Impact of hip abductor and adductor strength on dynamic balance and ankle biomechanics in young elite female Basketball players

This study aimed to evaluate, in an isolated and relative manner, hip abductor (ABD) and adductor (AD) strength and to study the extent to which these factors are related to balance and ankle dorsiflexion mobility in young elite female basketball players. Sixty trainee-level elite female basketball players (13-18 years old), who voluntarily agreed to participate in the study, were divided into three subgroups based on competition age divisions (U14, U16, U18). Isometric hip ABD and AD strength in each leg was evaluated using the ForceFrame Strength Testing System, also calculating the strength ratio and imbalance between legs. Y Balance Test (YBT) and ankle dorsiflexion mobility were also assessed. ANOVA was used for between-group differences analysis. Likewise, the impact of hip strength on balance and ankle mobility was analyzed using Pearson's correlation coefficient. A linear regression model for dependent variables was created with all variables that exhibited significant correlations. A between-group comparison analysis for the three competition age subgroups (U14, U16, U18) revealed non-significant differences (p > 0.005) for the hip strength variables except for hip ABD strength. The correlation study showed low-moderate effect sizes for hip ABD (in both the contralateral and homolateral limb) and AD strength (only the homolateral limb) with YBT and ankle dorsiflexion. However, when performing a regression model, only right hip ABD significantly predicted right limb YBT scores (β = 0.592, p = 0.048). The present study indicated that, although both hip ABD and AD strength correlate with balance and ankle mobility with low-moderate effect sizes, only hip ABD strength was found to significantly predict YBT scores. Therefore, the potential role of hip ABD strength in particular, but also hip AD strength, for monitoring and enhancing balance and ankle mobility outcomes, should be taken into consideration when designing and implementing preventive strategies for lower-limb injuries

Using fire to enhance rewilding when agricultural policies fail

Rewilding has been proposed as an opportunity for biodiversity conservation in abandoned landscapes. However, rewilding is challenged by the increasing fire risk associated with more flammable landscapes, and the loss of open-habitat specialist species. Contrastingly, supporting High Nature Value farmlands (HNVf) has been also highlighted as a valuable option, but the effective implementation of agricultural policies often fails leading to uncertain scenarios wherein the effects of wildfire management remain largely unexplored. Herein, we simulated fire-landscape dynamics to evaluate howfire suppression scenarios affect fire regime and biodiversity (102 species of vertebrates) under rewilding and HNVf policies in the future (2050), in a transnational biosphere reserve (Gerês-Xurés Mountains, Portugal-Spain). Rewilding and HNVf scenarios were modulated by three different levels of fire suppression effectiveness. Then, we quantified scenario effects on fire regime (burned and suppressed areas) and biodiversity (habitat suitability change for 2050). Simulations confirm HNVf as a longterm opportunity for fire suppression (up to 30,000 ha of additional suppressed areas between 2031 and 2050 in comparison to rewilding scenario) and for conservation (benefiting around 60% of species). Rewilding benefits some species (20%), including critically endangered, vulnerable and endemic taxa, while several species (33%) also profit from open habitats created by fire. Although HNVf remains the best scenario, rewilding reinforced by low fire suppression management may provide a nature-based solution when societal support through agricultural policies failsinfo:eu-repo/semantics/acceptedVersio

Titin domains with reduced core hydrophobicity cause dilated cardiomyopathy.

The underlying genetic defect in most cases of dilated cardiomyopathy (DCM), a common inherited heart disease, remains unknown. Intriguingly, many patients carry single missense variants of uncertain pathogenicity targeting the giant protein titin, a fundamental sarcomere component. To explore the deleterious potential of these variants, we first solved the wild-type and mutant crystal structures of I21, the titin domain targeted by pathogenic variant p.C3575S. Although both structures are remarkably similar, the reduced hydrophobicity of deeply buried position 3575 strongly destabilizes the mutant domain, a scenario supported by molecular dynamics simulations and by biochemical assays that show no disulfide involving C3575. Prompted by these observations, we have found that thousands of similar hydrophobicity-reducing variants associate specifically with DCM. Hence, our results imply that titin domain destabilization causes DCM, a conceptual framework that not only informs pathogenicity assessment of gene variants but also points to therapeutic strategies counterbalancing protein destabilization.S

A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families

Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Ethnic group inequalities in coverage with reproductive, maternal and child health interventions:cross-sectional analyses of national surveys in 16 Latin American and Caribbean countries

Background Latin American and Caribbean populations include three main ethnic groups: indigenous people, people of African descent, and people of European descent. We investigated ethnic inequalities among these groups in population coverage with reproductive, maternal, newborn, and child health interventions. Methods We analysed 16 standardised, nationally representative surveys carried out from 2004 to 2015 in Latin America and the Caribbean that provided information on ethnicity or a proxy indicator (household language or skin colour) and on coverage of reproductive, maternal, newborn, and child health interventions. We selected four outcomes: coverage with modern contraception, antenatal care coverage (defined as four or more antenatal visits), and skilled attendants at birth for women aged 15-49 years; and coverage with three doses of diphtheria-pertussis-tetanus (DPT3) vaccine among children aged 12-23 months. We classified women and children as indigenous, of African descent, or other ancestry (reference group) on the basis of their self-reported ethnicity or language. Mediating variables included wealth quintiles (based on household asset indices), woman's education, and urban-rural residence. We calculated crude and adjusted coverage ratios using Poisson regression. Findings Ethnic gaps in coverage varied substantially from country to country. In most countries, coverage with modern contraception (median coverage ratio 0.82, IQR 0.66-0.92), antenatal care (0.86, 0.75-0.94), and skilled birth attendants (0.75, 0.68-0.92) was lower among indigenous women than in the reference group. Only three countries (Nicaragua, Panama, and Paraguay) showed significant gaps in DPT3 coverage between the indigenous and the reference groups. The differences were attenuated but persisted after adjustment for wealth, education, and residence. Women and children of African descent showed similar coverage to the reference group in most countries. Interpretation The lower coverage levels for indigenous women are pervasive, and cannot be explained solely by differences in wealth, education, or residence. Interventions delivered at community level-such as vaccines-show less inequality than those requiring access to services, such as birth attendance. Regular monitoring of ethnic inequalities is essential to evaluate existing initiatives aimed at the inclusion of minorities and to plan effective multisectoral policies and programmes.Entidad financiadora: Bill & Melinda Gates Foundation; Wellcome Trus

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.NovartisEli Lilly and CompanyAstraZenecaAbbViePfizer UKCelgeneEisaiGenentechMerck Sharp and DohmeRocheCancer Research UKGovernment of CanadaArray BioPharmaGenome CanadaNational Institutes of HealthEuropean CommissionMinistère de l'Économie, de l’Innovation et des Exportations du QuébecSeventh Framework ProgrammeCanadian Institutes of Health Researc