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Abstract Background We aimed to develop risk tools for dementia, stroke, myocardial infarction (MI), and diabetes, for adults aged ≥ 65 years using shared risk factors. Methods Data were obtained from 10 population-based cohorts (N = 41,755) with median follow-up time (years) for dementia, stroke, MI, and diabetes of 6.2, 7.0, 6.8, and 7.4, respectively. Disease-free participants at baseline were included, and 22 risk factors (sociodemographic, medical, lifestyle, laboratory biomarkers) were evaluated. Two risk tools (DemNCD and DemNCD-LR based on Fine and Gray sub-distribution and logistic regression [LR], respectively) were developed and validated. Predictive accuracies of these risk tools were assessed using Harrel’s C-statistics and area under the curve (AUC) and 95% confidence interval (CI). Model calibration was conducted using Hosmer–Lemeshow goodness of fit test along calibration plots. Results Both the DemNCD and DemNCD-LR resulted in similar predictive accuracy for each outcome. The overall AUC (95% CI) for dementia, stroke, MI, and diabetes risk tool were 0·68 (0·65, 0·70), 0·58 (0·54, 0·61), 0·65 (0·61, 0·68), and 0·68 (0·64, 0·72), respectively, for males. For females, these figures were 0·65 (0·63, 0·67), 0·55 (0·52, 0·57), 0·65 (0·62, 0·68), and 0·61 (0·57, 0·65). Conclusions The DemNCD is the first tool to predict both dementia and multiple cardio-metabolic diseases using comprehensive risk factors and provided similar predictive accuracy to existing risk tools. It has similar predictive accuracy as tools designed for single outcomes in this age-group. DemNCD has the potential to be used in community and clinical settings as it includes self-reported and routinely available clinical measures.

Abstract Aims Parameters derived from reservoir‐excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir‐excess pressure parameters could have a detrimental effect on highly‐perfused organs like the heart. We aimed to cross‐sectionally determine whether reservoir‐excess pressure parameters were associated with N‐terminal pro‐brain‐type natriuretic peptide (NT‐proBNP) in older adults. Methods We studied 868 older adults with diverse cardiovascular risk. Reservoir‐excess pressure parameters were obtained through radial artery tonometry including reservoir pressure integral, peak reservoir pressure, excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC). Plasma levels of NT‐proBNP, as a biomarker of cardiac overload, were analysed by the Proximity Extension Assay technology. Results Multivariable linear regression analyses revealed that all reservoir‐excess pressure parameters studied were associated with NT‐proBNP after adjusting for age and sex. After further adjustments for conventional cardiovascular risk factors, INTXSP [β = 0.191 (95% confidence interval, CI: 0.099, 0.283), P

Abstract Wildlife disease surveillance programs and research studies track infection and identify risk factors for wild populations, humans and agriculture. Often, several types of samples are collected from individuals to provide more complete information about an animal's infection history. Methods that jointly analyse multiple data streams to study disease emergence and drivers of infection via epidemiological process models remain underdeveloped. Joint‐analysis methods can more thoroughly analyse all available data, more precisely quantifying epidemic processes, outbreak status, and risks. We contribute a paired data modelling approach that analyses multiple samples from individuals. We use ‘characterization maps’ to link paired data to epidemiological processes through a hierarchical statistical observation model. Our approach can provide both Bayesian and frequentist estimates of epidemiological parameters and state. Our approach can also incorporate test sensitivity and specificity, and we propose model fit diagnostics. We motivate our approach through the need to use paired pathogen and antibody detection tests to estimate parameters and infection trajectories for the widely applicable susceptible, infectious, recovered (SIR) model. We contribute general formulas to link characterization maps to arbitrary process models and datasets and an extended SIR model that better accommodates paired data. We find via simulation that paired data can more efficiently estimate SIR parameters than unpaired data, requiring samples from 5 to 10 times fewer individuals. We use our method to study SARS‐CoV‐2 in wild white‐tailed deer (Odocoileus virginianus) from three counties in the United States. Estimates for average infectious times corroborate captive animal studies. The estimated average cumulative proportion of infected deer across the three counties is 73%, and the basic reproductive number (R0) is 1.88. Wildlife disease surveillance programs and research studies can use our methods to jointly analyse paired data to estimate epidemiological process parameters and track outbreaks. Paired data analyses can improve precision and accuracy when sampling is limited. Our methods use general statistical theory to let applications extend beyond the SIR model we consider and to more complicated examples of paired data. The methods can also be embedded in larger hierarchical models to provide landscape‐scale risk assessment and identify drivers of infection.

Bicky Thapa,1,* Navonil De Sarkar,2– 4,* Subhajit Giri,2,3 Komal Sharma,2– 4 Mingee Kim,5 Deepak Kilari1 1Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 2Medical College of Wisconsin Cancer Center, Milwaukee, WI, USA; 3Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA; 4Data Science Institute, Medical College of Wisconsin, Milwaukee, WI, USA; 5School of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA*These authors Contributed equally to this workCorrespondence: Deepak Kilari, Email dkilari@mcw.eduAbstract: Metastatic castrate-resistant prostate cancer (mCRPC) is associated with poor prognosis. DNA damage response (DDR) genes are commonly altered in mCRPC rendering them as promising therapeutic targets. Poly (ADP ribose) polymerase inhibitors (PARPi) demonstrated antitumor activity in mCRPC patients with DDR gene mutations through synthetic lethality. Multiple clinical trials with PARPi monotherapy exhibited encouraging clinical outcomes in selected patients with mCRPC. More recently, three Phase III randomized clinical trials (RCTs) combining PARPi with androgen receptor signaling inhibitors (ARSIs) demonstrated improved antitumor activity compared to ARSI monotherapy in mCRPC patients as the first-line therapy. Clinical benefit was more pronounced in patients harboring DDR alterations, specifically BRCA1/2. Interestingly, antitumor activity was also observed irrespective of DDR gene mutations, highlighting BRCAness phenotype with androgen receptor blockade resulting in synergistic activity between ARSIs and PARPi. In this review, we discuss the clinical efficacy and safety data of the combination of PARPi plus ARSI in all Phase 3 randomized controlled trials (RCTs), emphasizing strategies for patient selection and highlighting emerging trends based on clinical trial data.Keywords: PARP inhibitors, talazoparib, ARSI, DDR genes, HRD, metastatic CRPC

Abstract Background The COVID-19 pandemic has claimed around 170,000 lives among nursing home residents and staff in the United States through April 2023. In a cluster randomized controlled trial (RCT) with 136 nursing homes, we delivered training to improve COVID-19 infection control best practices. We sought to assess the implementation of infection control practices in participating nursing homes. Methods Concurrent with the delivery of the RCT (January-November 2021), we surveyed nursing home administrators (NHAs, n = 38) at baseline and 6-month follow-up. Using validated items from the Centers for Disease Control and Prevention (CDC), the surveys inquired about 80 infection control best-practice activities (yes/no). The survey also asked seven scales corresponding to inner setting factors that may have impacted implementation. We assessed changes in infection control practices and inner setting factors between baseline and 6-month follow-up. Results Overall, the implementation of 11 best practices changed over time. NHAs reported an increase in the availability of informational materials for residents and families (84% vs. 100%, p = 0.031), the use of alcohol-based hand sanitizer over soap (76% vs. 97%, p = 0.008), and the development of contingency plans for increased postmortem care (53% vs. 82%, p = 0.013). The implementation of four best-practice visitation policies and three communal restrictions decreased between baseline and 6-month follow-up (all p

Abstract Purpose Radiolabelled fibroblast activation protein inhibitors (FAPIs) are becoming increasingly important for imaging various tumour diseases. However, it is essential to be aware of potential pitfalls. Here, we investigate FAP expression in the thyroid gland in autoimmune thyroiditis (AIT). Methods AIT patients with pathological thyroid uptake on [68Ga]Ga-FAPI PET were compared with glucose metabolism on 2-[18F]FDG PET in terms of SUVmax/SUVpeak/SUVmean/tissue-to-background ratio (TBR), and with a healthy control group. Results Between September 2019 and July 2021, 6 patients presented with a visually increased thyroid uptake and TBR on [68Ga]Ga-FAPI PET. In the retrospective clinical work-up, all patients had known or newly diagnosed AIT. Compared to a matched healthy control group, FAP expression and glucose metabolism were significantly increased ([68Ga]Ga-FAPI (SUVpeak): 7.0 vs. 1.7; p = 0.004/(TBRbloodpool): 6.8 vs. 1.7; p = 0.002; 2-[18F]FDG (SUVpeak): 3.9 vs. 1.4; p = 0.004/(TBRbloodpool): 4.0 vs. 1.2; p = 0.041). However, there was no significant difference in median uptake between [68Ga]Ga-FAPI and 2-[18F]FDG PET (SUVpeak: 7.3 vs. 5.6; p = 0.104). Conclusion Patients with AIT show higher thyroid uptake on [68Ga]Ga-FAPI and 2-[18F]FDG PET. Incidental thyroid uptake is another pitfall in the interpretation of [68Ga]Ga-FAPI PET and should prompt a clinical work-up.

Abstract The spatial organization of a neuronal circuit is critically important for its function since the location of neurons is often associated with function. In the cerebellum, the major output of the cerebellar cortex are synapses made from Purkinje cells onto neurons in the cerebellar nuclei, yet little has been known about the spatial organization of these synapses. We explored this question using whole-cell electrophysiology and optogenetics in acute sagittal cerebellar slices to produce spatial connectivity maps of cerebellar cortical output in mice. We observed non-random connectivity where Purkinje cell inputs clustered in cerebellar transverse zones: while many nuclear neurons received inputs from a single zone, several multi-zonal connectivity motifs were also observed. Single neurons receiving input from all four zones were overrepresented in our data. These findings reveal that the output of the cerebellar cortex is spatially structured and represents a locus for multimodal integration in the cerebellum.

Background: Per- and polyfluoroalkyl substances (PFAS) are ubiquitous chemicals routinely detected in personal care products (PCPs). However, few studies have evaluated the impact of PCP use on PFAS concentrations in pregnant and lactating populations. Objective: We investigated associations between PCP use and PFAS concentrations in prenatal plasma and human milk. Methods: We leveraged the Maternal-Infant Research on Environmental Chemicals (MIREC) Study to evaluate the contribution of PCP use on PFAS concentrations in prenatal plasma (6 to 13 weeks’ gestation; n = 1,940) and human-milk (2 to 10 weeks’ postpartum; n = 664). Participants reported frequency of use across 8 PCP categories during the 1st and 3rd trimesters, 1 to 2 days postpartum, and 2 to 10 weeks’ postpartum. We used adjusted linear regression models to quantify percent differences and corresponding 95 % confidence intervals. Results: In 1st trimester pregnant people, we found higher use of nailcare products (≥once a week vs. never: perfluorooctanoic acid (PFOA): 21 % [9.7 %, 32 %]; perfluorooctane-sulfonic acid (PFOS): 11 % [0.3 %, 23 %]), fragrances (daily vs. never: PFOA: 14 % [7.8 %, 21 %]; PFOS: 7.8 % [1.3 %, 15 %]), makeup (daily vs. never: PFOA: 14 % [5.8 %, 23 %]), hair dyes (never vs. 1-2 times during pregnancy: PFOA: 8.3 % [2.4 %, 15 %]), and hair sprays or gels (daily vs. never: PFOA: 12 % [5.0 %, 19 %], PFOS: 7.1 % [0.2 %, 15 %]) were associated with higher plasma PFAS concentrations. Similar results were observed for 3rd trimester PCP use and 2 to 10 weeks’ postpartum human-milk PFAS concentrations. In addition, we also found that people using colored-permanent dye 1 to 2 days postpartum had higher Sm-PFOS (18 % [2.7 %, 35 %]), PFOA (16 % [4.3 %, 29 %]), and perfluorononanoic acid (17 % [3.6 %, 33 %]) postpartum human-milk concentrations. Conclusions: Our results show that PCP use may be a modifiable source of PFAS exposure in pregnant and lactating populations. These results along with growing scientific evidence can help inform PFAS regulation and guide individual choices to reduce PFAS exposure.

Abstract Objectives The Dunning–Kruger effect (DKE) is a cognitive bias wherein individuals who are unskilled overestimate their abilities, while those who are skilled tend to underestimate their capabilities. The purpose of this investigation is to determine if the DKE exists among American Board of Emergency Medicine (ABEM) in‐training examination (ITE) participants. Methods This is a prospective, cross‐sectional survey of residents in Accreditation Council for Graduate Medical Education (ACGME)‐accredited emergency medicine (EM) residency programs. All residents who took the 2022 ABEM ITE were eligible for inclusion. Residents from international programs, residents in combined training programs, and those who did not complete the voluntary post‐ITE survey were excluded. Half of the residents taking the ITE were asked to predict their self‐assessment of performance (percent correct), and the other half were asked to predict their performance relative to peers at the same level of training (quintile estimate). Pearson's correlation (r) was used for parametric interval data comparisons and a Spearman's coefficient (ρ) was determined for quintile‐to‐quintile comparisons. Results A total of 7568 of 8918 (84.9%) residents completed their assigned survey question. A total of 3694 residents completed self‐assessment (mean predicted percentage correct 67.4% and actual 74.6%), with a strong positive correlation (Pearson's r 0.58, p

Highly social top marine predators, including many cetaceans, exhibit culturally learned ecological behaviours such as diet preference and foraging strategy that can affect their resilience to competition or anthropogenic impacts. When these species are also endangered, conservation efforts require management strategies based on a comprehensive understanding of the variability in these behaviours. In the northeast Pacific Ocean, three partially sympatric populations of resident killer whales occupy coastal ecosystems from California to Alaska. One population (southern resident killer whales) is endangered, while another (southern Alaska resident killer whales) has exhibited positive abundance trends for the last several decades. Using 185 faecal samples collected from both populations between 2011 and 2021, we compare variability in diet preference to provide insight into differences in foraging patterns that may be linked with the relative success and decline of these populations. We find broad similarities in the diet of the two populations, with differences arising from spatiotemporal and social variability in resource use patterns, especially in the timing of shifts between target prey species. The results described here highlight the importance of comprehensive longitudinal monitoring of foraging ecology to inform management strategies for endangered, highly social top marine predators.

Abstract Background This study investigated the role of emotion regulation in relation to the links between fear of missing out (i.e., FOMO) and two components of problematic internet use: problematic social media use and doomscrolling. Methods Participants (N = 603, M age = 30.41, SD age = 7.64; 49.1% male-identifying) completed measures of fear of missing out, intrapersonal and interpersonal emotion regulation, and problematic social media use, and doomscrolling. A parallel mediation model was tested to examine the nature of the associations between fear of missing out, intrapersonal, and interpersonal emotion regulation, in accounting for variance in the outcome measures. Results Analyses revealed that the effect of fear of missing out on problematic social media use was fully mediated by both intrapersonal and interpersonal emotion regulation. In contrast, the effect on doomscrolling was fully mediated by intrapersonal emotion regulation only. Conclusions Findings clarify the role of emotion regulation in explaining the relationship between fear of missing out and two types of problematic internet use, indicating a need to consider individual differences in emotion regulation in an evolving social media landscape.

Abstract Background Plastic pollution is a severe threat to marine ecosystems. While some microbial enzymes can degrade certain plastics, the ability of the global ocean microbiome to break down diverse environmental plastics remains limited. We employed metatranscriptomic data from an international ocean survey to explore global and regional patterns in microbial plastic degradation potential. Results On a global oceanic scale, we found no significant correlation between levels of plastic pollution and the expression of genes encoding enzymes putatively identified as capable of plastic degradation. Even when looking at different regional scales, ocean depth layers, or plastic types, we found no strong or even moderate correlation between plastic pollution and relative abundances of transcripts for enzymes with presumed plastic biodegradation potential. Our data, however, indicate that microorganisms in the Southern Ocean show a higher potential for plastic degradation, making them more appealing candidates for bioprospecting novel plastic-degrading enzymes. Conclusion Our research contributes to understanding the complex global relationship between plastic pollution and microbial plastic degradation potential. We reveal that the transcription of putative plastic-degrading genes in the global ocean microbiome does not correlate to marine plastic pollution, highlighting the ongoing danger that plastic poses to marine environments threatened by plastic pollution.

Abstract Background Prenatal or early childhood secondhand tobacco smoke (SHS) exposure increases obesity risk. However, the potential mechanisms underlying this association are unclear, but obesogenic eating behaviors are one pathway that components of SHS could perturb. Our aim was to assess associations of prenatal and early childhood SHS exposure with adolescent eating behaviors. Methods Data came from a prospective pregnancy and birth cohort (N = 207, Cincinnati, OH). With multiple informant models, we estimated associations of prenatal (mean of 16 and 26 weeks of gestation maternal serum cotinine concentrations) and early childhood cotinine (average concentration across ages 12, 24, 36, and 48 months) with eating behaviors at age 12 years (Child Eating Behaviors Questionnaire). We tested whether associations differed by exposure periods and adolescent’s sex. Models adjusted for maternal and child covariates. Results We found no statistically significant associations between cotinine measures and adolescent’s eating behaviors. Yet, in females, prenatal cotinine was associated with greater food responsiveness (β: 0.23; 95% CI: 0.08, 0.38) and lower satiety responsiveness (β: -0.14; 95% CI: -0.26, -0.02); in males, prenatal and postnatal cotinine was related to lower food responsiveness (prenatal: β: -0.25; 95% CI: -0.04, -0.06; postnatal: β: -0.36; 95% CI: -0.06, -0.11). No significant effect modification by sex or exposure window was found for other eating behaviors. Conclusion Prenatal and early childhood SHS exposures were not related to adolescent’s eating behavior in this cohort; however, biological sex may modify these associations.

Abstract Protein synthesis terminates when a stop codon enters the ribosome’s A-site. Although termination is efficient, stop codon readthrough can occur when a near-cognate tRNA outcompetes release factors during decoding. Seeking to understand readthrough regulation we used a machine learning approach to analyze readthrough efficiency data from published HEK293T ribosome profiling experiments and compared it to comparable yeast experiments. We obtained evidence for the conservation of identities of the stop codon, its context, and 3’-UTR length (when termination is compromised), but not the P-site codon, suggesting a P-site tRNA role in readthrough regulation. Models trained on data from cells treated with the readthrough-promoting drug, G418, accurately predicted readthrough of premature termination codons arising from CFTR nonsense alleles that cause cystic fibrosis. This predictive ability has the potential to aid development of nonsense suppression therapies by predicting a patient’s likelihood of improvement in response to drugs given their nonsense mutation sequence context.

Objective To compare a remotely supervised weight loss and exercise intervention to lifestyle counseling for effects on cardiovascular disease risk, disease activity, and patient‐reported outcomes in older patients with rheumatoid arthritis (RA) and overweight/obesity. Methods Twenty older (60–80 years), previously sedentary participants with seropositive RA and overweight/obesity were randomized to 16 weeks of either Supervised Weight loss and Exercise Training (SWET) or Counseling Health As Treatment (CHAT). The SWET group completed aerobic training (150 minutes/week moderate‐to‐vigorous intensity), resistance training (two days/week), and a hypocaloric diet (7% weight loss goal). The CHAT control group completed two lifestyle counseling sessions followed by monthly check‐ins. The primary outcome was a composite metabolic syndrome z‐score (MSSc) derived from fasting glucose, triglycerides, high density lipoprotein–cholesterol, minimal waist circumference, and mean arterial pressure. Secondary outcomes included RA disease activity and patient‐reported outcomes. Results Both groups improved MSSc (absolute change −1.67 ± 0.64 in SWET; −1.34 ± 1.30 in CHAT; P

Mihyeon Kim,1 Sarah Lyon-Caen,2 Sam Bayat,3 Claire Philippat,2 Sabine Plancoulaine1,4 1Université Paris Cité and Université Sorbonne Paris Nord, Inserm, INRAE, Center for Research in Epidemiology and StatisticS (CRESS), Paris, F-75004, France; 2University Grenoble Alpes, Inserm U1209, CNRS UMR 5309, Team of Environmental Epidemiology applied to Development and Respiratory Health, Institute for Advanced Biosciences, Grenoble, France; 3STROBE Inserm UA7 Laboratory & Grenoble University Hospital, Sept. of Pulmonology, Grenoble, France; 4Université Claude Bernard Lyon 1, CNRS, INSERM, Centre de Recherche en Neurosciences de Lyon CRNL U1028 UMR5292, WAKING, Bron, F-69500, FranceCorrespondence: Sabine Plancoulaine, INSERM U1153, Team 6 EAROH, 16 Avenue Paul Vaillant Couturier, Villejuif Cedex, 94807, France, Email sabine.plancoulaine@inserm.frObjective: We investigated maternal and paternal sleep evolution from 3 to 36 months postpartum, their interrelations and predictors in the SEPAGES cohort.Methods: Sleep information (night sleep duration [NSD], weekend daytime sleep duration [DSD] and subjective sleep loss [SSL]) was collected by self-administered questionnaires at 3, 18, 24 and 36 months postpartum in the SEPAGES French cohort that included 484 mothers and 410 fathers. Group-based multi-trajectory modelling was used to identify maternal, paternal and couple sleep multi-trajectory groups among 188 couples reporting sleep data for at least 2 time points. Multinomial logistic regression was used to assess associations between parental sleep multi-trajectories and early characteristics such as sociodemographic, chronotypes, child sex, birth seasonality or breastfeeding duration.Results: We identified three maternal (M1-M3), paternal (F1-F3) and couple (C1-C3) sleep multi-trajectory groups with similar characteristics: a group with short NSD and high SSL prevalence (M1, F2, C2), a group with long NSD but medium SSL prevalence (M2, F3, C3) and a group with long NSD and low SSL prevalence (M3, F1, C1). Mothers with the shortest NSD (M1) were less likely to have a partner with long NSD (F2). As compared with long NSD and low SSL prevalence (C1), couples with short NSD and high SSL prevalence (C2) were less likely to have had a first child born in the autumn and fathers in C2 had a later chronotype.Conclusion: We identified distinct sleep multi-trajectory groups for mothers, fathers and couples from 3- to 36-month postpartum. Sleep patterns within couples were homogeneous.Keywords: multi group-based-trajectory modelling, parental sleep, sleep epidemiology, sleep interrelation

Introduction The growing population of older drivers presents challenges for road safety attributed to age-related declines and increased crash fatality rates. However, enabling older people to maintain their health and independence through continued safe driving is important. This study focuses on the urgent need for cost-effective interventions that reduce crash risk while supporting older drivers to remain driving safely for longer. Our study aims to evaluate the effectiveness of three behavioural interventions for older driver safety. These include an online road-rules refresher workshop, tailored feedback on driving performance and two tailored driving lessons.Methods and analysis A single-blind three-parallel group superiority randomised controlled trial will be conducted with 198 urban licensed drivers aged 65 years and older, allowing for 4% attrition. This sample size provides 80% power to detect a difference with an alpha of 0.05. Participants will be selected based on a standardised on-road test that identifies them as moderately unsafe drivers. Interventions, spanning a 3-month period, aim to improve driving safety. Their effectiveness will be assessed through a standardised on-road assessment of driving safety at 3 months (T1) and 12 months postintervention (T2). Additionally, monthly self-reported driving diaries will provide data on crashes and incidents.This trial has the potential to identify cost-effective approaches for improving safety for older drivers and contribute to evidence-based health policy, clinical practice and guidelines.Ethics and dissemination Ethical approval was obtained by the University of New South Wales Human Research Ethics Committee (HC190439, 22 August 2019). The results of the study will be disseminated in peer-reviewed journals and research conferences.Trial registration number ACTRN12622001515785.

Background and purpose: Deep-learning (DL) models for segmentation of the gross tumor volume (GTV) in radiotherapy are generally based on clinical delineations which suffer from inter-observer variability. The aim of this study was to compare performance of a DL-model based on clinical glioblastoma GTVs to a model based on a single-observer edited version of the same GTVs. Materials and methods: The dataset included imaging data (Computed Tomography (CT), T1, contrast-T1 (T1C), and fluid-attenuated-inversion-recovery (FLAIR)) of 259 glioblastoma patients treated with post-operative radiotherapy between 2012 and 2019 at a single institute. The clinical GTVs were edited using all imaging data. The dataset was split into 207 cases for training/validation and 52 for testing.GTV segmentation models (nnUNet) were trained on clinical and edited GTVs separately and compared using Surface Dice with 1 mm tolerance (sDSC1mm). We also evaluated model performance with respect to extent of resection (EOR), and different imaging combinations (T1C/T1/FLAIR/CT, T1C/FLAIR/CT, T1C/FLAIR, T1C/CT, T1C/T1, T1C). A Wilcoxon test was used for significance testing. Results: The median (range) sDSC1mm of the clinical-GTV-model and edited-GTV-model both evaluated with the edited contours, was 0.76 (0.43–0.94) vs. 0.92 (0.60–0.98) respectively (p

Emerging infectious diseases with zoonotic potential often have complex socioecological dynamics and limited ecological data, requiring integration of epidemiological modeling with surveillance. Although our understanding of SARS-CoV-2 has advanced considerably since its detection in late 2019, the factors influencing its introduction and transmission in wildlife hosts, particularly white-tailed deer (Odocoileus virginianus), remain poorly understood. We use a Susceptible-Infected-Recovered-Susceptible epidemiological model to investigate the spillover risk and transmission dynamics of SARS-CoV-2 in wild and captive white-tailed deer populations across various simulated scenarios. We found that captive scenarios pose a higher risk of SARS-CoV-2 introduction from humans into deer herds and subsequent transmission among deer, compared to wild herds. However, even in wild herds, the transmission risk is often substantial enough to sustain infections. Furthermore, we demonstrate that the strength of introduction from humans influences outbreak characteristics only to a certain extent. Transmission among deer was frequently sufficient for widespread outbreaks in deer populations, regardless of the initial level of introduction. We also explore the potential for fence line interactions between captive and wild deer to elevate outbreak metrics in wild herds that have the lowest risk of introduction and sustained transmission. Our results indicate that SARS-CoV-2 could be introduced and maintained in deer herds across a range of circumstances based on testing a range of introduction and transmission risks in various captive and wild scenarios. Our approach and findings will aid One Health strategies that mitigate persistent SARS-CoV-2 outbreaks in white-tailed deer populations and potential spillback to humans.

Problematic pornography use is a growing area of interest necessitating a deeper understanding of its contributing factors. Loneliness and emotion regulation difficulties have been advanced as factors that may exacerbate or perpetuate PPU, however, to date, researchers typically consider these factors in isolation. In addition, the evolving landscape of problematic pornography is further shaped by the emergence of pornography content creators. This study explores the relationships between loneliness, emotion regulation difficulties and problematic pornography use and individuals’ interactions with pornography content creators. Specifically, we examine whether emotion regulation difficulties mediate the relationship between loneliness and PPU and whether this mediation is contingent on interactions with content creators. A total of 213 adults (Mage = 35.57 years, SD = 16.90; 77.50 % men) participants completed an online questionnaire assessing PPU, emotion regulation difficulties and loneliness. Results revealed loneliness is associated with increased PPU and emotion regulation difficulties. Emotion regulation difficulties, in turn, relate to PPU. Though interaction with pornographic content creators was associated with reduced PPU, interacting with content creators did not moderate the effect of emotion regulation on the relationship between loneliness and PPU. Our findings support the hypothesised model, suggesting that emotion regulation difficulties mediate the relationship between loneliness and PPU. The identified mediating role of emotion regulation difficulties provides a foundation for further investigations into the underlying mechanisms connecting emotional well-being and problematic pornography use, offering potential directions for future research.

One Health recognizes the health of humans, agriculture, wildlife, and the environment are interrelated. The concept has been embraced by international health and environmental authorities such as WHO, WOAH, FAO, and UNEP, but One Health approaches have been more practiced by researchers than national or international authorities. To identify priorities for operationalizing One Health beyond research contexts, we conducted 41 semi-structured interviews with professionals across One Health sectors (public health, environment, agriculture, wildlife) and institutional contexts, who focus on national-scale and international applications. We identify important challenges, solutions, and priorities for delivering the One Health agenda through government action. Participants said One Health has made progress with motivating stakeholders to attempt One Health approaches, but achieving implementation needs more guidance (action plans for how to leverage or change current government infrastructure to accommodate cross-sector policy and strategic mission planning) and facilitation (behavioral change, dedicated personnel, new training model).

Abstract We implicated the X-chromosome THOC2 gene, which encodes the largest subunit of the highly-conserved TREX (Transcription-Export) complex, in a clinically complex neurodevelopmental disorder with intellectual disability as the core phenotype. To study the molecular pathology of this essential eukaryotic gene, we generated a mouse model based on a hypomorphic Thoc2 exon 37–38 deletion variant of a patient with ID, speech delay, hypotonia, and microcephaly. The Thoc2 exon 37–38 deletion male (Thoc2 Δ/Y ) mice recapitulate the core phenotypes of THOC2 syndrome including smaller size and weight, and significant deficits in spatial learning, working memory and sensorimotor functions. The Thoc2 Δ/Y mouse brain development is significantly impacted by compromised THOC2/TREX function resulting in R-loop accumulation, DNA damage and consequent cell death. Overall, we suggest that perturbed R-loop homeostasis, in stem cells and/or differentiated cells in mice and the patient, and DNA damage-associated functional alterations are at the root of THOC2 syndrome.

Abstract Background Cannabidiol (CBD) has therapeutic potential in companion animals. Shorter‐term studies have determined that CBD is well tolerated in dogs with mild adverse effects and an increase in alkaline phosphatase (ALP) activity. There is need to assess CBD's long‐term tolerability. Hypothesis Determine the long‐term tolerability of CBD administered PO to healthy dogs for 36 weeks at dosages of 5 and 10 mg/kg body weight (BW)/day. Our hypothesis was that CBD would be well tolerated by dogs. Methods Eighteen healthy adult beagle dogs were randomly assigned to 3 groups of 6 each that received 0, 5, or 10 mg/kg BW/day CBD PO. Dogs were adapted to their housing for 3 weeks and received treatment for 36 weeks once daily with food. Adverse events (AEs) were recorded daily. Blood biochemistry profiles were monitored every 4 weeks. Data were analyzed as repeated measures over time using a mixed model, with significance at α = 0.05. Results The 0 and 5 mg/kg treatment groups had similar fecal scores, and the 10 mg/kg treatment group had higher frequency of soft feces. No other significant AEs were noted. An increase (P

Abstract Besides vaccines, the development of antiviral drugs targeting SARS-CoV-2 is critical for preventing future COVID outbreaks. The SARS-CoV-2 main protease (Mpro), a cysteine protease with essential functions in viral replication, has been validated as an effective drug target. Here, we show that Mpro is subject to redox regulation in vitro and reversibly switches between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues. These include a disulfide-dithiol switch between the catalytic cysteine C145 and cysteine C117, and generation of an allosteric cysteine-lysine-cysteine SONOS bridge that is required for structural stability under oxidative stress conditions, such as those exerted by the innate immune system. We identify homo- and heterobifunctional reagents that mimic the redox switching and inhibit Mpro activity. The discovered redox switches are conserved in main proteases from other coronaviruses, e.g. MERS-CoV and SARS-CoV, indicating their potential as common druggable sites.

Jihye Lim,1 Hyeon-Gi Jeon,2 Yeonjoo Seo,1 Moonjin Kim,3 Ja Un Moon,4 Se Hyun Cho1 1Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Department of Core Platform Team, SOCAR Incorporated, Seoul, Republic of Korea; 3Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea; 4Department of Pediatrics, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Se Hyun Cho, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Yeouido St. Mary`s Hospital, College of Medicine, The Catholic University of Korea, 63-ro 10, Yeongdeungpo-gu, Seoul, 07345, Republic of Korea, Tel +82-2-3779-1269, Fax +82-02-780-3132, Email chowhang@catholic.ac.krPurpose: Accurate estimation of survival is of utmost importance in patients with hepatocellular carcinoma (HCC) and extrahepatic metastasis. This study aimed to develop a survival prediction model using real-world data.Patients and Methods: A total of 993 patients with treatment-naïve HCC and extrahepatic metastasis were included from 13 Korean hospitals between 2013 and 2018. Patients were randomly divided into a training set (70.0%) and a test set (30.0%). The eXtreme Gradient Boosting (XGBoost) algorithm was applied to predict survival at 3, 6, and 12 months.Results: The mean age of the patients was 60.8 ± 12.3 years, and 85.4% were male. During the study period, 96.1% died, and median survival duration was 4.0 months. In multivariate analysis, Child-Pugh class, number and size of tumors, presence of vascular or bile duct invasion, lung or bone metastasis, serum AFP, and primary anti-HCC treatment were associated with survival. We constructed a model for survival prediction based on the relevant variables, which is available online (https://metastatic-hcc.onrender.com/form). Our model demonstrated high performance, with areas under the receiver operating characteristic curves of 0.778, 0.794, and 0.784 at 3, 6, and 12 months, respectively. Feature importance analysis indicated that the primary anti-HCC treatment had the highest importance.Conclusion: We developed a model to predict the survival of patients with HCC and extrahepatic metastasis, which demonstrated good discriminative ability. Our model would be helpful for personalized treatment and for improving the prognosis.Keywords: liver neoplasms, prognosis, survival rate, probability, algorithms

Mycoviruses are highly genetically diverse and can significantly change their fungal host’s phenotype, yet they are generally under-described in genotypic and biological studies. We propose Botrytis cinerea as a model mycovirus system in which to develop a deeper understanding of mycovirus epidemiology including diversity, impact, and the associated cellular biology of the host and virus interaction. Over 100 mycoviruses have been described in this fungal host. B. cinerea is an ideal model fungus for mycovirology as it has highly tractable characteristics—it is easy to culture, has a worldwide distribution, infects a wide range of host plants, can be transformed and gene-edited, and has an existing depth of biological resources including annotated genomes, transcriptomes, and isolates with gene knockouts. Focusing on a model system for mycoviruses will enable the research community to address deep research questions that cannot be answered in a non-systematic manner. Since B. cinerea is a major plant pathogen, new insights may have immediate utility as well as creating new knowledge that complements and extends the knowledge of mycovirus interactions in other fungi, alone or with their respective plant hosts. In this review, we set out some of the critical steps required to develop B. cinerea as a model mycovirus system and how this may be used in the future.

Very preterm (VPT) infants (born at less than 32 weeks gestational age) are at high risk for various adverse neurodevelopmental deficits. Unfortunately, most of these deficits cannot be accurately diagnosed until the age of 2-5 years old. Given the benefits of early interventions, accurate diagnosis and prediction soon after birth are urgently needed for VPT infants. Previous studies have applied deep learning models to learn the brain structural connectome (SC) to predict neurodevelopmental deficits in the preterm population. However, none of these models are specifically designed for graph-structured data, and thus may potentially miss certain topological information conveyed in the brain SC. In this study, we aim to develop deep learning models to learn the SC acquired at term-equivalent age for early prediction of neurodevelopmental deficits at 2 years corrected age in VPT infants. We directly treated the brain SC as a graph, and applied graph convolutional network (GCN) models to capture complex topological information of the SC. In addition, we applied the supervised contrastive learning (SCL) technique to mitigate the effects of the data scarcity problem, and enable robust training of GCN models. We hypothesize that SCL will enhance GCN models for early prediction of neurodevelopmental deficits in VPT infants using the SC. We used a regional prospective cohort of ∼280 VPT infants who underwent MRI examinations at term-equivalent age from the Cincinnati Infant Neurodevelopment Early Prediction Study (CINEPS). These VPT infants completed neurodevelopmental assessment at 2 years corrected age to evaluate cognition, language, and motor skills. Using the SCL technique, the GCN model achieved mean areas under the receiver operating characteristic curve (AUCs) in the range of 0.72∼0.75 for predicting three neurodevelopmental deficits, outperforming several competing models. Our results support our hypothesis that the SCL technique is able to enhance the GCN model in our prediction tasks.

Abstract Current predictors of clinical outcomes after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are largely limited to preoperative clinical characteristics. N‐terminal‐pro‐brain natriuretic peptide (NT‐pro‐BNP), a biomarker of right ventricular dysfunction, has not yet been well described as one such predictor. From 2017 to 2021, 816 patients with CTEPH referred to the University of California, San Diego for PTE were reviewed for differences in NT‐pro‐BNP to predict preoperative characteristics and postoperative outcomes up to 30 days post‐PTE. For analysis, NT‐pro‐BNP was dichotomized to less than/equal to or greater than 1000 pg/mL based on the mean of the study population. Mean NT‐pro‐BNP was 1095.9 ±1783.4 pg/mL and median was 402.5 pg/mL (interquartile range: 119.5–1410.8). Of the 816 patients included, 250 had NT‐pro‐BNP > 1000 pg/mL. Those with NT‐pro‐BNP > 1000 pg/mL were significantly more likely to have worse preoperative functional class (III–IV) and worse preoperative hemodynamics. Patients with NT‐pro‐BNP > 1000 pg/mL also tended to have more postoperative complications including reperfusion pulmonary edema (22% vs. 5.1%, p 1000 pg/mL had a 2.48 times higher odds (95% confidence interval: 1.45–4.00) of reaching a combined endpoint that included the above complications. Preoperative NT‐pro‐BNP > 1000 pg/mL is a strong predictor of more severe preoperative hemodynamics and identifies patients at higher risk for postoperative complications.

Killer whales (Orcinus orca) are currently recognized as a single ecologically and morphologically diverse, globally distributed species. Multiple morphotypes or ecotypes have been described, often associated with feeding specialization, and several studies have suggested taxonomic revision to include multiple subspecies or species in the genus. We review the ecological, morphological and genetic data for the well-studied ‘resident’ and Bigg’s (aka ‘transient’) ecotypes in the eastern North Pacific and use quantitative taxonomic guidelines and standards to determine whether the taxonomic status of these killer whale ecotypes should be revised. Our review and new analyses indicate that species-level status is justified in both cases, and we conclude that eastern North Pacific Bigg’s killer whales should be recognized as Orcinus rectipinnus (Cope in Scammon, 1869) and resident killer whales should be recognized as Orcinus ater (Cope in Scammon, 1869).

Summary: An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.

Abstract Contact among animals is crucial for various ecological processes, including social behaviors, disease transmission, and predator–prey interactions. However, the distribution of contact events across time and space is heterogeneous, influenced by environmental factors and biological purposes. Previous studies have assumed that areas with abundant resources and preferred habitats attract more individuals and, therefore, lead to more contact. To examine the accuracy of this assumption, we used a use-available framework to compare landscape factors influencing the location of contacts between wild pigs (Sus scrofa) in two study areas in Florida and Texas (USA) from those influencing non-contact space use. We employed a contact-resource selection function (RSF) model, where contact locations were defined as used points and locations without contact as available points. By comparing outputs from this contact RSF with a general, population-level RSF, we assessed the factors driving both habitat selection and contact. We found that the landscape predictors (e.g., wetland, linear features, and food resources) played different roles in habitat selection from contact processes for wild pigs in both study areas. This indicated that pigs interacted with their landscapes differently when choosing habitats compared to when they encountered other individuals. Consequently, relying solely on the spatial overlap of individual or population-level RSF models may lead to a misleading understanding of contact-related ecology. Our findings challenge prevailing assumptions about contact and introduce innovative approaches to better understand the ecological drivers of spatially explicit contact. By accurately predicting the spatial distribution of contact events, we can enhance our understanding of contact based ecological processes and their spatial dynamics.

Abstract Background The food and beverages served in family childcare homes (FCCHs) may play an important role in the development of childhood overweight and obesity. This analysis examines whether children’s diet quality mediates the relationship between foods and beverages served in FCCHs and preschool-aged children’s weight status. Methods Trained and certified staff conducted observations for two days in each FCCH, using the Environment and Policy Assessment and Observation (EPAO) measure to determine the foods and beverages served to children (N = 370) in FCCHs (N = 120). They also used the Dietary Observation in Child Care (DOCC) protocol to assess children’s food and beverage intake during childcare, from which we calculated the Healthy Eating Index-2015 (HEI), a measure of diet quality. Height and weight were measured for each child with parent consent from which the child’s body mass index (BMI) z-scores were calculated. A multilevel mediation analysis was conducted to indicate whether children’s diet quality mediates the relations between food and beverage served in FCCHs and preschool-aged children’s weight status. Results Children’s total HEI scores significantly mediated the relationship between the EPAO subscale Food Provided and children’s BMI z-scores (B=-0.01, p

Children need to be repeatedly and consistently exposed to a variety of vegetables from an early age to achieve an increase in vegetable intake. A focus on enjoyment and learning to like eating vegetables at an early age is critical to forming favourable lifelong eating habits. Coordinated work is needed to ensure vegetables are available and promoted in a range of settings, using evidence-based initiatives, to create an environment that will support children’s acceptance of vegetables. This will help to facilitate increased intake and ultimately realise the associated health benefits. The challenges and evidence base for a new approach are described.

Abstract Background Suicide is a serious public health issue. Distress has been identified as a common risk factor, with research also suggesting that a lack of social connectedness is involved. Methods This quantitative, cross-sectional study investigated the role of perceived burdensomeness and thwarted belongingness in the psychological distress/suicidal ideation pathway in a community sample of 480 Australian adults. Results As expected, distress was found to be a strong predictor of suicidal ideation. Perceived burdensomeness and thwarted belongingness both moderated and mediated the relationship between distress and suicidal ideation. Specifically, distress was more strongly linked to suicide ideation when burdensomeness or thwarted belongingness were also high. This moderating effect was stronger for thwarted belongingness than it was for burdensomeness. These variables also mediated the pathway, in that higher distress related to higher burdensomeness and thwarted belonging, which in turn related to higher suicide ideation. This mediating effect was stronger for burdensomeness than for thwarted belonging. Conclusions Overall, the findings confirm the importance of our social relatedness in suicide. Increasing belongingness and reducing the perception of being a burden on others may be an important intervention strategy for weakening the link between distress and suicide ideation.

Abstract Background Gut microbiota play a key role in the nutrition of many marine herbivorous fishes through hindgut fermentation of seaweed. Gut microbiota composition in the herbivorous fish Kyphosus sydneyanus (family Kyphosidae) varies between individuals and gut sections, raising two questions: (i) is community composition stable over time, especially given seasonal shifts in storage metabolites of dietary brown algae, and (ii) what processes influence community assembly in the hindgut? Results We examined variation in community composition in gut lumen and mucosa samples from three hindgut sections of K. sydneyanus collected at various time points in 2020 and 2021 from reefs near Great Barrier Island, New Zealand. 16S rRNA gene analysis was used to characterize microbial community composition, diversity and estimated density. Differences in community composition between gut sections remained relatively stable over time, with little evidence of temporal variation. Clostridia dominated the proximal hindgut sections and Bacteroidia the most distal section. Differences were detected in microbial composition between lumen and mucosa, especially at genus level. Conclusions High variation in community composition and estimated bacterial density among individual fish combined with low variation in community composition temporally suggests that initial community assembly involved environmental selection and random sampling/neutral effects. Community stability following colonisation could also be influenced by historical contingency, where early colonizing members of the community may have a selective advantage. The impact of temporal changes in the algae may be limited by the dynamics of substrate depletion along the gut following feeding, i.e. the depletion of storage metabolites in the proximal hindgut. Estimated bacterial density, showed that Bacteroidota has the highest density (copies/mL) in distal-most lumen section V, where SCFA concentrations are highest. Bacteroidota genera Alistipes and Rikenella may play important roles in the breakdown of seaweed into useful compounds for the fish host.

Understanding the epidemiology and transmission dynamics of transboundary animal diseases (TADs) among wild pigs (Sus scrofa) will aid in preventing the introduction or containment of TADs among wild populations. Given the challenges associated with studying TADs in free-ranging populations, a surrogate pathogen system may predict how pathogens may circulate and be maintained within wild free-ranging swine populations, how they may spill over into domestic populations, and how management actions may impact transmission. We assessed the suitability of Torque teno sus virus 1 (TTSuV1) to serve as a surrogate pathogen for molecular epidemiological studies in wild pigs by investigating the prevalence, persistence, correlation with host health status and genetic variability at two study areas: Archbold’s Buck Island Ranch in Florida and Savannah River Site in South Carolina. We then conducted a molecular epidemiological case study within Archbold’s Buck Island Ranch site to determine how analysis of this pathogen could inform transmission dynamics of a directly transmitted virus. Prevalence was high in both study areas (40%, n = 190), and phylogenetic analyses revealed high levels of genetic variability within and between study areas. Our case study showed that pairwise host relatedness and geographic distance were highly correlated to pairwise viral genetic similarity. Molecular epidemiological analyses revealed a distinct pattern of direct transmission from pig to pig occurring within and between family groups. Our results suggest that TTSuV1 is highly suitable for molecular epidemiological analyses and will be useful for future studies of transmission dynamics in wild free-ranging pigs.

Wild pigs (Sus scrofa) are one of the most destructive invasive species in the US, known for causing extensive damage to agricultural commodities, natural resources, and property, and for transmitting diseases to livestock. Following the establishment of the National Feral Swine Damage Management Program (NFSDMP) in 2014, the expansion of wild pig populations has been successfully slowed. This paper combines two modeling approaches across eight separate models to characterize the expansion of wild pig populations in the absence of intervention by the NFSDMP and forecasts the value of a subset of resources safeguarded from the threat of wild pigs. The results indicate that if wild pigs had continued spreading at pre-program levels, they would have spread extensively across the US, with significant geographic variation across modeling scenarios. Further, by averting the threat of wild pigs, a substantial amount of crops, land, property, and livestock was safeguarded by the NFSDMP. Cumulatively, between 2014 and 2021, wild pig populations were prevented from spreading to an average of 724 counties and an average of USD 40.2 billion in field crops, pasture, grasses, and hay was safeguarded. The results demonstrate that intervention by the NFSDMP has delivered significant ecological and economic benefits that were not previously known.

Worldwide, the incidence of renal cell carcinoma (RCC) is rising, accounting for approximately 2% of all cancer diagnoses and deaths. The etiology of RCC is still obscure. Here, we assessed the presence of HPyVs in paraffin-embedded tissue (FFPE) resected tissue from patients with RCC by using different molecular techniques. Fifty-five FFPE tissues from 11 RCC patients were included in this study. Consensus and HPyV-specific primers were used to screen for HPyVs. Both PCR approaches revealed that HPyV is frequently detected in the tissues of RCC kidney resections. A total of 78% (43/55) of the tissues tested were positive for at least one HPyV (i.e., MCPyV, HPyV6, HPyV7, BKPyV, JCPyV, or WUyV). Additionally, 25 tissues (45%) were positive for only one HPyV, 14 (25%) for two HPyVs, 3 (5%) for three HPyVs, and 1 one (1%) tissue specimen was positive for four HPyVs. Eleven (20%) RCC specimens were completely devoid of HPyV sequences. MCPyV was found in 24/55 RCC tissues, HPyV7 in 19, and HPyV6 in 8. The presence of MCPyV and HPyV6 was confirmed by specific FISH or RNA-ISH. In addition, we aimed to confirm HPyV gene expression by IHC. Our results strongly indicate that these HPyVs infect RCC and nontumor tissues, possibly indicating that kidney tissues serve as a reservoir for HPyV latency. Whether HPyVs possibly contribute to the etiopathogenesis of RCC remains to be elucidated.

Abstract Objective STXBP1‐related disorders are rare genetic epilepsies and neurodevelopmental disorders, but the impact of symptoms across clinical domains is poorly understood. Disease concept models are formal frameworks to assess the lived experience of individuals and their families and provide a basis for generating outcome measures. Methods We conducted semistructured, qualitative interviews with 19 caregivers of 16 individuals with STXBP1‐related disorders and 7 healthcare professionals. We systematically coded themes using NVivo software and grouped concepts into the domains of symptoms, symptom impact, and caregiver impact. We quantified the frequency of concepts throughout the lifespan and across clinical subgroups stratified by seizure history and developmental trajectories. Results Over 25 hours of interviews, we coded a total of 3626 references to 38 distinct concepts. In addition to well‐recognized clinical features such as developmental delay (n = 240 references), behavior (n = 201), and seizures (n = 147), we identified previously underrepresented symptoms including gastrointestinal (n = 68) and respiratory symptoms (n = 24) and pain (n = 30). The most frequently referenced symptom impacts were autonomy (n = 96), socialization (n = 64), and schooling (n = 61). Emotional impact (n = 354), support (n = 200), and daily life & activities (n = 108) were highly cited caregiver impacts. We found that seizures were more commonly referenced in infancy than in other age groups, while behavior and socialization were more likely to be referred to in childhood. We found that caregivers of individuals with ongoing seizures were less likely to reference developmental delay, possibly due to the relatively high impact of seizures. Significance STXBP1‐related disorders are complex conditions affecting a wide range of clinical and social domains. We comprehensively mapped symptoms and their impact on families to generate a comprehensive disease model as a foundation for clinical endpoints in future trials.

Abstract Environmental surveillance can allow early detection of diseases, which increases management options and can improve disease trajectories. Chronic wasting disease (CWD) in cervids is a significant prion disease that has been spreading across North America since the 1960s, leading to cervid population declines and concern from hunters and state wildlife agencies. White‐tailed deer have a unique breeding season behaviour called scraping, where they deposit urine and saliva at shared sites. Since both these fluids can contain CWD prions, scrape sites have the potential to serve as sentinel sites for environmental surveillance of CWD. To examine this potential, we used camera traps to monitor deer behaviour and collected environmental samples from 105 scrape sites. The 48 km2 study site was located at the centre of the CWD zone in southwestern Tennessee, where CWD prevalence is ~50%. We also sampled scrapes in northern Mississippi at the leading edge of the same CWD distribution to test the potential for early CWD detection using scrape sampling. From camera data, we identified 218 unique bucks visiting 105 scrapes, with a mean of 12.2 ± 7.5 bucks per scrape (mean ± SD, range 1–39) and individual bucks visiting a mean of 5.9 ± 4.6 monitored scrapes each (range 1–23). Using real‐time quaking‐induced conversion (RT‐QuIC), we detected prion seeding activity in 20% of the soil and 41% of the licking branches of the scrape sites within the CWD study area, and in 25% of the soil and 11% of the licking branches of scrape sites sampled at the edge of the known CWD distribution. Our data show there is environmental prion contamination at scrape sites. This supports the idea that scrapes could serve as early warning sentinel sites for CWD surveillance through testing soil and licking branches for prion seeding activity, especially in areas with limited access to harvested deer samples.

African swine fever (ASF) causes significant morbidity and mortality in both domestic and wild suids (Sus scrofa), and disease outbreaks convey profound economic costs to impacted industries due to death loss, the cost of culling exposed/infected animals as the primary disease control measure, and trade restrictions. The co-occurrence of domestic and wild suids significantly complicates ASF management given the potential for wild populations to serve as persistent sources for spillover. We describe the unique threat of African swine fever virus (ASFV) introduction to the United States from epidemiological and ecological perspectives with a specific focus on disease management at the wild-domestic swine interface. The introduction of ASF into domestic herds would require a response focused on containment, culling, and contact tracing. However, detection of ASF among invasive wild pigs would require a far more complex and intensive response given the challenges of detection, containment, and ultimately elimination among wild populations. We describe the state of the science available to inform preparations for an ASF response among invasive wild pigs, describe knowledge gaps and the associated studies needed to fill those gaps, and call for an integrated approach for preparedness that incorporates the best available science and acknowledges sociological attributes and the policy context needed for an integrated disease response.

Many pathogens of humans and livestock also infect wildlife that can act as a reservoir and challenge disease control or elimination. Efficient and effective prioritization of research and management actions requires an understanding of the potential for new tools to improve elimination probability with feasible deployment strategies that can be implemented at scale. Wildlife vaccination is gaining interest as a tool for managing several wildlife diseases. To evaluate the effect of vaccinating white-tailed deer (Odocoileus virginianus), in combination with harvest, in reducing and eliminating bovine tuberculosis from deer populations in Michigan, we developed a mechanistic age-structured disease transmission model for bovine tuberculosis with integrated disease management. We evaluated the impact of pulse vaccination across a range of vaccine properties. Pulse vaccination was effective for reducing disease prevalence rapidly with even low (30%) to moderate (60%) vaccine coverage of the susceptible and exposed deer population and was further improved when combined with increased harvest. The impact of increased harvest depended on the relative strength of transmission modes, i.e., direct vs indirect transmission. Vaccine coverage and efficacy were the most important vaccine properties for reducing and eliminating disease from the local population. By fitting the model to the core endemic area of bovine tuberculosis in Michigan, USA, we identified feasible integrated management strategies involving vaccination and increased harvest that reduced disease prevalence in free-ranging deer. Few scenarios led to disease elimination due to the chronic nature of bovine tuberculosis. A long-term commitment to regular vaccination campaigns, and further research on increasing vaccines efficacy and uptake rate in free-ranging deer are important for disease management.

BackgroundOwing to structural-level, interpersonal-level, and individual-level barriers, Latino men have disproportionately high rates of physical inactivity and experience related chronic diseases. Despite these disparities, few physical activity (PA) interventions are culturally targeted for Latino men. ObjectiveThis study reported the feasibility and acceptability of Hombres Saludables PA intervention for Latino men. We also reported the preliminary efficacy of the intervention on PA change and provided the results of the exploratory moderator and mediator analysis. MethodsWe completed a 6-month, single-blind, pilot randomized controlled trial of Hombres Saludables with Latino men aged between 18 and 65 years. Men were randomized to either (1) a theory-driven, individually tailored, internet-based and SMS text message–based, Spanish-language PA intervention arm or (2) a nutrition and wellness attention contact control arm that was also delivered via the web and SMS text message. We assessed the primary study outcomes of feasibility using participant retention and acceptability using postintervention survey and open-ended interview questions. We measured the preliminary efficacy via change in minutes of moderate to vigorous PA per week using ActiGraph wGT3X-BT accelerometry (primary measure) and self-reported minutes per week using 7-day Physical Activity Recall. Participants completed the assessments at study enrollment and after 6 months. ResultsThe 38 participants were predominantly Dominican (n=8, 21%) or Guatemalan (n=5, 13%), and the mean age was 38.6 (SD 12.43) years. Retention rates were 91% (21/23) for the PA intervention arm and 100% (15/15) for the control arm. Overall, 95% (19/20) of the intervention arm participants reported that the Hombres study was somewhat to very helpful in getting them to be more physically active. Accelerometry results indicated that participants in the intervention group increased their PA from a median of 13 minutes per week at study enrollment to 34 minutes per week at 6 months, whereas the control group participants showed no increases. On the basis of self-reports, the intervention group was more likely to meet the US PA guidelines of 150 minutes per week of moderate to vigorous PA at 6-month follow-up, with 42% (8/19) of the intervention participants meeting the PA guidelines versus 27% (4/15) of the control participants (odds ratio 3.22, 95% CI 0.95-13.69). Exploratory analyses suggested conditional effects on PA outcomes based on baseline stage of motivational readiness, employment, and neighborhood safety. ConclusionsThe PA intervention demonstrated feasibility and acceptability. Results of this pilot study indicate that the Hombres Saludables intervention is promising for increasing PA in Latino men and suggest that a fully powered trial is warranted. Our technology-based PA intervention provides a potentially scalable approach that can improve health in a population that is disproportionately affected by low PA and related chronic disease. Trial RegistrationClinicalTrials.gov NCT03196570; https://classic.clinicaltrials.gov/ct2/show/NCT03196570 International Registered Report Identifier (IRRID)RR2-10.2196/23690

Abstract The discovery and characterization of antigen-specific CD8+ T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapt single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We use this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then construct SCT libraries to capture SARS-CoV-2 specific CD8+ T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes is validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.

Patients with rheumatoid arthritis (RA) remain at an increased risk for cardiovascular disease (CVD) and mortality. RA CVD results from a combination of traditional risk factors and RA‐related systemic inflammation. One hypothetical means of improving overall RA CVD risk is through reduction of excess body weight and increased physical activity. Together, weight loss and physical activity can improve traditional cardiometabolic health through fat mass loss, while also improving skeletal muscle health. Additionally, disease‐related CVD risk may improve as both fat mass loss and exercise reduce systemic inflammation. To explore this hypothesis, 26 older persons with RA and overweight/obesity will be randomized to 16 weeks of a usual care control arm or to a remotely Supervised Weight Loss Plus Exercise Training (SWET) program. A caloric restriction diet (targeting 7% weight loss) will occur via a dietitian‐led intervention, with weekly weigh‐ins and group support sessions. Exercise training will consist of both aerobic training (150 minutes/week moderate‐to‐vigorous exercise) and resistance training (twice weekly). The SWET remote program will be delivered via a combination of video conference, the study YouTube channel, and study mobile applications. The primary cardiometabolic outcome is the metabolic syndrome Z score, calculated from blood pressure, waist circumference, high‐density lipoprotein cholesterol, triglycerides, and glucose. RA‐specific CVD risk will be assessed with measures of systemic inflammation, disease activity, patient‐reported outcomes, and immune cell function. The SWET‐RA trial will be the first to assess whether a remotely supervised, combined lifestyle intervention improves cardiometabolic health in an at‐risk population of older individuals with RA and overweight/obesity.

Abstract Objective: To describe the feasibility, acceptability and results of Strong Families Start at Home, a 6-month pilot trial of a home-based food parenting/nutrition intervention. Design: Pilot randomised controlled trial. Setting: Participants received six visits with a community health worker trained in motivational interviewing (three home visits, three phone calls); an in-home cooking or reading activity; personalised feedback on a recorded family meal or reading activity; text messages and tailored printed materials. Participants: Parents and their 2–5-year-old child were randomised into intervention (responsive food parenting practices/nutrition) or control (reading readiness) groups. Results: Parents (n 63) were mostly mothers (90 %), Hispanic/Latinx (87 %), born outside the USA (62 %), with household incomes

Abstract Background Three-dimensional (3D) human brain spheroids are instrumental to study central nervous system (CNS) development and (dys)function. Yet, in current brain spheroid models the limited variety of cell types hampers an integrated exploration of CNS (disease) mechanisms. Methods Here we report a 5-month culture protocol that reproducibly generates H9 embryonic stem cell-derived human cortical spheroids (hCSs) with a large cell-type variety. Results We established the presence of not only neuroectoderm-derived neural progenitor populations, mature excitatory and inhibitory neurons, astrocytes and oligodendrocyte (precursor) cells, but also mesoderm-derived microglia and endothelial cell populations in the hCSs via RNA-sequencing, qPCR, immunocytochemistry and transmission electron microscopy. Transcriptomic analysis revealed resemblance between the 5-months-old hCSs and dorsal frontal rather than inferior regions of human fetal brains of 19–26 weeks of gestational age. Pro-inflammatory stimulation of the generated hCSs induced a neuroinflammatory response, offering a proof-of-principle of the applicability of the spheroids. Conclusions Our protocol provides a 3D human brain cell model containing a wide variety of innately developing neuroectoderm- as well as mesoderm-derived cell types, furnishing a versatile platform for comprehensive examination of intercellular CNS communication and neurological disease mechanisms.

While our direct observations of the features or behaviours of the stimuli around us tell us much about them (e.g., should they be feared?), the origin of much of our knowledge is often untethered from directly observable properties (e.g., through what we have learned or have been told about them, or “semantic knowledge”). Here, we ask whether otherwise neutral visual stimuli that participants learn to associate with emotional qualities in the lab cause the stimuli to be attended in a similar way as stimuli whose emotional qualities can be discerned through their visual properties. In Experiment 1, participants learned to associate negative or neutral characteristics with neutral faces, which then served as valid or invalid spatial cues to targets in an attentional disengagement paradigm. The performance of participants higher in trait anxiety was consistent with attentional avoidance of faces with learned negative associations, while participants lower in trait anxiety showed a general response slowing in trials with these stimuli, compared to those with neutral associations. In contrast, in Experiment 2, using (visually) expressive (angry) faces, the performance of participants higher in trait anxiety was consistent with difficulty disengaging from visually threatening faces, while the performance of those with lower trait anxiety appeared unaffected by the valence of the stimuli. These findings suggest that (1) emotionality acquired indirectly via learned semantic knowledge impacts how attention is allocated to face stimuli, and this impact is influenced by trait anxiety, and (2) there are differences in the effects of stimulus emotionality depending on whether it is acquired indirectly or directly via the perceptual features of the stimulus. These differences are discussed in the context of the variability of attention bias effects reported in the literature and the time course of impacts of emotionality on stimulus processing.

Background: CFTR nonsense alleles generate negligible CFTR protein due to the nonsense mutation: 1) triggering CFTR mRNA degradation by nonsense-mediated mRNA decay (NMD), and 2) terminating CFTR mRNA translation prematurely. Thus, people with cystic fibrosis (PwCF) who carry nonsense alleles cannot benefit from current modulator drugs, which target CFTR protein. In this study, we examined whether PTBP1 and HNRNPL, two RNA binding proteins that protect a subset of mRNAs with a long 3’ untranslated region (UTR) from NMD, similarly affect CFTR mRNA.Silencing RNAs were used to deplete PTBP1 or HNRNPL in 16HBE14o- human bronchial epithelial cells expressing WT, G542X, or W1282X CFTR. CFTR mRNA abundance was measured relative to controls by quantitative PCR. PTBP1 and HNRNPL were also exogenously expressed in each cell line and CFTR mRNA levels were similarly quantified. Results: PTBP1 depletion reduced CFTR mRNA abundance in all three 16HBE14o- cell lines; HRNPL depletion reduced CFTR mRNA abundance in only the G542X and W1282X cell lines. Notably, decreased CFTR mRNA abundance correlated with increased mRNA decay. Exogenous expression of PTBP1 or HNRNPL increased CFTR mRNA abundance in all three cell lines; HNRNPL overexpression generally increased CFTR to a greater extent in G542X and W1282X 16HBE14o- cells.Our data indicate that PTBP1 and HNRNPL regulate CFTR mRNA abundance by protecting CFTR transcripts from NMD. This suggests that PTBP1 and/or HNRNPL may represent potential therapeutic targets to increase CFTR mRNA abundance and enhance responses to CFTR modulators and other therapeutic approaches in PwCF.

IntroductionAfrican swine fever (ASF) is a notifiable disease of swine that impacts global pork trade and food security. In several countries across the globe, the disease persists in wild boar (WB) populations sympatric to domestic pig (DP) operations, with continued detections in both sectors. While there is evidence of spillover and spillback between the sectors, the frequency of occurrence and relative importance of different risk factors for transmission at the wildlife-livestock interface remain unclear.MethodsTo address this gap, we leveraged ASF surveillance data from WB and DP across Eastern Poland from 2014–2019 in an analysis that quantified the relative importance of different risk factors for explaining variation in each of the ASF surveillance data from WB and DP.ResultsASF prevalence exhibited different seasonal trends across the sectors: apparent prevalence was much higher in summer (84% of detections) in DP, but more consistent throughout the year in WB (highest in winter with 45%, lowest in summer at 15%). Only 21.8% of DP-positive surveillance data included surveillance in WB nearby (within 5 km of the grid cell within the last 4 weeks), while 41.9% of WB-positive surveillance samples included any DP surveillance samples nearby. Thus, the surveillance design afforded twice as much opportunity to find DP-positive samples in the recent vicinity of WB-positive samples compared to the opposite, yet the rate of positive WB samples in the recent vicinity of a positive DP sample was 48 times as likely than the rate of positive DP samples in the recent vicinity of a positive WB sample. Our machine learning analyses found that positive samples in WB were predicted by WB-related risk factors, but not to DP-related risk factors. In contrast, WB risk factors were important for predicting detections in DP on a few spatial and temporal scales of data aggregation.DiscussionOur results highlight that spillover from WB to DP might be more frequent than the reverse, but that the structure of current surveillance systems challenge quantification of spillover frequency and risk factors. Our results emphasize the importance of, and provide guidance for, improving cross-sector surveillance designs.