Featured
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| Open AccessAberrant dynamics of cognitive control and motor circuits predict distinct restricted and repetitive behaviors in children with autism
Restricted and repetitive behaviors (RRBs) are a core clinical feature of autism, yet the brain basis of RRBs is unknown. Here, the authors demonstrate that aberrant cognitive control and motor circuit dynamics differentially predict three distinct symptom clusters that define RRBs.
- Kaustubh Supekar
- , Srikanth Ryali
- & Vinod Menon
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Article
| Open AccessMOGONET integrates multi-omics data using graph convolutional networks allowing patient classification and biomarker identification
Our understanding of human disease can be improved by integrating the abundance of high throughput biomedical data. Here, the authors use deep learning methods successfully used on images to integrate various types of omics data to improve patient classification and identify disease biomarkers.
- Tongxin Wang
- , Wei Shao
- & Kun Huang
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Article
| Open AccessA multicentre validation study of the diagnostic value of plasma neurofilament light
Cerebrospinal fluid neurofilament light (NfL) is a biomarker for neurodegeneration that can also be assessed in blood. Here the authors show in a validation study the potential for plasma NfL as a biomarker for several neurodegenerative diseases.
- Nicholas J. Ashton
- , Shorena Janelidze
- & Oskar Hansson
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| Open AccessSARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care
Here the authors use RT-qPCR and mass spectrometry to analyze longitudinal blood samples from intensive care unit (ICU) COVID-19 patients and controls. They find that viral RNA and pentraxin-3 predict 28-day ICU mortality and that galectin-3-binding protein is an interaction partner of SARS-CoV-2 spike glycoprotein with antiviral properties.
- Clemens Gutmann
- , Kaloyan Takov
- & Manuel Mayr
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Article
| Open AccessOPG/TRAIL ratio as a predictive biomarker of mortality in patients with type A acute aortic dissection
Despite many therapeutic improvements, mortality risk in patients with type A acute aortic dissection remains high. Here the authors construct a biomarker-guided risk stratification tool to predict death, which could potentially contribute to treatment decision-making and improvement of the prognosis.
- Jie Lu
- , Ping Li
- & Yulin Li
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Article
| Open AccessImaging-based spectrometer-less optofluidic biosensors based on dielectric metasurfaces for detecting extracellular vesicles
The authors engineer a type of bound states in the continuum in diatomic dielectric metasurfaces, allowing for high-quality resonances with accessible enhanced fields. Metasurface microarrays are integrated with microfluidics on an imaging platform for real-time detection of biosamples, based on reconstructing spectral shift information.
- Yasaman Jahani
- , Eduardo R. Arvelo
- & Hatice Altug
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Article
| Open AccessMultimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden
Liquid biopsies enable minimally invasive applications for diagnosis and treatment monitoring. Here the authors analyse fragmentation patterns of circulating tumour DNA on multiple levels and develop a bioinformatic tool, LIQUORICE, to accurately detect and classify paediatric cancers with low mutational burden.
- Peter Peneder
- , Adrian M. Stütz
- & Eleni M. Tomazou
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Article
| Open AccessIdentification of microbial markers across populations in early detection of colorectal cancer
The gut microbiome plays an important role in colorectal carcinogenesis and predictive microbiome signatures have been proposed for colorectal cancer (CRC) diagnosis. Here the authors perform a meta-analysis of 16S rRNA-based profiles to identify microbial markers able to discriminate patients with adenoma from control and CRC, building a model that can be applied for the early detection of CRC.
- Yuanqi Wu
- , Na Jiao
- & Lixin Zhu
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Article
| Open AccessDeep learning predicts cardiovascular disease risks from lung cancer screening low dose computed tomography
Low dose computed tomography (LDCT) for lung cancer screening offers an opportunity for simultaneous CVD risk estimation in at-risk patients. Here, the authors develop a deep learning model to perform this task, showing human-level performance.
- Hanqing Chao
- , Hongming Shan
- & Pingkun Yan
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Article
| Open AccessGene-level metagenomic architectures across diseases yield high-resolution microbiome diagnostic indicators
Here, combing the massive gene-universe of the gut microbiome to identify strain-specific, cross-disease, associations across seven human diseases, the authors introduce the concept of microbiome architecture, defined as the complete set of positive and negative associations between microbial genes and human host disease, highlighting microbiome architectures as potential diagnostic indicators.
- Braden T. Tierney
- , Yingxuan Tan
- & Chirag J. Patel
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Article
| Open AccessA machine learning model for identifying patients at risk for wild-type transthyretin amyloid cardiomyopathy
Transthyretin amyloid cardiomyopathy is a treatable but often unrecognized cause of heart failure. We derived and validated a machine learning model based on medical diagnostic codes that identifies heart failure patients at risk for wild-type transthyretin amyloid cardiomyopathy.
- Ahsan Huda
- , Adam Castaño
- & Sanjiv J. Shah
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Article
| Open AccessTaxonomic signatures of cause-specific mortality risk in human gut microbiome
Gut microbiome composition has a role in health and disease. Here the authors show that microbiome signatures related to the Enterobacteriaceae family are associated with cause-specific mortality risk in a well phenotyped Finish population over a 15-year follow-up.
- Aaro Salosensaari
- , Ville Laitinen
- & Teemu Niiranen
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Article
| Open AccessComprehensive cell type decomposition of circulating cell-free DNA with CelFiE
Tissue damage and turnover lead to the release of DNA in the blood and can be used to monitor changes in tissue state. Here, the authors developed a tool to accurately estimate the proportion of cell types contributing to cell-free DNA in the blood, with an application to pregnant women and ALS patients.
- Christa Caggiano
- , Barbara Celona
- & Noah Zaitlen
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Article
| Open AccessGenetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
Plasma levels of liver enzymes provide insights into hepatic function and related diseases. Here, the authors perform a genome-wide association study on three liver enzymes, identifying genetic variants associated with their plasma concentration as well as links to metabolic and cardiovascular diseases.
- Raha Pazoki
- , Marijana Vujkovic
- & Rachel B. Ramoni
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Article
| Open AccessProtein analysis of extracellular vesicles to monitor and predict therapeutic response in metastatic breast cancer
A thermophoretic aptasensor can be used to profile cancer-associated proteins of extracellular vesicles (EVs) in patients’ plasma. Here, the authors use this technique to develop an EV-signature able to discriminate metastatic breast cancer, monitor treatment response, and predict patients’ progression-free survival.
- Fei Tian
- , Shaohua Zhang
- & Jiashu Sun
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Article
| Open AccessNext generation plasma proteome profiling to monitor health and disease
The proximity extension assay (PEA) is a popular tool to measure plasma protein levels. Here, the authors extend the proteome coverage of PEA by combining it with next-generation sequencing, enabling the analysis of nearly 1500 proteins from minute amounts of plasma.
- Wen Zhong
- , Fredrik Edfors
- & Mathias Uhlén
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Article
| Open AccessBlood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies
Associations between of omega-3 fatty acids and mortality are not clear. Here the authors report that, based on a pooled analysis of 17 prospective cohort studies, higher blood omega-3 fatty acid levels correlate with lower risk of all-cause mortality.
- William S. Harris
- , Nathan L. Tintle
- & Dariush Mozaffarian
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Article
| Open AccessIncidence and predictive biomarkers of Clostridioides difficile infection in hospitalized patients receiving broad-spectrum antibiotics
Here, the authors report the incidence of Clostridioides difficile infection (CDI) and assess potential clinical characteristics and biomarkers to predict CDI in 1,007 patients of 50 years and above receiving newly initiated antibiotic treatment.
- Cornelis H. van Werkhoven
- , Annie Ducher
- & Odile Launay
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Article
| Open AccessMicrobiota-based markers predictive of development of Clostridioides difficile infection
Clostridioides difficile infection (CDI) is the most common cause of antibiotic-associated diarrhoea (AAD); however, markers predictive of CDI or AAD development are as yet lacking. Here, to identify markers predictive of CDI, the authors profile the intestinal microbiota of 945 hospitalised patients from 34 hospitals in 6 different European countries and show distinct microbiota enriched in Enterococcus and depleted of Ruminococcus, Blautia, Prevotella and Bifidobacterium compared to non-CDI patients.
- Matilda Berkell
- , Mohamed Mysara
- & Odile Launay
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| Open AccessFasting alters the gut microbiome reducing blood pressure and body weight in metabolic syndrome patients
Nutritional modification including fasting has been shown to reduce cardiometabolic risk linked to western diet. Here the authors show implementation of fasting resulted in alterations to the intestinal microbiota, and circulating immune cells, improving blood pressure and body weight in patients with metabolic syndrome.
- András Maifeld
- , Hendrik Bartolomaeus
- & Sofia K. Forslund
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| Open AccessA haemagglutination test for rapid detection of antibodies to SARS-CoV-2
Serological detection of antibodies against SARS-CoV-2 can help establish rates of seroconversion. Here the authors develop a red cell agglutination test to detect antibodies against the receptor binding domain for distribution free of charge to qualified research groups.
- Alain Townsend
- , Pramila Rijal
- & Etienne Joly
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Article
| Open AccessN-protein presents early in blood, dried blood and saliva during asymptomatic and symptomatic SARS-CoV-2 infection
Here the authors develop a single molecule array (Simoa) immunoassay for detection of SARS-CoV-2 nucleocapsid protein in venous and dried capillary blood as well as saliva. The assay shows good performance in symptomatic, asymptomatic, and pre-symptomatic PCR+ individuals.
- Dandan Shan
- , Joseph M. Johnson
- & Andrew J. Ball
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Article
| Open AccessWhole-genome sequencing reveals progressive versus stable myeloma precursor conditions as two distinct entities
The factors that are associated with myeloma precursor condition progression are not well understood. Here the authors find that monoclonal gammopathies of undetermined significance and smoldering myelomas that did not progress to multiple myelomas have a distinct genomic profile and emerge later in the patient’s life.
- Bénedith Oben
- , Guy Froyen
- & Francesco Maura
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Article
| Open AccessNAC blocks Cystatin C amyloid complex aggregation in a cell system and in skin of HCCAA patients
HCCAA is a dominantly inherited disease which causes brain hemorrhages as a result of mutant cystatin C aggregation in carriers. Here, the authors show that n- acetyl cysteine can prevent aggregation of mutant protein in a cell model system and reverse protein deposition in the skin of mutation-carrying subjects.
- Michael E. March
- , Alvaro Gutierrez-Uzquiza
- & Hakon Hakonarson
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Article
| Open AccessA wearable patch for continuous analysis of thermoregulatory sweat at rest
Low secretion rates and evaporation pose challenges for collecting resting thermoregulatory sweat for non-invasive analysis of body physiology. Here the authors present wearable microfluidics-based patches for continuous sweat monitoring at rest that enable detection of pH, Cl−, and levodopa for dynamic sweat analysis related to routine activities, stress events, hypoglycemia-induced sweating, and Parkinson’s disease.
- Hnin Yin Yin Nyein
- , Mallika Bariya
- & Ali Javey
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Article
| Open AccessNeurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy
X-linked adrenoleukodystophy (X-ALD) is a highly variable, progressive neurodegenerative disorder. In this study, neurofilament light chain protein (NfL) was identified as a potential early distinguishing biomarker.
- Isabelle Weinhofer
- , Paulus Rommer
- & Johannes Berger
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Article
| Open AccessA homogeneous split-luciferase assay for rapid and sensitive detection of anti-SARS CoV-2 antibodies
Serological tests are important diagnostic and disease surveillance tools for addressing the COVID-19 pandemic. Here, the authors present a tri-part Nanoluciferase based assay to detect antibodies against SARS-CoV-2.
- Zhong Yao
- , Luka Drecun
- & Igor Stagljar
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Article
| Open AccessCirculating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy
Immune checkpoint inhibition (ICI) shows potential for cancer therapies, but response rates vary. Here, the authors use single-cell analyses to show that, in a 28 patient cohort, patients stratified by mucosal-associated invariant T (MAIT) percentages show different response rates, and ICI responders have more MAIT cells expressing CXCR4 and granzyme B.
- Sara De Biasi
- , Lara Gibellini
- & Andrea Cossarizza
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| Open AccessIntegrated cytokine and metabolite analysis reveals immunometabolic reprogramming in COVID-19 patients with therapeutic implications
Metabolism changes can modulate immune responses in many contexts, and vice versa. Here the authors associate metabolomic, as well as cytokine and chemokine, data from stratified COVID-19 patients to find that arginine, tryptophan and purine metabolic pathways correlate with hyperproliferation, thus hinting at potential therapeutic targets for severe COVID-19 patients.
- Nan Xiao
- , Meng Nie
- & Zeping Hu
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Article
| Open AccessHuman-interpretable image features derived from densely mapped cancer pathology slides predict diverse molecular phenotypes
Computational methods have made progress in improving classification accuracy and throughput of pathology workflows, but lack of interpretability remains a barrier to clinical integration. Here, the authors present an approach for predicting clinically-relevant molecular phenotypes from whole-slide histopathology images using human-interpretable image features.
- James A. Diao
- , Jason K. Wang
- & Amaro Taylor-Weiner
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Matters Arising
| Open AccessFormal reply to “Alternative lengthening of telomeres is not synonymous with mutations in ATRX/DAXX”
- Lars Feuerbach
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Article
| Open AccessStability of person-specific blood-based infrared molecular fingerprints opens up prospects for health monitoring
Health status transitions are reflected as characteristic changes in molecular composition of biofluids. Here, the authors apply infrared molecular fingerprinting and reveal that blood-based phenotypes are sufficiently stable over time, providing the basis for time- and cost-effective health monitoring.
- Marinus Huber
- , Kosmas V. Kepesidis
- & Mihaela Žigman
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Article
| Open AccessPoint-of-care bulk testing for SARS-CoV-2 by combining hybridization capture with improved colorimetric LAMP
Current SARS-CoV-2 diagnostic methods are sensitive yet poorly suited to testing whole communities on a regular basis. Here the authors present Cap-iLAMP that tests gargle lavage samples with an improved colorimetric RT-LAMP.
- Lukas Bokelmann
- , Olaf Nickel
- & Stephan Riesenberg
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Article
| Open AccessVirus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis
Checkpoint blocking therapies are used to treat metastatic melanoma, but can have adverse immune-mediated effects, including liver pathology. Here the authors identify an expanded pool of CD4+ effector memory T cells resulting from prior CMV exposure as a risk factor for this adverse effect in these patients.
- James A. Hutchinson
- , Katharina Kronenberg
- & Sebastian Haferkamp
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| Open AccessRevealing the role of the human blood plasma proteome in obesity using genetic drivers
Blood circulating proteins reflect biological processes, thus providing insight into complex traits. Here the authors study the relationship between 1000 plasma proteins and body mass index (BMI), highlighting widespread proteome changes and causal relationships between BMI and specific proteins.
- Shaza B. Zaghlool
- , Sapna Sharma
- & Karsten Suhre
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Article
| Open AccessPolygenic hazard score is associated with prostate cancer in multi-ethnic populations
A polygenic hazard score (PHS1) improves prostate cancer screening accuracy in European patients. Here, the authors test the performance of a version compatible with OncoArray genotypes (PHS2) in a multi-ethnic dataset and find that it risk-stratifies men for any, aggressive, and fatal prostate cancer.
- Minh-Phuong Huynh-Le
- , Chun Chieh Fan
- & Tyler M. Seibert
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Article
| Open AccessExploring beyond clinical routine SARS-CoV-2 serology using MultiCoV-Ab to evaluate endemic coronavirus cross-reactivity
Serology is an important way to monitor SARS-CoV-2 infection in the population and support vaccine development. Here the authors develop a multiplex immunoassay including spike and nucleocapsid proteins of SARS-CoV-2 and the endemic human coronaviruses with high specificity and sensitivity.
- Matthias Becker
- , Monika Strengert
- & Nicole Schneiderhan-Marra
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Article
| Open AccessBiological and therapeutic implications of a unique subtype of NPM1 mutated AML
Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.
- Arvind Singh Mer
- , Emily M. Heath
- & Benjamin Haibe-Kains
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Article
| Open AccessReal-time prediction of COVID-19 related mortality using electronic health records
Identifying COVID-19 patients with the highest mortality risk early is critical to enable effective intervention and optimal prioritisation of care. Here, the authors present a clinical risk scoring system trained on a large data set of patients from 69 healthcare institutions in multiple countries.
- Patrick Schwab
- , Arash Mehrjou
- & Stefan Bauer
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Matters Arising
| Open AccessReply to ‘Hypothermic machine perfusion before viability testing of previously discarded human livers’
- Hynek Mergental
- , Richard W. Laing
- & Darius F. Mirza
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Article
| Open AccessFacilitation of molecular motion to develop turn-on photoacoustic bioprobe for detecting nitric oxide in encephalitis
Nitric oxide plays key roles in regulating many pathological processes and it is important to monitor NO and related diseases. Here, the authors report on the development of a molecular motion based NO responsive photoacoustic probe and demonstrate application in detecting encephalitis in vivo.
- Ji Qi
- , Leyan Feng
- & Ben Zhong Tang
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Article
| Open AccessGenome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology
Serum liver enzymes are used as markers of liver disease, their concentration influenced in part by genetic factors. Here the authors meta-analyse genome-wide association studies on the UK Biobank and BioBank Japan to evaluate the association of three liver enzymes with liver and other metabolic diseases.
- Vincent L. Chen
- , Xiaomeng Du
- & Elizabeth K. Speliotes
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Article
| Open AccessWhole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival
Skull base chordomas are treated with surgery and chemotherapy but often recur due to incomplete resection, understanding the molecular underpinnings of the tumours may provide additional therapeutic strategies. Here, the authors carry out whole genome sequencing of 80 skull base chordoma tumours and identify the SWI/SNF component—PBRM1—as a frequently mutated gene.
- Jiwei Bai
- , Jianxin Shi
- & Xiaohong R. Yang
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Article
| Open AccessA multiplex chemiluminescent immunoassay for serological profiling of COVID-19-positive symptomatic and asymptomatic patients
Antibody responses to SARS-CoV-2 may be important biomarkers for assessing the risk for viral transmission. Here the authors present serological antibody profiling results of COVID-19 patients using a new multiplex assay to show distinct kinetics and dynamics of IgG, IgM and IgA responses in patients with different disease severity.
- Allison N. Grossberg
- , Lilia A. Koza
- & Daniel A. Linseman
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Article
| Open AccessA glucose meter interface for point-of-care gene circuit-based diagnostics
Getting synthetic biology circuit-based sensors into field applications is still a challenge. Here the authors combine a circuit sensor with a glucose meter for small analyte and nucleic acid detection.
- Evan Amalfitano
- , Margot Karlikow
- & Keith Pardee
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Article
| Open AccessPretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors
There is an unmet clinical need for simple, accessible biomarkers to select patients who are more likely to respond to immune checkpoint therapy. Here the authors show that a lower neutrophil-to-lymphocyte ratio is associated with better overall and progressive-free survival, as well as higher rate of response, in a multi-cancer cohort of patients treated with immune checkpoint inhibitors.
- Cristina Valero
- , Mark Lee
- & Luc G. T. Morris
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Article
| Open AccessGenome-wide association study identifies risk loci for progressive chronic lymphocytic leukemia
The clinical course of chronic lymphocytic leukaemia (CLL) is variable and difficult to predict. Here, the authors conduct a genome wide association study meta-analysis for time to first treatment in CLL patients and report two loci associating with progressive disease.
- Wei-Yu Lin
- , Sarah E. Fordham
- & James M. Allan
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Article
| Open AccessGenome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women
Muscle weakness has been associated with morbidity and mortality in older people. Here, the authors have investigated this trait further by performing a genome-wide meta-analysis of grip strength and Mendelian randomization to discover causal relationships between muscle weakness and other diseases.
- Garan Jones
- , Katerina Trajanoska
- & Luke C. Pilling
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Article
| Open AccessInterplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis
Patients with solid cancers have high rates of clonal haematopoiesis associated with increased risk of secondary leukemias. Here, by using peripheral blood sequencing data from patients with solid non-hematologic cancer, the authors profile the landscape of mosaic chromosomal alterations and gene mutations, defining patients at high risk of leukemia progression.
- Teng Gao
- , Ryan Ptashkin
- & Elli Papaemmanuil