ProtVar: mapping and contextualizing human missense variation.

Genomic variation can impact normal biological function in complex ways and so understanding variant effects requires a broad range of data to be coherently assimilated. Whilst the volume of human variant data and relevant annotations has increased, the corresponding increase in the breadth of participating fields, standards and versioning mean that moving between genomic, coding, protein and structure positions is increasingly complex. In turn this makes investigating variants in diverse formats and assimilating annotations from different resources challenging. ProtVar addresses these issues to facilitate the contextualization and interpretation of human missense variation with unparalleled flexibility and ease of accessibility for use by the broadest range of researchers. By precalculating all possible variants in the human proteome it offers near instantaneous mapping between all relevant data types. It also combines data and analyses from a plethora of resources to bring together genomic, protein sequence and function annotations as well as structural insights and predictions to better understand the likely effect of missense variation in humans. It is offered as an intuitive web server https://www.ebi.ac.uk/protvar where data can be explored and downloaded, and can be accessed programmatically via an API.

Rechallenge with Anti-EGFR Treatment in RAS/BRAF wt Metastatic Colorectal Cancer (mCRC) in Real Clinical Practice: Experience of the GITuD Group.

BACKGROUND: There are few third- and fourth-line therapeutic options for metastatic colorectal cancer (mCRC). In RAS/BRAF wild-type (wt) mCRC previously treated with anti-epidermal growth factor receptor (anti-EGFR) (first-line) and relapsed after a good response, retreatment with anti-EGFR (rechallenge) emerges as a therapeutic alternative. OBJECTIVE: The aim was to show the activity and safety of anti-EGFR rechallenge in RAS/BRAF wt mCRC in real-world practice. PATIENTS AND METHODS: A multicenter, retrospective, observational study (six hospitals of the Galician Group of Research in Digestive Tumors) was conducted. Adult patients with RAS/BRAF wt mCRC, evaluated by liquid biopsy, were included. They received anti-EGFR rechallenge (cetuximab, panitumumab) as monotherapy, or combined with chemotherapy, in third- or subsequent lines. Efficacy (overall response rate [ORR], disease control rate [DCR], overall survival [OS], and progression-free survival [PFS]) and safety (incidence of adverse events [AEs]) were assessed. RESULTS: Thirty-one patients were analyzed. Rechallenge (median 6 cycles [range 1-27], mainly cetuximab [80.7%]), started at a median anti-EGFR-free time of 18.4 months (1.7-37.5 months) after two (38.7%) or more (61.3%) lines of treatment; 64.5% of patients received a full dose. Median OS and PFS were 9.8 months (95% confidence interval [CI] 8.2-11.4) and 2.6 months (95% CI 1.7-3.4), respectively. ORR was 10%, and DCR was 30%. The most common AEs were diarrhea (35.5%), anemia (29%), emesis (6.4%), and neutropenia (6.4%); < 5% grade ≥ 3; 48.4% of patients reported anti-EGFR-related skin toxicity (grade > 1). Hypomagnesemia required supplements in 29% of patients. Dose delays (≥ 3 days) and reduction (≥ 20%) were reported in 11 (35.5%) and seven patients (22.6%), respectively. CONCLUSIONS: In RAS/BRAF wt mCRC patients, an anti-EGFR rechallenge provides a feasible therapeutic option with clinical benefit (survival) and a manageable safety profile.

BRCA1/BARD1 ubiquitinates PCNA in unperturbed conditions to promote continuous DNA synthesis.

Deficiencies in the BRCA1 tumor suppressor gene are the main cause of hereditary breast and ovarian cancer. BRCA1 is involved in the Homologous Recombination DNA repair pathway and, together with BARD1, forms a heterodimer with ubiquitin E3 activity. The relevance of the BRCA1/BARD1 ubiquitin E3 activity for tumor suppression and DNA repair remains controversial. Here, we observe that the BRCA1/BARD1 ubiquitin E3 activity is not required for Homologous Recombination or resistance to Olaparib. Using TULIP2 methodology, which enables the direct identification of E3-specific ubiquitination substrates, we identify substrates for BRCA1/BARD1. We find that PCNA is ubiquitinated by BRCA1/BARD1 in unperturbed conditions independently of RAD18. PCNA ubiquitination by BRCA1/BARD1 avoids the formation of ssDNA gaps during DNA replication and promotes continuous DNA synthesis. These results provide additional insight about the importance of BRCA1/BARD1 E3 activity in Homologous Recombination.

Revisiting the impact of Health at Every Size® interventions on health and cardiometabolic related outcomes: An updated systematic review with meta-analysis.

AIMS: To (1) synthesise evidence from Health at Every Size® interventions on physical and psychological health in people with overweight and obesity and (2) report between-group differences within interventions evaluating the impact of Health at Every Size® interventions on health and health-related outcomes. METHODS: Six databases (Medline, Embase, Cochrane, PsychInfo, CINAHL, and Scopus) were searched from inception until November 2022. Included studies were conducted in adults with overweight or obesity, used Health at Every Size®-based interventions compared with control interventions and reported dietary, physical and/or psychological outcomes, including diet quality, anthropometry, or quality of life. Data on between-group differences were extracted. Risk of bias was assessed using ROB2. Random-effects meta-analyses were undertaken for outcomes with at least three studies reporting the same or comparable data. RESULTS: From 128 studies identified, 19 full-text articles (10 unique studies, 6 published since 2017), were included. Meta-analysis found a significant reduction for susceptibility to hunger in Health at Every Size® intervention groups relative to controls (p = 0.005), with no significant difference (p > 0.05) between Health at Every Size® interventions and control groups for anthropometric, psychological or cardiometabolic outcomes (total cholesterol, HDL cholesterol, triglycerides, systolic or diastolic blood pressure). CONCLUSION: Health at Every Size® interventions had similar results compared with weight-based interventions on anthropometric outcomes and cardiometabolic outcomes. Health at Every Size® interventions had a significant benefit for reducing susceptibility to hunger. The decision to use a Health at Every Size®-based intervention should be personalised to individual needs. Further research in more diverse populations is required using standardised outcome measures to facilitate future meta-analyses.

NMR characterization and ligand binding site of the stem loop 2 motif (s2m) from the Delta variant of SARS-CoV-2.

The stem loop 2 motif (s2m) in SARS-CoV-2 (SCoV-2) is located in the 3'-UTR. Although s2m has been reported to display characteristics of a mobile genomic element that might lead to an evolutionary advantage, its function has remained unknown. The secondary structure of the original SCoV-2 RNA sequence (Wuhan-Hu-1) was determined by NMR in late 2020, delineating the base pairing pattern and revealing substantial differences in secondary structure compared to SARS-CoV-1 (SCoV-1). The existence of a single G29742-A29756 mismatch in the upper stem of s2m leads to its destabilization and impedes a complete NMR analysis. With Delta, a variant of concern has evolved with one mutation compared to the original sequence that replaces G29742 by U29742. We show here that this mutation results in a more defined structure at ambient temperature accompanied by a rise in melting temperature. Consequently, we were able to identify over 90 % of the relevant NMR resonances using a combination of selective RNA labeling and filtered 2D NOESY as well as 4D NMR experiments. We present a comprehensive NMR analysis of the secondary structure, (sub-) nanosecond dynamics and ribose conformation of s2m Delta based on heteronuclear 13C NOE and T1 measurements and ribose carbon chemical shift-derived canonical coordinates. We further show that the G29742U mutation in Delta has no influence on the druggability of s2m compared to the Wuhan-Hu-1 sequence. With the assignment at hand, we identify the flexible regions of s2m as primary site for small molecule binding.

[Correlation between transcutaneous bilirubinometry and serum bilirubin in newborns ≥ 35 weeks]. / Correlación entre bilirrubinometría transcutánea y bilirrubina sérica en recién nacidos ≥ 35 semanas.

Clinical control and monitoring of bilirubin in the neonatal stage are essential to avoid toxicity in the central nervous system. OBJECTIVE: to determine the correlation between transcutaneous bilirubin (TcB) and total serum bilirubin (TSB) levels in newborns ≥ 35 weeks. PATIENTS AND METHOD: observational, cross-sectional, analytical, retrospective study that included 90 neonates of gestational age ≥ 35 weeks with mucocutaneous jaundice who underwent TcB and TSB measurement simultaneously between June 1, 2022, and January 31, 2023. Both variables were compared, determining their correlation. RESULTS: the validity indicators were analyzed, obtaining 100% sensitivity and negative predictive value. The mean of TcB determinations was 14.84 mg/dl ± 2.27 and that of TSB was 13.1 mg/dl ± 2.39. The correlation obtained indicates that both variables are related, which is a direct correlation and, according to the prediction equation, there is an appropriate correlation between them. It was determined that TcB overestimated TSB in 95.56% of the determinations, and underestimated TSB in the rest (4.44%). Simultaneous measurements of TcB and TSB were different in all determinations with a mean difference of 1.72 ± 1.48. CONCLUSIONS: the non-invasive TcB method can be used as an initial screening tool for the neonatal population ≥ 35 weeks, given its adequate sensitivity and negative predictive value.

Market analysis of the presence of endocrine disrupting chemicals in cosmetic products intended for oncological patients and other vulnerable groups.

There is growing concern about the presence of endocrine disrupting chemicals (EDCs) in cosmetics. We aimed to identify the main cosmetic ingredients with suspected endocrine-disrupting properties, and analyse their presence in current marketed products. Particular attention was given to products intended for susceptible (due to physiological status) and vulnerable (due to specific pathologies) groups with a view to informing cosmetologists and related health professionals of the scientific basis and current status of any concerns. Suspected EDCs used as cosmetic ingredients, included in lists published by regulatory agencies, were documented and investigated by weight of evidence analysis based on endocrine-related toxicity studies. In total, 49 suspected EDCs were identified from a sample of over a thousand cosmetic products marketed in the European Union. Suspected EDCs were found in approximately one third of products, with a similar frequency in products intended for susceptible and vulnerable groups. Avobenzone (CAS number:70356-09-1), octisalate (CAS number: 118-60-5), and butylated hydroxytoluene (CAS number: 128-37-0) were mostly commonly identified. The presence of EDCs was particularly high for sun care cosmetic products. Our results highlight potentially significant exposure through cosmetics to substances currently studied by regulatory institutions as suspected endocrine disrupters. EDCs are not yet universally regulated, and informing health professionals and educating the population as a precaution are options to reduce individual exposure levels, especially in vulnerable and susceptible groups. Special recommendations are needed for products intended for oncological patients.

Cross-cultural adaptation, reliability and validity of the Spanish version of the long-term quality of life questionnaire.

Purpose: The aim of this study was to translate, culturally adapt, and evaluate the psychometric properties of the Spanish Long-Term Quality of Life (LTQL) questionnaire. Methods: The LTQL was initially translated into Spanish and cross-culturally adapted based on established guidelines. The Spanish LTQL was administered to patients with breast cancer who had completed their initial treatment 5 years earlier, along with other self-report measures: Quality of Life in Adult Cancer Survivors (QLACS), Hospital Anxiety and Depression Scale (HADS) and EORT-QLQ-BR23. Reliability was evaluated using internal consistency and test-retest. Convergent and known-groups validity were examined. Structural validity as determined by confirmatory factor analysis (CFA) and Rasch analyses was used to assess the unidimensionality and item-functioning of the LTQL domains. Results: Cronbach's alpha were above 0.7 in all domains. Test-retest coefficients were between 0.72 to 0.96 for LTQL domains. LTQL total score was correlated with others total scores of other measures: QLACS (r=-0.39), HADS depression (r=-0.57), HADS anxiety (-0.45) and EORTC-QLQ-BR23 (r=-0.50). CFA provided satisfactory fit indices, with RMSEA value of 0.077 and TLI and CFI values of 0.901 and 0.909, respectively. All factor loadings were higher than 0.40 and statistically significant (P<0.001). Rasch analysis showed that Somatic Concerns domain had 4 misfitting items, and Philosophical/Spiritual View of Life and social Support domains only 1 misfit item. However, unidimensionality was supported for the four domains. Conclusion: The findings support the validity and reliability of the Spanish version of LTQL questionnaire to be used in long-term cancer female survivors.

Structural and quantum chemical basis for OCP-mediated quenching of phycobilisomes.

Cyanobacteria use large antenna complexes called phycobilisomes (PBSs) for light harvesting. However, intense light triggers non-photochemical quenching, where the orange carotenoid protein (OCP) binds to PBS, dissipating excess energy as heat. The mechanism of efficiently transferring energy from phycocyanobilins in PBS to canthaxanthin in OCP remains insufficiently understood. Using cryo-electron microscopy, we unveiled the OCP-PBS complex structure at 1.6- to 2.1-angstrom resolution, showcasing its inherent flexibility. Using multiscale quantum chemistry, we disclosed the quenching mechanism. Identifying key protein residues, we clarified how canthaxanthin's transition dipole moment in its lowest-energy dark state becomes large enough for efficient energy transfer from phycocyanobilins. Our energy transfer model offers a detailed understanding of the atomic determinants of light harvesting regulation and antenna architecture in cyanobacteria.

Machine Learning-Based Prediction of Changes in the Clinical Condition of Patients With Complex Chronic Diseases: 2-Phase Pilot Prospective Single-Center Observational Study.

BACKGROUND: Functional impairment is one of the most decisive prognostic factors in patients with complex chronic diseases. A more significant functional impairment indicates that the disease is progressing, which requires implementing diagnostic and therapeutic actions that stop the exacerbation of the disease. OBJECTIVE: This study aimed to predict alterations in the clinical condition of patients with complex chronic diseases by predicting the Barthel Index (BI), to assess their clinical and functional status using an artificial intelligence model and data collected through an internet of things mobility device. METHODS: A 2-phase pilot prospective single-center observational study was designed. During both phases, patients were recruited, and a wearable activity tracker was allocated to gather physical activity data. Patients were categorized into class A (BI≤20; total dependence), class B (2060; moderate or mild dependence, or independent). Data preprocessing and machine learning techniques were used to analyze mobility data. A decision tree was used to achieve a robust and interpretable model. To assess the quality of the predictions, several metrics including the mean absolute error, median absolute error, and root mean squared error were considered. Statistical analysis was performed using SPSS and Python for the machine learning modeling. RESULTS: Overall, 90 patients with complex chronic diseases were included: 50 during phase 1 (class A: n=10; class B: n=20; and class C: n=20) and 40 during phase 2 (class B: n=20 and class C: n=20). Most patients (n=85, 94%) had a caregiver. The mean value of the BI was 58.31 (SD 24.5). Concerning mobility aids, 60% (n=52) of patients required no aids, whereas the others required walkers (n=18, 20%), wheelchairs (n=15, 17%), canes (n=4, 7%), and crutches (n=1, 1%). Regarding clinical complexity, 85% (n=76) met patient with polypathology criteria with a mean of 2.7 (SD 1.25) categories, 69% (n=61) met the frailty criteria, and 21% (n=19) met the patients with complex chronic diseases criteria. The most characteristic symptoms were dyspnea (n=73, 82%), chronic pain (n=63, 70%), asthenia (n=62, 68%), and anxiety (n=41, 46%). Polypharmacy was presented in 87% (n=78) of patients. The most important variables for predicting the BI were identified as the maximum step count during evening and morning periods and the absence of a mobility device. The model exhibited consistency in the median prediction error with a median absolute error close to 5 in the training, validation, and production-like test sets. The model accuracy for identifying the BI class was 91%, 88%, and 90% in the training, validation, and test sets, respectively. CONCLUSIONS: Using commercially available mobility recording devices makes it possible to identify different mobility patterns and relate them to functional capacity in patients with polypathology according to the BI without using clinical parameters.

Non-valvular atrial fibrillation in patients on peritoneal dialysis, prevalence, treatment and professionals involved.

Atrial fibrillation is the most frequent chronic arrhythmia in patients with chronic kidney disease. Oral anticoagulation with vitamin K antagonists and now direct oral anticoagulants have been and are the fundamental pillars for the prevention of thromboembolic events. However, there are no randomized clinical trials on the risk-benefit profile of oral anticoagulation in patients with chronic kidney disease stage 5 on peritoneal dialysis and there is little evidence in the literature in this population. The objective of our study was to know the prevalence, treatment and professionals involved in the management of atrial fibrillation in peritoneal dialysis patients. For this purpose, we performed a descriptive analysis through a survey sent to different peritoneal dialysis units in Spain. A total of 1,403 patients on peritoneal dialysis were included in the study, of whom 186 (13.2%) had non-valvular atrial fibrillation. In addition, the assessment of the scores of thromboembolic and bleeding risks for the indication of oral anticoagulation was mainly carried out by the cardiologist (60% of the units), as well as its prescription (cardiologist 47% or in consensus with the nephrologist 43%). In summary, patients on peritoneal dialysis have a remarkable prevalence of non-valvular atrial fibrillation. Patients frequently receive oral anticoagulation with vitamin K antagonists, as well as direct oral anticoagulants. The data obtained regarding the scores used for the assessment of thromboembolic and bleeding risk, treatment and involvement by Nephrology indicates that there is a need for training and involvement of the nephrologist in this pathology.

Effectiveness of interventions to improve adherence to antidepressant medication in patients with depressive disorders: a cluster randomized controlled trial.

Aim: To assess the effectiveness of two interventions of knowledge transfer and behavior modification to improve medication adherence in patients with depressive disorders. Methods: An open, multicenter, three-arm clinical trial with random allocation by cluster to usual care or to one of the two interventions. The intervention for psychiatrists (PsI) included an educational program based on a patient-centered care model. The intervention for patients and relatives (PtI) included a collaborative care program plus a reminder system that works using an already available medication reminder application. The primary outcome was patient adherence to antidepressant treatment assessed through the Sidorkiewicz Adherence Instrument. Secondary measures were depression severity, comorbid anxiety and health-related quality of life. Mixed regression models with repeated measures were used for data analysis. Results: Ten psychiatrists and 150 patients diagnosed with depressive disorder from eight Community Mental Health Units in the Canary Islands (Spain) were included. Compared with usual care, no differences in long-term adherence were observed in either group PsI or PtI. The PsI group had significantly improved depression symptoms (B = -0.39; 95%CI: -0.65, -0.12; p = 0.004) during the follow-up period. The PtI group presented improved depression symptoms (B = -0.63; 95%CI: -0.96, -0.30; p < 0.001) and mental quality of life (B = 0.08; 95%CI: 0.004, 0.15; p = 0.039) during the follow-up period. Conclusion: The assessed interventions to improve adherence in patients with depressive disorder were effective for depression symptoms and mental quality of life, even over the long term. However, no effect on antidepressant adherence was observed.

[Effectiveness of interventions to help mitigate the influence of social networks on anorexia and bulimia nervosa: a systematic review].

BACKGROUND: The study aim to analyze the impact of interventions to help mitigate the influence of social networks on anorexia and bulimia nervosa. METHODOLOGY: A systematic review was conducted using PubMed, Scopus, PsycINFO and Web of Science. The inclusion criteria were: randomized clinical trials, published between 2013 and 2023 with a score = 5 points on the Van Tulder methodological quality scale. RESULTS: Eight studies were selected, most carried out in secondary education centers or universities; one was online. The study sample consisted of 5,084 participants mainly young women and adolescents with an average age between 12 and 32 years. As for the social networks, some studies described their impact at a general level, while others focused on Instagram, Facebook, Tik-Tok, Twitter, and Snapchat. A positive correlation was found between the exposure to unrealistic beauty ideals found in social networks with greater concern and dissatisfaction with body image. All studies used instruments to assess the effectiveness of the interventions. The interventions helped reduce the influence of the media and social networks, improve self-perception and self-esteem assessments, reduce anxiety levels and internalization of the thin beauty ideal, reduce dietary restrictions, and make use of social networks differently. CONCLUSIONS: Longer-lasting interventions can improve body satisfaction (one year) and depressive symptoms (six months), especially in women. Interventions should include attention to self-criticism, self-perception, self-esteem, body image, nutritional management, and media literacy skills.

Untangling the mess of CGRP levels as a migraine biomarker: an in-depth literature review and analysis of our experimental experience.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is the most promising candidate to become the first migraine biomarker. However, literature shows clashing results and suggests a methodological source for such discrepancies. We aimed to investigate some of these methodological factors to evaluate the actual role of CGRP as biomarker. METHODS: Previous to the experimental part, we performed a literature review of articles measuring CGRP in migraine patients. Using our 399 bio-bank sera samples, we performed a series of experiments to test the validity of different ELISA kits employed, time of sample processing, long-term storage, sampling in rest or after moderate exercise. Analysis of in-house data was performed to analyse average levels of the peptide and the effect of sex and age. RESULTS: Literature review shows the high variability in terms of study design, determination methods, results and conclusions obtained by studies including CGRP determinations in migraine patients. CGRP measurements depends on the method and specific kit employed, also on the isoform detected, showing completely different ranges of concentrations. Alpha-CGRP and beta-CGRP had median with IQR levels of 37.5 (28.2-54.4) and 4.6 (2.4-6.4)pg/mL, respectively. CGRP content is preserved in serum within the 24 first hours when samples are stored at 4°C after clotting and immediate centrifugation. Storages at -80°C of more than 6 months result in a decrease in CGRP levels. Moderate exercise prior to blood extraction does not modulate the concentration of the peptide. Age positively correlates with beta-CGRP content and men have higher alpha-CGRP levels than women. CONCLUSIONS: We present valuable information for CGRP measurements in serum. ELISA kit suitability should be tested prior to the experiments. Alpha and beta-CGRP levels should be analysed separately as they can show different behaviours even within the same condition. Samples can be processed in a 24-h window if they have been kept in 4°C and should not be stored for more than 6 months at -80°C before assayed. Patients do not need to rest before the blood extraction unless they have performed a high-endurance exercise. For comparative studies, sex and age should be accounted for as these parameters can impact CGRP concentrations.

Benefits of applying hourly resolution in the assessment of the climate aptitude to manage tourist activities in arid regions.

The availability of reliable information on local climatic-tourism conditions is a growing need due to the influence it exerts on the quality of the organizational strategy of tourist destination's, and travel experience. Evaluations of the tourism potential of the climate have been carried out on a daily or monthly resolution, thus limiting the collection of detailed information that makes it possible to fine-tune tourism management and operational decision-making on an intraday scale. This research is the first case study to analyse the climatic suitability for nature tourism, using the weather types method at hourly resolution. The study applies to arid tourist destinations in Isfahan province (Iran). The detailed resolution has made it possible to identify the time slots favourable to the development of nature tourism in those periods of the year recognized as critical in the daily resolution analyses. In the same way, the hourly resolution has also identified critical bands in those periods indicated as favourable in the evaluations to daily resolution. The hourly resolution provides detailed information that can allow tourists and also tourism managers to establish intraday adaptation strategies that make it possible to develop the activity even in places with extreme climates.

Novel Oliveros-like Clade C Mammarenaviruses from Rodents in Argentina, 1990-2020.

Following an Argentine Hemorrhagic Fever (AHF) outbreak in the early 1990s, a rodent survey for Junín virus, a New World Clade B arenavirus, in endemic areas of Argentina was conducted. Since 1990, INEVH has been developing eco-epidemiological surveillance of rodents, inside and outside the Argentine Hemorrhagic Fever endemic area. Samples from rodents captured between 1993 and 2019 that were positive for Arenavirus infection underwent Sanger and unbiased, Illumina-based high-throughput sequencing, which yielded 5 complete and 88 partial Mammarenaviruses genomes. Previously, 11 genomes representing four species of New World arenavirus Clade C existed in public records. This work has generated 13 novel genomes, expanding the New World arenavirus Clade C to 24 total genomes. Additionally, two genomes exhibit sufficient genetic diversity to be considered a new species, as per ICTV guidelines (proposed name Mammarenavirus vellosense). The 13 novel genomes exhibited reassortment between the small and large segments in New World Mammarenaviruses. This work demonstrates that Clade C Mammarenavirus infections circulate broadly among Necromys species in the Argentine Hemorrhagic Fever endemic area; however, the risk for Clade C Mammarenavirus human infection is currently unknown.