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BACKGROUND: Cardiometabolic disease risk factors are disproportionately prevalent in bipolar disorder (BD) and are associated with cognitive impairment. It is, however, unknown which health risk factors for cardiometabolic disease are relevant to cognition in BD. This study aimed to identify the cardiometabolic disease risk factors that are the most important correlates of cognitive impairment in BD; and to examine whether the nature of the relationships vary between mid and later life. METHODS: Data from the UK Biobank were available for 966 participants with BD, aged between 40 and 69 years. Individual cardiometabolic disease risk factors were initially regressed onto a global cognition score in separate models for the following risk factor domains; (1) health risk behaviors (physical activity, sedentary behavior, smoking, and sleep) and (2) physiological risk factors, stratified into (2a) anthropometric and clinical risk (handgrip strength, body composition, and blood pressure), and (2b) cardiometabolic disease risk biomarkers (CRP, lipid profile, and HbA1c). A final combined multivariate regression model for global cognition was then fitted, including only the predictor variables that were significantly associated with cognition in the previous models. RESULTS: In the final combined model, lower mentally active and higher passive sedentary behavior, higher levels of physical activity, inadequate sleep duration, higher systolic and lower diastolic blood pressure, and lower handgrip strength were associated with worse global cognition. CONCLUSIONS: Health risk behaviors, as well as blood pressure and muscular strength, are associated with cognitive function in BD, whereas other traditional physiological cardiometabolic disease risk factors are not.

Contains fulltext : 292525.pdf (Publisher’s version ) (Open Access), BACKGROUND: Detrimental associations of sedentary behaviour (time spent sitting) with musculoskeletal pain (MSP) conditions have been observed. However, findings on those with, or at risk of, type 2 diabetes (T2D) have not been reported. We examined the linear and non-linear associations of device-measured daily sitting time with MSP outcomes according to glucose metabolism status (GMS). METHODS: Cross-sectional data from 2827 participants aged 40-75 years in the Maastricht Study (1728 with normal glucose metabolism (NGM); 441 with prediabetes; 658 with T2D), for whom valid data were available on activPAL-derived daily sitting time, MSP [neck, shoulder, low back, and knee pain], and GMS. Associations were examined by logistic regression analyses, adjusted serially for relevant confounders, including moderate-to-vigorous intensity physical activity (MVPA) and body mass index (BMI). Restricted cubic splines were used to further examine non-linear relationships. RESULTS: The fully adjusted model (including BMI, MVPA, and history of cardiovascular disease) showed daily sitting time to be significantly associated with knee pain in the overall sample (OR = 1.07, 95%CI: 1.01-1.12) and in those with T2D (OR = 1.11, 95%CI: 1.00-1.22); this was not statistically significant in those with prediabetes (OR = 1.04, 95%CI: 0.91-1.18) or NGM (OR = 1.05, 95%CI: 0.98-1.13). There were no statistically significant associations between daily sitting time and neck, shoulder, or low back pain in any of the models. Furthermore, the non-linear relationships were statistically non-significant. CONCLUSION: Among middle-aged and older adults with T2D, daily sitting time was significantly associated with higher odds of knee pain, but not with neck, shoulder, or low back pain. No significant association was observed in those without T2D for neck, shoulder, low back, or knee pain. Future studies, preferably those utilising prospective designs, could examine additional attributes of daily sitting

Type 2 diabetes (T2D) is disproportionately prevalent in bipolar disorder (BD) and is associated with cognitive deficits in psychiatrically healthy cohorts. Whether there is an interaction effect between T2D and BD on cognition remains unclear. Using the UK Biobank, we explored interactions between T2D, BD and cognition during mid and later life; and examined age-related cognitive performance effects in BD as a function of T2D. Data were available for 1511 participants with BD (85 T2D), and 81,162 psychiatrically healthy comparisons (HC) (3430 T2D). BD and T2D status were determined by validated measures created specifically for the UK Biobank. Diagnostic and age-related associations between T2D status and cognition were tested using analyses of covariance or logistic regression. There was a negative association of T2D with visuospatial memory that was specific to BD. Processing speed and prospective memory performance were negatively associated with T2D, irrespective of BD diagnosis. Cognitive deficits were evident in BD patients with T2D compared to those without, with scores either remaining the same (processing speed) or improving (visuospatial memory) as a function of participant age. In contrast, cognitive performance in BD patients without T2D was worse as participant age increased, although the age-related trajectory remained broadly equivalent to the HC group. BD and T2D associated with cognitive performance deficits across the mid-life period; indicating comorbid T2D as a potential risk factor for cognitive dysfunction in BD. In comparison to BD participants without T2D and HCs, age-independent cognitive impairments in BD participants with comorbid T2D suggest a potential premature deterioration of cognitive functioning compared to what would normally be expected.

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with "neoantigen-like" NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies.

Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (NE) markers. Molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent mCRPC by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing from 210 tumors. AR-/NE- tumors were clinically and molecularly distinct from other mCRPC subtypes, with the shortest survival, amplification of the chromatin remodeler CHD7, and PTEN loss. Methylation changes in CHD7 candidate enhancers were linked to elevated CHD7 expression in AR-/NE+ tumors. Genome-wide methylation analysis nominated KLF5 as a driver of the AR-/NE- phenotype, and KLF5 activity was linked to RB1 loss. These observations reveal the aggressiveness of AR-/NE- mCRPC and could facilitate the identification of therapeutic targets in this highly aggressive disease.

The MYC proto-oncogene contributes to the pathogenesis of more than half of human cancers. Malignant transformation by MYC transcriptionally up-regulates the core pre-mRNA splicing machinery and causes misregulation of alternative splicing. However, our understanding of how splicing changes are directed by MYC is limited. We performed a signaling pathway-guided splicing analysis to identify MYC-dependent splicing events. These included an HRAS cassette exon repressed by MYC across multiple tumor types. To molecularly dissect the regulation of this HRAS exon, we used antisense oligonucleotide tiling to identify splicing enhancers and silencers in its flanking introns. RNA-binding motif prediction indicated multiple binding sites for hnRNP H and hnRNP F within these cis-regulatory elements. Using siRNA knockdown and cDNA expression, we found that both hnRNP H and F activate the HRAS cassette exon. Mutagenesis and targeted RNA immunoprecipitation implicate two downstream G-rich elements in this splicing activation. Analyses of ENCODE RNA-seq datasets confirmed hnRNP H regulation of HRAS splicing. Analyses of RNA-seq datasets across multiple cancers showed a negative correlation of HNRNPH gene expression with MYC hallmark enrichment, consistent with the effect of hnRNP H on HRAS splicing. Interestingly, HNRNPF expression showed a positive correlation with MYC hallmarks and thus was not consistent with the observed effects of hnRNP F. Loss of hnRNP H/F altered cell cycle progression and induced apoptosis in the PC3 prostate cancer cell line. Collectively, our results reveal mechanisms for MYC-dependent regulation of splicing and point to possible therapeutic targets in prostate cancers.

Contains fulltext : 298476.pdf (Publisher’s version ) (Open Access)

Insects are under pressure from agricultural intensification. To protect pollinators, conservation measures such as the EU agri-environment schemes (AES) promote planting wildflowers along fields. However, this can potentially alter disease ecology by serving as transmission hubs or by diluting infections. We tested this by measuring plant–pollinator interactions and virus infections (DWV-A, DWV-B and ABPV) across pollinator communities in agricultural landscapes over a year. AES had a direct effect on DWV-B, reducing prevalence and load in honeybees, with a tentative general dilution effect on load in early summer. DWV-A prevalence was reduced both under AES and with increasing niche overlap between competent hosts, likely via a dilution effect. By contrast, AES had no impact on ABPV, its prevalence driven by the proportion of bumblebees in the community. Epidemiological differences were also reflected in the virus phylogenies, with DWV-B showing recent rapid expansion, while DWV-A and ABPV showed slower growth rates and geographical population structure. Phylogenies indicate that all three viruses freely circulate across their host populations. Our study illustrates how complex interactions between environmental, ecological and evolutionary factors may influence wildlife disease dynamics. Supporting pollinator nutrition can mitigate the transmission of important bee diseases, providing an unexpected boost to pollinator conservation.

The pearl whipray Fontitrygon margaritella (Compagno & Roberts, 1984) is a common elasmobranch in coastal western African waters. However, knowledge on their life-history and trophic ecology remains limited. Therefore, we aimed to determine the growth, maturity and diet of F. margaritella from the Bijagós Archipelago in Guinea-Bissau. Growth was modelled with: von Bertalanffy, Gompertz and logistic functions. Model selection revealed no model significantly outperformed another. The sampled age ranged from less than 1 to 7 years (1.8 ± 1.9 cm, mean ± standard deviation) and size (disc width) ranged from 12.2 to 30.6 cm (18.7 ± 5.2 cm). Size-at-maturity was estimated at 20.3 cm (95% CI [18.8-21.8 cm]) for males and 24.3 cm for females (95% CI [21.9-26.5 cm]), corresponding ages of 2.2 and 3.9 years. The diet differed significantly among young-of-the-year (YOY), juveniles and adults (p = 0.001). Diet of all life stages consisted mainly of crustaceans (27.4%, 28.5%, 33.3%) and polychaetes (12.5%, 26.7%, 20.3%), for YOY, juveniles and adults respectively. This study shows that F. margaritella is relatively fast-growing, matures early and experiences ontogenetic diet shifts. These results contribute to status assessments and conservation efforts of F. margaritella and closely related species.

Abstract Background Higher levels of time spent sitting (sedentary behavior) contribute to adverse health outcomes, including earlier death. This effect may be modified by other lifestyle factors. We examined the association of television viewing (TV), a common leisure-time sedentary behavior, with all-cause mortality, and whether this is modified by body mass index (BMI), physical activity, smoking, alcohol intake, soft drink consumption, or diet-associated inflammation. Methods Using data from participants in the Melbourne Collaborative Cohort Study, flexible parametric survival models assessed the time-dependent association of self-reported TV time (three categories: < 2 h/day, 2–3 h/day, > 3 h/day) with all-cause mortality. Interaction terms were fitted to test whether there was effect modification of TV time by the other risk factors. Results From 19,570 participants, 4,417 deaths were reported over a median follow up of 14.5 years. More TV time was associated with earlier mortality; however, this relationship diminished with increasing age. The hazard ratio (HR) and 95% confidence interval (95% CI) for > 3 h/day compared with < 2 h/day of TV time was 1.34 (1.16, 1.55) at 70 years, 1.14 (1.04, 1.23) at 80 years, and 0.95 (0.84, 1.06) at 90 years. The TV time/mortality relationship was more evident in participants who were physically inactive (compared with active; p for interaction < 0.01) or had a higher dietary inflammatory index score (compared with a lower score; p for interaction = 0.03). No interactions were detected between TV time and BMI, smoking, alcohol intake, nor soft-drink consumption (all p for interaction&

Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide-major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.

By 2050, 20% of the world's population will be over the age of 65 years, with projections that 80% of older adults will be living in low- to middle-income countries. Physical inactivity and sedentary time are particularly high in older adults, presenting unique public health challenges. In this article, we first review evidence that points to multiple beneficial outcomes of active aging, including better physical function, cognitive function, mental health, social health, and sleep, and we suggest the need to shift the research focus from chronic disease outcomes to more relevantoutcomes that affect independence and quality of life. Second, we review the critical role of age-friendly environments in facilitating active aging equitably across different countries and cultures. Finally, we consider emerging opportunities related to social engagement and technology-enabled mobility that can facilitate active aging. In all these contexts, it is a priority to understand and address diversity within the global aging population.

In 1977, a sample of diseased adult honeybees (Apis mellifera) from Egypt was found to contain large amounts of a previously unknown virus, Egypt bee virus, which was subsequently shown to be serologically related to deformed wing virus (DWV). By sequencing the original isolate, we demonstrate that Egypt bee virus is in fact a fourth unique, major variant of DWV (DWV-D): more closely related to DWV-C than to either DWV-A or DWV-B. DWV-A and DWV-B are the most common DWV variants worldwide due to their close relationship and transmission by Varroa destructor. However, we could not find any trace of DWV-D in several hundred RNA sequencing libraries from a worldwide selection of honeybee, varroa and bumblebee samples. This means that DWV-D has either become extinct, been replaced by other DWV variants better adapted to varroa-mediated transmission, or persists only in a narrow geographic or host range, isolated from common bee and beekeeping trade routes.

In 1977, a sample of diseased adult honeybees (Apis mellifera) from Egypt was found to contain large amounts of a previously unknown virus, Egypt bee virus, which was subsequently shown to be serologically related to deformed wing virus (DWV). By sequencing the original isolate, we demonstrate that Egypt bee virus is in fact a fourth unique, major variant of DWV (DWV-D): more closely related to DWV-C than to either DWV-A or DWV-B. DWV-A and DWV-B are the most common DWV variants worldwide due to their close relationship and transmission by Varroa destructor. However, we could not find any trace of DWV-D in several hundred RNA sequencing libraries from a worldwide selection of honeybee, varroa and bumblebee samples. This means that DWV-D has either become extinct, been replaced by other DWV variants better adapted to varroa-mediated transmission, or persists only in a narrow geographic or host range, isolated from common bee and beekeeping trade routes.

In 1977, a sample of diseased adult honeybees (Apis mellifera) from Egypt was found to contain large amounts of a previously unknown virus, Egypt bee virus, which was subsequently shown to be serologically related to deformed wing virus (DWV). By sequencing the original isolate, we demonstrate that Egypt bee virus is in fact a fourth unique, major variant of DWV (DWV-D): more closely related to DWV-C than to either DWV-A or DWV-B. DWV-A and DWV-B are the most common DWV variants worldwide due to their close relationship and transmission by Varroa destructor. However, we could not find any trace of DWV-D in several hundred RNA sequencing libraries from a worldwide selection of honeybee, varroa and bumblebee samples. This means that DWV-D has either become extinct, been replaced by other DWV variants better adapted to varroa-mediated transmission, or persists only in a narrow geographic or host range, isolated from common bee and beekeeping trade routes.

BACKGROUND: Higher levels of time spent sitting (sedentary behavior) contribute to adverse health outcomes, including earlier death. This effect may be modified by other lifestyle factors. We examined the association of television viewing (TV), a common leisure-time sedentary behavior, with all-cause mortality, and whether this is modified by body mass index (BMI), physical activity, smoking, alcohol intake, soft drink consumption, or diet-associated inflammation. METHODS: Using data from participants in the Melbourne Collaborative Cohort Study, flexible parametric survival models assessed the time-dependent association of self-reported TV time (three categories: < 2 h/day, 2-3 h/day, > 3 h/day) with all-cause mortality. Interaction terms were fitted to test whether there was effect modification of TV time by the other risk factors. RESULTS: From 19,570 participants, 4,417 deaths were reported over a median follow up of 14.5 years. More TV time was associated with earlier mortality; however, this relationship diminished with increasing age. The hazard ratio (HR) and 95% confidence interval (95% CI) for > 3 h/day compared with < 2 h/day of TV time was 1.34 (1.16, 1.55) at 70 years, 1.14 (1.04, 1.23) at 80 years, and 0.95 (0.84, 1.06) at 90 years. The TV time/mortality relationship was more evident in participants who were physically inactive (compared with active; p for interaction < 0.01) or had a higher dietary inflammatory index score (compared with a lower score; p for interaction = 0.03). No interactions were detected between TV time and BMI, smoking, alcohol intake, nor soft-drink consumption (all p for interaction > 0.16). CONCLUSIONS: The relationship between TV time and all-cause mortality may change with age. It may also be more pronounced in those who are otherwise inactive or who have a pro-inflammatory diet.

An essential characteristic of a healthy and sustainable city is a physically active population. Effective policies for healthy and sustainable cities require evidence-informed quantitative targets. We aimed to identify the minimum thresholds for urban design and transport features associated with two physical activity criteria: at least 80% probability of engaging in any walking for transport and WHO's target of at least 15% relative reduction in insufficient physical activity through walking. The International Physical Activity and the Environment Network Adult (known as IPEN) study (N=11 615; 14 cities across ten countries) provided data on local urban design and transport features linked to walking. Associations of these features with the probability of engaging in any walking for transport and sufficient physical activity (≥150 min/week) by walking were estimated, and thresholds associated with the physical activity criteria were determined. Curvilinear associations of population, street intersection, and public transport densities with walking were found. Neighbourhoods exceeding around 5700 people per km2, 100 intersections per km2, and 25 public transport stops per km2 were associated with meeting one or both physical activity criteria. Shorter distances to the nearest park were associated with more physical activity. We use the results to suggest specific target values for each feature as benchmarks for progression towards creating healthy and sustainable cities.

Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.SignificanceIn prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.

Tissue-specific antigens can serve as targets for adoptive T cell transfer-based cancer immunotherapy. Recognition of tumor by T cells is mediated by interaction between peptide-major histocompatibility complexes (pMHCs) and T cell receptors (TCRs). Revealing the identity of peptides bound to MHC is critical in discovering cognate TCRs and predicting potential toxicity. We performed multimodal immunopeptidomic analyses for human prostatic acid phosphatase (PAP), a well-recognized tissue antigen. Three physical methods, including mild acid elution, coimmunoprecipitation, and secreted MHC precipitation, were used to capture a thorough signature of PAP on HLA-A*02:01. Eleven PAP peptides that are potentially A*02:01-restricted were identified, including five predicted strong binders by NetMHCpan 4.0. Peripheral blood mononuclear cells (PBMCs) from more than 20 healthy donors were screened with the PAP peptides. Seven cognate TCRs were isolated which can recognize three distinct epitopes when expressed in PBMCs. One TCR shows reactivity toward cell lines expressing both full-length PAP and HLA-A*02:01. Our results show that a combined multimodal immunopeptidomic approach is productive in revealing target peptides and defining the cloned TCR sequences reactive with prostatic acid phosphatase epitopes.

In 1977, a sample of diseased adult honeybees (Apis mellifera) from Egypt was found to contain large amounts of a previously unknown virus, Egypt bee virus, which was subsequently shown to be serologically related to deformed wing virus (DWV). By sequencing the original isolate, we demonstrate that Egypt bee virus is in fact a fourth unique, major variant of DWV (DWV-D): more closely related to DWV-C than to either DWV-A or DWV-B. DWV-A and DWV-B are the most common DWV variants worldwide due to their close relationship and transmission by Varroa destructor. However, we could not find any trace of DWV-D in several hundred RNA sequencing libraries from a worldwide selection of honeybee, varroa and bumblebee samples. This means that DWV-D has either become extinct, been replaced by other DWV variants better adapted to varroa-mediated transmission, or persists only in a narrow geographic or host range, isolated from common bee and beekeeping trade routes.

PURPOSE: This study was undertaken to collect baseline growth parameters in children with achondroplasia who might enroll in interventional trials of vosoritide, and to establish a historical control. METHODS: In this prospective, observational study, participants (≤17 years) underwent a detailed medical history and physical examination and were followed every 3 months until they finished participating in the study by enrolling in an interventional trial or withdrawing. RESULTS: A total of 363 children were enrolled (28 centers, 8 countries). Mean (SD) follow up was 20.4 (15.0) months. In participants <1 year, mean annualized growth velocity (AGV) was 11.6 cm/year for girls and 14.6 cm/year for boys. By age 1 year, mean AGV decreased to 7.4 cm/year in girls and 7.1 cm/year in boys. By age 10 years, mean AGV decreased to 3.6 cm/year for both sexes. Mean height z-score in participants <1 year was -2.5 for girls and -3.2 for boys and decreased up to the age 5 years (-5.3 for girls; -4.6 for boys). Girls and boys had a disproportionate upper-to-lower body segment ratio. Mean ratio was highest in participants aged <1 year (2.9 for girls; 2.8 for boys) and decreased gradually to approximately 2 in both sexes from 4 years of age onward. CONCLUSION: This study represents one of the largest datasets of prospectively collected medical and longitudinal growth data in children with achondroplasia. It serves as a robust historical control to measure therapeutic interventions against and to further delineate the natural history of this condition.

OBJECTIVE: Higher neighbourhood walkability would be expected to contribute to better health, but the relevant evidence is inconsistent. This may be because residents' dietary attributes, which vary with socio-economic status (SES) and influence their health, can be related to walkability. We examined associations of walkability with dietary attributes and potential effect modification by area-level SES. DESIGN: The exposure variable of this cross-sectional study was neighbourhood walkability, calculated using residential density, intersection density and destination density within 1-km street-network buffer around each participant's residence. The outcome variables were dietary patterns (Western, prudent and mixed) and total dietary energy intake, derived from a FFQ. Main and interaction effects with area-level SES were estimated using two-level linear regression models. SETTING: Participants were from all states and territories in Australia. PARTICIPANTS: The analytical sample included 3590 participants (54 % women, age range 34 to 86). RESULTS: Walkability was not associated with dietary attributes in the whole sample. However, we found interaction effects of walkability and area-level SES on Western diet scores (P < 0·001) and total energy intake (P = 0·012). In low SES areas, higher walkability was associated with higher Western dietary patterns (P = 0·062) and higher total energy intake (P = 0·066). In high SES areas, higher walkability was associated with lower Western diet scores (P = 0·021) and lower total energy intake (P = 0·058). CONCLUSIONS: Higher walkability may not be necessarily conducive to better health in socio-economically disadvantaged areas. Public health initiatives to enhance neighbourhood walkability need to consider food environments and socio-economic contexts.

BACKGROUND: Allogeneic stem cell transplantation (allo-SCT) is a potentially lifesaving treatment for high-risk hematological malignancy, but survivors experience markedly elevated rates of cardiovascular disease and associated functional impairment. Mounting evidence suggests regular exercise, combined with a reduction in sedentary time through replacement with light exercise may be a useful therapeutic strategy for the prevention of cardiovascular comorbidities. However, this type of intervention has yet to be evaluated in patients undergoing allo-SCT. The ALLO-Active study will evaluate the efficacy of a ~ 4 month multi-faceted exercise intervention, commenced upon admission for allo-SCT, to preserve peak oxygen uptake (VO2peak) and peak cardiac output, compared with usual care. The study will also evaluate the effect of the intervention on functional independence, quality of life, and symptoms of fatigue. METHODS: Sixty adults with hematological malignancy scheduled for allo-SCT will be randomly assigned to usual care (n = 30) or the exercise and sedentary behaviour intervention (n = 30). Participants assigned to the intervention will complete a thrice weekly aerobic and progressive resistance training program and concomitantly aim to reduce daily sedentary time by 30 min with short, frequent, light-intensity exercise bouts. Participants will undergo testing prior to, immediately after inpatient discharge, and 12 weeks after discharge. To address aim 1, VO2peak and peak cardiac output (multiple primary outcomes, p < 0.025) will be assessed via cardiopulmonary exercise testing and exercise cardiac magnetic resonance imaging, respectively. Secondary outcomes include functional independence (defined as VO2peak ≥ 18.mL.kg-1.min-1), quality of life, and fatigue (assessed via validated questionnaire). Exploratory outcomes will include indices of resting cardiac, vascular, and skeletal muscle structure and function, cardiovascular biomarkers, anxiety and depression, tr

BACKGROUND: Bodily pain is a common presentation in several chronic diseases, yet the influence of sedentary behaviour, common in ageing adults, is unclear. Television-viewing (TV) time is a ubiquitous leisure-time sedentary behaviour, with a potential contribution to the development of bodily pain. We examined bodily pain trajectories and the longitudinal relationships of TV time with the bodily pain severity; and further, the potential moderation of the relationships by type 2 diabetes (T2D) status. METHOD: Data were from 4099 participants (aged 35 to 65 years at baseline) in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), who took part in the follow-ups at 5 years, 12 years, or both. Bodily pain (from SF36 questionnaire: a 0 to 100 scale, where lower scores indicate more-severe pain), TV time, and T2D status [normal glucose metabolism (NGM), prediabetes, and T2D] were assessed at all three time points. Multilevel growth curve modelling used age (centred at 50 years) as the time metric, adjusting for potential confounders, including physical activity and waist circumference. RESULTS: Mean TV time increased, and bodily pain worsened (i.e., mean bodily pain score decreased) across the three time points. Those with T2D had higher TV time and more-severe bodily pain than those without T2D at all time points. In a fully adjusted model, the mean bodily pain score for those aged 50 years at baseline was 76.9(SE: 2.2) and worsened (i.e., bodily pain score decreased) significantly by 0.3(SE: 0.03) units every additional year (p <0.001). Those with initially more-severe pain had a higher rate of increase in pain severity. At any given time point, a one-hour increase in daily TV time was significantly associated with an increase in pain severity [bodily pain score decreased by 0.69 (SE: 0.17) units each additional hour; p <0.001], accounting for the growth factor (age) and confounders' effects. The association was more-pronounced in those with T2D than in tho

BACKGROUND: While physical inactivity is associated with adverse psychological outcomes, less is known about the psychological outcomes associated with sedentary behaviour, and specifically, its mentally active and passive forms. The COVID-19 pandemic represents a unique opportunity to study associations between these variables in light of widespread stay-at-home mandates and restrictions on outdoor exercise/social activities. Using a cross-sectional dataset acquired during the COVID-19 pandemic in Australia, we examined whether physical activity and sedentary behaviour were associated with subjective quality of life (sQoL) and subjective cognitive dysfunction, and whether these associations were mediated by depressive symptoms. METHODS: 658 participants (males = 169, females = 489) self-reported data on physical activity and sedentary behaviour in an online survey during May 2020-May 2021. Data on physical activity and sedentary behaviour (both mentally active and passive types) was compared according to whether it was collected during or out of a lockdown period. Regression models were used to test associations of physical activity and sedentary behaviour with sQoL and subjective cognitive dysfunction, and whether these associations were mediated by depression severity. RESULTS: Physical activity was beneficially associated with sQoL, whereas sedentary behaviour (both total hours and the reduction of mentally active/increase in mentally passive behaviour) was detrimentally associated with sQoL. These associations were mediated by depression severity. Physical activity and sedentary behaviour were also indirectly associated with subjective cognitive dysfunction by virtue of their associations with depression severity. CONCLUSIONS: There are important differences in the psychological correlates of mentally passive and active sedentary behaviours. Our findings suggest that health promotion strategies should focus on not only increasing physical activity but also redu

Open scholarship has transformed research, and introduced a host of new terms in the lexicon of researchers. The ‘Framework for Open and Reproducible Research Teaching’ (FORRT) community presents a crowdsourced glossary of open scholarship terms to facilitate education and effective communication between experts and newcomers.

Open scholarship has transformed research, introducing a host of new terms in the lexicon of researchers. The Framework of Open and Reproducible Research Teaching (FORRT) community presents a crowd-sourced glossary of open scholarship terms to facilitate education and effective communication between experts and newcomers.

Open scholarship has transformed research, introducing a host of new terms in the lexicon of researchers. The Framework of Open and Reproducible Research Teaching (FORRT) community presents a crowd-sourced glossary of open scholarship terms to facilitate education and effective communication between experts and newcomers.

In 1977, a sample of diseased adult honeybees (Apis mellifera) from Egypt was found to contain large amounts of a previously unknown virus, Egypt bee virus, which was subsequently shown to be serologically related to deformed wing virus (DWV). By sequencing the original isolate, we demonstrate that Egypt bee virus is in fact a fourth unique, major variant of DWV (DWV-D): more closely related to DWV-C than to either DWV-A or DWV-B. DWV-A and DWV-B are the most common DWV variants worldwide due to their close relationship and transmission by Varroa destructor. However, we could not find any trace of DWV-D in several hundred RNA sequencing libraries from a worldwide selection of honeybee, varroa and bumblebee samples. This means that DWV-D has either become extinct, been replaced by other DWV variants better adapted to varroa-mediated transmission, or persists only in a narrow geographic or host range, isolated from common bee and beekeeping trade routes.

Context/purposeObservational and acute laboratory intervention research has shown that excessive sedentary time is associated adversely with cardiometabolic biomarkers. This systematic review with meta-analyses synthesises results from free living interventions targeting reductions in sedentary behaviour alone or combined with increases in physical activity.MethodsSix electronic databases were searched up to August 2019 for sedentary behaviour interventions in adults lasting for ≥7 days publishing cardiometabolic biomarker outcomes covering body anthropometry, blood pressure, glucose and lipid metabolism, and inflammation (54 studies). The pooled effectiveness of intervention net of control on 15 biomarker outcomes was evaluated using random effects meta-analyses in the studies with control groups not providing other relevant interventions (33 studies; 6–25 interventions analysed).ResultsInterventions between 2 weeks and <6 months in non-clinical populations from North America, Europe and Australia comprised much of the evidence base. Pooled effects revealed small, significant (p<0.05) beneficial effects on weight (≈ −0.6 kg), waist circumference (≈ −0.7 cm), percentage body fat (≈ −0.3 %), systolic blood pressure (≈ −1.1 mm Hg), insulin (≈ −1.4 pM) and high-density lipoprotein cholesterol (≈ 0.04 mM). Pooled effects on the other biomarkers (p>0.05) were also small, and beneficial in direction except for fat-free mass (≈ 0.0 kg). Heterogeneity ranged widely (I2=0.0–72.9).ConclusionsOur review of interventions targeting sedentary behaviour reductions alone, or combined with increases in physical activity, found evidence of effectiveness for improving some cardiometabolic risk biomarkers to a small degree. Ther

PURPOSE: In healthy adults, the impairment of vascular function associated with prolonged sitting can be mitigated with intermittent brief bouts of activity. It is unknown whether these benefits extend to women with polycystic ovary syndrome (PCOS), in whom vascular function is typically impaired and sitting time is high. We examined the acute effect of regularly interrupting sitting time with brief simple resistance activities (SRA) on vascular function in PCOS. METHODS: In a randomized crossover trial, 13 physically inactive women with PCOS (18-45 yr) completed two 3.5-h conditions: 1) uninterrupted sitting (SIT) and 2) sitting interrupted by 3-min bouts of SRA every 30 min. Femoral artery flow-mediated dilation (FMD), resting shear rate, and resting blood flow were measured at 0, 1, and 3.5 h. RESULTS: Mean resting femoral shear rate, averaged across the 3.5 h, significantly increased in the SRA condition relative to the SIT condition (40.1 ± 6.1 vs 62.8 ± 6.1 s-1, P < 0.0001). In addition, mean resting blood flow also significantly increased across the 3.5 h for SRA relative to SIT (45.0 ± 9.8 vs 72.8 ± 9.9 mL·min-1, P < 0.0001). There were no differences between conditions in the temporal change in femoral artery FMD across 3.5 h (Ptime-condition > 0.05 for all). CONCLUSION: Frequently interrupting sitting with SRA acutely increased resting shear rate and blood flow in women with PCOS but did not alter FMD. With sedentary behavior increasing in prevalence, longer-term studies of similar interventions to reduce and break up sitting time are warranted.

This feasibility study explored the contextual factors influencing office workers’ adherence to an e-health intervention targeting total and prolonged sedentary time over 12 weeks. A three-arm quasi-randomized intervention included prompts at 30 or 60 min intervals delivered via a smartphone application, and a no-prompt comparison arm. Fifty-six office workers completed baseline (64% female) and 44 completed the 12 week follow-up (80% retention). Ecological momentary assessments (EMA) captured contextual data, with 82.8 ± 24.9 EMA prompt questionnaires completed weekly. Two focus groups with n = 8 Prompt 30 and 60 participants were conducted one-month post-intervention to address intervention acceptability and feasibility. Contextual findings indicate that when working on a sedentary task (i.e., reading or screen-based work) and located at an individual workstation, hourly prompts may be more acceptable and feasible for promoting a reduction in total and prolonged sedentary time compared to 30 min prompts. Interpersonal support also appears important for promoting subtle shifts in sedentary working practices. This novel study gives a real-time insight into the factors influencing adherence to e-health prompts. Findings identified unique, pragmatic considerations for delivering a workplace e-health intervention, indicating that further research is warranted to optimize the method of intervention delivery prior to evaluation of a large-scale intervention.

OBJECTIVE: To determine whether interrupting sitting with brief bouts of simple resistance activities (SRAs) at different frequencies improves postprandial glucose, insulin, and triglycerides in adults with medication-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Participants (n = 23, 10 of whom were female, with mean ± SD age 62 ± 8 years and BMI 32.7 ± 3.5 kg · m-2) completed a three-armed randomized crossover trial (6- to 14-day washout): sitting uninterrupted for 7 h (SIT), sitting with 3-min SRAs (half squats, calf raises, gluteal contractions, and knee raises) every 30 min (SRA3), and sitting with 6-min SRAs every 60 min (SRA6). Net incremental areas under the curve (iAUCnet) for glucose, insulin, and triglycerides were compared between conditions. RESULTS: Glucose and insulin 7-h iAUCnet were attenuated significantly during SRA6 (glucose 17.0 mmol · h · L-1, 95% CI 12.5, 21.4; insulin 1,229 pmol · h · L-1, 95% CI 982, 1,538) in comparison with SIT (glucose 21.4 mmol · h · L-1, 95% CI 16.9, 25.8; insulin 1,411 pmol · h · L-1, 95% CI 1,128, 1,767; P < 0.05) and in comparison with SRA3 (for glucose only) (22.1 mmol · h · L-1, 95% CI 17.7, 26.6; P = 0.01) No significant differences in glucose or insulin iAUCnet were observed in comparison of SRA3 and SIT. There was no statistically significant effect of condition on triglyceride iAUCnet. CONCLUSIONS: In adults with medication-controlled T2D, interrupting prolonged sitting with 6-min SRAs every 60 min reduced postprandial glucose and insulin responses. Other frequencies of interruptions and potential longer-term benefits require examination to clarify clinical relevance.

Cancer transcriptomes frequently exhibit RNA dysregulation. As the resulting aberrant transcripts may be translated into cancer-specific proteins, there is growing interest in exploiting RNA dysregulation as a source of tumor antigens (TAs) and thus novel immunotherapy targets. Recent advances in high-throughput technologies and rapid accumulation of multiomic cancer profiling data in public repositories have provided opportunities to systematically characterize RNA dysregulation in cancer and identify antigen targets for immunotherapy. However, given the complexity of cancer transcriptomes and proteomes, important conceptual and technological challenges exist. Here, we highlight the expanding repertoire of TAs arising from RNA dysregulation and introduce multiomic and big data strategies for identifying optimal immunotherapy targets. We discuss extant barriers for translating these targets into effective therapies as well as the implications for future research.

Exercise is a treatment in rheumatoid arthritis, but participation in moderate-to-vigorous exercise is challenging for some patients. Light-intensity breaks in sitting could be a promising alternative. We compared the acute effects of active breaks in sitting with those of moderate-to-vigorous exercise on cardiometabolic risk markers in patients with rheumatoid arthritis. In a crossover fashion, 15 women with rheumatoid arthritis underwent three 8-h experimental conditions: prolonged sitting (SIT), 30-min bout of moderate-to-vigorous exercise followed by prolonged sitting (EX), and 3-min bouts of light-intensity walking every 30 min of sitting (BR). Postprandial glucose, insulin, c-peptide, triglycerides, cytokines, lipid classes/subclasses (lipidomics), and blood pressure responses were assessed. Muscle biopsies were collected following each session to assess targeted proteins/genes. Glucose [-28% in area under the curve (AUC), P = 0.036], insulin (-28% in AUC, P = 0.016), and c-peptide (-27% in AUC, P = 0.006) postprandial responses were attenuated in BR versus SIT, whereas only c-peptide was lower in EX versus SIT (-20% in AUC, P = 0.002). IL-1b decreased during BR, but increased during EX and SIT (P = 0.027 and P = 0.085, respectively). IL-1ra was increased during EX versus BR (P = 0.002). TNF-a concentrations decreased during BR versus EX (P = 0.022). EX, but not BR, reduced systolic blood pressure (P = 0.013). Lipidomic analysis showed that 7 of 36 lipid classes/subclasses were significantly different between conditions, with greater changes being observed in EX. No differences were observed for protein/gene expression. Brief active breaks in sitting can offset markers of cardiometabolic disturbance, which may be particularly useful for patients who may find it difficult to adhere to exercise.

Background: Regular physical activity reduces the risk of depression onset and is an effective treatment for mood disorders. Recent studies have reported that sedentary behavior (SB) increases the risk of depression in adults, but relationships of different types of SBs with depression have not been examined systematically. We explored longitudinal relationships of passive (e.g. watching TV) and mentally-active (e.g. office-work) SBs with incident major depressive disorder (MDD). Methods: Self-report questionnaires were completed by 40,569 Swedish adults in 1997; responses were linked to clinician-diagnosed MDD obtained from medical registers until 2010. Relationships between passive, mentally-active and total SBs with incident MDD were explored using survival analysis with Cox proportional hazards regression. Models controlled for leisure time moderate-vigorous physical activity and occupational physical activity. Moderating effects of gender were examined. Results: In fully-adjusted models, including only non-depressed adults at baseline, those reporting ≥ 3 h of mentally-active SBs on a typical day (versus < 3 h) had significant lower hazards of incident MDD at follow-up (HR = 0.74, 95% CI = 0.58–0.94, p = 0.018). There was a non-significant positive relationship of passive SBs with incident MDD (HR = 1.20, 95% CI = 0.96–1.52, p = 0.106). The association between total SBs (passive and mentally-active combined) was not significant (HR = 0.91, 95% CI = 0.75–1.10, p = 0.36). Gender did not moderate these associations. Limitations: Physical activity and SBs were self-reported. Conclusion: Mentally-active SBs may have beneficial effects on adults’ mental well-being. These effects are largely independent of habitual physical activity levels

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.

Small cell carcinoma of the bladder (SCCB) is a rare and lethal phenotype of bladder cancer. The pathogenesis and molecular features are unknown. Here, we established a genetically engineered SCCB model and a cohort of patient SCCB and urothelial carcinoma samples to characterize molecular similarities and differences between bladder cancer phenotypes. We demonstrate that SCCB shares a urothelial origin with other bladder cancer phenotypes by showing that urothelial cells driven by a set of defined oncogenic factors give rise to a mixture of tumor phenotypes, including small cell carcinoma, urothelial carcinoma, and squamous cell carcinoma. Tumor-derived single-cell clones also give rise to both SCCB and urothelial carcinoma in xenografts. Despite this shared urothelial origin, clinical SCCB samples have a distinct transcriptional profile and a unique transcriptional regulatory network. Using the transcriptional profile from our cohort, we identified cell surface proteins (CSPs) associated with the SCCB phenotype. We found that the majority of SCCB samples have PD-L1 expression in both tumor cells and tumor-infiltrating lymphocytes, suggesting that immune checkpoint inhibitors could be a treatment option for SCCB. We further demonstrate that our genetically engineered tumor model is a representative tool for investigating CSPs in SCCB by showing that it shares a similar a CSP profile with clinical samples and expresses SCCB-up-regulated CSPs at both the mRNA and protein levels. Our findings reveal distinct molecular features of SCCB and provide a transcriptional dataset and a preclinical model for further investigating SCCB biology.

The increased treatment of metastatic castration-resistant prostate cancer (mCRPC) with second-generation antiandrogen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost dependence on androgen receptor (AR) signaling. These AR-independent tumors may also transdifferentiate to express neuroendocrine lineage markers and are termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing several AR-independent to AR-dependent prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-independent cell lines. Clinical NEPC patient samples and NEPC patient-derived xenografts displayed upregulated RET transcript and RET pathway activity. Genetic knockdown or pharmacologic inhibition of RET kinase in multiple mouse and human models of NEPC dramatically reduced tumor growth and decreased cell viability. Our results suggest that targeting RET in NEPC tumors with high RET expression could be an effective treatment option. Currently, there are limited treatment options for patients with aggressive neuroendocrine prostate cancer and none are curative. IMPLICATIONS: Identification of aberrantly expressed RET kinase as a driver of tumor growth in multiple models of NEPC provides a significant rationale for testing the clinical application of RET inhibitors in patients with AVPC.