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While only distantly related to mammals, the anatomy of Permian gorgonopsians has shed light on the functional biology of non-mammalian synapsids and on the origins of iconic ‘mammal-like’ anatomical traits. However, little is known of gorgonopsian behaviour or physiology, which would aid in reconstructing the paleobiological context in which familiar mammalian features arose. Using multi-modal imaging, we report a discrete osseous lesion in the forelimb of a late Permian-aged gorgonopsian synapsid, recording reactive periosteal bone deposition and providing insights into the origins and diversity of skeletal healing responses in premammalian synapsids. We suggest that the localized lesion on the anterolateral (preaxial) shaft of the left radius represents acute periostitis and, conservatively, most likely developed as a subperiosteal haematoma with subsequent bone deposition and limited internal remodelling. The site records an inner zone of reactive cortical bone forming irregular to radial bony spicules and an outer, denser zone of slowed subperiosteal bone apposition, all of which likely occurred within a single growing season. In surveys of modern reptiles—crocodylians, varanids—such haematomas are rare compared to other documented osteopathologies. The extent and rapidity of the healing response is reminiscent of mammalian and dinosaurian bone pathologies, and may indicate differing behaviour or bone physiology compared to non-dinosaurian reptiles. This report adds to a growing list of putative disease entities recognized in early synapsids and broadens comparative baselines for pathologies and the evolution of bone response to disease in mammalian forebears. This article is part of the theme issue ‘Vertebrate palaeophysiology’.

The Encyclopedia of DNA Elements (ENCODE) project has established a genomic resource for mammalian development, profiling a diverse panel of mouse tissues at 8 developmental stages from 10.5 days after conception until birth, including transcriptomes, methylomes and chromatin states. Here we systematically examined the state and accessibility of chromatin in the developing mouse fetus. In total we performed 1,128 chromatin immunoprecipitation with sequencing (ChIP–seq) assays for histone modifications and 132 assay for transposase-accessible chromatin using sequencing (ATAC–seq) assays for chromatin accessibility across 72 distinct tissue-stages. We used integrative analysis to develop a unified set of chromatin state annotations, infer the identities of dynamic enhancers and key transcriptional regulators, and characterize the relationship between chromatin state and accessibility during developmental gene regulation. We also leveraged these data to link enhancers to putative target genes and demonstrate tissue-specific enrichments of sequence variants associated with disease in humans. The mouse ENCODE data sets provide a compendium of resources for biomedical researchers and achieve, to our knowledge, the most comprehensive view of chromatin dynamics during mammalian fetal development to date. Analysis of chromatin state and accessibility in mouse tissues from twelve sites and eight developmental stages provides a comprehensive view of chromatin dynamics.

Background: Drinking water in multiple water districts in the Mid-Ohio Valley has been contaminated with perfluorooctanoic acid (PFOA), which was released by a nearby DuPont chemical plant. Two highly contaminated water districts began granular activated carbon filtration in 2007. Objectives: To determine the rate of decline in serum PFOA, and its corresponding half-life, during the first year after filtration. Methods: Up to six blood samples were collected from each of 200 participants from May 2007 until August 2008. The primary source of drinking water varied over time for some participants; our analyses were grouped according to water source at baseline in May—June 2007. Results: For Lubeck Public Service District customers, the average decrease in serum PFOA concentrations between May—June 2007 and May—August 2008 was 32 ng/mL (26%) for those primarily consuming public water at home (n = 130), and 16 ng/mL (28%) for those primarily consuming bottled water at home (n = 17). For Little Hocking Water Association customers, the average decrease in serum PFOA concentrations between November—December 2007 and May—June 2008 was 39 ng/mL (11%) for consumers of public water (n = 39) and 28 ng/mL (20%) for consumers of bottled water (n = 11). The covariate-adjusted average rate of decrease in serum PFOA concentration after water filtration was 26% per year (95% confidence interval, 25-28% per year). Conclusions: The observed data are consistent with first-order elimination and a median serum PFOA half-life of 2.3 years. Ongoing follow-up will lead to improved half-life estimation.

IntroductionThe phase III SELECT-MONOTHERAPY trial (NCT02706951) demonstrated the safety and efficacy of upadacitinib (UPA) monotherapy through 84 weeks in patients with rheumatoid arthritis who responded inadequately to methotrexate. Here we report week 260 results.MethodsPatients were randomised to continue methotrexate or UPA 15 mg (UPA15) or 30 mg (UPA30) monotherapy for 14 weeks. From week 14, patients continuing methotrexate switched to UPA15 or UPA30 per prespecified assignment; patients randomised to UPA continued treatment. Following a protocol amendment, all cohorts switched to open-label UPA15. Safety was summarised using exposure-adjusted event and incidence rates. Efficacy was reported as observed and using non-responder imputation (NRI).ResultsOf 648 randomised patients, 598 entered the long-term extension. Of these, 249 (41.6%) discontinued study drug by week 260 primarily due to adverse events (14.5%), consent withdrawal (9.9%), lost to follow-up (3.3%), lack of efficacy (2.2%), COVID-19 (0.7%) or other reasons (11.0%). Rates of herpes zoster, non-melanoma skin cancer, hepatic disorder, neutropenia, lymphopenia and creatine kinase elevation were higher with UPA30 versus UPA15. Long-term UPA safety data were consistent with the established UPA safety profile. Based on NRI, >39% of patients treated continuously with UPA achieved low disease activity per Clinical Disease Activity Index ≤10 (UPA15, n=93/217; UPA30, n=91/215) and 28-joint Disease Activity Score using C reactive protein ≤3.2 (UPA15, n=90/217; UPA30, n=94/215) at week 260. Efficacy was similar among patients switching from methotrexate to UPA.ConclusionNo new safety risks were identified with long-term UPA treatment. UPA monotherapy was efficacious in treating rheumatoid arthritis through week 260.Trial registration numberNCT02706951.

Tatsuhiro Shibata, David Wheeler, Hiroyuki Aburatani and colleagues report the genomic, exomic and oncoviral sequencing of hundreds of liver cancers from the United States and Japan. The authors analyzed mutation patterns and identified signatures unique to the Asian cases. Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

Background: Several epidemiological cross-sectional studies have found positive associations between serum concentrations of lipids and perfluorooctanoic acid (PFOA, or C8). A longitudinal study should be less susceptible to biases from uncontrolled confounding or reverse causality. Methods: We investigated the association between within-individual changes in serum PFOA and perfluorooctanesulfonic acid (PFOS) and changes in serum lipid levels (low-density lipoprotein [LDL] cholesterol, high-density lipoprotein cholesterol, total cholesterol, and triglycerides) over a 4.4-year period. The study population consisted of 560 adults living in parts of Ohio and West Virginia where public drinking water had been contaminated with PFOA. They had participated in a cross-sectional study in 2005—2006, and were followed up in 2010, by which time exposure to PFOA had been substantially reduced. Results: Overall serum concentrations of PFOA and PFOS fell by half from initial geometric means of 74.8 and 18.5 ng/mL, respectively, with little corresponding change in LDL cholesterol (mean increase 1.8%, standard deviation 26.6%). However, there was a tendency for people with greater declines in serum PFOA or PFOS to have greater LDL decrease. For a person whose serum PFOA fell by half, the predicted fall in LDL cholesterol was 3.6% (95% confidence interval = 1.5—5.7%). The association with a decline in PFOS was even stronger, with a 5% decrease in LDL (2.5—7.4%). Conclusions: Our findings from this longitudinal study support previous evidence from cross-sectional studies of positive associations between PFOA and PFOS in serum and LDL cholesterol.

Background: Golf-related lower extremity (LE) orthopaedic injuries are frequently seen in emergency departments (EDs) across the United States (US). This study analyzes trends in mechanisms and distribution of these injuries. Hypotheses: We hypothesized that (1) the LE injury incidence would increase from 2013 to 2022; (2) golf carts would be a significant injury mechanism; and (3) injury patterns would vary by age group. Study Design: Descriptive epidemiology study. Methods: The National Electronic Injury Surveillance System (NEISS) database was queried for all LE golf-related injuries presenting to US EDs from January 1, 2013, to December 31, 2022. National estimates (NE) were calculated utilizing the NEISS statistical sample weight for each hospital. Linear regressions were used to determine trends in injury patterns—including year, age group, body part, injury mechanism, diagnosis, and disposition. Results: There were 1949 golf-related LE injuries (NE = 97,492), with men accounting for 67.3% of cases. Injuries were highest among >60 years (49%) and 10 to 19-year-old golfers (11%). Most commonly involved LE body parts were the knee (n = 586; NE = 31,539; 32%), lower leg (n = 498; NE = 24,729; 25%), ankle (n = 453; NE = 21,860; 22%), and foot (n = 263; NE = 12,814; 13%). The most commonly identifiable mechanisms of injury were 38,889 cart-related (40%), 15,287 falls (16%), and 11,181 overuse injuries (11%). There was an increasing annual trend in LE injury involving golf carts (236 per year; P = .001). However, there was no statistically significant trend in overall golf-related LE injuries. Conclusion: Our study revealed that golf cart-related injuries accounted for a disproportionate percentage of LE golf injuries (40%). The lack of increase in overall LE injuries may reflect fewer non-golf cart-related injuries among an increasing pool of younger golfers. Preventive measures should target adolescents and those >60 years. Improved safety measures for golf cart use are also recommended.

In January 2020, a workshop was held at EMBL-EBI (Hinxton, UK) to discuss data requirements for the deposition and validation of cryoEM structures, with a focus on single-particle analysis. The meeting was attended by 47 experts in data processing, model building and refinement, validation, and archiving of such structures. This report describes the workshop's motivation and history, the topics discussed, and the resulting consensus recommendations. Some challenges for future methods-development efforts in this area are also highlighted, as is the implementation to date of some of the recommendations.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03089-4.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.