Head and neck squamous cell carcinoma (HNSCC) includes diverse cancers arising in the oral cavity, oropharynx, and larynx, with the main risk factors being environmental exposures such as tobacco, alcohol, and human papillomavirus (HPV) infection. The genetic factors contributing to susceptibility across different populations and tumour subsites remain incompletely understood. Here we show, through a genome-wide association and fine mapping study of over 19,000 HNSCC cases and 38,000 controls from multiple ancestries, 18 genetic risk variants and 11 signals from fine mapping of the human leukocyte antigen (HLA) region, all previously unreported. rs78378222, a regulatory variant for TP53 is associated with a 40% reduction in overall HNSCC risk. We also identify gene-environment interactions, with BRCA2 and ADH1B variants showing effects modified by smoking and alcohol use. Subsite-specific analysis of the HLA region reveals distinct immune-related associations across HPV-positive and HPV-negative tumours. These findings refine the genetic architecture of HNSCC and highlight mechanisms linking inherited variation, immunity, and environmental exposures.

• MeSH
• Alcohol Dehydrogenase genetics   MeSH
• Genome-Wide Association Study MeSH
• Squamous Cell Carcinoma of Head and Neck * genetics   MeSH
• Genetic Predisposition to Disease MeSH
• HLA Antigens genetics   MeSH
• Papillomavirus Infections genetics   complications   MeSH
• Gene-Environment Interaction MeSH
• Polymorphism, Single Nucleotide MeSH
• Smoking adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Tumor Suppressor Protein p53 genetics   MeSH
• Head and Neck Neoplasms * genetics   MeSH
• Alcohol Drinking MeSH
• BRCA2 Protein genetics   MeSH
• Risk Factors MeSH
• Carcinoma, Squamous Cell * genetics   MeSH
• Case-Control Studies MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• ADH1B protein, human MeSH Browser
• Alcohol Dehydrogenase MeSH
• BRCA2 protein, human MeSH Browser
• HLA Antigens MeSH
• Tumor Suppressor Protein p53 MeSH
• BRCA2 Protein MeSH
• TP53 protein, human MeSH Browser

The biogenesis of mitochondria relies on the import of hundreds of different precursor proteins from the cytosol. Most of these proteins are synthesized with N-terminal presequences which serve as mitochondrial targeting signals. Presequences consistently form amphipathic helices, but they considerably differ with respect to their primary structure and length. Here we show that presequences can be classified into seven different groups based on their specific features. Using a test set of different presequences, we observed that group A presequences endow precursor proteins with improved in vitro import characteristics. We developed IQ-Compete (for Import and de-Quenching Competition assay), a novel assay based on fluorescence de-quenching, to monitor the import efficiencies of mitochondrial precursors in vivo. With this assay, we confirmed the increased import competence of group A presequences. Using mass spectrometry, we found that the presequence of the group A protein Oxa1 specifically recruits the tetratricopeptide repeat (TPR)-containing protein TOMM34 to the cytosolic precursor protein. TOMM34, and the structurally related yeast co-chaperone Cns1, apparently serve as presequence-specific targeting factors which increases the import efficiency of a specific subset of mitochondrial precursor proteins. Our results suggest that presequences contain a protein-specific priority code that encrypts the targeting mechanism of individual mitochondrial precursor proteins.

• MeSH
• Nuclear Proteins MeSH
• Mitochondrial Precursor Protein Import Complex Proteins MeSH
• Mitochondrial Proteins * metabolism   genetics   MeSH
• Mitochondria * metabolism   MeSH
• Protein Precursors metabolism   MeSH
• Electron Transport Complex IV MeSH
• Saccharomyces cerevisiae Proteins * metabolism   genetics   MeSH
• Saccharomyces cerevisiae metabolism   MeSH
• Protein Transport MeSH
• Mitochondrial Membrane Transport Proteins metabolism   MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Nuclear Proteins MeSH
• Mitochondrial Precursor Protein Import Complex Proteins MeSH
• Mitochondrial Proteins * MeSH
• OXA1 protein MeSH Browser
• Protein Precursors MeSH
• Electron Transport Complex IV MeSH
• Saccharomyces cerevisiae Proteins * MeSH
• Mitochondrial Membrane Transport Proteins MeSH

The influence of surgical volume on partial nephrectomy (PN) outcomes is a subject of debate. The European Association of Urology (EAU) renal cell carcinoma (RCC) guideline panel performed a protocol-driven systematic review of the association between hospital volume (HV) and oncological, functional, and complication outcomes following PN for RCC. The intervention was PN performed in a higher-volume hospital (defined according to the number of procedures per unit time) and the comparator was PN performed in a lower-volume hospital. Ten studies involving a total of 106 569 patients were included in the review. Higher HV was associated with lower complication rates, shorter length of stay, lower positive surgical margin rates, and lower transfusion rates. For six studies, multivariable analyses showed that low HV was an independent risk factor for inpatient complications, PSM presence, longer LOS, and failure to achieve a trifecta of no complications, warm ischemia time <25 min, and negative surgical margins. Most studies were judged to have high risk of bias. The available evidence suggests a potential association between higher HV and better PN outcomes in RCC. The EAU RCC guidelines panel encourages the development and rigorous evaluation of indicators of surgery quality in RCC to better inform the designation of high-quality centers within models of centralized care.

• Keywords
• Evidence synthesis, High-volume center, Hospital volume, Learning curve, Partial nephrectomy, Referral center, Renal cell cancer, Systematic review,
• MeSH
• Hospitals, Low-Volume * statistics & numerical data   MeSH
• Length of Stay MeSH
• Carcinoma, Renal Cell * surgery   MeSH
• Humans MeSH
• Kidney Neoplasms * surgery   MeSH
• Nephrectomy * methods   standards   adverse effects   MeSH
• Postoperative Complications epidemiology   MeSH
• Practice Guidelines as Topic MeSH
• Hospitals, High-Volume * statistics & numerical data   MeSH
• Urology standards   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Systematic Review MeSH
• Geographicals
• Europe MeSH

Science is crucial for evidence-based decision-making. Public trust in scientists can help decision makers act on the basis of the best available evidence, especially during crises. However, in recent years the epistemic authority of science has been challenged, causing concerns about low public trust in scientists. We interrogated these concerns with a preregistered 68-country survey of 71,922 respondents and found that in most countries, most people trust scientists and agree that scientists should engage more in society and policymaking. We found variations between and within countries, which we explain with individual- and country-level variables, including political orientation. While there is no widespread lack of trust in scientists, we cannot discount the concern that lack of trust in scientists by even a small minority may affect considerations of scientific evidence in policymaking. These findings have implications for scientists and policymakers seeking to maintain and increase trust in scientists.

• MeSH
• Adult MeSH
• Trust * MeSH
• Middle Aged MeSH
• Humans MeSH
• Politics MeSH
• Decision Making MeSH
• Science * MeSH
• Public Opinion * MeSH
• Policy Making * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Although variation in effect sizes and predicted values among studies of similar phenomena is inevitable, such variation far exceeds what might be produced by sampling error alone. One possible explanation for variation among results is differences among researchers in the decisions they make regarding statistical analyses. A growing array of studies has explored this analytical variability in different fields and has found substantial variability among results despite analysts having the same data and research question. Many of these studies have been in the social sciences, but one small "many analyst" study found similar variability in ecology. We expanded the scope of this prior work by implementing a large-scale empirical exploration of the variation in effect sizes and model predictions generated by the analytical decisions of different researchers in ecology and evolutionary biology. We used two unpublished datasets, one from evolutionary ecology (blue tit, Cyanistes caeruleus, to compare sibling number and nestling growth) and one from conservation ecology (Eucalyptus, to compare grass cover and tree seedling recruitment). The project leaders recruited 174 analyst teams, comprising 246 analysts, to investigate the answers to prespecified research questions. Analyses conducted by these teams yielded 141 usable effects (compatible with our meta-analyses and with all necessary information provided) for the blue tit dataset, and 85 usable effects for the Eucalyptus dataset. We found substantial heterogeneity among results for both datasets, although the patterns of variation differed between them. For the blue tit analyses, the average effect was convincingly negative, with less growth for nestlings living with more siblings, but there was near continuous variation in effect size from large negative effects to effects near zero, and even effects crossing the traditional threshold of statistical significance in the opposite direction. In contrast, the average relationship between grass cover and Eucalyptus seedling number was only slightly negative and not convincingly different from zero, and most effects ranged from weakly negative to weakly positive, with about a third of effects crossing the traditional threshold of significance in one direction or the other. However, there were also several striking outliers in the Eucalyptus dataset, with effects far from zero. For both datasets, we found substantial variation in the variable selection and random effects structures among analyses, as well as in the ratings of the analytical methods by peer reviewers, but we found no strong relationship between any of these and deviation from the meta-analytic mean. In other words, analyses with results that were far from the mean were no more or less likely to have dissimilar variable sets, use random effects in their models, or receive poor peer reviews than those analyses that found results that were close to the mean. The existence of substantial variability among analysis outcomes raises important questions about how ecologists and evolutionary biologists should interpret published results, and how they should conduct analyses in the future.

• Keywords
• Analytical heterogeneity, Many-analyst, Metascience, Replication crisis, Reproducibility,
• MeSH
• Biological Evolution * MeSH
• Ecology * methods   MeSH
• Eucalyptus growth & development   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Science is integral to society because it can inform individual, government, corporate, and civil society decision-making on issues such as public health, new technologies or climate change. Yet, public distrust and populist sentiment challenge the relationship between science and society. To help researchers analyse the science-society nexus across different geographical and cultural contexts, we undertook a cross-sectional population survey resulting in a dataset of 71,922 participants in 68 countries. The data were collected between November 2022 and August 2023 as part of the global Many Labs study "Trust in Science and Science-Related Populism" (TISP). The questionnaire contained comprehensive measures for individuals' trust in scientists, science-related populist attitudes, perceptions of the role of science in society, science media use and communication behaviour, attitudes to climate change and support for environmental policies, personality traits, political and religious views and demographic characteristics. Here, we describe the dataset, survey materials and psychometric properties of key variables. We encourage researchers to use this unique dataset for global comparative analyses on public perceptions of science and its role in society and policy-making.

• MeSH
• Trust MeSH
• Climate Change * MeSH
• Communication * MeSH
• Humans MeSH
• Attitude * MeSH
• Cross-Sectional Studies MeSH
• Surveys and Questionnaires MeSH
• Science * MeSH
• Public Opinion * MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Dataset MeSH

T-cell lymphomas (TCLs) are a rare and heterogeneous subgroup of non-Hodgkin lymphomas (NHLs), forming only 10 % of all NHL cases in Western countries. Resulting from their low incidence and heterogeneity, the current treatment outcome is generally unfavorable, with limited availability of novel therapeutic approaches. Therefore, the recent success of immune checkpoint inhibitors (ICIs) in cancer treatment motivated their clinical investigation in TCLs as well. Multiple studies showed promising results; however, cases of TCL hyperprogression following ICI treatment and secondary T-cell-derived malignancies associated with ICI treatment of other cancer types were also reported. In our review, we first briefly summarize classification of T-cell-derived malignancies, general anti-tumor immune response, immune evasion, and immune checkpoint signaling. Next, we provide an overview of immune checkpoint molecule deregulation in TCLs, summarize available studies of ICIs in TCLs, and review the above-mentioned safety concerns associa-ted with ICI treatment and T-cell-derived malignancies. Despite initial promising results, further studies are necessary to define the most suitable clinical applications and ICI therapeutic combinations with other novel treatment approaches within TCL treatment. ICIs, and their combinations, might hopefully bring the long awaited improvement for the treatment of T-cell-derived malignancies.

• Keywords
• ALCL, CTLA-4, ENKTL, LAG-3, MF, OX40/OX40L, PD-1, PD-L1, PTCL, SS, Sézary syndrome, T-cell lymphoma, T-cell-derived malignancies, TIGIT, TIM-3, anaplastic large cell lymphoma, anti-CTLA-4, anti-PD-1, anti-PD-L1, atezolizumab, avelumab, durvalumab, extranodal NK/T-cell lymphoma, geptanolimab, immune checkpoint inhibitors, immune checkpoints, ipilimumab, mycosis fungoides, nivolumab, pembrolizumab, peripheral T-cell lymphoma, sintilimab, toripalimab,
• MeSH
• Immune Checkpoint Inhibitors * therapeutic use   MeSH
• Humans MeSH
• Lymphoma, T-Cell * drug therapy   immunology   MeSH
• Immune Checkpoint Proteins metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Immune Checkpoint Inhibitors * MeSH
• Immune Checkpoint Proteins MeSH

BACKGROUND AND AIMS: Risk stratification of sudden cardiac death after myocardial infarction and prevention by defibrillator rely on left ventricular ejection fraction (LVEF). Improved risk stratification across the whole LVEF range is required for decision-making on defibrillator implantation. METHODS: The analysis pooled 20 data sets with 140 204 post-myocardial infarction patients containing information on demographics, medical history, clinical characteristics, biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging. Separate analyses were performed in patients (i) carrying a primary prevention cardioverter-defibrillator with LVEF ≤ 35% [implantable cardioverter-defibrillator (ICD) patients], (ii) without cardioverter-defibrillator with LVEF ≤ 35% (non-ICD patients ≤ 35%), and (iii) without cardioverter-defibrillator with LVEF > 35% (non-ICD patients >35%). Primary outcome was sudden cardiac death or, in defibrillator carriers, appropriate defibrillator therapy. Using a competing risk framework and systematic internal-external cross-validation, a model using LVEF only, a multivariable flexible parametric survival model, and a multivariable random forest survival model were developed and externally validated. Predictive performance was assessed by random effect meta-analysis. RESULTS: There were 1326 primary outcomes in 7543 ICD patients, 1193 in 25 058 non-ICD patients ≤35%, and 1567 in 107 603 non-ICD patients >35% during mean follow-up of 30.0, 46.5, and 57.6 months, respectively. In these three subgroups, LVEF poorly predicted sudden cardiac death (c-statistics between 0.50 and 0.56). Considering additional parameters did not improve calibration and discrimination, and model generalizability was poor. CONCLUSIONS: More accurate risk stratification for sudden cardiac death and identification of low-risk individuals with severely reduced LVEF or of high-risk individuals with preserved LVEF was not feasible, neither using LVEF nor using other predictors.

• Keywords
• Implantable cardioverter-defibrillator, Myocardial infarction, Primary prevention, Sudden cardiac death,
• MeSH
• Defibrillators, Implantable * MeSH
• Electrocardiography MeSH
• Risk Assessment methods   MeSH
• Myocardial Infarction * mortality   complications   MeSH
• Humans MeSH
• Death, Sudden, Cardiac * prevention & control   epidemiology   etiology   MeSH
• Stroke Volume * physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

• Publication type
• Published Erratum MeSH

A genomic database of all Earth's eukaryotic species could contribute to many scientific discoveries; however, only a tiny fraction of species have genomic information available. In 2018, scientists across the world united under the Earth BioGenome Project (EBP), aiming to produce a database of high-quality reference genomes containing all ~1.5 million recognized eukaryotic species. As the European node of the EBP, the European Reference Genome Atlas (ERGA) sought to implement a new decentralised, equitable and inclusive model for producing reference genomes. For this, ERGA launched a Pilot Project establishing the first distributed reference genome production infrastructure and testing it on 98 eukaryotic species from 33 European countries. Here we outline the infrastructure and explore its effectiveness for scaling high-quality reference genome production, whilst considering equity and inclusion. The outcomes and lessons learned provide a solid foundation for ERGA while offering key learnings to other transnational, national genomic resource projects and the EBP.

• Publication type
• Journal Article MeSH