cells: 43.7 vs. 74.7, p < 0.001), and limit the mitotic proliferation of keratinocytes (Ki67+: 25.94% vs. 38.85%, p < 0.001) . Despite its efficacy in other aspects, UVA-induced damage of mitochondrial DNA does not seem to be mitigated by oral supplementation of PLE, as no statistically significant difference has been found in the rate of “common deletion” (CD) after 2–3 MED-A radiation ( p = 0.06) . However, a low sample size (n = 10) and the simultaneous use of SC ad libitum could have affected the power of this specific study .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p67
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[11]
|
3.2.2. Experimental and Clinical Evidence
| 4.078125 |
biomedical
|
Study
|
[
0.99951171875,
0.00022864341735839844,
0.00023865699768066406
] |
[
0.9990234375,
0.00016617774963378906,
0.0008134841918945312,
0.000054895877838134766
] |
Regarding the preservation of immunosurveillance, Gonzalez et al. confirmed that topical and oral PLE were the only agents which preserved the dendritic morphology of LCs when compared to placebo and SPF15+ SC. Additionally, systemic administration of PLE completely prevented the depletion of LCs after midday summer sun radiation ( Table 6 ) . Nevertheless, this outcome was not replicated by Middelkamp et al. , as no difference in LC density was detected when compared to the placebo (24.8/mm 2 vs. 18.56/mm 2 , p > 0.05).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p68
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[12]
|
3.2.2. Experimental and Clinical Evidence
| 3.824219 |
biomedical
|
Review
|
[
0.99853515625,
0.0009412765502929688,
0.0004119873046875
] |
[
0.34033203125,
0.005786895751953125,
0.6533203125,
0.0007143020629882812
] |
Notwithstanding these promising results, several biases and characteristics of the studies necessitate cautious interpretation. As only two trials compared the use of PLE with standard photoprotection, there are currently no data available on its relative efficacy compared to commonly used SCs . This is crucial in the clinical setting, as dermatologists and other physicians need, on a daily basis, to determine the most appropriate SC for each patient based on its efficacy, tolerance, safety, and expected adherence. Additionally, it would be interesting to specifically investigate whether the simultaneous use of oral PLE with other topical SCs has a synergistic effect in the prevention of AKs and skin cancer, especially in severely photodamaged or high-risk individuals.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p69
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[13]
|
3.2.2. Experimental and Clinical Evidence
| 3.445313 |
biomedical
|
Study
|
[
0.99755859375,
0.0016660690307617188,
0.0009236335754394531
] |
[
0.9580078125,
0.03411865234375,
0.00733184814453125,
0.00038313865661621094
] |
Special consideration should be given to the moderate dropout ratio (approximately 15%) detected in three of the trials, which could hint at a potentially improvable compliance in patients with longer treatment durations (3–12 months) . For these reasons, it would also be interesting to assess whether the adherence of real-life patients could be improved if the use of PLE was selectively encouraged in seasons or places with a higher UV index.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p70
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[14]
|
3.2.2. Experimental and Clinical Evidence
| 3.199219 |
biomedical
|
Study
|
[
0.99853515625,
0.0006818771362304688,
0.0007696151733398438
] |
[
0.6904296875,
0.276611328125,
0.031982421875,
0.0010118484497070312
] |
On the other hand, since immunosuppressed individuals were excluded from all trials, their outcomes cannot be extrapolated to transplanted patients, which are precisely one of the population subsets at higher risk of developing NMSC and are thus in dire need of strong and persistent photoprotective agents.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277730_p71
|
PMC11277730
|
sec[2]/sec[1]/sec[1]/p[15]
|
3.2.2. Experimental and Clinical Evidence
| 2.484375 |
biomedical
|
Study
|
[
0.9970703125,
0.0012950897216796875,
0.0017185211181640625
] |
[
0.57421875,
0.1820068359375,
0.240234375,
0.0032520294189453125
] |
Information is still lacking on the overall safety of topical and oral PLE. Only in one study was this concern explicitly addressed, although in a vague manner without specific outcomes . Indirect observations may suggest oral PLE has an adequate tolerability, as it increased the adherence to overall photoprotection habits in AK patients .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p72
|
PMC11277730
|
sec[2]/sec[2]/p[0]
|
3.3. Green Tea Polyphenols
| 2.072266 |
biomedical
|
Other
|
[
0.97314453125,
0.001750946044921875,
0.025054931640625
] |
[
0.00921630859375,
0.98828125,
0.0020580291748046875,
0.000576019287109375
] |
Tea, the second most popular beverage worldwide after water, is obtained from the fresh leaves and buds of the plant Camellia sinensis . Depending on the oxidation and polymerisation state of its polyphenolic compounds, it is commercially available in three different forms: black tea, green tea (GT), and oolong tea .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p73
|
PMC11277730
|
sec[2]/sec[2]/p[1]
|
3.3. Green Tea Polyphenols
| 3.568359 |
biomedical
|
Review
|
[
0.9990234375,
0.00030803680419921875,
0.0006546974182128906
] |
[
0.265380859375,
0.04901123046875,
0.6845703125,
0.00099945068359375
] |
Recently, botanical supplements such as GT have garnered considerable interest among researchers and consumers due to their antioxidant, photoprotective, and anti-inflammatory effects . Epidemiological studies have hinted at a link between GT consumption and a lower risk of developing cancers of the esophagus, oropharynx, stomach, bladder, liver, and urinary tract .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p74
|
PMC11277730
|
sec[2]/sec[2]/p[2]
|
3.3. Green Tea Polyphenols
| 3.132813 |
biomedical
|
Other
|
[
0.9951171875,
0.0004146099090576172,
0.004344940185546875
] |
[
0.1905517578125,
0.79931640625,
0.0095062255859375,
0.000759124755859375
] |
GT is rich in epicatechins, such as (-)-epicatechin, (-)-epicatechin-3-gallate, (-)-epigallocatechin, and (-)-epigallocatechin-3-gallate (EGCG) . These, especially EGCG, are considerably more antioxidant than theaflavins and thearubigins, the main constituents of black tea .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277730_p75
|
PMC11277730
|
sec[2]/sec[2]/p[3]
|
3.3. Green Tea Polyphenols
| 3.972656 |
biomedical
|
Study
|
[
0.99951171875,
0.0001289844512939453,
0.0001856088638305664
] |
[
0.99609375,
0.000629425048828125,
0.0031681060791015625,
0.00008994340896606445
] |
The initial evidence of the photoprotective effects of GT was reported by Wang et al. in 1991. SKH-1 hairless mice, which were topically or systemically administered GT extracts, showed a dose-dependent prolongation in the mean time for developing UVB-induced sunburn reaction, skin cancer, and immunosuppression .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p76
|
PMC11277730
|
sec[2]/sec[2]/p[4]
|
3.3. Green Tea Polyphenols
| 2.751953 |
biomedical
|
Study
|
[
0.998046875,
0.00029206275939941406,
0.0014858245849609375
] |
[
0.970703125,
0.0213775634765625,
0.00745391845703125,
0.0004029273986816406
] |
To date, three experimental trials on the photoprotective effects of green tea polyphenols (GTPs) on human skin have been published ( Table 7 ) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p77
|
PMC11277730
|
sec[2]/sec[2]/p[5]
|
3.3. Green Tea Polyphenols
| 3.998047 |
biomedical
|
Study
|
[
0.99853515625,
0.0013856887817382812,
0.00026297569274902344
] |
[
0.998046875,
0.00150299072265625,
0.00035500526428222656,
0.00016546249389648438
] |
The methodology was similar among them: GTPs were topically administered for 15–30 min on non-exposed sites (buttocks and back) before solar-simulated UVB radiation (0.5–4 MEDs) . The acute clinical and histological effects were assessed with a chromameter and biopsies 1–3 days after irradiation .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p78
|
PMC11277730
|
sec[2]/sec[2]/p[6]
|
3.3. Green Tea Polyphenols
| 4.050781 |
biomedical
|
Study
|
[
0.99951171875,
0.00017976760864257812,
0.00033402442932128906
] |
[
0.9990234375,
0.00021469593048095703,
0.0008769035339355469,
0.00004792213439941406
] |
GTPs have been shown to protect from sunburns, especially UVB-induced erythema . Katiyar et al. first showed that pretreatment with GTPs significantly reduced the appearance of erythema (−84%). This was later confirmed by Elmets et al. , who observed that GTPs acted in a dose-dependent manner. The 10% GTP solution offered almost complete protection 48 and 72 h after the initial radiation ( Table 7 ) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p79
|
PMC11277730
|
sec[2]/sec[2]/p[7]
|
3.3. Green Tea Polyphenols
| 4.167969 |
biomedical
|
Study
|
[
0.99951171875,
0.00022518634796142578,
0.00016891956329345703
] |
[
0.99853515625,
0.00023984909057617188,
0.000988006591796875,
0.00007021427154541016
] |
GTPs prevent UV-induced DNA damage and immunosuppression in vivo. Sites pretreated with GTP cream displayed a remarkably lower percentage of epidermal CPD-positive cells and less 8-OHdG 1 day after UVB radiation (4 MEDs) . This finding was later replicated by Elmets et al. Analyzing the biopsies taken 24 h after UVB radiation (2 MEDs) of sites pretreated with 1–10% GTP solution, they found less sunburn cells (1.9 ± 0.3/mm 2 vs. 5.8 ± 0.7/mm 2 , p < 0.01), a higher density of LCs (377 ± 28/mm 2 vs. 88 ± 29/mm 2 , p < 0.01), and reduced epidermal DNA damage detected through 32 P labelling .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p80
|
PMC11277730
|
sec[2]/sec[2]/p[8]
|
3.3. Green Tea Polyphenols
| 4.042969 |
biomedical
|
Study
|
[
0.99951171875,
0.00018012523651123047,
0.0002684593200683594
] |
[
0.99951171875,
0.00020945072174072266,
0.00031685829162597656,
0.000049054622650146484
] |
Camouse et al. detected, in biopsies taken 24 h after UVB radiation (2 MEDs), that GTPs partially protected against LC depletion (−35% vs. −57%, p = 0.03), although no statistically significant differences were found when compared to white tea (WT) ( p = 0.09).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p81
|
PMC11277730
|
sec[2]/sec[2]/p[9]
|
3.3. Green Tea Polyphenols
| 3.042969 |
biomedical
|
Study
|
[
0.998046875,
0.0006060600280761719,
0.0015659332275390625
] |
[
0.71728515625,
0.0152740478515625,
0.2666015625,
0.0008349418640136719
] |
Despite promising results, these three studies show remarkable limitations that require careful and thorough interpretation. Most had a low sample size (n < 10), follow-up periods were extremely short (1–3 days), and did not consider several factors (clinical indications, adherence, type of vehicle, safety) which are important in real-life skin photoprotection.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999994 |
PMC11277730_p82
|
PMC11277730
|
sec[2]/sec[2]/p[10]
|
3.3. Green Tea Polyphenols
| 2.052734 |
biomedical
|
Other
|
[
0.99609375,
0.00099945068359375,
0.00269317626953125
] |
[
0.470703125,
0.50537109375,
0.0208587646484375,
0.00289154052734375
] |
Unfortunately, the only clinical response addressed in these studies was UV-induced erythema. For this reason, nothing is known about the possible impact of GTPs on photoaging (colour, wrinkles, texture) and different clinical indications (such as AKs).
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p83
|
PMC11277730
|
sec[2]/sec[2]/p[11]
|
3.3. Green Tea Polyphenols
| 2.378906 |
biomedical
|
Study
|
[
0.998046875,
0.000507354736328125,
0.0015420913696289062
] |
[
0.85546875,
0.1395263671875,
0.0036792755126953125,
0.00106048583984375
] |
Since only healthy subjects were recruited, the effects of GTPs on patients with a personal history of cancer or moderate-to-severe photodamage or those under immunosuppression still need to be elucidated.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277730_p84
|
PMC11277730
|
sec[2]/sec[2]/p[12]
|
3.3. Green Tea Polyphenols
| 3.617188 |
biomedical
|
Review
|
[
0.99853515625,
0.000629425048828125,
0.000606536865234375
] |
[
0.1365966796875,
0.0526123046875,
0.81005859375,
0.000766754150390625
] |
Considering all of the limitations mentioned, clinical evidence of GTPs’ photoprotective effects is still limited for recommending their use in the general population. RCTs with larger sample sizes and longer follow-up periods are thus needed to discern whether GTPs prevent the development of cutaneous premalignant and malignant disorders.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p85
|
PMC11277730
|
sec[2]/sec[3]/p[0]
|
3.4. Punica granatum
| 4.058594 |
biomedical
|
Study
|
[
0.99951171875,
0.00015115737915039062,
0.00042128562927246094
] |
[
0.9970703125,
0.00025010108947753906,
0.0027256011962890625,
0.00005251169204711914
] |
An extract of Punica granatum ( Punicaceae ) seeds has been studied. An investigation conducted by Kaur and Saraf showed an improvement in facial skin mechanical (viscoelasticity) and biochemical parameters (catalase and ascorbic acid concentration) when applying an ethanolic extract of Punica granatum through nanotransfersomes. In addition, a reduction in malondialdehyde levels was also noted . These results showed the antiaging effect of the nanotransfersome-loaded cream . The investigators also compared the effect of Punica granatum through various formulations, obtaining the following order: nanotransfersomal cream > conventional cream > blank nanotransfersomal cream > base cream . The observed antiaging effect was pointed out as a feature of antioxidants such as anthocyanins, ellagic acid, and hydrolysable tannins present in the extract .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277730_p86
|
PMC11277730
|
sec[2]/sec[4]/p[0]
|
3.5. Resveratrol
| 4.09375 |
biomedical
|
Study
|
[
0.99951171875,
0.0001666545867919922,
0.00019180774688720703
] |
[
0.99609375,
0.00027871131896972656,
0.00365447998046875,
0.0000775456428527832
] |
Resveratrol is a naturally occurring polyphenolic compound with strong antioxidant properties . It is abundantly found in nuts, grapes, berries, and red wine . Jang et al. firstly reported the chemopreventive property of resveratrol in 1997. Aziz et al. studied the protective effect of resveratrol against chronic UVB exposure-mediated damages to SKH-1 hairless mouse skin . The data from this study demonstrated that topical application of resveratrol to mouse skin (both pre- and post-UVB treatment) resulted in a highly significant inhibition in tumor incidence and multiplicity as well as a delay in the onset of tumorigenesis . Another study of the same group showed that resveratrol protection against UVB-mediated damages to mouse skin is based on the apoptotic elimination of damaged cells via an inhibition of the survivin pathway .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277730_p87
|
PMC11277730
|
sec[2]/sec[5]/p[0]
|
3.6. Forskolin
| 4.222656 |
biomedical
|
Study
|
[
0.99951171875,
0.00022029876708984375,
0.0003218650817871094
] |
[
0.8984375,
0.0020084381103515625,
0.09918212890625,
0.0002980232238769531
] |
Forskolin is a naturally derived diterpenoid extracted from the roots of the Plectranthus barbatus ( Coleus forskolii ) plant that grows in Asia and that has long been traditionally used in teas and therapeutic preparations . Forskolin, which is a skin-permeable compound, directly activates adenylate cyclase to induce production of cAMP . Pharmacologic stimulation of cAMP using forskolin may protect the skin in multiple ways . Firstly, it has shown the capacity of inducing melanin production. Moreover, in the existing literature, cAMP has proven to enhance keratinocyte migration to promote wound healing and to decrease blister formation . Other studies reported that forskolin protects against oxidative stress generation by decreasing nitric oxide levels and enhancing stimulation of the cytoplasmic antioxidant enzyme copper/zinc superoxide dismutase (Cu/ZnSOD) .
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277730_p88
|
PMC11277730
|
sec[3]/p[0]
|
4. Conclusions
| 3.890625 |
biomedical
|
Review
|
[
0.98681640625,
0.005218505859375,
0.0081939697265625
] |
[
0.002185821533203125,
0.00406646728515625,
0.9931640625,
0.0005121231079101562
] |
The exploration of “active photoprotection” through the utilization of DNA-repair enzymes and naturally occurring antioxidant molecules represents a significant advancement in sun protection research. Our review underscores the importance of moving beyond conventional approaches towards interventions capable of not only preventing but also partially reversing UV-induced damage.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277730_p89
|
PMC11277730
|
sec[3]/p[1]
|
4. Conclusions
| 3.986328 |
biomedical
|
Review
|
[
0.9951171875,
0.0017185211181640625,
0.0030040740966796875
] |
[
0.01238250732421875,
0.002262115478515625,
0.98486328125,
0.0002772808074951172
] |
Through an analysis of state-of-the-art research, including clinical trials and in vivo models, it becomes evident that photolyases, Polypodium leucotomos extract, and other bioactive compounds offer multifaceted benefits in safeguarding skin health, reducing the risk of mutagenesis, carcinogenesis, and premature aging. Their synergistic effects highlight the potential for combination therapies. Continued research into their mechanisms of action, optimal formulations, and clinical efficacy is needed for confirming these findings.
|
[
"Emilio Garcia-Mouronte",
"Luis Alfonso Pérez-González",
"Jorge Naharro-Rodriguez",
"Montserrat Fernández Guarino"
] |
https://doi.org/10.3390/life14070822
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277743_p0
|
PMC11277743
|
sec[0]/p[0]
|
Case report
| 3.951172 |
clinical
|
Clinical case
|
[
0.09320068359375,
0.9033203125,
0.00334930419921875
] |
[
0.009124755859375,
0.01270294189453125,
0.004241943359375,
0.97412109375
] |
A 70-year-old active smoker without any prior surgical history nor a known family history for aortic diseases presented to the emergency department with a 2-week history of intermittent chest pain, hoarseness, and dry cough. Computed tomography (CT) angiography revealed a 13-cm TAA with left-side pleural effusion . The patient had a bovine configuration with a type II arch. The landing zone length between the left common carotid artery (LCCA) and left subclavian artery (LSA) was 13 mm measured on centerline and 18 mm on the outer, as well as 13 mm on the inner curvature. The left vertebral artery was chronically occluded. Given the risk of impending rupture and the anatomical configuration of the patient’s vessels, the patient was scheduled for an urgent TEVAR with ISLF for the LSA and a chimney for the LCCA. In this particular case, the chimney technique for LCCA was used due to the patient’s bovine arch with a large common origin of the brachiocephalic trunk and LCCA and the early takeoff of the LCCA from this common origin. The chimney technique allowed maintaining antegrade flow to both arteries without resorting to open surgery on the neck or chest. Fig 1 Preoperative three-dimensional reconstructions of 13-cm thoracic aortic aneurysm ( TAA ) that was treated with implantation of a thoracic stent graft with proximal landing with partial coverage of the left common carotid artery ( LCCA ) and the left subclavian artery ( LSA ). The LCCS was revascularized with a chimney stent graft, and the LSA with in situ laser fenestration ( ISLF ) and stent graft implantation in this fenestration.
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277743_p1
|
PMC11277743
|
sec[0]/p[1]
|
Case report
| 3.888672 |
biomedical
|
Study
|
[
0.9697265625,
0.02972412109375,
0.0005068778991699219
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[
0.67236328125,
0.300537109375,
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0.022491455078125
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The ISLF technique has been previously described by several authors. 5 , 6 , 7 Briefly, with the patient under general anesthesia, open exposure of the left brachial and left carotid arteries was performed, while the common femoral artery was accessed percutaneously bilaterally. Additionally, access to the left femoral vein for caval occlusion was obtained.
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277743_p2
|
PMC11277743
|
sec[0]/p[2]
|
Case report
| 3.904297 |
biomedical
|
Other
|
[
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[
0.215087890625,
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0.1151123046875
] |
Cook Zenith Alpha tapered (42 mm-38 mm-173 mm) endograft and COOK Zenith Alpha distal component (38 mm-38 mm-197 mm) (Cook Medical LLC) were introduced through the right femoral access and deployed under caval occlusion. Caval occlusion was performed using Coda balloon catheter (Cook Medical LLC). It was inserted into the inferior caval vein through the femoral vein and inflated before deploying the stent graft. Caval occlusion was used to decrease aortic pressure and flow, which minimized the potential downstream shift of the stent graft.
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277743_p3
|
PMC11277743
|
sec[0]/p[3]
|
Case report
| 3.935547 |
clinical
|
Clinical case
|
[
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0.8525390625,
0.0027618408203125
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[
0.0204620361328125,
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An 8-mm Advanta V12 (Atrium) was deployed in the LCCA using the chimney graft technique. Subsequently, a steerable sheet was used to access the LSA, and an ISLF was performed with a 1.7-mm Turbo-Elite Laser Catheter (Philips), with an 0.018 wire passing into the ascending aorta through the ISLF fenestration. The fenestration was ballooned up to 5 mm afterwards. After the creation of the ISLF, a 9-mm Gore Viabahn VBX Balloon Expandable Endoprosthesis (W. L. Gore & Associates) was deployed. Completion angiography revealed normal flow to the LSA and LCCA, with complete endovascular exclusion of the TAA without any visible signs of stent compression or endoleaks . The patient was discharged after 7 days with single antiplatelet therapy (ASA) and without any complications. Fig 2 Completion angiography demonstrating a fully patent left subclavian artery ( LSA ) bridge stent after in situ laser fenestration ( ISLF ) technique ( green arrowhead ).
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277743_p4
|
PMC11277743
|
sec[0]/p[4]
|
Case report
| 3.855469 |
clinical
|
Clinical case
|
[
0.0721435546875,
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[
0.01068878173828125,
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The first follow-up CT angiography 2 months postoperatively showed a significant stenosis of the LSA bridging stent graft . The patient was scheduled for a reintervention. Imaging at time of reintervention showed a fully fractured LSA stent . Successful cannulation of the LSA was performed through left brachial access, and the stent graft was realigned with a 9-mm Advanta V12 . Completion angiography showed good flow to the LSA and no visible endoleaks. The patient had uneventful recoveries after both procedures, and no spinal cord protection measures were necessary. The patient underwent a follow-up CT scan 2 months after the reintervention and had a clinic visit a month later without any signs of restenosis. Fig 3 A, Three-dimensional reconstruction of the fractured left subclavian artery ( LSA ) bridging stent ( red arrow ). B, Two-month computed tomography ( CT ) scan showing significant stenosis of the LSA bridging stent graft ( red arrow ). C, Intraoperative image of the fractured bridging stent graft ( red arrow ). Fig 4 A-C, Left subclavian artery ( LSA ) bridging stent fracture was re-lined with a 9-mm Advanta V12 ( blue arrows ).
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277743_p5
|
PMC11277743
|
sec[1]/p[0]
|
Discussion
| 4.015625 |
biomedical
|
Study
|
[
0.99951171875,
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] |
[
0.98876953125,
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0.0079193115234375,
0.0001996755599975586
] |
Stent graft fracture has been previously described as a possible source of endoleak and target vessel instability after complex aortic endovascular reconstructions with custom-made devices. 8 According to bench-testing of aortic endografts, performed by Grima et al, Dacron endografts have the most favorable results with ISLF. 6
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277743_p6
|
PMC11277743
|
sec[1]/p[1]
|
Discussion
| 3.847656 |
biomedical
|
Study
|
[
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[
0.47314453125,
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In-situ fenestration is considered an alternative endovascular option when aortic pathologies involve the supra-aortic vessels. 9 , 10 Complication rates for ISLF are considered to be relatively low, and they mostly include failure of fenestration, endoleaks (mostly type III), and dissection of target vessels. 10
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277743_p7
|
PMC11277743
|
sec[1]/p[2]
|
Discussion
| 4.199219 |
biomedical
|
Clinical case
|
[
0.84033203125,
0.1583251953125,
0.0012006759643554688
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[
0.3837890625,
0.061920166015625,
0.007541656494140625,
0.546875
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In this paper, we describe the first case of bridging stent graft fracture after ISLF during TEVAR. According to existing literature, balloon expandable stents are more rigid and straight, which makes them more susceptible to collapse and fractures when the external pressure is high. 11 , 12 The non-reinforced character of the ISLF makes the bridging stent grafts theoretically more prone to instability. One of the possible mechanics advocated is that of a direct compression due to the metal struts of the TEVAR stent graft. This could lead to a considerable mechanical stress in the region of the ISLF. A systematic analysis conducted by Prendes et al suggests the use of multifilament polyethylene terephthalate, followed by dilation with noncompliant balloons, as the most durable in vitro technique for ISLF. 5
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277743_p8
|
PMC11277743
|
sec[1]/p[3]
|
Discussion
| 3.386719 |
biomedical
|
Other
|
[
0.896484375,
0.100341796875,
0.0033473968505859375
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[
0.123291015625,
0.51171875,
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0.36328125
] |
In this particular case, the Gore Viabahn VBX Balloon Expandable Endoprosthesis configuration, consisting of individual stent rings with PTFE graft in-between, could have contributed to its instability through the ISLF.
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277743_p9
|
PMC11277743
|
sec[1]/p[4]
|
Discussion
| 3.4375 |
clinical
|
Clinical case
|
[
0.073974609375,
0.923828125,
0.00235748291015625
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[
0.0216217041015625,
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0.853515625
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Considering the unexpected complication that occurred after the ISLF during this emergent TEVAR, an individualized follow-up plan was utilized for this patient. The first CT scan was performed 2 months after the reintervention, with a yearly CT scan being planned. Any target vessel instability seen during the follow-up scan would be addressed accordingly. The open conversion (ie, a carotid-subclavian bypass or a total debranching based on the patency of the chimney to the left common carotid artery) could be considered as an option.
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277743_p10
|
PMC11277743
|
sec[2]/p[0]
|
Conclusion
| 3.914063 |
biomedical
|
Other
|
[
0.87939453125,
0.11981201171875,
0.0008177757263183594
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[
0.25732421875,
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0.01202392578125,
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ISLF is a promising technique allowing rapid customization of TEVAR stent graft for acute treatment of aortic arch pathology that requires supra-aortic vessel revascularization. The current report, however, underlines the risk for bridging stent graft instability with this new technique. Close postoperative follow-up is advocated after ISLF treatment of aortic arch pathology, with dedicated evaluation of bridging stent graft integrity with CT imaging.
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277743_p11
|
PMC11277743
|
sec[3]/p[0]
|
Disclosures
| 1.007813 |
other
|
Other
|
[
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0.990234375
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[
0.0021076202392578125,
0.99658203125,
0.0007061958312988281,
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] |
K.M reports institutional grant from and consulting for Cook Medical Inc. A.W. reports institutional grant from 10.13039/100010479 Cook Medical Inc.
|
[
"Austėja Račytė",
"Luis H. Arzola",
"Anders Wanhainen",
"Giuseppe Asciutto",
"Marek Kuzniar",
"Kevin Mani"
] |
https://doi.org/10.1016/j.jvscit.2024.101550
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277760_p0
|
PMC11277760
|
sec[0]/p[0]
|
Introduction
| 3.791016 |
biomedical
|
Study
|
[
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[
0.8359375,
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Estimation of population total or means has significance while considering the survey data. Various researchers have proposed different estimators to estimate population total and mean under different sampling designs and by considering different problems in survey data. Liu and Arslan proposed the estimators for population mean using auxiliary proportions. Ahmad et al. suggested the generalized estimators for population mean. Wang et al. Derived estimators for population mean by simple and double sampling in situations of extreme values. The calibration technique was derived by Deville and Särndal to obtain an estimator of the population total using some sample weights called calibrated weights. These weights are obtained by minimizing the distance to the Horvitz-Thompson weights ( d k = 1 π k ) with the condition on the calibration equations to be satisfied. The resulting weights will be a function of the auxiliary variables.
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277760_p1
|
PMC11277760
|
sec[0]/p[1]
|
Introduction
| 4.238281 |
biomedical
|
Study
|
[
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0.00026106834411621094,
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[
0.998046875,
0.0013513565063476562,
0.0006709098815917969,
0.00004655122756958008
] |
Suppose we wish to estimate the total of the variable of interest Y in a finite population U = { Y 1 … , Y k , … , Y N } . A probability sample s is selected from the population with sampling design p ( s ) , and y k is the value of k -th unit of the study variable Y for all k ∈ s (complete response) with a known inclusion probability π k > 0 for each element k , and the corresponding sampling design weight d k . A vector of p auxiliary variables X k T = ( x k 1 , … , x k j , … , x k p ) is the transposed vector whose elements are the values of the auxiliary variables for the k t h unit associated with y k . We observe ( y k , X k ) for the elements k ∈ s . The population total of X is t x = ∑ U X k is known and Horvitz-Thompson estimators is t ˆ x π = ∑ s d k X k . Deville and Särndal suggested the calibration estimator defined in equation (1.1) as (1.1) t ˆ y w = ∑ s w k y k where w k weights selected to satisfy ∑ s w k X k = ∑ U X k
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999999 |
PMC11277760_p2
|
PMC11277760
|
sec[0]/p[2]
|
Introduction
| 2.697266 |
other
|
Study
|
[
0.302001953125,
0.0006284713745117188,
0.697265625
] |
[
0.62890625,
0.369140625,
0.0013628005981445312,
0.0005908012390136719
] |
To minimize the distance between the design weights w k and initial weights d k , any distance function G k suggested by Deville and Särndal can be minimized under some basic conditions with constraints given in eq. (1.2) . Thus, calibration weights are linear functions of design weights and available auxiliary information. If λ = { λ 1 , … , λ j , … , λ p } Langrange multipliers vector. Then the Lanragian equation can be written as equation (1.2) . (1.2) ∑ s d k G ( w k , d k ) − λ ( ∑ s w k X k − ∑ U X k ) = 0
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277760_p3
|
PMC11277760
|
sec[0]/p[3]
|
Introduction
| 3.037109 |
biomedical
|
Study
|
[
0.72412109375,
0.0007719993591308594,
0.275390625
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[
0.5205078125,
0.478271484375,
0.0009398460388183594,
0.0004379749298095703
] |
So φ s ( λ ) = ( t x − t ˆ x π ) and λ can be found by the method of Newton's optimization discussed in equation (1.3) as: (1.3) λ v + 1 = λ v + { φ s ( λ v ) } − 1 { t x − t ˆ x π − φ s ( λ v ) } so the value of λ is λ = ( ∑ s d k q k X k X ´ k ) − 1 ( t x − t ˆ x π )
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277760_p4
|
PMC11277760
|
sec[0]/p[4]
|
Introduction
| 2.003906 |
other
|
Other
|
[
0.349609375,
0.0012006759643554688,
0.6494140625
] |
[
0.20654296875,
0.791015625,
0.0013475418090820312,
0.0008788108825683594
] |
Hence we get the calibrated weights in equation (1.4) as: (1.4) w k = d k F ( q k x k T λ ) = d k F ( u ) where u = q k x ´ k λ .
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277760_p5
|
PMC11277760
|
sec[0]/p[5]
|
Introduction
| 4.175781 |
biomedical
|
Study
|
[
0.96044921875,
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] |
[
0.96728515625,
0.0020999908447265625,
0.0305328369140625,
0.00011980533599853516
] |
The proposed calibrated weights gave the different results for different distance functions. Deville and Särndal suggested different distance functions. The chi square distance function gave the class of calibrated weights such as (1.5) w k = d k ( 1 + q k x k T λ ) where q k in equation (1.5) is the parameter that can be chosen to for improved calibrated weights and relative efficiency. Estevao and Särndal used arbitrary positive value of q k to improve the calibrated estimator. Which is the same as the generalized regression estimator (GREG) proposed by Cassel et al. and the obtained estimator can be deduced as a model-based and design-based estimator Cardot et al., 2017. . (1.6) t ˆ G R E G = ∑ s w k y k = t ˆ x π + b ˆ s ( t x − t ˆ x π ) where b ˆ s = ( ∑ s d k q k x k T x k ) − 1 ∑ s d k q k x k T y k in equation (1.6) . However, this minimum distance technique in calibration offers almost identical estimators for different distance functions. For studying the properties of calibrated estimators, Estevao and Särndal suggested calibration estimators under two-phase sampling. Shehzad and Goga and Shehzad produced the penalized calibrated estimators. Shehzad et al. and Brirah et al. proposed modified calibration methods for estimating the population total. Alam and Hanif proposed cosmetic calibration estimators. Kott , Kott , Särndal , and Kim also used the calibration technique for different conditions to derive the calibrated estimators. Park and Kim proposed model-based instrumental-variable calibrated estimators to minimize the anticipated variance in calibration estimator also used under two-phase sampling. Endogeneity is a classical problem which arises due to the correlation between the independent variables and error terms. Wooldridge suggested to use an instrumental variable Z k . Which are highly correlated with each endogenous component of X but independent of e to deal the problem of endogeneity. In survey data, the problem of endogeneity also arises when we model the data to estimate the population total. When endogeneity is present in the auxiliary variables, the calibration using endogenous auxiliary variables may produce biasedness and increase variance due to inappropriate model assumptions. This estimation problem has not been addressed in calibration estimation.
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277760_p6
|
PMC11277760
|
sec[0]/p[6]
|
Introduction
| 3.396484 |
biomedical
|
Study
|
[
0.70556640625,
0.0006418228149414062,
0.2939453125
] |
[
0.99169921875,
0.00745391845703125,
0.0006108283996582031,
0.0001323223114013672
] |
In this paper, we proposed the instrumental-variable calibration estimator using model-assisted and model-based approaches when some auxiliary variables are endogenous. The mathematical properties of the proposed estimator were verified, and the performance of the proposed estimator was evaluated using a simulation study and real data. In sections 3 , 4 , properties of proposed estimators are presented. In section 5 , the performance of the estimators has been evaluated by a simulation study and a real data example.
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277760_p7
|
PMC11277760
|
sec[1]/p[0]
|
Instrumental variables (IV) regression
| 4.128906 |
biomedical
|
Study
|
[
0.75146484375,
0.0006947517395019531,
0.2476806640625
] |
[
0.96728515625,
0.027801513671875,
0.00460052490234375,
0.00017821788787841797
] |
One of the most important assumptions of the Classical Linear Regression Model (CLRM) is that the regressors are exogenous. The violation of this assumption C o v ( X i , e i ) ≠ 0 , that is, the regressors are correlated with the error term, is called Endogeneity. The solution to this violation is the method of Instrumental-variables (IV). An estimator for which the endogenous and instrumental variables are the same is referred to as just or exact identified. An estimator for which the instrumental variables are more than the endogenous variables is called the over-identified estimator . Wright first introduced instrumental variables and used them to estimate supply and demand elasticity for butter and flaxseed. Reiersøl applied the same method in the context of errors-in-variables models in his dissertation. Let X = ( X 1 , X 2 , … , X p ) be a n n × p matrix of known regressors and suppose the following super population regression model. (2.1) Y = X β + e Y is a ( n × 1 ) vector of the dependent variable, and X is ( n × p ) non-random matrix of independent variables. Also ( X T X ) is a full-rank matrix and e is a ( n × 1 ) vector of residuals also assumed that the expected value of e is zero and e p are uncorrelated. The variance of e is constant (homoscedastic), i.e. , v a r ( e ) = σ 2 I , also assumed that X and e are independent, i.e. c o v ( X , e ) = 0 . It means that the explanatory variables are exogenous and β is ( n × 1 ) vector of unknown parameters. Then the ordinary least square (OLS) estimator is β ˆ O L S = ( X T X ) − 1 X T y
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277760_p8
|
PMC11277760
|
sec[1]/p[1]
|
Instrumental variables (IV) regression
| 3.226563 |
biomedical
|
Other
|
[
0.873046875,
0.0008640289306640625,
0.1260986328125
] |
[
0.19384765625,
0.8046875,
0.0009045600891113281,
0.0003726482391357422
] |
The ordinary least square estimator β ˆ O L S is unbiased and has minimum variance such as v a r . c o v ( β ˆ O L S ) = E [ ( y − X β ˆ O L S ) ( y − X β ˆ O L S ) T ] = σ ˆ 2 ( X T X ) − 1
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277760_p9
|
PMC11277760
|
sec[1]/p[2]
|
Instrumental variables (IV) regression
| 4.007813 |
biomedical
|
Study
|
[
0.9462890625,
0.0003287792205810547,
0.0533447265625
] |
[
0.93701171875,
0.061798095703125,
0.0012874603271484375,
0.00012874603271484375
] |
Hence β ˆ O L S is an unbiased and consistent estimator of β . On the other hand, when X and e are correlated, that is c o v ( X , e ) ≠ 0 , it means that the explanatory variable X is endogenous then the OLS estimator is biased and inconsistent. In this situation, it is good to use the estimates to predict the value of the dependent variable given the value of X . However, the estimate does not recover the causal effect of X on y . So, to estimate the parameter β consider a set of variables Z (instrumental variables) which are highly correlated with each endogenous component of X but independent of e . If the relationship between each endogenous component of x i and the instrument is defined in equation (2.2) and given as: (2.2) x i = Z i δ + u i
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277760_p10
|
PMC11277760
|
sec[1]/p[3]
|
Instrumental variables (IV) regression
| 3.361328 |
biomedical
|
Study
|
[
0.9677734375,
0.0005540847778320312,
0.031829833984375
] |
[
0.5224609375,
0.4755859375,
0.0015020370483398438,
0.00048661231994628906
] |
Then the instrumental variable (IV) estimator is (2.3) β ˆ I V = ( Z T X ) − 1 Z T y
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999997 |
PMC11277760_p11
|
PMC11277760
|
sec[1]/p[4]
|
Instrumental variables (IV) regression
| 2.574219 |
biomedical
|
Study
|
[
0.79345703125,
0.0007290840148925781,
0.205810546875
] |
[
0.74365234375,
0.25390625,
0.001850128173828125,
0.0005588531494140625
] |
Instrumental–variable estimator β ˆ I V in equation (2.3) is unbiased and consistent under certain regularity conditions.
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277760_p12
|
PMC11277760
|
sec[2]/p[0]
|
Instrumental-variable calibration approach
| 2.546875 |
biomedical
|
Other
|
[
0.87548828125,
0.0009427070617675781,
0.12347412109375
] |
[
0.271728515625,
0.72607421875,
0.0015420913696289062,
0.00060272216796875
] |
The calibration approach is usually used without assuming the super population model . The calibration technique consists of estimating the population total ( t y = ∑ i N Y i ) such as t ˆ y w = ∑ s W k y k
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999995 |
PMC11277760_p13
|
PMC11277760
|
sec[2]/p[1]
|
Instrumental-variable calibration approach
| 1.589844 |
other
|
Other
|
[
0.283447265625,
0.00220489501953125,
0.71435546875
] |
[
0.10968017578125,
0.8876953125,
0.00162506103515625,
0.0012073516845703125
] |
with constraint in equation (1.2) i.e. W s T X s = 1 u X
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999998 |
PMC11277760_p14
|
PMC11277760
|
sec[2]/p[2]
|
Instrumental-variable calibration approach
| 3.068359 |
biomedical
|
Other
|
[
0.78955078125,
0.0008769035339355469,
0.20947265625
] |
[
0.486572265625,
0.51171875,
0.0012178421020507812,
0.0005350112915039062
] |
The distance function (chi-square distance) is ( W s − d s ) T П s ( W s − d s ) where П s = d i a g ( q k − 1 d k − 1 ) . Then Lagrange multiplier is (3.1) L = ( W s − d s ) T П s ( W s − d s ) − λ ( W s T X s − 1 u X ) = 0
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.857141 |
PMC11277760_p15
|
PMC11277760
|
sec[2]/p[3]
|
Instrumental-variable calibration approach
| 3.384766 |
biomedical
|
Study
|
[
0.7705078125,
0.0005483627319335938,
0.228759765625
] |
[
0.8955078125,
0.10357666015625,
0.0006222724914550781,
0.0002294778823852539
] |
So taking derivatives of L co n c e r n i n g w in equation (3.1) we obtained the value of λ . By putting the value of λ we finally get the weights as: w s , c = d s + П s − 1 X s ( X s T П s − 1 X s ) − 1 ( 1 T u X − d s T X s ) T (3.2) w s , c = d s + ( 1 u T X − d s T X s ) ( X s T П s − 1 X s ) − 1 X s T П s − 1 hence the calibration estimator of t y using equation (3.2) becomes t ˆ y = w s , c T y s = d s T y s + ( 1 u T X − d s T X s ) ( X s T П s − 1 X s ) − 1 X s T П s − 1 y s
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
PMC11277760_p16
|
PMC11277760
|
sec[2]/p[4]
|
Instrumental-variable calibration approach
| 2.986328 |
biomedical
|
Study
|
[
0.8896484375,
0.0005054473876953125,
0.11004638671875
] |
[
0.884765625,
0.11431884765625,
0.0007371902465820312,
0.0003342628479003906
] |
We propose the instrumental-variable calibration estimator by the instrumental-variable calibration approach proposed by Ref. without using the distance minimum function approach such as t ˆ y w = W k y k where W k is the calibrated weight obtained by the instrumental-variable approach subject to W s T X s = 1 u X
|
[
"Muhammad Nadeem Intizar",
"Muhammad Ahmed Shehzad",
"Haris Khurram",
"Soofia Iftikhar",
"Aamna Khan",
"Abdul Rauf Kashif"
] |
https://doi.org/10.1016/j.heliyon.2024.e33969
|
N/A
|
https://creativecommons.org/licenses/by/4.0/
|
en
| 0.999996 |
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