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Abstract Increasing studies have investigated the link between physical activity (PA) and sedentary behavior with venous thromboembolism (VTE) but the existing findings are not consistent and the independent relationship is uncertain. This meta-analysis aimed to comprehensively assess the shape of dose-response relationship between PA and sedentary behavior with VTE and further explore whether the relationship is independent after mutual adjustment. We systematically searched PubMed, Embase and Web of Science from inception to August 1, 2024. PA exposures were converted into MET-h/wk. Categorical meta-analyses and a cubic spline model were performed to evaluate the association between PA, sedentary behavior and VTE. Twenty-five articles including 31 studies were included. A curvilinear dose-response relationship between PA and VTE was observed, with steeper gradients even at lower PA levels. After adjustment for sedentary behavior, higher level of PA was independently associated with a reduced VTE risk (OR = 0.83, 95%CI:0.77–0.89). Based on population attributable fraction analyses, 2.37% (95%CI: 1.90-2.85%) of incident VTE could have been prevented if all adults had achieved half the PA minimum recommended level. A linear dose-response relationship between sedentary behavior and VTE risk was found, and there was a 2% higher risk of VTE (OR = 1.02, 95%CI: 1.00-1.03) for 1 h increment of sedentary behavior per day. After adjustment for PA, sedentary behavior was independently associated with an increased VTE risk (OR = 1.19, 95CI%:1.01–1.39). Our analyses demonstrated PA and sedentary time were indeed independently associated with the risk of VTE after mutually adjusting for sedentary time or PA, highlighting a unique perspective on their individual contributions. Further studies assessing the effects of different combinations of PA and sedentary time for assessing joint effects on VTE are needed.

Objective: Discrimination is a social determinant contributing to health inequities in the United States (US). This study investigated the prevalence of, and sociodemographic disparities in, perceived everyday discrimination among a national sample of US adults. Methods: We used data from the 2023 National Health Interview Survey (n = 27,538) and estimated the prevalence of three perceived everyday discrimination outcomes (1) any discrimination, (2) unique components of the discrimination experience, and (3) the Everyday Discrimination Scale (EDS) (range: 0–20) overall and by age, sex assigned at birth, race and ethnicity, sexual orientation, educational attainment, income-to-poverty ratio, and urban-rural status. Results: Over half of US adults experienced any discrimination (55.8 %), and the most common form of perceived discrimination was being treated with less respect (45.2 %). Adults who were younger (aged 18–44), female, non-Hispanic Black, sexual minority, some college-educated, low income, or urban-living generally reported higher discrimination. For example, among the sample, non-Hispanic Black (vs. non-Hispanic White) (OR: 1.61, 95 % CI: 1.44–1.81) and sexual minority (vs. heterosexual) (OR: 2.48, 95 % CI: 2.12–2.90) adults had the highest odds of any discrimination and EDS scores (β: 1.38 (95 % CI: 1.17–1.59) and β: 1.65 (95 % CI: 1.35–1.94), respectively). The odds of perceived discrimination varied in magnitude by specific experience; for example, sexual minority adults had the highest odds of being threatened or harassed (OR: 2.93, 95 % CI: 2.52–3.42). Conclusions: Perceived everyday discrimination is prevalent and differentially affects adults, especially members of marginalized and underserved populations. Understanding discrimination patterns will benefit public health and medical efforts aimed at mitigating exposure and deleterious health consequences.

Abstract In situ Electron Energy Loss Spectroscopy (EELS) combined with Transmission Electron Microscopy (TEM) has traditionally been pivotal for understanding how material processing choices affect local structure and composition. However, the ability to monitor and respond to ultrafast transient changes, now achievable with EELS and TEM, necessitates innovative analytical frameworks. Here, we introduce a machine learning (ML) framework tailored for the real-time assessment and characterization of in operando EELS Spectrum Images (EELS-SI). We focus on 2D MXenes as the sample material system, specifically targeting the understanding and control of their atomic-scale structural transformations that critically influence their electronic and optical properties. This approach requires fewer labeled training data points than typical deep learning classification methods. By integrating computationally generated structures of MXenes and experimental datasets into a unified latent space using Variational Autoencoders (VAE) in a unique training method, our framework accurately predicts structural evolutions at latencies pertinent to closed-loop processing within the TEM. This study presents a critical advancement in enabling automated, on-the-fly synthesis and characterization, significantly enhancing capabilities for materials discovery and the precision engineering of functional materials at the atomic scale.

Introduction Perianal fistulising Crohn’s disease (pfCD) is a distinct and debilitating phenotype seen in around one-third of patients with CD. Clinical trials in pfCD are increasingly using magnetic resonance imaging (MRI) criteria as a primary endpoint, but there is heterogeneity in the radiological definition of a healed perianal fistula that currently limits our ability to perform meaningful meta-analyses of studies. Our aim is to standardise outcomes through the generation of an international consensus definition of a radiologically healed fistula.Methods and analysis This international Delphi consensus study employs a two-part strategy.The first is a systematic review to identify a longlist of variables used to define radiological healing in pfCD. MRI-based indices used to score fistula severity and healing will be assessed for their methodological quality using Consensus-based Standards for the selection of health Measurement Instruments (COSMIN). The systematic review protocol will be conducted using COSMIN methodology and reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses.The second part will be an online Delphi consensus, guided by the results of the systematic review. Radiologists, gastroenterologists and colorectal surgeons with expertise in the management of pfCD will be invited to take part in two to three rounds of online surveys. Once an a priori threshold of >80% agreement is reached on individual radiological components used to define ‘healing’ and ‘healed’, a final meeting of key stakeholders will be organised to generate a consensus definition of a healed fistula.Ethics and dissemination The study has been deemed exempt from a formal Research Ethics Committee review as no patients will participate directly in the consensus process, given the technical nature of the research question. The study is registered with the local R&D department (Reference RD24/007). Publication of this study will help standardise radiological endpoint measurement in clinical trials of pfCD and improve the synthesis and meta-analysis of comparative studies.PROSPERO registration number CRD42024504334.

Introduction: Both electronic cigarette (e-cigarette) and social media use among youth are public health concerns. While the health impacts of extensive social media use and frequent use of e-cigarettes have been discussed independently in the literature, little is known about the relationship between the two. This study aims to examine the potential association between extensive social media use and the frequency of current, e-cigarette use among United States (US) youth. Methods: Data from the 2022 National Youth Tobacco Survey (NYTS) were analyzed. The sample included 23,655 middle and high school students aged 9–18 years. Frequency of current e-cigarette use was categorized based on past-30 day use (i.e., never/former, 1–9 days, 10–29 days, or 30 days). Social media use was dichotomized into less than 4 hours daily and 4+ hours daily (i.e., extensive use). Multivariable multinomial logistic regression estimated the relationship between social media use and e-cigarette use frequency. Results: Over one-third (35.8 %) of youth used social media extensively and 8.6 % reported current use of e-cigarettes. Extensive social media use was associated with daily e-cigarette use (OR: 1.94, 95 % CI: 1.48–2.56) but not with other use categories. Older age, female sex, lower grades, current other tobacco use, and family tobacco use were also associated with daily e-cigarette use. Conclusions: Extensive social media use is associated with daily e-cigarette use among US youth. Public health interventions should consider the influence of social media on tobacco use behaviors and tailor prevention strategies to address this potential modifiable risk factor.

Introduction: Cannabis use is increasing due to several factors including the adoption of laws legalizing its use across the United States (US). We examined changes in current cannabis use among US youth and adults and by key sociodemographic groups. Methods: Using data from the 2013–2022 National Survey on Drug Use and Health (n=543,195), we estimated the prevalence of (2013–2019, 2020, 2021–2022) and trends in (2013–2019, 2021–2022) current (i.e., past 30-day) cannabis use among US youth (aged 12–17) and adults (aged 18+) overall and by age, gender, race and ethnicity, educational attainment, and total annual family income. We also examined sociodemographic factors associated with use from 2013 to 2019, in 2020, and from 2021 to 2022. Results: Cannabis use increased from 7.59 % to 11.48 % in 2013–2019, was 11.54 % in 2020, and increased again from 13.13 % to 15.11 % in 2021–2022. Among youth, cannabis use remained constant from 2013 to 2019 and 2021–2022. In 2022, use was highest among aged 18–34, male, non-Hispanic multiracial, and generally lower SES adults. From 2021–2022, cannabis use increased among several groups such as adults who were aged 35–49 (14.25–17.23 %), female (11.21–13.00 %), and Hispanic (10.42–13.50 %). Adults who were aged 18–25, male, non-Hispanic multiracial, some college educated, and of lower annual family income had consistently higher odds of current cannabis use from 2013 to 2019, in 2020, and from 2021 to 2022. Conclusions: Cannabis use is increasing overall and among certain sociodemographic groups. Our findings inform prevention and harm reduction efforts aimed at mitigating the prevalence of cannabis use in the US.

Background Ulcerative colitis is an autoimmune reaction to imbalanced colonic microbiome in genetically predisposed patients. There have been four published randomised controlled trials of faecal microbiota transplant versus placebo in ulcerative colitis; three being positive. However, the methodology used varied and mechanistic data were sparse. Objective To identify an optimal faecal microbiota transplant delivery route to test in a future efficacy-powered randomised controlled trial. Design Prospective, multicentre, open-label, parallel-group, randomised pilot study. Participants were randomised in a 1 : 1 ratio to faecal microbiota transplant by nasogastric or by colonoscopy, minimised by partial Mayo score and current smoking status. Setting Three secondary care hospitals in the United Kingdom. Participants Thirty adult patients with mild to moderately active ulcerative colitis (partial Mayo score of ≥4 and ≤8). Interventions Faecal microbiota transplant samples were prepared at the University of Birmingham Microbiome Treatment Centre and administered to participants either via a nasogastric tube on 4 consecutive days repeated after a month (nasogastric) or by colonoscopy followed by 7 weekly enemas (COLON). Each treatment course was from a single matched donor. Participants and researchers underwent qualitative interviews regarding the faecal microbiota transplant experience. Main outcome measure Composite assessment of qualitative and quantitative data based on efficacy, acceptability and safety. Clinical response (primary measure of efficacy) was defined as a ≥3 point and ≥30% reduction in full Mayo score from randomisation to week 8 and a ≥1 point reduction in rectal bleeding subscore or absolute rectal bleeding subscore of 0 or 1. Results Thirty ulcerative colitis patients were randomised: 16 to nasogastric; 14 to COLON. Seven participants in the nasogastric arm and two in the COLON arm withdrew from treatment and clinical follow-up. Eight of 16 (50%) nasogastric participants were adherent compared to 12/14 (86%) COLON participants. Clinical response data were available for 20 of 30 randomised participants. Clinical response was seen in 2/8 (25%) nasogastric participants versus 9/12 (75%) COLON participants: adjusted risk ratio 2.94 (95% CI 0.84 to 10.30). Adverse events were reported in 11/16 (69%) nasogastric participants versus 11/14 (79%) COLON participants. There were three serious adverse events in two nasogastric participants. Faecal microbiota transplant was deemed an acceptable treatment for ulcerative colitis, with greater participant and clinician acceptability for the COLON route. Faecal microbiota transplant responders had a greater reduction in faecal calprotectin compared to non-responders (t-test p = 0.03) and increase in faecal microbiome diversity (Shannon diversity p < 0.01). In the whole cohort, a negative association between faecal calprotectin and diversity was seen (Kendall’s tau z = −2.8231, p = 0.004757). There were increases in faecal acetate (p = 0.05) and butyrate (p = 0.03) after faecal microbiota transplant intervention, but these were not associated with clinical response. A limitation was that this was an open-label pilot study, which was not powered to assess for efficacy of faecal microbiota transplant. Conclusions Faecal microbiota transplant delivered by the colonic route was considered safe and better tolerated than the nasogastric route. The colonic route was preferred by both participants and clinicians. Mechanistic signals indicated reduction in colonic inflammation and increased microbiome diversity in faecal microbiota transplant responders. Future work An efficacy-powered randomised controlled trial. Trial registration This trial is registered as ISRCTN74072945 and EudraCT 2015-005753-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 13/179/01) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 14. See the NIHR Funding and Awards website for further award information. Plain language summary Ulcerative colitis, a chronic inflammatory condition affecting the colon, results from the body’s immune response to imbalance in colonic microbes (microbiota). Faecal microbiota transplantation involves transferring processed donated stool samples from carefully screened healthy donors to ulcerative colitis patients aiming to correct the imbalance and reduce inflammation. There have been four trials comparing faecal microbiota transplant with placebo (dummy no treatment) to treat ulcerative colitis, and one which investigated faecal microbiota transplant with dietary intervention. Three of these studies showed encouraging benefit for faecal microbiota transplant. However, these studies varied in the methods used, with faecal microbiota transplant delivered either to the stomach or colon, or both. The aim of this study was to identify the best route of faecal microbiota transplant administration before undertaking a large-scale trial comparing faecal microbiota transplant with placebo. Between March 2018 and 30 April 2019 ulcerative colitis patients from three hospitals were randomly allocated to receive faecal microbiota transplant via either a tube inserted through the nose into the stomach on 4 consecutive days repeated after a month (nasogastric group; 16 participants) or by colonoscopy followed by 7 weekly enemas (COLON group; 14 participants). Faecal microbiota transplant was well accepted, with both patients with ulcerative colitis and healthcare staff stating a preference for the colonic route. Only 8 of 16 in the nasogastric group completed the study compared to 12 of 14 in the COLON group. Altogether, 9/12 (75%) in the COLON group improved compared with 2/8 (25%) in the nasogastric group. The majority of participants [11/14 (79%) COLON vs. 11/16 (69%) nasogastric] had mild, short-lived side effects following faecal microbiota transplant. There were three serious adverse events. Faecal calprotectin (indicating colonic inflammation) fell in responders and stool samples showed an increase in the number of microbial species after faecal microbiota transplant. At the end of the study, a recommendation was made by the Independent Oversight Committee to proceed to a large placebo-controlled randomised trial using the colonic route. Scientific summary Background Ulcerative colitis (UC) results from an exaggerated immune response to an imbalanced (dysbiotic) colonic microbiome in genetically predisposed patients. At the inception of this study, there had been four published randomised controlled trials (RCTs) comparing faecal microbiota transplantation (FMT) with placebo to treat UC in adults. Of these four seminal studies, three involved delivery of FMT via the colonic route and one a combination of delivery to the foregut and colon. This latter study was the only one of the four not to show a difference in efficacy compared to placebo. Foregut-delivered FMT is extensively and successfully used in clinical practice to treat Clostridioides difficile infection (CDI). From the results of the UC trials, FMT appeared to have therapeutic potential for UC. However, the methodology employed in these studies was varied and, taking into account the efficacy of FMT delivered to the foregut to treat CDI, there was uncertainty regarding the best route of delivery in the context of UC. Objectives The aims of this pilot study were as follows: to determine which FMT administration route [nasogastric (NG) or colonic (COLON)] should be investigated in a randomised double-blind, placebo-controlled trial to determine whether a full-scale RCT was feasible. In order to achieve these aims, the pilot study had the following clinical objectives. To assess the following: whether FMT by the NG route induces clinical response in patients with active UC whether FMT by the COLON route induces clinical response in patients with active UC tolerability and safety which route of FMT delivery (if any) was suitable to investigate in a full-scale RCT. The aims of the qualitative research were to assess the following: patient and clinician acceptability of FMT (NG route) patient and clinician acceptability of FMT (COLON route). The aims of the nested-mechanistic substudy were to assess the following: whether FMT by either route is associated with a change in faecal calprotectin as a surrogate marker of colonic inflammation changes in the colonic microbiome induced by FMT via each route changes in the metabolome [short-chain fatty acids (SCFAs)] induced by FMT via each route effect of diet (donors) time from stool donation to treatment. Methods In this prospective, multicentre, open-label, parallel group, randomised pilot study, adult patients with mild to moderate active UC (partial Mayo score of ≥4 and ≤8) were recruited from three centres in the UK (Birmingham, Glasgow and St Mark’s, London). Patients were randomised to receive FMT delivered either via a NG tube for delivery to the stomach (foregut-NG) on 4 consecutive days repeated after a month or by a combination of delivery through a colonoscope followed by 7 weekly enemas (hindgut-COLON). All participants underwent a treatment schedule using FMT derived, in each case, from a single donor. The primary outcome was a composite assessment of both qualitative and quantitative data based on efficacy, acceptability and safety. Clinical response (primary measure of efficacy) was defined as a ≥3 point and a ≥30% reduction in full Mayo score from randomisation to week 8 and a ≥1 point reduction in the rectal bleeding subscore or an absolute rectal bleeding subscore of 0 or 1. Patient and clinician acceptability of FMT and preference of treatment route was assessed through semi-structured qualitative research interviews. Interviews also explored reasons for adherence to treatment allocation and patients’ perspectives on FMT and trial experience. Participants were interviewed face to face or by telephone at two time points, first following the screening visit and prior to randomisation, and second after the 12-week follow-up period. Safety was assessed by the number of participants experiencing adverse events (AEs) and serious adverse events (SAEs). For the translational research, stool samples were taken from participants at baseline and then at 2 weekly intervals throughout the study to assess microbiome diversity (by 16S rRNA sequencing) and to examine the effect of FMT on faecal calprotectin. Donor stool samples were also analysed by 16S rRNA sequencing. Biopsy samples were taken from the colon at the time of endoscopy (baseline and week 8) to analyse mucosa-associated microbiome by 16S rRNA sequencing. SCFA levels in stool samples were also measured throughout the study and blood was taken from participants to look for changes in C-reactive protein (CRP) in response to FMT. Donors were asked to fill in a dietary questionnaire in order to look for associations between dietary components in their habitual diet and the efficacy of their donated FMT samples. Results Thirty patients with UC were randomised between March 2018 and April 2019; 16 to NG; 14 to COLON route. Seven participants in the NG arm and two participants in the colonic arm withdrew from the study. Clinical response was achieved in a higher proportion of participants in the colonic arm [9/12 (75%)] compared with the NG arm [2/8 (25%)]; [adjusted risk ratio 2.94 (95% confidence interval, 0.84 to 10.30)]. In the colonic arm, 12/14 (86%) participants were considered adherent compared with 8/16 (50%) in the NG arm. AEs were reported in 11/14 (79%) participants in the colonic arm and 11/16 (69%) in the NG arm. There were three SAEs in two participants in the NG arm, and none in the colonic arm. Qualitative research found a high level of enthusiasm for the trial among both patients and staff. Patients were more positive about the colonic treatment route than the NG route, both before randomisation and after the patients had been through the study. Lower calprotectin levels, implying reduced colonic inflammation, averaged over the last half of the treatment course (weeks 4, 6 and 8), were seen in the responders (N = 11, mean 508.6 mg/kg) versus the non-responders (N = 9, mean 853.6 mg/kg) (p = 0.03). Furthermore, there was a negative association between faecal microbiome alpha diversity [rarefied total operational taxonomic unit (OTU) richness] and calprotectin levels (p < 0.01). This is the first time that change in faecal calprotectin, a widely used clinical inflammatory biomarker in UC, has been reported in response to FMT in inflammatory bowel disease (IBD). With respect to SCFAs, there were significant and large increases observed in the concentration of acetate (45% increase, p = 0.05) and butyrate (57% increase, p = 0.03) across all participants (N = 19) from baseline to week 2 following FMT treatment. This effect was also observed over the course of the entire FMT treatment period from baseline to 8 weeks (N = 16, acetate 21% increase, p = 0.02; butyrate 39% increase, p = 0.08). Significant changes were not observed for the other SCFAs measured, notably propionate (2 weeks p = 0.46, 8 weeks p = 0.36). The observed increase in acetate and butyrate was not associated with clinical response, and in fact when restricted to the responder group (N = 9) changes at both 2 and 8 weeks were no longer significant, although increases were still observed. Across all participants that completed FMT to day 56, and for whom baseline and week 8 DNA was available (N = 13), there was no significant change in faecal microbiome alpha diversity, as measured by rarefied Shannon diversity of 3% OTUs (p = 0.43). However, when restricted to the colonic arm only (N = 8), there was a significant increase in alpha diversity (p = 0.01) observed after FMT. Again, for those participants in the colonic arm that responded to FMT, there was a significant increase in alpha diversity (rarefied Shannon diversity, p < 0.01) compared to those who did not. No differences were seen in alpha diversity of mucosa-associated bacteria pre and post treatment. Donor microbiome diversity, as measured by rarefied 16S rRNA gene Shannon diversity, varied substantially between donors. There was a non-significant positive association between clinical response and donor diversity (p = 0.19) with the treatment arm taken into account. In this pilot study, CRP values were lower at baseline in the colonic arm (4.2 mg/l) compared with the NG arm (11.3 mg/l). Similarly, CRP values at weeks 4, 6 and 8 were also lower in the colonic arm than in the NG arm. With regard to data derived from diet questionnaires administered to donors, higher milk and milk product intakes were associated with higher alpha diversity, but this was not statistically significant. The mean number of days from stool donation to FMT treatment was similar in participants who achieved a clinical response compared with those who did not achieve a clinical response. There was no association between time from stool donation and treatment, and clinical response when added to the primary intention-to-treat analysis model. Conclusion This pilot study suggests that in patients with active UC, FMT delivered via the colonic route appears to be safe and better tolerated with signals suggesting greater efficacy compared to the NG route. The pilot study was welcomed by patients and clinicians, and FMT appears, at least in the short term, to be safe and well tolerated. On review of these data, the Independent Oversight Committee recommended progressing to the planned placebo-controlled randomised trial, which would be powered to assess efficacy, and would have enabled more detailed mechanistic studies to assess for strains engrafting from donors to recipients, which are associated with clinical response. Patients remain very interested in FMT as a potential treatment for UC as this microbiome manipulation affords an alternative therapy to immune system suppression as a means to treat UC. The trial management group involved in this pilot believe that further studies to assess the efficacy of FMT in UC with a focus on understanding mechanisms are warranted as the first step towards developing precision live biotherapeutics for IBD. Trial registration This trial is registered as ISRCTN74072945 and EudraCT 2015-005753-12. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 13/179/01) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 14. See the NIHR Funding and Awards website for further award information.

Biodiversity genomics research requires reliable organismal identification, which can be difficult based on morphology alone. DNA-based identification using DNA barcoding can provide confirmation of species identity and resolve taxonomic issues but is rarely used in studies generating reference genomes. Here, we describe the development and implementation of DNA barcoding for the Darwin Tree of Life Project (DToL), which aims to sequence and assemble high quality reference genomes for all eukaryotic species in Britain and Ireland. We present a standardised framework for DNA barcode sequencing and data interpretation that is then adapted for diverse organismal groups. DNA barcoding data from over 12,000 DToL specimens has identified up to 20% of samples requiring additional verification, with 2% of seed plants and 3.5% of animal specimens subsequently having their names changed. We also make recommendations for future developments using new sequencing approaches and streamlined bioinformatic approaches.

Abstract Background Limited evidence exists on how temperature increases are associated with hospital visits from alcohol- and substance-related disorders, despite plausible behavioral and physiological pathways. Methods In the present study, we implemented a case-crossover design, which controls for seasonal patterns, long-term trends, and non- or slowly-varying confounders, with distributed lag non-linear temperature terms (0–6 days) to estimate associations between daily ZIP Code-level temperature and alcohol- and substance-related disorder hospital visit rates in New York State during 1995–2014. We also examined four substance-related disorder sub-causes (cannabis, cocaine, opioid, sedatives). Results Here we show that, for alcohol-related disorders, a daily increase in temperature from the daily minimum (−30.1 °C (−22.2 °F)) to the 75th percentile (18.8 °C (65.8 °F)) across 0–6 lag days is associated with a cumulative 24.6% (95%CI,14.6%–34.6%) increase in hospital visit rates, largely driven by increases on the day of and day before hospital visit, with an association larger outside New York City. For substance-related disorders, we find evidence of a positive association at temperatures from the daily minimum (−30.1 °C (−22.2 °F)) to the 50th percentile (10.4 °C (50.7 °F)) (37.7% (95%CI,27.2%–48.2%), but not at higher temperatures. Findings are consistent across age group, sex, and social vulnerability. Conclusions Our work highlights how hospital visits from alcohol- and substance-related disorders are currently impacted by elevated temperatures and could be further affected by rising temperatures resulting from climate change. Enhanced social infrastructure and health system interventions could mitigate these impacts.

Introduction Characterised by chronic inflammation of the gastrointestinal tract, inflammatory bowel disease (IBD) symptoms including diarrhoea, abdominal pain and fatigue can significantly impact patient’s quality of life. Therapeutic developments in the last 20 years have revolutionised treatment. However, clinical trials and real-world data show primary non-response rates up to 40%. A significant challenge is an inability to predict which treatment will benefit individual patients.Current understanding of IBD pathogenesis implicates complex interactions between host genetics and the gut microbiome. Most cohorts studying the gut microbiota to date have been underpowered, examined single treatments and produced heterogeneous results. Lack of cross-treatment comparisons and well-powered independent replication cohorts hampers the ability to infer real-world utility of predictive signatures.IBD-RESPONSE will use multi-omic data to create a predictive tool for treatment response. Future patient benefit may include development of biomarker-based treatment stratification or manipulation of intestinal microbial targets. IBD-RESPONSE and downstream studies have the potential to improve quality of life, reduce patient risk and reduce expenditure on ineffective treatments.Methods and analysis This prospective, multicentre, observational study will identify and validate a predictive model for response to advanced IBD therapies, incorporating gut microbiome, metabolome, single-cell transcriptome, human genome, dietary and clinical data. 1325 participants commencing advanced therapies will be recruited from ~40 UK sites. Data will be collected at baseline, week 14 and week 54. The primary outcome is week 14 clinical response. Secondary outcomes include clinical remission, loss of response in week 14 responders, corticosteroid-free response/remission, time to treatment escalation and change in patient-reported outcome measures.Ethics and dissemination Ethical approval was obtained from the Wales Research Ethics Committee 5 (ref: 21/WA/0228). Recruitment is ongoing. Following study completion, results will be submitted for publication in peer-reviewed journals and presented at scientific meetings. Publications will be summarised at www.ibd-response.co.uk.Trial registration number ISRCTN96296121.

We present a genome assembly from an individual specimen of Luzula sylvatica (great wood-rush; Tracheophyta; Magnoliopsida; Poales; Juncaceae). The genome sequence is 444.5 megabases in span. Most of the assembly is scaffolded into 6 chromosomal pseudomolecules. The mitochondrial and plastid genome assemblies have lengths of 633.36 kilobases and 201.32 kilobases in length, respectively.

Introduction Associations between exposure to nature and positive mental health outcomes have been established. Although the Internet is a popular source of accessing mental health information, little is known about the readability of such online information. Thus, the goal of this study was to assess the readability of online information regarding the association between exposure to nature and mental health. Methods A search of webpages was conducted using the following search terms: ‘mental health and urban greening’, ‘stress and urban greening’, ‘mental health and nature’, ‘stress and nature’, ‘mental health and outdoors’, and ‘stress and outdoors’. Readability of the 255 webpages identified was determined by the Flesch-Kincaid Grade Level measure. Results On average, webpage content was written at an 11th grade reading level (Flesch-Kincaid Grade Level mean=11.95, SD=2.68), and fewer than 2% of webpages met readability guidelines (i.e. ≤6th grade reading level). Conclusions Most online content related to nature and mental health should be written at a more appropriate level for general audiences. Web content developers should prioritize adherence to readability guidelines.

The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD +to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss-of-function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.

Abstract The gut microbiota (GM) exerts a strong influence over the host immune system and dysbiosis of this microbial community can affect the clinical phenotype in chronic inflammatory conditions. To explore the role of the GM in lupus nephritis, we colonized NZM2410 mice with Segmented Filamentous Bacteria (SFB). Gut colonization with SFB was associated with worsening glomerulonephritis, glomerular and tubular immune complex deposition and interstitial inflammation compared to NZM2410 mice free of SFB. With SFB colonization mice experienced an increase in small intestinal lamina propria Th17 cells and group 3 innate lymphoid cells (ILC3s). However, although serum IL-17A expression was elevated in these mice, Th17 cells and ILC3s were not detected in the inflammatory infiltrate in the kidney. In contrast, serum and kidney tissue expression of the macrophage chemoattractants MCP-1 and CXCL1 were significantly elevated in SFB colonized mice. Furthermore, kidney infiltrating F4/80+CD206+M2-like macrophages were significantly increased in these mice. Evidence of increased gut permeability or “leakiness” was also detected in SFB colonized mice. Finally, the intestinal microbiome of SFB colonized mice at 15 and 30 weeks of age exhibited dysbiosis when compared to uncolonized mice at the same time points. Both microbial relative abundance as well as biodiversity of colonized mice was found to be altered. Collectively, SFB gut colonization in the NZM2410 mouse exacerbates kidney disease, promotes kidney M2-like macrophage infiltration and overall intestinal microbiota dysbiosis.

Introduction Cardiovascular disease (CVD) is a critical public health issue, with tobacco smoking the leading preventable cause. Perceptions of CVD risk in specific populations may differ by tobacco use status, potentially necessitating customized tobacco prevention measures. Methods Using data from the Youth Appalachian Tobacco Study (n=1104), CVD risk perceptions were defined by responses to three statements: ‘smoking causes heart disease’, ‘smoking causes strokes’ and ‘smoking causes high blood pressure’. Tobacco use status was characterized as never users, ever cigarette users, and ever non-cigarette users. Sociodemographic differences in CVD risk perceptions and tobacco use status were evaluated. Logistic regression analyses, adjusted for gender, race/ethnicity, and household tobacco use, were conducted. Results Among the sample, 24.1% were ever cigarette users and 10.1% were ever non-cigarette users. Compared to never users, ever cigarette users had higher odds of disagreeing that smoking causes heart disease (AOR=1.83; 95% CI: 1.23–2.73), stroke (AOR=1.54; 95% CI: 1.08–2.18) and hypertension (AOR=1.41; 95% CI: 1.00–1.99). White youth (vs racial/ethnic minorities) had fewer odds of disagreeing that smoking causes hypertension (AOR=0.44; 95% CI: 0.29– 0.68), and females (vs males) had fewer odds of disagreeing that smoking causes heart disease (AOR=0.69; 95% CI: 0.48–0.99). Conclusions Among Appalachian youth, CVD risk perceptions differed by tobacco use status and sociodemographic groups, such as race/ethnicity and gender. Findings from this study may be helpful in development of tobacco prevention efforts, such as health messaging for Appalachian youth.

Abstract Recent advances in detectors for imaging and spectroscopy have afforded in situ, rapid acquisition of hyperspectral data. While electron energy loss spectroscopy (EELS) data acquisition speeds with electron counting are regularly reaching 400 frames per second with near-zero read noise, signal to noise ratio (SNR) remains a challenge owing to fundamental counting statistics. In order to advance understanding of transient materials phenomena during rapid acquisition EELS, trustworthy analysis of noisy spectra must be demonstrated. In this study, we applied machine learning techniques to denoise high frame rate spectra, benchmarking with slower frame rate “ground truths”. The results provide a foundation for reliable use of low SNR data acquired in rapid, in-situ spectroscopy experiments. Such a tool-set is a first step toward both automation in microscopy as well as use of these methods to interrogate otherwise poorly understood transformations.

Introduction Crohn’s disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating disease, and subsequent surgical resection. Therapeutics are effective but associated with certain side-effects and relatively expensive. There is therefore an urgent need for robust methods to predict which newly diagnosed patients will develop disabling disease, to identify patients who are most likely to benefit from early, advanced therapies. We aim to determine if magnetic resonance enterography (MRE) features at diagnosis improve prediction of disabling CD within 5 years of diagnosis.Methods and analysis We describe the protocol for a multicentre, non-randomised, single-arm, prospective study of adult patients with newly diagnosed CD. We will use patients already recruited to the METRIC study and extend their clinical follow-up, as well as a separate group of newly diagnosed patients who were not part of the METRIC trial (MRE within 3 months of diagnosis), to ensure an adequate sample size. Follow-up will extend for at least 4 years. The primary outcome is to evaluate the comparative predictive ability of prognostic models incorporating MRE severity scores (Magnetic resonance Enterography Global Score (MEGS), simplified MAgnetic Resonance Index of Activity (sMaRIA) and Lémann Index) versus models using standard characteristics alone to predict disabling CD (modified Beaugerie definition) within 5 years of new diagnosis.Ethics and dissemination This study protocol achieved National Health Service Research Ethics Committee (NHS REC), London—Hampstead Research Ethics Committee approval (IRAS 217422). Our findings will be disseminated via conference presentations and peer-reviewed publications.Trial registration number ISRCTN76899103.

Introduction Exposure to green spaces is beneficial to mental health in a variety of ways, ranging from stress reduction to increased attentiveness and elevated selfesteem. The impact of views of greenness, as opposed to direct exposure, has been examined, but the association between self-reported views and depressive symptoms is not known. The purpose of this study is to examine the relationship between views of greenness and Patient Health Questionnaire–9 (PHQ-9) score. Methods Questionnaire responses from 191 participants in the Health, Environment, and Action in Louisville (HEAL) study were examined. Univariate statistical analyses included Mann-Whitney U, Kruskal-Wallis, and Spearman rank tests. Inferential statistical analysis was linear regression. Results Participant satisfaction with residential greenness was significantly associated with reduced PHQ-9 score (partially adjusted: linear coefficient = -0.42; 95% CI: -0.70 – -0.14; fully adjusted: linear coefficient = -0.21; 95% CI: -0.44 – 0.02). Additionally, being satisfied with local greenness was significantly associated with having views of greenness from home (linear coefficient = 1.97; 95% CI: 1.23–2.68). Conclusions Though views of greenness were not directly associated with depression, satisfaction with local greenness was associated with reduced PHQ-9 score, and having views of greenness from home was crudely associated with increased greenness satisfaction. The findings suggest urban greening interventions that focus on greenness satisfaction may be a strategy to reduce depression. Further research is necessary to better understand these relationships.

Introduction Sleep deficiency is associated with health risks, and time outdoors is related to health benefits. This study assessed time outdoors and its association with sleep normality. Methods As part of a health study in Louisville, Kentucky, 735 participants completed questionnaires on their health status, behaviors, neighborhoods, and demographics in 2018–2019. The measures included information on sleep, time outdoors, and mental and physical health. Participant characteristics were assessed by dichotomized sleep normality (N=728), and logistic regression (N=709) examined potential associations between time outdoors and sleep. Results As time spent outdoors increased from ≤4 hours to >4 – ≤8 hours (OR=1.04; 95% CI: 0.65–1.64) and >8 – ≤12 hours (OR=1.17; 95% CI: 0.63–2.17), odds of normal sleep increased; however, those who spent >12 – ≤16 hours (OR=0.63; 95% CI: 0.31–1.27) or >16 hours (OR=0.83; 95% CI: 0.45–1.53) outdoors had a lower likelihood of normal sleep. No associations between time outdoors and sleep were significant. There was a significant trend of less bodily pain associated with normal sleep (p

Introduction E-cigarettes are the most popular tobacco product among youth. Although harm perceptions have been linked to youth e-cigarette use, little research focuses on vulnerable populations, such as Appalachian youth. This study examines associations between e-cigarette harm perceptions and tobacco use among a sample of Appalachian youth. Methods Using data from the 2014–2016 Youth Appalachian Tobacco Study (n=1074), distributions of six e-cigarette harm perceptions by tobacco use (never, ever non-e-cigarette, ever e-cigarette) were examined, and multivariable multinomial logistic regression was used. Results Nearly one-fourth (23.4%) of the sample were ever e-cigarette users. More e-cigarette users were male (53.4%) and in high school (57.0%). Fewer e-cigarette users strongly agreed that e-cigarettes cause health problems (15.1%), breathing problems (20.3%), and oral health problems (18.7%) and that e-cigarettes are addictive (25.1%), compared to never and non-e-cigarette users. More e-cigarette users strongly agreed (32.3%) that e-cigarettes are healthier alternatives to cigarettes compared to never (24.1%) and non-e-cigarette (25.7%) users. Regression models indicate that e-cigarette users had greater odds of strongly disagreeing with e-cigarettes being harmful or addictive, compared to never users. E-cigarette users had approximately six-fold odds of strongly disagreeing with e-cigarettes causing health problems (OR=6.12; 95% CI: 3.16–11.90) and two times greater odds of disagreeing with e-cigarettes being addictive (OR=2.09; 95% CI: 1.07–4.08) compared to never users. Conclusions Appalachian youth ever e-cigarette users perceive e-cigarettes as less harmful and less addictive compared to never users. Better informing youth, especially youth tobacco users, of the harms associated with e-cigarettes is vital.

Introduction Despite decreases in the overall US smoking rate, tobacco use remains more common in some areas and by some groups. Deeper understanding of group differences is needed in order to tailor public health campaigns to the interests, perceptions and experiences of targeted audiences. Although some differences have been identified across African American and Caucasian smokers in the United States, additional insight is needed regarding factors that differentiate these groups. This study examined tobacco related perceptions and practices, with an emphasis on identifying differences across African American and Caucasian smokers. Toward this goal, we examined key demographic variables of race and age, and tobacco use characteristics. Methods The sample consisted of 284 people from the Jackson, Mississippi area who participated in focus groups and completed surveys addressing a variety of tobacco related topics, including knowledge and perceptions of products as well as use and health information seeking behavior. The selection criteria and recruitment approach ensured a balance across race (black, white), age (18–34, >35 years), sex, and cigarette smoking status (current, former, never). Statistical analyses were performed using SAS (v.9.4). Results Differences were observed across demographic subgroups regarding type and pattern of tobacco products used (e.g. mentholated, markers of nicotine dependence, hookah). Differences in preferred sources of health information based on age as well as perceptions of risk as a function of age, smoking status and race were also noted. Exposure to secondhand smoke and perceptions of its risks, quitting efforts and cessation methods differed by race. Conclusions Study findings suggest key differences across important subgroups. Knowledge of such differences has the potential to improve strategic public health messaging, allowing health campaigns to more effectively prevent tobacco product uptake as well as promote interest in quitting tobacco.

Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. Here, we demonstrate that H. pylori augmented gastric injury in INS-GAS mice under iron-deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori–infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. The severity of gastric injury was further augmented when H. pylori–infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori–induced injury under conditions of iron deficiency. To translate these findings to human populations, we evaluated the association between bile acid sequestrant use and gastric cancer risk in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid sequestrant use. Further, expression of the bile acid receptor transmembrane G protein–coupled bile acid receptor 5 (TGR5) paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori–induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

Studies reporting clinical symptoms related to electronic nicotine delivery systems (ENDS) usage, especially types of devices and e-liquids, are sparse. The sample included 1,432 current ENDS users, ages 18–64, from a nationwide online survey conducted in 2016. ENDS use included device types, nicotine content, flavors, and e-liquid used. Outcomes included any e-cigarette, or vaping, product use-associated lung injury (EVALI)-like symptoms (e.g., cough, shortness of breath, nausea) as well as any clinical symptoms. Of the sample, 50% were female, 23% non-Hispanic (NH) White, 23% NH Black, 54% Hispanic, 18% aged 18–24, 17% LGBTQ, 41% with

BackgroundDuring the last few years, the continuous emergence of new psychoactive substances (NPS) has become an important public health challenge. The use of NPS has been rising in two different ways: buying and consuming NPS knowingly and the presence of NPS in traditional drugs as adulterants. The rise of NPS use is increasing the number of different substances in the market to an extent impossible to study with current scientific methodologies. This has caused a remarkable absence of necessary information about newer drug effects on people who use drugs, mental health professionals, and policy makers. Current scientific methodologies have failed to provide enough data in the timeframe when critical decisions must be made, being not only too slow but also too square. Last but not least, they dramatically lack the high resolution of phenomenological details. ObjectiveThis study aims to characterize a population of e-psychonauts and the subjective effects of the NPS they used during the study period using a new, internet-based, fast, and inexpensive methodology. This will allow bridging an evidence gap between online surveys, which do not provide substance confirmation, and clinical trials, which are too slow and expensive to keep up with the new substances appearing every week. MethodsTo cover this purpose, we designed a highly personalized, observational longitudinal study methodology. Participants will be recruited from online communities of people who use NPS, and they will be followed online by means of a continuous objective and qualitative evaluation lasting for at least 1 year. In addition, participants will send samples of the substances they intend to use during that period, so they can be analyzed and matched with the effects they report on the questionnaires. ResultsThe research protocol was approved by the Institutional Review Board of the Hospital del Mar Research Institute on December 11, 2018. Data collection started in August 2019 and was still ongoing when the protocol was submitted (September 2020). The first data collection period of the study ended in October 2020. Data analysis began in November 2020, and it is still ongoing. The authors expect to submit the first results for publication by the end of 2021. A preliminary analysis was conducted when the manuscript was submitted and was reviewed after it was accepted in February 2021. ConclusionsIt is possible to conduct an institutional review board–approved study using this new methodology and collect the expected data. However, the meaning and usefulness of these data are still unknown. International Registered Report Identifier (IRRID)DERR1-10.2196/24433

Objective Authorship and number of publications are important criteria used for making decisions about promotions and research funding awards. Given the increase in the number of author positions over the last few decades, this study sought to determine if there had been a shift in the distribution of authorship among those publishing in high-impact academic medical journals over the last 12 years.Design This study analysed the distribution of authorship across 312 222 original articles published in 134 medium-impact to high-impact academic medical journals between 1 January 2008 and 31 December 2019. Additionally, this study compared the trends in author distributions across nine medical specialties and a collection of cross-specialty high-impact journal articles.Primary outcome measures The distribution of authorship was assessed using the Gini coefficient (GC), a widely used measure of economic inequality.Results The overall GC for all articles sampled across the 12-year study period was 0.49, and the GCs for the first and last authorship positions were 0.30 and 0.44, respectively. Since 2008, there was a significant positive correlation between year and GC for the overall authorship position (r=0.99, p

Introduction Given that Appalachian youth tobacco use rates are higher than the US national average, it is important to understand whether sex differences shape associations between receiving and sharing product information and using tobacco. Methods Middle and high school students in rural Appalachia (n=1038) were surveyed about tobacco-related perceptions and behaviors, including ways youth receive and share conventional tobacco-related and e-cigarette-related information. Youth were characterized as tobacco users (i.e. ever or current users of cigarettes, smokeless tobacco, or e-cigarettes) or never users. Descriptive characteristics were compared by tobacco use and sex. Adjusted logistic regression models evaluated associations between communication channels and tobacco use. Models were stratified by sex to examine effect modification. Results Approximately one-third of Appalachian youth (33.8%) were tobacco users and use varied by sex (males: 54.4%; females: 45.6%). Male (OR=1.75; 95% CI: 1.18–2.60) and female (OR=2.30; 95% CI: 1.53–3.47) youth who received e-cigarette-related information through friends and family (FF) had higher odds of tobacco use. Additionally, females who received e-cigarette-related information through public displays and digital media had nearly two-fold increased odds of tobacco use. Although sharing conventional tobacco-related and e-cigarette-related information through FF was associated with increased odds of tobacco use among both sexes, these relationships were stronger among females. Conclusions Although specific communication channels were associated with tobacco use, associations involving receiving and sharing e-cigarette information were more pronounced in female tobacco users. Consideration of sex differences in how youth receive and share tobacco-related information may benefit tobacco prevention interventions.

Among youth who use electronic nicotine delivery systems (ENDS), e-cigarettes are often the first tobacco product tried. Flavor is a common reason for experimentation with e-cigarettes. This study assessed flavor preferences and the choice of ENDS as an initial product among youth by selected demographic characteristics. The analysis sample included 1549 participants who had ever tried ENDS, drawn from a national online survey of youth aged 13–18 in 2017. Fruit was the most common favorite flavor among ENDS users, followed by menthol/mint/wintergreen. Preference for flavor varied by age, sex and racial/ethnic background. ENDS were the tobacco products most likely to be tried first, particularly among participants under age 17. Those who preferred fruit flavor were twice as likely to have tried ENDS first, compared to those with other flavor preferences, while those who preferred menthol/mint/wintergreen flavor were half as likely to have tried ENDS first. Our findings support an association between flavor and ENDS use. Our research supports previous findings indicating that: 1) flavor is one of the primary reasons for experimentation with ENDS among youth; 2) fruit flavor is strongly associated with use of ENDS as the first tobacco product; and 3) preference of fruit flavor varies by age, sex and racial/ethnic background. These findings have relevance for developing targeted messages for specific youth audiences and implications for tobacco regulatory policies. In addition to January 2020 federal regulations, the authors recommend tighter restrictions, specifically that the marketing and sale of all e-cigarette flavors other than tobacco be eliminated.

Appalachian youth tobacco use rates exceed the national average. Additional inquiry is needed to better understand youth product perceptions and use patterns. This study examined tobacco harm perceptions and their relationship with tobacco use among Appalachian youth. From 2014 to 2016, a survey of Appalachian middle and high school students (N = 1,136) was conducted. Tobacco harm perceptions were assessed by tobacco use status, categorized as never user, cigarette only user, smokeless only user, e-cigarette only user, or polytobacco user. Descriptive characteristics were compared by tobacco use status and harm perceptions. Adjusted multivariable logistic regression models assessed the relationship between tobacco use status and harm perceptions. Over one-third of participants were tobacco users (34.6%; 4.7% cigarette only users, 3.3% smokeless only users, 5.6% e-cigarette only users, and 21.0% polytobacco users). Approximately half agreed that e-cigarettes cause health problems (54.4%), and 64.7% agreed that e-cigarettes are addictive. Most participants (83.4–92.3%) agreed that smoking and smokeless tobacco cause health problems and are addictive. Tobacco users more often disagreed that tobacco products cause health problems than did never users. Compared to never users, e-cigarette only users were more likely to disagree that smoking (AOR: 2.99, 95% CI: 1.30–6.90) and e-cigarettes cause health problems (AOR: 2.79, 95% CI: 1.64–4.75) and that e-cigarettes cause addiction (AOR: 2.48, 95% CI: 1.48–4.16). Most youth were aware of health dangers associated with smoking, but perceptions were split on whether e-cigarettes were associated with health problems or addiction.The findings indicate the need for additional youth tobacco use prevention efforts.

Abstract In many cases, electron counting with direct detection sensors offers improved resolution, lower noise, and higher pixel density compared to conventional, indirect detection sensors for electron microscopy applications. Direct detection technology has previously been utilized, with great success, for imaging and diffraction, but potential advantages for spectroscopy remain unexplored. Here we compare the performance of a direct detection sensor operated in counting mode and an indirect detection sensor (scintillator/fiber-optic/CCD) for electron energy-loss spectroscopy. Clear improvements in measured detective quantum efficiency and combined energy resolution/energy field-of-view are offered by counting mode direct detection, showing promise for efficient spectrum imaging, low-dose mapping of beam-sensitive specimens, trace element analysis, and time-resolved spectroscopy. Despite the limited counting rate imposed by the readout electronics, we show that both core-loss and low-loss spectral acquisition are practical. These developments will benefit biologists, chemists, physicists, and materials scientists alike.

Abstract Fibrosis-related events play a part in most blinding diseases worldwide. However, little is known about the mechanisms driving this complex multifactorial disease. Here we have carried out the first genome-wide RNA-Sequencing study in human conjunctival fibrosis. We isolated 10 primary fibrotic and 7 non-fibrotic conjunctival fibroblast cell lines from patients with and without previous glaucoma surgery, respectively. The patients were matched for ethnicity and age. We identified 246 genes that were differentially expressed by over two-fold and p

Abstract Stem cells have been predicted to improve disease outcomes and patient lives. Steering stem cell fate - through controlling cell shape - may substantially accelerate progress towards this goal. As mesenchymal stromal cells (MSCs) are continuously exposed in vivo to a dynamically changing biomechanical environment, we hypothesized that exogenous forces can be applied for engineering a variety of significantly different MSC shapes. We applied specific cyclic stretch regimens to human MSCs and quantitatively measured the resulting cell shape, alignment, and expression of smooth muscle (SMC) differentiation markers, as those have been associated with elongated morphology. As proof of principle, a range of different shapes, alignments, and correlating SMC marker levels were generated by varying strain, length, and repetition of stretch. However, the major determinant of biomechanically engineering cellular shape was the repetition of a chosen stretch regimen, indicating that the engineered shape and associated differentiation were complex non-linear processes relying on sustained biomechanical stimulation. Thus, forces are key regulators of stem cell shape and the targeted engineering of specific MSC shapes through biomechanical forces represents a novel mechanobiology concept that could exploit naturally occurring in vivo forces for improving stem cell fate in clinical regenerative therapies.

Abstract Due to their antimicrobial properties, silver nanoparticles (AgNPs) are being used in non-edible and edible consumer products. It is not clear though if exposure to these chemicals can exert toxic effects on the host and gut microbiome. Conflicting studies have been reported on whether AgNPs result in gut dysbiosis and other changes within the host. We sought to examine whether exposure of Sprague-Dawley male rats for two weeks to different shapes of AgNPs, cube (AgNC) and sphere (AgNS) affects gut microbiota, select behaviors, and induces histopathological changes in the gastrointestinal system and brain. In the elevated plus maze (EPM), AgNS-exposed rats showed greater number of entries into closed arms and center compared to controls and those exposed to AgNC. AgNS and AgNC treated groups had select reductions in gut microbiota relative to controls. Clostridium spp., Bacteroides uniformis, Christensenellaceae, and Coprococcus eutactus were decreased in AgNC exposed group, whereas, Oscillospira spp., Dehalobacterium spp., Peptococcaeceae, Corynebacterium spp., Aggregatibacter pneumotropica were reduced in AgNS exposed group. Bacterial reductions correlated with select behavioral changes measured in the EPM. No significant histopathological changes were evident in the gastrointestinal system or brain. Findings suggest short-term exposure to AgNS or AgNC can lead to behavioral and gut microbiome changes.

Abstract The inhibition of ENaC may have therapeutic potential in CF airways by reducing sodium hyperabsorption, restoring lung epithelial surface fluid levels, airway hydration and mucociliary function. The challenge has been to deliver siRNA to the lung with sufficient efficacy for a sustained therapeutic effect. We have developed a self-assembling nanocomplex formulation for siRNA delivery to the airways that consists of a liposome (DOTMA/DOPE; L), an epithelial targeting peptide (P) and siRNA (R). LPR formulations were assessed for their ability to silence expression of the transcript of the gene encoding the α-subunit of the sodium channel ENaC in cell lines and primary epithelial cells, in submerged cultures or grown in air-liquid interface conditions. LPRs, containing 50 nM or 100 nM siRNA, showed high levels of silencing, particularly in primary airway epithelial cells. When nebulised these nanocomplexes still retained their biophysical properties and transfection efficiencies. The silencing ability was determined at protein level by confocal microscopy and western blotting. In vivo data demonstrated that these nanoparticles had the ability to silence expression of the α-ENaC subunit gene. In conclusion, these findings show that LPRs can modulate the activity of ENaC and this approach might be promising as co-adjuvant therapy for cystic fibrosis.

Introduction Imbalance of the gut microbiome is key to the pathogenesis of ulcerative colitis (UC). Faecal microbiota transplant (FMT) is the transfer of homogenised and filtered faeces from a healthy individual to the gastrointestinal tract of a patient with disease. Published datasets show a positive signal for the use of FMT to treat UC, but the optimal route and dose of FMT remain unanswered.Methods and analysis This prospective, multi-centre open-label, randomised pilot study will assess two possible routes of FMT delivery, via the nasogastric (NG) route or by delivery to the COLON, in 30 patients with active UC recruited from three sites in the UK. Stool will be collected from healthy screened donors, processed, frozen and stored under a Medicines and Healthcare products Regulatory Agency (MHRA) “specials” manufacturing licence held at the University of Birmingham Microbiome Treatment Centre. Thawed FMT samples will be administered to patients either via eight nasogastric infusions given initially over 4 days starting on the day of randomisation, and then again for 4 days in week 4 for foregut delivery (total of 240 g of stool) or via one colonoscopic infusion followed by seven weekly enemas according to the hindgut protocol (total of 360 g of stool). Patients will be followed up weekly for 8 weeks, and then at 12 weeks. The aims of this pilot study are (1) to determine which FMT administration route (NG or COLON) should be investigated in a randomised double-blind, placebo-controlled trial and (2) to determine if a full randomised controlled trial is feasible. The primary outcome will be a composite assessment of both qualitative and quantitative data based on efficacy (clinical response), acceptability and safety. At the end of the pilot study, decisions will be made regarding the feasibility of a full randomised double-blind, placebo-controlled trial and, if deemed feasible, which route of administration should be used in such a study.Ethics and dissemination Ethical approval for this study has been obtained from the East Midlands-Nottingham Research Ethics Committee (REC 17/EM/0274). At the end of the study, findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals.Trial registration number ISRCTN74072945

Somatic mutations in the Tp53 tumor suppressor gene are the most commonly seen genetic alterations in cancer, and germline mutations in Tp53 predispose individuals to a variety of early-onset cancers. Development of appropriate translational animal models that carry mutations in Tp53 and recapitulate human disease are important for drug discovery, biomarker development and disease modeling. Current Tp53 mouse and rat models have significant phenotypic and genetic limitations, and often do not recapitulate certain aspects of human disease. We used a marker-assisted speed congenic approach to transfer a well-characterized Tp53-mutant allele from an outbred rat to the genetically inbred Fischer-344 (F344) rat to create the F344-Tp53tm1(EGFP-Pac)Qly/Rrrc (F344-Tp53) strain. On the F344 genetic background, the tumor spectrum shifted, with the primary tumor types being osteosarcomas and meningeal sarcomas, compared to the hepatic hemangiosarcoma and lymphoma identified in the original outbred stock model. The Fischer model is more consistent with the early onset of bone and central nervous system sarcomas found in humans with germline Tp53 mutations. The frequency of osteosarcomas in F344-Tp53 homozygous and heterozygous animals was 57% and 36%, respectively. Tumors were highly representative of human disease radiographically and histologically, with tumors found primarily on long bones with frequent pulmonary metastases. Importantly, the rapid onset of osteosarcomas in this promising new model fills a current void in animal models that recapitulate human pediatric osteosarcomas and could facilitate studies to identify therapeutic targets.

We examine the effects of the COVID-19 pandemic on a community-based research project. This clinical trial investigates whether increased neighborhood greenness lowers the risk of cardiovascular diseases through reduction of air pollution. Facilitating the project involves considerable community engagement, and the project relies on successful collaboration across a multidisciplinary team. As concerns surrounding SARS-CoV-2 increased, adjustments to our research were needed. When cases of COVID-19 escalated, clinical trials were halted. In this analysis, we employ a dialectical approach to examine the competing tensions evidenced in community work during the pandemic. From the vantage point of dialectical theory, competing feelings can occur simultaneously (such as concurrent experiences of dissatisfaction/satisfaction or need for progress/safety) and influence experience. This analysis considers the dialectical tensions created by the pandemic as well as the means of reconciling some tensions and wrestling with others.

Abstract Background The eosinophilic response to clozapine is well described in the literature, causing a variety of responses, from serositis to colitis. However, there are not case reports describing a clozapine-induced marked eosinophilia resulting in multiorgan dysfunction. Case presentation In this case report, we describe a 24 year old Caucasian male who presented with severe systemic eosinophilia resulting in eosinophilic GI tract infiltration, myocarditis, pericardial and pleural effusions with dramatic improvement following drug withdrawal. Conclusions Clozapine associated eosinophilia should be suspected in the setting of eosinophilic infiltration of multiple organs.

BackgroundCritical care intensity is known to vary across regions and centers, yet the mechanisms remain unidentified. Physician behaviors have been implicated in the variability of intensive care near the end of life, but physician characteristics that may underlie this association have not been determined.PurposeWe sought to identify behavioral attributes that vary among intensivists to generate hypotheses for mechanisms of intensivist-attributable variation in critical care delivery.MethodsWe administered a questionnaire to intensivists who participated in a prior cohort study in which intensivists made prognostic estimates. We evaluated the degree to which scores on six attribute measures varied across intensivists. Measures were selected for their relevance to preference-sensitive critical care: a modified End-of-Life Preferences (EOLP) scale, Life Orientation Test-Revised (LOT-R), Jefferson Scale of Empathy (JSE), Physicians' Reactions to Uncertainty (PRU) scale, Collett-Lester Fear of Death (CLFOD) scale, and a test of omission bias. We conducted regression analyses assessing relationships between intensivists' attribute scores and their prognostic accuracy, as physicians' prognostic accuracy may influence preference-sensitive decisions.Results20 of 25 eligible intensivists (80%) completed the questionnaire. Intensivists' scores on the EOLP, LOT-R, PRU, CLFOD, and omission bias measures varied considerably, while their responses on the JSE scale did not. There were no consistent associations between attribute scores and prognostic accuracy.ConclusionsIntensivists vary in feasibly measurable attributes relevant to preference-sensitive critical care delivery. These attributes represent candidates for future research aimed at identifying mechanisms of clinician-attributable variation in critical care and developing effective interventions to reduce undue variation.

Patients engaging in shared decision making must weigh the likelihood of positive and negative outcomes and deal with uncertainty and negative emotions in the situations where desirable options might not be available. The use of "nudges," or communication techniques that influence patients' choices in a predictable direction, may assist patients in making complex decisions. However, nudging patients may be perceived as inappropriate influence on patients' choices. We sought to determine whether key stakeholders, physicians, and laypersons without clinical training consider the use of nudges to be ethical and appropriate in medical decision making. Eighty-nine resident-physicians and 336 Mechanical-Turk workers (i.e., non-clinicians) evaluated two hypothetical preference-sensitive situations, in which a patient with advanced cancer chooses between chemotherapy and hospice care. We varied the following: (1) whether or not the patient's decision was influenced by a mistaken judgment (i.e., decision-making bias) and (2) whether or not the physician used a nudge. Each participant reported the extent to which the communication was ethical, appropriate, and desirable. Both physicians and non-clinicians considered using nudges more positively than not using them, regardless of an initial decision-making bias in patients' considerations. Decomposing this effect, we found that physicians viewed the nudge that endorsed hospice care more favorably than the nudge that endorsed chemotherapy, while non-clinicians viewed the nudge that endorsed chemotherapy more favorably than the nudge that endorsed hospice care. We discuss implications and propose exploring further physicians' and patients' differences in the perception of nudges; the differences may suggest limitations for using nudges in medical decisions.

Prior to the advent of genetic engineering in the mouse, the rat was the model of choice for investigating the etiology of cancer. Now, recent advances in the manipulation of the rat genome, combined with a growing recognition of the physiological differences between mice and rats, have reignited interest in the rat as a model of human cancer. Two recently developed rat models, the polyposis in the rat colon (Pirc) and Kyoto Apc Delta (KAD) strains, each carry mutations in the intestinal-cancer-associated adenomatous polyposis coli (Apc) gene. In contrast to mouse models carrying Apc mutations, in which cancers develop mainly in the small intestine rather than in the colon and there is no gender bias, these rat models exhibit colonic predisposition and gender-specific susceptibility, as seen in human colon cancer. The rat also provides other experimental resources as a model organism that are not provided by the mouse: the structure of its chromosomes facilitates the analysis of genomic events, the size of its colon permits longitudinal analysis of tumor growth, and the size of biological samples from the animal facilitates multiplexed molecular analyses of the tumor and its host. Thus, the underlying biology and experimental resources of these rat models provide important avenues for investigation. We anticipate that advances in disease modeling in the rat will synergize with resources that are being developed in the mouse to provide a deeper understanding of human colon cancer.