Medicine

eLife assessment

This fundamental study substantially advances our understanding of the role of zinc in metabolism, specifically a newly established clinical link between mutations in the zinc transporter SLC39A5, elevated serum zinc levels, and a reduction in the risk of Type 2 Diabetes. The provided evidence is solid with state-of-the-art genetic analysis of large human cohorts followed by a comprehensive analysis of a mouse SLC39A5 knockout mutant, establishing that SLC39A5 plays a role in hepatic lipid handling through AMPK signaling, although the limited analysis of a pancreatic phenotype that has previously been described constitutes a weakness. This study will be of relevance to researchers interested in metabolism, fatty liver disease, and the biology of trace elements.

eLife assessment

This paper presents a valuable pipeline based on state-of-the-art analytical software that was used to study genetic pleiotropy between neuropsychiatric disorders. The presented evidence supporting the claims is solid, although the paper is lacking an appropriate comparison to previously published methods as well as a more detailed exploration of some of the findings. The created pipeline is made publicly available and can thus be used by researchers from diverse fields to study different combinations of diseases and traits.

eLife assessment

This study presents valuable findings that could be utilized for the identification of women at risk for preeclampsia prior to the onset of the disease. The novel aspect of this study lies in the utilization of exosomes with two different sizes. However, the data is incomplete: the patient population has not been well-defined, and the study only measured the proteins at a single time point.

eLife assessment

This study presents valuable findings on genetic risk factors for type 1 diabetes and celiac disease using a large cohort from the Environmental Determinants of Diabetes in the Young (TEDDY) study. The evidence supporting the claims of the authors is solid, although the inclusion of the genetic effect of this locus on individuals with different genetic backgrounds would have strengthened the study. The work will be of interest to population geneticists working on diabetes and celiac disease.

eLife assessment

The increased risk of fracture without decreased bone density in type 2 diabetes (T2D), the so-called "diabetic bone paradox", is mainly attributed to the limitation of assessing risk of fracture based on bone density alone in the current practice. Now we have learnt that poor bone quality and increased risk of falling due to concomitant co-morbidities partially explains it. This study this presents useful findings that clinical risk factors (though not genetic factors) related to T2D are associated with risk of fracture in T2D patients. The new approach of using Mendelian randomization to explain the relationship of two complex conditions is solid, and the discovery of 10 loci shared between T2D and fracture risk is intriguing. However, including clinically more relevant risk factors for fracture risk in T2D patients in their observational analysis would have strengthened the study.

eLife assessment

This manuscript uses genetic mouse modeling to delve deeper into a rare human disease of aging. The targeted approaches employed lend greater pathophysiologic insight and makes this paper valuable to the field art large. Additionally, the approaches used are rigorous and solid in supporting their conclusions. Some minor weaknesses were noted along with suggestions to add greater clarity.

eLife assessment

This study addresses a pertinent and important topic related to prolonged delays in cervical cancer screening and the need to maintain routine and timely screening services in a large health maintenance network in Boston. The findings provide a solid, yet incomplete roadmap for implementing simple strategies to help patients return to essential health services.

eLife assessment

The authors establish a Drosophila model to assess the severity of disease-linked alleles of Uba5 to study DEE44, a neurodevelopmental disease caused by UBA5 gene mutations. Using in vivo and in vitro experiments, this valuable study demonstrates that alleles fall into mild, intermediate, and severe classes, with convincing evidence to support their conclusion, which includes well-conserved relationships between UBA5 structure and function across humans and flies. This study establishes a model for further characterization of Uba5-related phenotypes in a powerful model system and will be useful in the future to study the functional effects of these mutations on nervous system development.

eLife assessment

This study presents a valuable deep learning-based model for predicting fracture within the next five years from just a standard distal radius and ulna scan obtained using high-resolution computed tomography images. The evidence supporting the conclusion that the model-predicted fracture prediction score can be used clinically to identify women at risk of fracture more effectively than with the current standard clinical approach is convincing. This work will be of interest to biomechanists and biomedical engineers working on osteoporosis.

eLife assessment

This study presents a valuable analysis of the effects of covariates, such as age, sex, socio-economic status, or biomarker levels, on the predictive accuracy of polygenic scores for body mass index; it also presents approaches for improving prediction accuracy by accounting for such covariates. While the analyses are solid, the study falls short of providing a cogent interpretation of key findings, which could be of great interest and utility. The work will be of interest to people using and developing methods for phenotypic prediction based on polygenic scores.

eLife assessment

This important work provides evidence regarding the impact of the COVID-19 pandemic on cervical cancer screening and precancer treatments in the USA. As there are few screening registries, the study provides solid evidence using a survey of health providers' impressions to assess whether cervical cancer screening services declined during the pandemic. The work will be of interest to public health professionals working in cancer prevention.

eLife assessment

This important manuscript, which describes the largest genetic association study to date, uses broadly compelling methods to address the genetic susceptibility to tuberculosis infection. A strength of the paper is that this multi-ancestry meta-analysis of genetic association studies than is more powerful than what has been done before. A weakness is that its main result is difficult to interpret due to the complexity of the genetic association signal.

eLife assessment

The authors have used a 'digital twin' strategy to recapitulate human pathophysiology of arrhythmia. These important findings have theoretical and practical implications beyond the single subfield of cardiovascular science for personalised medicine. The experimental design relies on state-of-the-art methodologies, with compelling results. The work will be of broad interest to colleagues in the general area of computational biology.

eLife assessment

Overall, this is an important study that characterizes human oral lichen planus via single-cell analysis. Although the work is descriptive, it can represent an important resource for future studies and highlights potentially relevant biology. However, the claims are a bit overstated and some of the analyses that lead to interpretations remain incomplete.

eLife assessment

This US study presents findings from an online survey and in-person interviews of healthcare providers in areas associated with cervical screening provision during the post-acute phase of the pandemic. The findings are valuable as they provide insights into a range of areas, from healthcare characteristics to screening barriers and HPV self-sampling. The evidence supporting the claims of the authors is solid, although the inclusion of a nationally-representative sample of healthcare providers and a greater gender/ethnicity/racial mix of interviewees would have strengthened the study. The work will be of interest to public health scientists and a cancer prevention and control audience.

eLife assessment

This important paper describes a valuable systematic review and meta-analysis of mental health problems in polycystic ovary syndrome (PCOS) that drive the excess economic burden associated with this common endocrine disorder. Interestingly, the cost of the diagnostic evaluation is only a relatively minor part of the total costs, but mental health disorders were identified as a significant component of the economic burden. These solid findings could not have been anticipated intuitively and are of considerable value for public health prioritization of PCOS.

eLife assessment

This manuscript addresses an important question, that in countries endemic for P. vivax the need to administer a primaquine (PQ) course adequate to prevent relapse in G6PD deficient persons poses a real dilemma. On one hand PQ will cause haemolysis; on the other hand, without PQ the chance of relapse is very high. As a result, out of fear of severe haemolysis, PQ has been under-used. This manuscript is convincing that regimen (1) can be used successfully to deliver within 3 weeks, under hospital conditions, the dose of PQ required to prevent P. vivax relapse.

eLife assessment

This important study tested the hypothesis that liver-derived but not serum-derived antibodies that are cross-reactive to E.coli and to host proteins can play a role in the hepatic damage found in severe alcoholic hepatitis (SAH). Using a solid methodology that includes state-of-the-art microscopy, proteome arrays, and gene ontology assays, it provides strong evidence that liver-derived IgG and IgA with cytotoxic properties and reactivity to both gut-derived E.coli and autoantigens accumulated in hepatocytes of SAH patients but not of healthy controls. The study would benefit from a broader analysis of gut microbiota proteome and further characterization of B cells infiltrating the liver tissue including their numbers/field and their origin (infiltrating versus resident cells). The work opens new avenues of understanding for the pathogenesis of severe alcoholic hepatitis and is of great interest to researchers and clinicians in the field.

eLife assessment

In this valuable study, patients homozygous for both minor frequency alleles of the APOL1 gene are shown to be at significant risk for progression into sepsis after infection. The study has enrolled a significant number of subjects and provides solid results. The study addresses to infectious diseases and critical care experts and one major weakness is the lack of inclusion of non-Black patients.

eLife assessment:

Autosomal dominant optic atrophy (DOA) in humans is associated with mutations in OPA1, a mitochondrial dynamin like GTPase. This study uses Drosophila as a model to recapitulate some aspects of the disease phenotype, and it supports and extends previously published data to provide valuable findings that have theoretical or practical implications in the field of rare retinal diseases. The approaches used are solid and allow to investigate differences between mutations that are supposed to be loss-of-function or acting as dominant negative with consequences in the optic system or in a version of DOA, in which other tissues are also affected. However, the main claims are only partially supported and additional information in the materials and methods and several figure legends is needed to complete the study.