EMT: 2016.

The significant parallels between cell plasticity during embryonic development and carcinoma progression have helped us understand the importance of the epithelial-mesenchymal transition (EMT) in human disease. Our expanding knowledge of EMT has led to a clarification of the EMT program as a set of multiple and dynamic transitional states between the epithelial and mesenchymal phenotypes, as opposed to a process involving a single binary decision. EMT and its intermediate states have recently been identified as crucial drivers of organ fibrosis and tumor progression, although there is some need for caution when interpreting its contribution to metastatic colonization. Here, we discuss the current state-of-the-art and latest findings regarding the concept of cellular plasticity and heterogeneity in EMT. We raise some of the questions pending and identify the challenges faced in this fast-moving field.

Community-Based Cluster-Randomized Trial to Reduce Opioid Overdose Deaths.

BACKGROUND: Evidence-based practices for reducing opioid-related overdose deaths include overdose education and naloxone distribution, the use of medications for the treatment of opioid use disorder, and prescription opioid safety. Data are needed on the effectiveness of a community-engaged intervention to reduce opioid-related overdose deaths through enhanced uptake of these practices. METHODS: In this community-level, cluster-randomized trial, we randomly assigned 67 communities in Kentucky, Massachusetts, New York, and Ohio to receive the intervention (34 communities) or a wait-list control (33 communities), stratified according to state. The trial was conducted within the context of both the coronavirus disease 2019 (Covid-19) pandemic and a national surge in the number of fentanyl-related overdose deaths. The trial groups were balanced within states according to urban or rural classification, previous overdose rate, and community population. The primary outcome was the number of opioid-related overdose deaths among community adults. RESULTS: During the comparison period from July 2021 through June 2022, the population-averaged rates of opioid-related overdose deaths were similar in the intervention group and the control group (47.2 deaths per 100,000 population vs. 51.7 per 100,000 population), for an adjusted rate ratio of 0.91 (95% confidence interval, 0.76 to 1.09; P = 0.30). The effect of the intervention on the rate of opioid-related overdose deaths did not differ appreciably according to state, urban or rural category, age, sex, or race or ethnic group. Intervention communities implemented 615 evidence-based practice strategies from the 806 strategies selected by communities (254 involving overdose education and naloxone distribution, 256 involving the use of medications for opioid use disorder, and 105 involving prescription opioid safety). Of these evidence-based practice strategies, only 235 (38%) had been initiated by the start of the comparison year. CONCLUSIONS: In this 12-month multimodal intervention trial involving community coalitions in the deployment of evidence-based practices to reduce opioid overdose deaths, death rates were similar in the intervention group and the control group in the context of the Covid-19 pandemic and the fentanyl-related overdose epidemic. (Funded by the National Institutes of Health; HCS ClinicalTrials.gov number, NCT04111939.).

The cross-domain functional organization of posterior lateral temporal cortex: insights from ALE meta-analyses of 7 cognitive domains spanning 12,000 participants.

The posterior lateral temporal cortex is implicated in many verbal, nonverbal, and social cognitive domains and processes. Yet without directly comparing these disparate domains, the region's organization remains unclear; do distinct processes engage discrete subregions, or could different domains engage shared neural correlates and processes? Here, using activation likelihood estimation meta-analyses, the bilateral posterior lateral temporal cortex subregions engaged in 7 domains were directly compared. These domains comprised semantics, semantic control, phonology, biological motion, face processing, theory of mind, and representation of tools. Although phonology and biological motion were predominantly associated with distinct regions, other domains implicated overlapping areas, perhaps due to shared underlying processes. Theory of mind recruited regions implicated in semantic representation, tools engaged semantic control areas, and faces engaged subregions for biological motion and theory of mind. This cross-domain approach provides insight into how posterior lateral temporal cortex is organized and why.

Graded functional organization in the left inferior frontal gyrus: evidence from task-free and task-based functional connectivity.

The left inferior frontal gyrus has been ascribed key roles in numerous cognitive domains, such as language and executive function. However, its functional organization is unclear. Possibilities include a singular domain-general function, or multiple functions that can be mapped onto distinct subregions. Furthermore, spatial transition in function may be either abrupt or graded. The present study explored the topographical organization of the left inferior frontal gyrus using a bimodal data-driven approach. We extracted functional connectivity gradients from (i) resting-state fMRI time-series and (ii) coactivation patterns derived meta-analytically from heterogenous sets of task data. We then sought to characterize the functional connectivity differences underpinning these gradients with seed-based resting-state functional connectivity, meta-analytic coactivation modeling and functional decoding analyses. Both analytic approaches converged on graded functional connectivity changes along 2 main organizational axes. An anterior-posterior gradient shifted from being preferentially associated with high-level control networks (anterior functional connectivity) to being more tightly coupled with perceptually driven networks (posterior). A second dorsal-ventral axis was characterized by higher connectivity with domain-general control networks on one hand (dorsal functional connectivity), and with the semantic network, on the other (ventral). These results provide novel insights into an overarching graded functional organization of the functional connectivity that explains its role in multiple cognitive domains.

ECO: the Evidence and Conclusion Ontology, an update for 2022.

The Evidence and Conclusion Ontology (ECO) is a community resource that provides an ontology of terms used to capture the type of evidence that supports biomedical annotations and assertions. Consistent capture of evidence information with ECO allows tracking of annotation provenance, establishment of quality control measures, and evidence-based data mining. ECO is in use by dozens of data repositories and resources with both specific and general areas of focus. ECO is continually being expanded and enhanced in response to user requests as well as our aim to adhere to community best-practices for ontology development. The ECO support team engages in multiple collaborations with other ontologies and annotating groups. Here we report on recent updates to the ECO ontology itself as well as associated resources that are available through this project. ECO project products are freely available for download from the project website (https://evidenceontology.org/) and GitHub (https://github.com/evidenceontology/evidenceontology). ECO is released into the public domain under a CC0 1.0 Universal license.

The Human Disease Ontology 2022 update.

The Human Disease Ontology (DO) (www.disease-ontology.org) database, has significantly expanded the disease content and enhanced our userbase and website since the DO's 2018 Nucleic Acids Research DATABASE issue paper. Conservatively, based on available resource statistics, terms from the DO have been annotated to over 1.5 million biomedical data elements and citations, a 10× increase in the past 5 years. The DO, funded as a NHGRI Genomic Resource, plays a key role in disease knowledge organization, representation, and standardization, serving as a reference framework for multiscale biomedical data integration and analysis across thousands of clinical, biomedical and computational research projects and genomic resources around the world. This update reports on the addition of 1,793 new disease terms, a 14% increase of textual definitions and the integration of 22 137 new SubClassOf axioms defining disease to disease connections representing the DO's complex disease classification. The DO's updated website provides multifaceted etiology searching, enhanced documentation and educational resources.

Subregions of DLPFC Display Graded yet Distinct Structural and Functional Connectivity.

The human dorsolateral prefrontal cortex (DLPFC; approximately corresponding to Brodmann areas 9 and 46) has demonstrable roles in diverse executive functions such as working memory, cognitive flexibility, planning, inhibition, and abstract reasoning. However, it remains unclear whether this is the result of one functionally homogeneous region or whether there are functional subdivisions within the DLPFC. Here, we divided the DLPFC into seven areas along rostral-caudal and dorsal-ventral axes anatomically and explored their respective patterns of structural and functional connectivity. In vivo probabilistic tractography (11 females and 13 males) and resting-state functional magnetic resonance imaging (fMRI; 57 females and 21 males) were employed to map out the patterns of connectivity from each DLPFC subregion. Structural connectivity demonstrated graded intraregional connectivity within the DLPFC. The patterns of structural connectivity between the DLPFC subregions and other cortical areas revealed that the dorsal-rostral subregions connections were restricted to other frontal and limbic areas, whereas the ventral-caudal region was widely connected to frontal, parietal, and limbic cortex. Functional connectivity analyses demonstrated that subregions of DLPFC were strongly interconnected to each other. The dorsal subregions were associated with the default mode network (DMN), while middle dorsal-rostral subregions were linked with the multiple demand network (MDN). The ventral-caudal subregion showed increased functional coupling with both DMN and MDN. Our results suggest that the connectivity of the DLPFC may be subdivided along a dorsorostral-ventrocaudal axis with differing (albeit graded) patterns of connectivity reflecting the integrative executive function of the DLPFC.SIGNIFICANCE STATEMENT Research has shown that the dorsolateral prefrontal cortex (DLPFC) plays a role in various executive functions. By dividing the DLPFC into seven areas along rostral-caudal and dorsal-ventral axes anatomically, we explored their patterns of structural and functional connectivity. The patterns of connectivity within DLPFC subregions demonstrated graded intraregional connectivity. There were distinctive patterns of connectivity with other cortical areas in dorsal-rostral and ventral-caudal DLPFC subregions. Divisions across DLPFC subregions seem to align with their structural and functional connectivity. Our results suggest that DLPFC may be subdivided by the diagonal axis of the dorsal-ventral axis and rostral-caudal axis, supporting the framework of a functional organization along the anterior-posterior axis in the lateral PFC.

Time-Lagged Multidimensional Pattern Connectivity (TL-MDPC): An EEG/MEG pattern transformation based functional connectivity metric.

Functional and effective connectivity methods are essential to study the complex information flow in brain networks underlying human cognition. Only recently have connectivity methods begun to emerge that make use of the full multidimensional information contained in patterns of brain activation, rather than unidimensional summary measures of these patterns. To date, these methods have mostly been applied to fMRI data, and no method allows vertex-to-vertex transformations with the temporal specificity of EEG/MEG data. Here, we introduce time-lagged multidimensional pattern connectivity (TL-MDPC) as a novel bivariate functional connectivity metric for EEG/MEG research. TL-MDPC estimates the vertex-to-vertex transformations among multiple brain regions and across different latency ranges. It determines how well patterns in ROI X at time point tx can linearly predict patterns of ROI Y at time point ty. In the present study, we use simulations to demonstrate TL-MDPC's increased sensitivity to multidimensional effects compared to a unidimensional approach across realistic choices of number of trials and signal-to-noise ratios. We applied TL-MDPC, as well as its unidimensional counterpart, to an existing dataset varying the depth of semantic processing of visually presented words by contrasting a semantic decision and a lexical decision task. TL-MDPC detected significant effects beginning very early on, and showed stronger task modulations than the unidimensional approach, suggesting that it is capable of capturing more information. With TL-MDPC only, we observed rich connectivity between core semantic representation (left and right anterior temporal lobes) and semantic control (inferior frontal gyrus and posterior temporal cortex) areas with greater semantic demands. TL-MDPC is a promising approach to identify multidimensional connectivity patterns, typically missed by unidimensional approaches.

Effect of Low-Fat Dietary Modification on Incident Open-Angle Glaucoma.

PURPOSE: We tested whether dietary modification (DM) altered the risk for incident primary open-angle glaucoma (POAG). DESIGN: Secondary analysis of a randomized intervention trial. PARTICIPANTS: We linked Medicare claims data to 45 203 women in the Women's Health Initiative Dietary Modification Trial, of which 23 776 participants were enrolled in fee-for-service Medicare Part B and had physician claims. METHODS: Women were randomized to follow either DM (a low-fat diet, with increased vegetable, fruit, and grain intake) or their usual diet without modification. Nine thousand three hundred forty women were randomized to the DM intervention, whereas 13 877 women were randomized to the control group. Our analyses were based on an intention-to-treat design, with a follow-up to the end of continuous Medicare coverage, death, or the last claims date (12/31/2018), whichever occurred first. Primary open-angle glaucoma was defined as the first claim with the International Classification of Diseases, Ninth or Tenth Revision, codes. Dietary data were assessed using a food frequency questionnaire. MAIN OUTCOME MEASURES: We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of POAG. Subgroup analyses were performed with P values for interaction. RESULTS: After exclusion of women with Medicare-derived glaucoma before randomization, the final analysis included 23 217 women (mean age, 64.4 ± 5.8 years). Baseline characteristics were balanced between the intervention and control groups. Primary open-angle glaucoma incidence was 11.1 per 1000 woman-years (mean follow-up, 11.6 ± 7.4 years; mean DM duration, 5.2 ± 3.2 years). We found no overall benefit of DM in reducing incident POAG (HR, 1.04; 95% CI, 0.96-1.12). Race and participant age did not modify this relation (P = 0.08 and P = 0.24 for interaction, respectively). In further analysis of baseline nutrient and food intake stratified by quartile groups, risk of open-angle glaucoma (OAG) in DM participants in the lowest quartile group for percentage calories (kilocalories) from total fat (33.8 or lower) was increased (HR, 1.22; 95% CI, 1.05-1.41; P = 0.007 for interaction). CONCLUSIONS: Analysis suggests that DM in participants in the lowest quartile group for percentage calories from total fat at baseline increased the risk of incident OAG among women regardless of age or race. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Marine diatoms record Late Holocene regime shifts in the Pikialasorsuaq ecosystem.

The Pikialasorsuaq (North Water polynya) is an area of local and global cultural and ecological significance. However, over the last decades, the region has been subject to rapid warming, and in some recent years, the seasonal ice arch that has historically defined the polynya's northern boundary has failed to form. Both factors are deemed to alter the polynya's ecosystem functioning. To understand how climate-induced changes to the Pikialasorsuaq impact the basis of the marine food web, we explored diatom community-level responses to changing conditions, from a sediment core spanning the last 3800 years. Four metrics were used: total diatom concentrations, taxonomic composition, mean size, and diversity. Generalized additive model statistics highlight significant changes at ca. 2400, 2050, 1550, 1200, and 130 cal years BP, all coeval with known transitions between colder and warmer intervals of the Late Holocene, and regime shifts in the Pikialasorsuaq. Notably, a weaker/contracted polynya during the Roman Warm Period and Medieval Climate Anomaly caused the diatom community to reorganize via shifts in species composition, with the presence of larger taxa but lower diversity, and significantly reduced export production. This study underlines the high sensitivity of primary producers to changes in the polynya dynamics and illustrates that the strong pulse of early spring cryopelagic diatoms that makes the Pikialasorsuaq exceptionally productive may be jeopardized by rapid warming and associated Nares Strait ice arch destabilization. Future alterations to the phenology of primary producers may disproportionately impact higher trophic levels and keystone species in this region, with implications for Indigenous Peoples and global diversity.

Antenatal and neonatal exposure to SARS-CoV-2 and children's development: a systematic review and meta-analysis.

OBJECTIVES: To conduct a systematic review of the impact of antenatal and neonatal exposure to SARS-CoV-2 on developmental outcomes in preterm and term-born infants. METHODS: We searched Embase, Emcare, MEDLINE, PsycINFO, Web of Science and grey literature on May 27, 2022 and updated on May 8, 2023. Studies defining exposure with a positive SARS-CoV-2 protein or genetic material, used a contemporaneous non-exposed cohort, and reported developmental outcomes up to 2 years of age were included. RESULTS: Four out of 828 screened studies were included. Meta-analysis included 815 infants screened for developmental delay (n = 306 exposed; n = 509 non-exposed) between 3- and 11-months of age. Among term-born infants, we did not find an increased risk of delay in communication (odd's ratio: 0.73 (95% CI: 0.24-2.24)), gross motor (1.50 (0.62, 3.62)), fine motor (2.90 (0.58, 14.43)), problem-solving (1.19 (0.54, 2.66)) or personal-social development (1.93 (0.78, 4.75)) in exposed infants. The number of preterm-born infants in the exposed (n = 37) and comparison cohorts (n = 41) were too few to report meaningful comparisons. CONCLUSION: Evidence regarding the potential impact of antenatal or neonatal exposure to SARS-CoV-2 infection on developmental outcomes in early infancy is limited and inconsistent. Larger cohorts with outcomes beyond the first year of life are needed. IMPACT: The current evidence examining associations between SARS-CoV-2 exposure during the neonatal period and developmental outcomes in infancy is limited by there being few studies with extremely small sample sizes. Based on sparse data there was no consistent association between antenatal or neonatal exposure to SARS-CoV-2 infection and an adverse impact on developmental outcomes below 12 months of age for babies born preterm or at term. This study highlights that larger cohorts with outcomes assessed beyond the first year are needed to determine the potential longer-term impact of SARS-CoV-2 infection exposure on child development.

Evaluating the scaling up of an effective implementation intervention (PACE) to increase the delivery of a mandatory physical activity policy in primary schools.

BACKGROUND: Physically Active Children in Education (PACE) is an effective implementation intervention for increasing the number of minutes classroom teachers schedule physical activity each week. To date, evaluations of PACE have included a smaller number of schools from only one region in New South Wales Australia. If PACE is to have population-wide benefits we must be able to deliver this support to a larger number of schools across multiple regions. This study aimed to evaluate the scale-up of PACE. METHODS: An uncontrolled before and after study, with 100 schools from three regions was conducted. Participating schools received PACE for approximately 12 months. We assessed the following outcomes: delivery of the evidence-based intervention (EBI) (i.e. minutes of physical activity scheduled by classroom teachers per week); delivery of the implementation strategies (i.e. reach, dose delivered, adherence and indicators of sustainability); and key determinants of implementation (i.e. acceptability of strategies and cost). Data were collected via project officer records, and principal and teacher surveys. Linear mixed models were used to assess EBI delivery by evaluating the difference in the mean minutes teachers scheduled physical activity per week from baseline to follow-up. Descriptive data were used to assess delivery of the implementation strategies and their perceived acceptability (i.e. PACE). A prospective, trial-based economic evaluation was used to assess cost. RESULTS: Delivery of the EBI was successful: teachers increas their average minutes of total physical activity scheduled across the school week by 26.8 min (95% CI: 21.2, 32.4, p < 0.001) after receiving PACE. Indicators for delivery of implementation strategies were high: 90% of consenting schools received all strategies and components (reach); 100% of strategies were delivered by the provider (dose); >50% of schools adhered to the majority of strategies (11 of the 14 components); and acceptability was > 50% agreement for all strategies. The incremental cost per additional minute of physical activity scheduled per week was $27 per school (Uncertainty Interval $24, $31). CONCLUSIONS: PACE can be successfully delivered across multiple regions and to a large number of schools. Given the ongoing and scalable benefits of PACE, it is important that we continue to extend and improve this program while considering ways to reduce the associated cost.

Characteristics and Patterns of Cigarette Smoking and Vaping By Past-Year Smokers Who Reported Using Electronic Nicotine Delivery System to Help Quit Smoking in the Past Year: Findings From the 2018-2019 Tobacco Use Supplement to the Current Population Survey.

INTRODUCTION: Cigarette smoking has declined, while electronic nicotine delivery system (ENDS) use has increased in the United States. Understanding the role of ENDS in adult smoking quit attempts and cessation is important for estimating their population health impact. AIMS AND METHODS: We used data from 2018 to 2019 tobacco use supplement to the current population survey to examine demographic characteristics and ENDS use patterns among adult ENDS users who reported quitting smoking in the past year by trying to switch to ENDS ("switchers") and smokers who did or did not make a quit attempt in the past year. χ2 tests of proportions and t-tests were used to compare characteristics between groups. RESULTS: In 2018-2019, about three-quarters of switchers reported daily use of ENDS compared to only one-third of dual users with a recent quit attempt by trying to switch to ENDS. Compared to dual users who made a quit attempt by trying to switch to ENDS, switchers were more likely to use menthol/mint-flavored ENDS exclusively (5.6% vs. 13.1%; p = .004) but less likely to use tobacco-flavored ENDS exclusively (21.2% vs. 13.7%; p = .01). CONCLUSIONS: ENDS users who quit smoking in the past year and reported trying to quit by switching to ENDS were more likely to use menthol/mint flavors exclusively and use ENDS daily compared to dual users who made a quit attempt by trying to switch to ENDS. Longer-term prospective data may better clarify the role of ENDS in smoking quit attempts and cessation. IMPLICATIONS: This study provides information on patterns of ENDS use in former smokers and current smokers who tried to quit smoking by switching to ENDS in a national sample of U.S. adults. These results can inform policy actions concerning ENDS products.

Transitions to smokeless tobacco use among adult cigarette smokers in the Population Assessment of Tobacco and Health (PATH) Study, Waves 3-5 (2015-2019).

OBJECTIVE: Examine patterns of dual use of cigarettes and smokeless tobacco and complete switching over time among adult current cigarette smokers using data from the Population Assessment of Tobacco and Health Study Wave 3 (2015-2016), Wave 4 (2016-2018) and Wave 5 (2018-2019). METHODS: We examined four tobacco use states among 6834 exclusive smokers and 372 dual users at Wave 3 with two waves of follow-up data: exclusive cigarette use, exclusive smokeless tobacco use, dual use and use of neither product. RESULTS: Among exclusive smokers at Wave 3, only 1.6% (95% CI: 1.3% to 2.1%) transitioned to dual use at Wave 4, and 0.1% (95% CI: 0.07% to 0.2%) switched to exclusive smokeless tobacco use. Among exclusive smokers who switched to dual use, 53.1% (95% CI: 40.9% to 64.9%) returned to exclusive cigarette smoking, 34.3% (95% CI: 23.8% to 46.6%) maintained dual use and 12.6% (95% CI: 7.0% to 21.7%) did not smoke cigarettes after an additional wave of follow-up. Dual users at Wave 3 were likely to maintain their dual use status at Wave 4, 51.2% (95% CI: 46.1% to 56.3%) and Wave 5, 47.9% (95% CI: 40.1% to 55.8%). CONCLUSIONS: Very few cigarette smokers transition to smokeless tobacco use, and among those who do, dual use is more common than exclusive smokeless tobacco use. Further, the majority of exclusive cigarette smokers who transition to dual use at Wave 4 continue smoking cigarettes at Wave 5, either as dual users or as exclusive smokers.

A cluster randomised controlled trial to assess the effectiveness of a multi-strategy sustainability intervention on teachers' sustained implementation of classroom physical activity breaks (energisers): study protocol.

BACKGROUND: Governments internationally have invested hugely in the implementation and scale-up of school-based physical activity interventions, but have little evidence of how to best sustain these interventions once active implementation support ceases. This study will assess the effectiveness of a multi-strategy sustainability intervention on classroom teachers' sustainment of energisers (short 3-5 min physical activity breaks during class-time) scheduled across the school day from baseline to 12 and 24-month follow-up. METHODS: A cluster randomised controlled trial will be conducted in 50 primary schools within the Hunter New England, Illawarra Shoalhaven, Murrumbidgee and Northern New South Wales (NSW) Local Health Districts of NSW Australia. Schools will be randomly allocated to receive either usual support or the multi-strategy sustainability intervention that includes: centralised technical assistance from a trained project officer; formal commitment and mandated change obtained from school principals; training in-school champions; reminders for teachers; educational materials provided to teachers; capturing and sharing local knowledge; and engagement of parents, carers and the wider school community. The primary trial outcome will be measured via a teacher logbook to determine the between-group difference in the change in mean minutes of energisers scheduled across the school day at 12 and 24-month follow-up compared to baseline. Analyses will be performed using an intention to treat framework. Linear mixed models will be used to assess intervention effects on the primary outcome at both follow-up periods. DISCUSSION: This study will be one of the first randomised controlled trials to examine the impact of a multi-strategy sustainability intervention to support schools' sustainment of a physical activity intervention. The proposed research will generate new evidence needed for the partnering organisations to protect their considerable investments to date in physical activity promotion in this setting and will provide seminal evidence for the field globally. TRIAL REGISTRATION: ACTRN12620000372987 version 1 registered 17th March 2020. Version 3 (current version) updated 4th August 2023.

Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project.

BACKGROUND AND PURPOSE: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid). METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis. RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00×10-9) and 4 novel loci at genome-wide significance (P<5.00×10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11×10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1. CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.

Task modulation of spatiotemporal dynamics in semantic brain networks: An EEG/MEG study.

How does brain activity in distributed semantic brain networks evolve over time, and how do these regions interact to retrieve the meaning of words? We compared spatiotemporal brain dynamics between visual lexical and semantic decision tasks (LD and SD), analysing whole-cortex evoked responses and spectral functional connectivity (coherence) in source-estimated electroencephalography and magnetoencephalography (EEG and MEG) recordings. Our evoked analysis revealed generally larger activation for SD compared to LD, starting in primary visual area (PVA) and angular gyrus (AG), followed by left posterior temporal cortex (PTC) and left anterior temporal lobe (ATL). The earliest activation effects in ATL were significantly left-lateralised. Our functional connectivity results showed significant connectivity between left and right ATL, PTC and right ATL in an early time window, as well as between left ATL and IFG in a later time window. The connectivity of AG was comparatively sparse. We quantified the limited spatial resolution of our source estimates via a leakage index for careful interpretation of our results. Our findings suggest that the different demands on semantic information retrieval in lexical and semantic decision tasks first modulate visual and attentional processes, then multimodal semantic information retrieval in the ATLs and finally control regions (PTC and IFG) in order to extract task-relevant semantic features for response selection. Whilst our evoked analysis suggests a dominance of left ATL for semantic processing, our functional connectivity analysis also revealed significant involvement of right ATL in the more demanding semantic task. Our findings demonstrate the complementarity of evoked and functional connectivity analysis, as well as the importance of dynamic information for both types of analyses.

Opioid Use Disorder Among Ohio's Medicaid Population: Prevalence Estimates From 19 Counties Using a Multiplier Method.

The decades-long overdose epidemic in the United States is driven by opioid misuse. Overdoses commonly, although not exclusively, occur in individuals with opioid use disorder (OUD). To allocate adequate resources and develop appropriately scaled public health responses, accurate estimation of the prevalence of OUD is needed. Indirect methods (e.g., a multiplier method) of estimating prevalence of problematic substance-use behavior circumvent some limitations of household surveys and use of administrative data. We used a multiplier method to estimate OUD prevalence among the adult Medicaid population (ages 18-64 years) in 19 Ohio counties that are highly affected by overdose. We used Medicaid claims data and the US National Vital Statistics System overdose death data, which were linked at the person level. A statistical model leveraged opioid-related death rate information from a group with known OUD to estimate prevalence among a group with unknown OUD status given recorded opioid-related deaths in that group. We estimated that 13.6% of the total study population had OUD in 2019. Men (16.7%) had a higher prevalence of OUD than women (11.4%), and persons aged 35-54 had the highest prevalence (16.7%). Our approach to prevalence estimation has important implications for OUD surveillance and treatment in the United States.

Inherited variants at 3q13.33 and 3p24.1 are associated with risk of diffuse large B-cell lymphoma and implicate immune pathways.

We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10-13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10-12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology.

Circulating levels of adiponectin, an adipocyte-secreted protein associated with cardiovascular and metabolic risk, are highly heritable. To gain insights into the biology that regulates adiponectin levels, we performed an exome array meta-analysis of 265,780 genetic variants in 67,739 individuals of European, Hispanic, African American, and East Asian ancestry. We identified 20 loci associated with adiponectin, including 11 that had been reported previously (p < 2 × 10-7). Comparison of exome array variants to regional linkage disequilibrium (LD) patterns and prior genome-wide association study (GWAS) results detected candidate variants (r2 > .60) spanning as much as 900 kb. To identify potential genes and mechanisms through which the previously unreported association signals act to affect adiponectin levels, we assessed cross-trait associations, expression quantitative trait loci in subcutaneous adipose, and biological pathways of nearby genes. Eight of the nine loci were also associated (p < 1 × 10-4) with at least one obesity or lipid trait. Candidate genes include PRKAR2A, PTH1R, and HDAC9, which have been suggested to play roles in adipocyte differentiation or bone marrow adipose tissue. Taken together, these findings provide further insights into the processes that influence circulating adiponectin levels.