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Summary: Background: Large-scale multicentre studies are needed to understand complex relationships between the gut microbiota, health and disease. Interrogating the mucosal microbiota may identify important biology not captured by stool analysis. Gold standard tissue cryopreservation (‘flash freezing’) limits large-scale study feasibility. We aimed to compare gut microbiota in gold standard and pragmatic mucosal biopsy storage conditions. Methods: We collected endoscopic recto-sigmoid biopsies from 20 adults with inflammatory bowel disease. Biopsies were preserved using three methods: (i) flash freezing (most proximal and distal biopsy sites); (ii) nucleic acid preservative reagents (QIAGEN Allprotect®, Invitrogen RNAlater™, and Zymo DNA/RNA Shield™); and (iii) formalin fixation with paraffin embedding (FFPE), which is used to preserve tissue for clinical histopathology within healthcare settings. Microbiota were sequenced on the MiSeq platform (V4 region, 16S rRNA gene). Findings: Tissue microbiota were consistent between most proximal and distal tissue suggesting any within-patient variation observed reflected storage condition, not biopsy location. There was no significant difference in alpha-diversity or microbial community profiles of reagent-preserved versus gold standard tissue. FFPE community structure was significantly dissimilar to other tissue samples, driven by differential relative abundance of obligate gut anaerobes; Faecalibacterium, Anaerostipes and Lachnospiraceae. Despite these differences, tissue microbiota grouped by participant regardless of preservation and storage conditions. Interpretation: Preservative reagents offer a convenient alternative to flash freezing tissue in prospective large-scale mucosal microbiota studies. Whilst less comparable, FFPE provides potential for retrospective microbiota studies using historical samples. Funding: Medical Research Council (MR/T032162/1) and The Leona M. and Harry B. Helmsley Charitable Trust (G-2002-04255).

Background This qualitative evaluation was embedded in the Rehabilitation Exercise and psycholoGical support After COVID-19 InfectioN (REGAIN) study, a randomised controlled trial (RCT) for those with post-COVID-19 condition (‘long COVID’) after hospital admission for COVID-19, comparing weekly home-based, live online supervised group exercise and psychological support sessions with ‘best practice usual care’ (a single session of advice).Objective To increase our understanding of how and why the REGAIN programme might have worked and what helped or hindered this intervention.Design A qualitative evaluation which utilised interviews with participants and practitioners delivering the intervention. Framework and thematic analysis were used to analyse the findings.Setting England and Wales, UK.Participants Adults discharged from National Health Service (NHS) hospitals at least 3 months previously after COVID-19, with ongoing physical and/or mental health sequelae.Results Twenty intervention participants, 20 control participants and five practitioners were interviewed.The themes from the group support sessions were: (1) you are not alone; (2) sharing experiences and addressing worries; (3) gaining new perspectives; (4) hope for progression; (5) peer support and bonding; (6) integration of facilitation skills; (7) modified activity pacing and goal setting, and (8) giving participants structure. The themes from group exercise were: (1) monitoring and modification of the online exercise; (2) catering for differing abilities; (3) feeling safe and confident to exercise; (4) progression of fitness; (5) optimal timing in the recovery trajectory; (6) group effect; (7) initial apprehension about exercise group; (8) gauging exercise capabilities; (9) translating exercises into life; and (10) on-demand supplementary videos. The 1:1 consultation sessions revealed patients needed to tell their stories.Conclusion Being listened to and being understood by someone ‘who got it’ was very important to people with post-COVID-19 condition. The group sessions of both exercise and psychological support were valued by participants, working together, and learning from each other in the face of a new disease within a global pandemic.

Abstract Venom is a remarkable innovation found across the animal kingdom, yet the evolutionary origins of venom systems in various groups, including spiders, remain enigmatic. Here, we investigated the organogenesis of the venom apparatus in the common house spider, Parasteatoda tepidariorum. The venom apparatus consists of a pair of secretory glands, each connected to an opening at the fang tip by a duct that runs through the chelicerae. We performed bulk RNA-seq to identify venom gland-specific markers and assayed their expression using RNA in situ hybridisation experiments on whole-mount time-series. These revealed that the gland primordium emerges during embryonic stage 13 at the chelicera tip, progresses proximally by the end of embryonic development and extends into the prosoma post-eclosion. The initiation of expression of an important toxin component in late postembryos marks the activation of venom-secreting cells. Our selected markers also exhibited distinct expression patterns in adult venom glands: sage and the toxin marker were expressed in the secretory epithelium, forkhead and sum-1 in the surrounding muscle layer, while Distal-less was predominantly expressed at the gland extremities. Our study provides the first comprehensive analysis of venom gland morphogenesis in spiders, offering key insights into their evolution and development.

Abstract Background and Aims Arterial function (specifically arterial stiffness) is an important cardiovascular risk factor. Pulse wave velocity (PWV) and augmentation index (Alx) are established indicators of arterial function. The present study aimed to evaluate the repeatability and reproducibility of PWV and Alx in healthy individuals. Methods Forty healthy participants (age 33 ± 11 years, 17 females) underwent resting supine PWV and Alx assessments. Measurements were made in triplicate and repeated 1 week apart. Alx was measured by brachial occlusion and PWV was measured from the carotid artery to the femoral artery via the tonometer‐oscillometric method. Repeatability and reproducibility were assessed using the intraclass correlation coefficient (ICC). Interoperator reproducibility was performed on 10 participants. Results The average values for week‐to‐week visits for PWV and Alx were 6.20 ± 0.91 versus 6.13 ± 0.91 ms−1 and 14.0 ± 11.8 versus 16.3 ± 12.2% respectively. For same‐day measurements, both PWV and Alx showed excellent repeatability (PWV: ICC = 0.96, 95% CI: 0.92–0.98, p

Objective This scoping review will map the extent and type of evidence in relation to the association between maternal long term health conditions (LTCs), including multimorbidity, and child oral health. Introduction Newer theories are emerging that detail the many factors that can influence child oral health at child, family and community levels. More recently, the association between maternal general health and child oral health has been explored, with preliminary evidence suggesting a link between shared environmental factors and diet/substance use during pregnancy causing childhood caries. Inclusion criteria All published studies that describe the relationship between maternal LTCs (including multimorbidity) and child oral health. There will be no limitation on the date of publication due to the limited number of studies available from the initial search of PubMed. The review will exclude case studies, abstracts, and grey literature. Literature must be in English language. Methods The following databases will be searched; CINAHL, Cochrane Library, Maternity and Infant Care, Medline via PubMed, Scopus, Web of Science. The search will include sources in English only and will be undertaken between April and July 2024. Studies to be included will be of any type of study design that describe a relationship between maternal long term health conditions, including maternal long term oral health conditions, and child oral health. Data extraction will be undertaken using tabulation of results by at least two independent reviewers. Narrative analysis of the evidence will be undertaken, and results will be presented in a narrative and tabular manner due to the heterogenous and limited evidence base found in the test search. This review has been registered prospectively on Open Science Framework, (https://doi.org/10.17605/OSF.IO/ECSWJ). The review will also inform an Evidence Gap Map (EGM) to illustrate the current evidence base regarding maternal health factors that influence child oral health.

Background Clinical trials are fundamental to healthcare, however, they also contribute to anthropogenic climate change. Following previous work to develop and test a method and guidance to calculate the carbon footprint of clinical trials, we have now applied the guidance to 10 further UK and international, academically sponsored clinical trials to continue the identification of hotspots and opportunities for lower carbon trial design.Methods 10 collaborating clinical trial units (CTUs) self-identified and a trial was selected from their portfolio to represent a variety of designs, health areas and interventions. Trial activity data was collated by trial teams across 10 modules spanning trial setup through to closure, then multiplied by emission factors provided in the guidance to calculate the carbon footprint. Feedback was collected from trial teams on the process, experience and ease of use of the guidance.Results We footprinted 10 trials: 6 investigational medicinal product trials, 1 nutritional, 1 surgical, 1 health surveillance and one complex intervention trial. Six of these were completed and four ongoing (two in follow-up and two recruiting). The carbon footprint of the 10 trials ranged from 16 to 765 tonnes CO2e. Common hotspots were identified as CTU emissions, trial-specific patient assessments and trial team meetings and travel. Hotspots for specific trial designs were also identified. The time taken to collate activity data and complete carbon calculations ranged from 5 to 60 hours. The draft guidance was updated to include new activities identified from the 10 trials and in response to user feedback.Discussion There are opportunities to reduce the impact of trials across all modules, particularly trial-specific meetings and travel, patient assessments and laboratory practice. A trial’s carbon footprint should be considered at the design stage, but work is required to make this common place.

BackgroundGrowing health care challenges resulting from a rapidly expanding aging population necessitate examining effective rehabilitation techniques that mitigate age-related comorbidity and improve quality of life. To date, exercise is one of a few proven interventions known to attenuate age-related declines in cognitive and sensorimotor functions critical to sustained independence. ObjectiveThis work aims to implement a multimodal imaging approach to better understand the mechanistic underpinnings of the beneficial exercise-induced adaptations to sedentary older adults’ brains and behaviors. Due to the complex cerebral and vascular dynamics that encompass neuroplastic change with aging and exercise, we propose an imaging protocol that will model exercise-induced changes to cerebral perfusion, cerebral vascular reactivity (CVR), and cognitive and sensorimotor task-dependent functional magnetic resonance imaging (fMRI) after prescribed exercise. MethodsSedentary older adults (aged 65-80 years) were randomly assigned to either a 12-week aerobic-based interval-based cycling intervention or a 12-week balance and stretching intervention. Assessments of cardiovascular fitness used the YMCA submaximal VO2 test, basal cerebral perfusion using arterial spin labeling (ASL), CVR using hypercapnic fMRI, and cortical activation using fMRI during verbal fluency and motor tapping tasks. A battery of cognitive-executive and motor function tasks outside the scanning environment will be performed before and after the interventions. ResultsOur studies and others show that improved cardiovascular fitness in older adults results in improved outcomes related to physical and cognitive health as well as quality of life. A consistent but unexplained finding in many of these studies is a change in cortical activation patterns during task-based fMRI, which corresponds with improved task performance (cognitive-executive and motor). We hypothesize that the 12-week aerobic exercise intervention will increase basal perfusion and improve CVR through a greater magnitude of reactivity in brain areas susceptible to neural and vascular decline (inferior frontal and motor cortices) in previously sedentary older adults. To differentiate between neural and vascular adaptations in these regions, we will map changes in basal perfusion and CVR over the inferior frontal and the motor cortices—regions we have previously shown to be beneficially altered during fMRI BOLD (blood oxygen level dependent), such as verbal fluency and motor tapping, through improved cardiovascular fitness. ConclusionsExercise is one of the most impactful interventions for improving physical and cognitive health in aging. This study aims to better understand the mechanistic underpinnings of improved health and function of the cerebrovascular system. If our hypothesis of improved perfusion and cerebrovascular reactivity following a 12-week aerobic exercise intervention is supported, it would add critically important insights into the potential of exercise to improve brain health in aging and could inform exercise prescription for older adults at risk for neurodegenerative disease brought on by cerebrovascular dysfunction. Trial RegistrationClinicalTrials.gov NCT05932069; https://clinicaltrials.gov/study/NCT05932069 International Registered Report Identifier (IRRID)DERR1-10.2196/58316

Abstract Hand osteoarthritis (OA) is an irreversible degenerative condition causing chronic pain and impaired functionality. Existing treatment options are often inadequate. Cannabidiol (CBD) has demonstrated analgesic and anti-inflammatory effects in preclinical models of arthritis. In this open-label feasibility trial, participants with symptomatically active hand OA applied a novel transdermal CBD gel (4% w/w) three times a day for four weeks to their most painful hand. Changes in daily self-reported pain scores were measured on a 0–10 Numeric Pain Rating Scale (NPRS). Hand functionality was determined via daily grip strength measures using a Bluetooth equipped squeeze ball and self-report questionnaire. Quality of life (QoL) ratings around sleep, anxiety, stiffness and fatigue were also measured. All self-report measures and grip strength data were gathered via smartphone application. Urinalysis was conducted at trial end to determine systemic absorption of CBD. Eighteen participants were consented and 15 completed the trial. Pain ratings were significantly reduced over time from pre-treatment baseline including current pain (− 1.91 ± 0.35, p

Introduction Severe Graves’ disease is a life-changing condition with poor outcomes from currently available treatments. It is caused by directly pathogenic thyroid-stimulating hormone receptor-stimulating antibodies (TRAb), which are secreted from plasma cells. The human anti-CD38 monoclonal antibody daratumumab was developed to target plasma cells which express high levels of CD38, and is currently licensed for treatment of the plasma cell malignancy, myeloma. However, it can also deplete benign plasma cells with the potential to reduce TRAb and alter the natural history of severe Graves’ disease. This study aims to establish proof of concept that daratumumab has efficacy in patients with severe Graves’ disease and will provide important data to inform a choice of dosing regimen for subsequent trials.Methods and analysis The Graves-PCD trial aims to determine if daratumumab modulates the humoral immune response in patients with severe Graves’ disease, and if so, over what time period, and to find an optimal dose. It is a single-blinded, randomised, dose-finding, adaptive trial using four different doses of daratumumab or placebo in 30 adult patients. Part 1 of the trial is dose-finding and, following an interim analysis, in part 2, the remaining patients will be randomised between the chosen dose(s) from the interim analysis or placebo. The primary outcome is the percentage change in serum TRAb from baseline to 12 weeks.Ethics and dissemination The trial received a favourable ethical opinion from London-Hampstead Research Ethics Committee (reference 21/LO/0449). The results of this trial will be disseminated at international meetings, in the peer-reviewed literature and through partner patient group newsletters and presentations at patient education events.Trial registration number ISRCTN81162400.

Abstract Division of labour is widely thought to increase the task efficiency of eusocial insects. Workers can switch their task to compensate for sudden changes in demand, providing flexible task allocation. In combination with automated tracking technology, we developed a robotic system to precisely control and spatiotemporally manipulate floor temperature over days, which allowed us to predictably drive brood transport behaviour in colonies of the ant Camponotus floridanus. Our results indicate that a small number of workers, usually minors belonging to the nurse social group, are highly specialised for brood transport. There was no difference in the speed at which workers transported brood, suggesting that specialisation does not correlate with efficiency. Workers often started to transport the brood only after having identified a better location. There was no evidence that workers shared information about the presence of a better location. Notably, once brood transporters had been removed, none of the remaining workers performed this task, and the brood transport completely stopped. When brood transporters were returned to their colony, brood transport was immediately restored. Taken together, our study reveals that brood transport is an inflexible task, achieved through the synchronous actions of a few privately informed specialist workers.

Abstract Background Approaching families of dying or newly deceased patients to donate organs requires specialized knowledge and a mastery of relational communication. As the transplantation field has progressed, Donation Professionals (DPs) are also leading conversations with family decision makers (FDMs) about the donation of uncommon anatomical gifts, such as face, hands, genitalia, referred to as Vascularized Composite Allotransplants (VCA) without much training or experience. To address the need for training, we adapted and beta tested an evidenced-based communication training program for donation discussions to VCA requests. The overarching goal of Communicating Effectively about Donation for Vascularized Composite Allotransplantation (CEaD-VCA) is to increase the number of VCA authorizations and to improve the socioemotional outcomes of FDMs. Methods We developed CEaD-VCA, an online, on-demand training program based on the previously tested, evidenced-based communication skills training program designed to train DPs to have conversations about solid organ donation. The training was modified utilizing data from a national telephone survey with DPs and results of 6 focus groups conducted with members of the general public. The survey and focus groups assessed knowledge, attitudes, and barriers to VCA donation. The training was shaped by a partnership with a leading industry partner, the Gift of Life Institute.™ Results Using the results as a guide, the existing CEaD training program, consisting of interactive eLearning modules, was adapted to include technical information about VCA, foundational communication skills, and two interactive example VCA donation request scenarios to facilitate active learning. Forty-two DPs from two partner Organ Procurement Organizations (OPOs) participated in the beta test of CEaD-VCA. Pre- and post-test surveys assessed the impact of the training. Conclusions The training was scored highly by DPs in effectiveness and ease of use. This project created a standardized, accessible, and comprehensive training for DPs to communicate about VCA donation. CEaD-VCA is an example of how to develop a communication skills training for difficult conversations utilizing input from stakeholders, guided by communication theory. It also demonstrates how gaps in communication skills during medical education can be filled utilizing advanced online Learning Management Systems. The training specifically addresses new CMS rules concerning OPO performance metrics.

Abstract Background Medical school acceptance rates in the United States (US) have been lower for applicants who identify as Underrepresented-in-Medicine (UiM) compared to non-UiM applicants. The gap between UiM and no-UiM groups is narrowing in recent years. Less well-studied are associations of acceptance decisions with family income and parental education. This study’s purpose is to evaluate the relationships between medical school acceptance and family income, parental education status, racial/ethnic background, Grade Point Average (GPA), Medical College Admission Test (MCAT) score, and participation in extracurricular activities. Methods This is a cross-sectional study of first-time US medical school applicants between 2017 and 2020. Acceptance rates for first-time applicants were calculated for first-generation (FG), low-income (LI), and UiM applicants. Associations of these attributes with MCAT scores, science GPAs, and seven categories of extracurricular activities were evaluated. Regression analyses estimated associations between acceptance to medical school with all variables with and without interaction terms (FG*URM, LI*URM, FG*LI). Results The overall acceptance rate for first-time applicants from 2017–2020 was 45.3%. The acceptance rates among FG, LI and UiM applicants were 37.9%, 39.6% and 44.2%, respectively. In univariable logistic regression analyses, acceptance was negatively associated with being FG (OR: 0.68, CI: 0.67–0.70), LI (OR: 0.70, CI: 0.69–0.72), and UiM (OR: 0.95, CI: 0.93–0.97). In multivariable regression, acceptance was most strongly associated with science GPA (OR: 7.15, CI: 6.78–7.54 for the highest quintile) and UiM (OR: 5.56, CI: 5.48–5.93) status and MCAT score (OR: 1.19, CI: 1.18–1.19), FG (OR: 1.14, CI: 1.10–1.18), and most extracurricular activities. Including interaction terms revealed a negative association between acceptance and LI (OR:0.90, CI: 0.87–0.94) and FG was no longer significant (OR:1.10, CI:0.96–1.08). Conclusions Collectively these results suggest medical school admissions committees may be relying on holistic admission practices. While MCAT and GPA scores continue to predict acceptance, individuals from racially and ethnically UiM backgrounds have favorable odds of acceptance when controlling for MCAT and GPA. However, these positive associations were not seen for low-income and first-generation applicants. Additional preparation for college and the MCAT for these latter groups may help further diversify the medical profession.

We present a genome assembly from an individual female Tetragnatha montana (the silver stretch spider; Arthropoda; Arachnida; Araneae; Tetragnathidae). The genome sequence is 784.7 megabases in span. Most of the assembly is scaffolded into 13 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 15.49 kilobases in length.

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.

Introduction The non-intoxicating plant-derived cannabinoid, cannabidiol (CBD), has demonstrated therapeutic potential in a number of clinical conditions. Most successful clinical trials have used relatively high (≥300 mg) oral doses of CBD. Relatively few studies have investigated the efficacy of lower (

Abstract Spaceflight induces widespread changes in human brain morphology. It is unclear if these brain changes differ with varying mission duration or spaceflight experience history (i.e., novice or experienced, number of prior missions, time between missions). Here we addressed this issue by quantifying regional voxelwise changes in brain gray matter volume, white matter microstructure, extracellular free water (FW) distribution, and ventricular volume from pre- to post-flight in a sample of 30 astronauts. We found that longer missions were associated with greater expansion of the right lateral and third ventricles, with the majority of expansion occurring during the first 6 months in space then appearing to taper off for longer missions. Longer inter-mission intervals were associated with greater expansion of the ventricles following flight; crew with less than 3 years of time to recover between successive flights showed little to no enlargement of the lateral and third ventricles. These findings demonstrate that ventricle expansion continues with spaceflight with increasing mission duration, and inter-mission intervals less than 3 years may not allow sufficient time for the ventricles to fully recover their compensatory capacity. These findings illustrate some potential plateaus in and boundaries of human brain changes with spaceflight.

OBJECTIVES/GOALS: Improving physical activity of African American women experiencing disproportionate health risks from sedentarism, educational and socio-environmental barriers. BeFit: Building Empowerment through Fitness is based on “What I Learned At Home” project, run by Women Under Construction Network, for residents of the Birmingham Housing Authority. METHODS/STUDY POPULATION: A qualitative study design to understand unique cultural context and challenges faced by African American women residing in the Birmingham Housing Authority, regarding physical activity engagement, including sedentarism. A needs assessment approach will help determine barriers, support systems, and social networks. Semi-structured, pre, mid, and post program focus groups will identify challenges and opportunities for health, such as diet and exercise, and will be analyzed by hand with a thematic analysis. The project framework uses exercise and home repair tools with a life-building/life repair curriculum to influence health, self-efficacy, and program engagement. The Study enrollment will include 50 women over two cohorts in a 12-week project. RESULTS/ANTICIPATED RESULTS: This research addresses the urgent health needs of African American women in low-income communities. These women face heightened health risks due to sedentary lifestyles, educational gaps, and socio-environmental barriers. This project targets the pronounced prevalence of allostatic burden in this population by applying a culturally sensitive, bottom-up approach. Our goal of incorporating healthy lifestyles to improve health in at-risk women and their families requires multiple projects. This project is a necessary first step in engaging with a community to identify local environmental circumstances and barriers to increasing the relevance of physical activity within the home. These barriers can then be addressed by adapting an exercise promotion program to the needs of this community. DISCUSSION/SIGNIFICANCE: Black women in under-resourced communities are more likely to be sedentary and have poor health. Exercise programs can be a powerful tool to address disparities and help prioritize health. The circumstances of women in public housing in Birmingham, AL, need community partners to adapt exercise engagement programs to meet environmental challenges.

Introduction Cardiac rehabilitation (CR) can reduce cardiovascular mortality and improve health-related quality of life. In the United Kingdom, patient uptake of CR remains low (52%), falling well short of the target in the 2019 National Health Service long-term plan (85%). Mobile health (mHealth) technologies, offering biometric data to patients and healthcare professionals, may bridge the gap between supervised exercise and physical activity advice, enabling patients to engage in regular long-term physically active lifestyles. This randomised controlled trial (RCT) will evaluate the feasibility of mHealth technology when incorporated into a structured home-based walking intervention, in people with recent myocardial infarction.Methods and analysis This is a feasibility, assessor blinded, parallel group RCT. Participants will be allocated to either CR standard care (control group) or CR standard care+mHealth supported exercise counselling (mHealth intervention group). Feasibility outcomes will include the number of patients approached, screened and eligible; the percentage of patients who decline CR (including reasons for declining), agree to CR and consent to being part of the study; the percentage of patients who enrol in standard CR and reasons for drop out; and the percentage of participants who complete clinical, physical and psychosocial outcomes to identify a suitable primary outcome for a future definitive trial.Ethics and dissemination The trial was approved in the UK by the Northwest—Greater Manchester East Research Ethics Committee (22/NW/0301) and is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Results will be published in peer-reviewed journals and presented at national and international scientific meetings.Trial registration numbers NCT05774587

Cardiopulmonary exercise testing (CPET) is the 'gold standard' method for evaluating functional capacity, with oxygen pulse (O2Pulse) inflections serving as a potential indicator of myocardial ischaemia. However, the reliability and agreement of identifying these inflections have not been thoroughly investigated. This study aimed to assess the inter- and intra-observer reliability and agreement of a subjective quantification method for identifying O2Pulse inflections during CPET, and to propose a more robust and objective novel algorithm as an alternative methodology. A retrospective analysis was conducted using baseline data from the HIIT or MISS UK trial. The O2Pulse curves were visually inspected by two independent examiners, and compared against an objective algorithm. Fleiss' Kappa was used to determine the reliability of agreement between the three groups of observations. The results showed almost perfect agreement between the algorithm and both examiners, with a Fleiss' Kappa statistic of 0.89. The algorithm also demonstrated excellent inter-rater reliability (ICC) when compared to both examiners (0.92-0.98). However, a significant level (P ≤0.05) of systematic bias was observed in Bland-Altman analysis for comparisons involving the novice examiner. In conclusion, this study provides evidence for the reliability of both subjective and novel objective methods for identifying inflections in O2Pulse during CPET. These findings suggest that further research into the clinical significance of O2Pulse inflections is warranted, and that the adoption of a novel objective means of quantification may be preferable to ensure equality of outcome for patients.

BackgroundIn low- and middle-income countries twin births have a high risk of complications partly due to barriers to accessing hospital care. This study compares pregnancy outcomes, maternal and neonatal morbidity and mortality of twin to singleton pregnancy in refugee and migrant clinics on the Thai Myanmar border.MethodsA retrospective review of medical records of all singleton and twin pregnancies delivered or followed at antenatal clinics of the Shoklo Malaria Research Unit from 1986 to 2020, with a known outcome and estimated gestational age. Logistic regression was done to compare the odds of maternal and neonatal outcomes between twin and singleton pregnancies.ResultsBetween 1986 and 2020 this unstable and migratory population had a recorded outcome of pregnancy of 28 weeks or more for 597 twin births and 59,005 singleton births. Twinning rate was low and stable (ConclusionIn this fragile setting where access to hospital care is difficult, three in four twins birthed vaginally. Twin pregnancies have a higher maternal morbidity and perinatal mortality, especially the second twin, compared to singleton pregnancies.

BackgroundChanges in regional levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) may indicate the potential for favorable responses to the treatment of stroke affecting the upper extremity. By selectively altering GABA levels during training, we may induce long-term potentiation and adjust excitatory/inhibitory balance (E/I balance). However, the impact of this alteration may be limited by neural damage or aging. Aerobic exercise has been shown to increase GABA levels in the sensorimotor cortex and improve motor learning by widening the dynamic range of E/I balance. The cross-sectional project, Effects of Acute Exercise on Functional Magnetic Resonance Spectroscopy Measures of GABA in Aging and Chronic Stroke (EASE), is designed to assess the functional relevance of changes in GABA concentration within the sensorimotor cortex before and after an acute aerobic exercise session.Methods/designEASE will enroll 30 participants comprised of healthy younger adults (18-35 years; n = 10), older adults (60+ years; n = 10), and persons with chronic stroke (n = 10) affecting distal upper extremity function. We will use resting magnetic resonance spectroscopy to measure all participants' GABA levels at rest before and after aerobic exercise. In addition, we will employ functional magnetic resonance spectroscopy using motor skill acquisition and recall tasks in healthy adults. We hypothesize that acute aerobic exercise will increase resting sensorimotor GABA concentration and that higher GABA resting levels will predict better motor learning performance on measures taken both inside and outside the magnet. We also hypothesize that a higher dynamic range of GABA during task-based spectroscopy in healthy adults will predict better motor skill acquisition and recall.DiscussionThe EASE project will evaluate the effect of acute exercise on GABA levels as a biomarker of upper extremity motor skill learning with two populations (aging adults and those with chronic stroke). We predict that acute exercise, higher sensorimotor GABA levels, and broader dynamic range will be related to better motor skill acquisition.

Background The urgency of the climate crisis requires attention from biomedical research, not least clinical trials which can involve significant greenhouse gas emissions. The Low Carbon Clinical Trials Working Group set out a strategy to reduce the emissions of clinical trials, starting with the development of a method to measure their carbon footprint (CO2e).Methods As a first step, we developed a process map defining clinical trial core activities. Corresponding emission factors were sourced to convert activity data into greenhouse gas emissions. The subsequent method was applied to two Cancer Research UK (CRUK)-funded trials (the international randomised sarcoma trial CASPS (ISRCTN63733470) and the UK cohort-based breast cancer trial PRIMETIME (ISRCTN41579286)). A guidance document defining the scope, method and assumptions was written to allow application to any publicly funded/investigator initiated clinical trial.Results Trial specific activities over and above routine care were grouped into 10 modules covering trial set up, conduct and closure. We identified emission factors for all trial activities within both trials and used them to estimate their total carbon footprint. The carbon footprint of CASPS, an international phase 2 trial of an investigational medicinal product with 47 participants, was 72 tonnes CO2e, largely attributable to clinical trials unit emissions and staff travel. PRIMETIME, a UK-based phase 3 non-investigational medicinal product trial with 1962 patients, produced 89 tonnes CO2e, largely attributable to trial-specific in-person participant assessments.Conclusion We have developed a method and guidance that trialists can use to determine the carbon footprint of clinical trials. The guidance can be used to identify carbon hotspots where alternative approaches to trial design and conduct could reduce a trial footprint, and where methodology research is required to investigate the potential impact of interventions taken to reduce carbon emissions. We will continue to refine the guidance to increase the potential application and improve usability.

BackgroundAtrial fibrillation (AF) is associated with significant morbidity/mortality. AF-ablation is an increasingly used treatment. Currently, first-time AF-ablation success is 40-80% at 1-year, depending on individual factors. There is growing evidence for improved outcomes through management of AF risk-factors/comorbidities via patient education/exercise-rehabilitation. There are no studies assessing combined prehabilitation/rehabilitation in this cohort. The aim of this randomised controlled trial is to assess efficacy of comprehensive prehabilitation/rehabilitation and combining supervised exercise-training with AF risk-factor modification/education compared with standard care in people undergoing first-time AF ablation.MethodsThis single-centre pragmatic randomised controlled trial will recruit 106 adults with paroxysmal/persistent AF listed for first-time AF-ablation. Participants will be randomised 1:1 to cardiac prehabilitation/rehabilitation/education (CREED AF) intervention or standard care. Both groups will undergo AF-ablation at 8-weeks post-randomisation as per usual care. The CREED AF intervention will involve 6-weeks of prehabilitation (before AF-ablation) followed by 6-weeks rehabilitation (after AF-ablation) consisting of risk factor education/modification and supervised exercise training. Standard care will include a single 30-minute session of risk-factor education. Outcomes will be measured at baseline, 10-weeks and 12-months post AF-ablation, by researchers blinded to treatment allocation. The primary outcome is cardiorespiratory-fitness (peak oxygen uptake, VO2peak) assessed using cardiopulmonary exercise testing (CPET) at 10-weeks post-ablation. Secondary outcomes include health-related quality of life, AF recurrence/burden assessed by 7-day Holter-monitor, requirement for repeat AF-ablation, study defined major adverse cardiovascular events, and cost-effectiveness (incremental cost per quality-adjusted life year (QALY)).ConclusionsThis study will assess clinical-efficacy/cost-effectiveness of comprehensive prehabilitation/rehabilitation/patient-education for people undergoing first time AF-ablation. Results will inform clinical care and design of future multi-centre clinical trials.Trial registrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT06042231.Date registered: September 18, 2023.

Abstract Validated methods of identifying childhood maltreatment (CM) in primary and secondary care data are needed. We aimed to create the first externally validated algorithm for identifying maltreatment using routinely collected healthcare data. Comprehensive code lists were created for use within GP and hospital admissions datasets in the SAIL Databank at Swansea University working with safeguarding clinicians and academics. These code lists build on and refine those previously published to include an exhaustive set of codes. Sensitivity, specificity and positive predictive value of previously published lists and the new algorithm were estimated against a clinically assessed cohort of CM cases from a child protection service secondary care-based setting—‘the gold standard’. We conducted sensitivity analyses to examine the utility of wider codes indicating Possible CM. Trends over time from 2004 to 2020 were calculated using Poisson regression modelling. Our algorithm outperformed previously published lists identifying 43–72% of cases in primary care with a specificity ≥ 85%. Sensitivity of algorithms for identifying maltreatment in hospital admissions data was lower identifying between 9 and 28% of cases with high specificity (> 96%). Manual searching of records for those cases identified by the external dataset but not recorded in primary care suggest that this code list is exhaustive. Exploration of missed cases shows that hospital admissions data is often focused on the injury being treated rather than recording the presence of maltreatment. The absence of child protection or social care codes in hospital admissions data poses a limitation for identifying maltreatment in admissions data. Linking across GP and hospital admissions maximises the number of cases of maltreatment that can be accurately identified. Incidence of maltreatment in primary care using these code lists has increased over time. The updated algorithm has improved our ability to detect CM in routinely collected healthcare data. It is important to recognize the limitations of identifying maltreatment in individual healthcare datasets. The inclusion of child protection codes in primary care data makes this an important setting for identifying CM, whereas hospital admissions data is often focused on injuries with CM codes often absent. Implications and utility of algorithms for future research are discussed.

Plain English summary Patient and public involvement (PPI) in research means research that is done ‘with’ or ‘by’ the public, not ‘to’, ‘about’, or ‘for’ them. Involving patients, family caregivers or the public (e.g. coordinators of patient organisations) in research activities means that they contribute to how research is designed, conducted, or disseminated. However, some diseases where patients have a short prognosis after diagnosis make it harder for patients or their family members to get involved. In this project we explored the perspectives of patients, public, and researchers on how PPI could be increased and maintained in research on mesothelioma—a rare cancer of the lining of the lung or of the peritoneum caused by exposure to asbestos. We conducted an online survey with mesothelioma researchers, and they indicated a number of PPI benefits but also challenges such as finding people living with mesothelioma well enough to participate. We also conducted six online workshops and thirteen interviews with patients, family members and coordinators of mesothelioma patient organisations—these were not PPI representatives but participants in research. All participants in the project were motivated by the wish to enhance outcomes for other patients. Their understanding of PPI improved during the project and they saw a number of challenges to others becoming involved in PPI, such as its abstract nature and the use of scientific language. We recommend that researchers engage long-term with mesothelioma support groups so that they have opportunities to explain what PPI means and involve people affected by mesothelioma in research.

Neutrophil extracellular trap formation (NETosis) is a mechanism used by neutrophils to capture pathogens with their own DNA. However, the exacerbation of this immune response is related to serious inflammatory diseases. Aging is known to lead to an excessive increase in NETosis associated with various diseases. Under this scenario, the search for strategies that regulate the release of NETosis in older people becomes relevant. High-intensity interval training (HIIT) involves repeated bouts of relatively intense exercise with alternating short recovery periods. This training has shown beneficial effects on health parameters during aging and disease. However, little is known about the potential role of HIIT in the regulation of NETosis in healthy older people. The aim of this study was to evaluate the induction of NETosis by serum from healthy young and older men, before and after 12 weeks of HIIT using healthy neutrophils as a biosensor. HIIT was performed 3 times per week for 12 weeks in young (YOUNG; 21 ± 1 years, BMI 26.01 ± 2.64 kg⋅m−2, n = 10) and older men (OLDER; 66 ± 5 years, BMI 27.43 ± 3.11 kg⋅m−2, n = 10). Serum samples were taken before and after the HIIT program and NETosis was measured with live cell imaging in donated neutrophils cultured with serum from the participants for 30 h. Our results showed that serum from older men at baseline induced greater baseline NETosis than younger men (p

OBJECTIVES/GOALS: We have evaluated the primary factors behind successful expansion of the predoctoral TL1 training grant at OHSU to all research-intensive universities in the state, evaluating the precepts that were key to integration. We also evaluate inclusion of social and behavioral sciences in clinical and translational science training, METHODS/STUDY POPULATION: OHSU contains three professional schools (medicine, nursing, and dentistry) as well as graduate studies in science. There are also three research-intensive universities in Oregon: Portland State University (PSU); Oregon State University (OSU) in Corvallis; and the University of Oregon (UO). We report evaluation of our 7-year experience with a predoctoral TL1 program and the precepts behind successful implementation of statewide outreach. We have tracked applicants from each university and program, trainee feedback, and success of the applicants as measured by persistence in research, inclusion of translational methods, additional training acquired, and subsequent research funding. We also evaluate participation by behavioral and social scientists. RESULTS/ANTICIPATED RESULTS: The predoctoral TL1 has included 40 scholars over 7 years, with 65% PhD graduate students and 35% MD students who pursue an additional research degree (PhD, MCR). Of PhD graduate students, the distribution is similar among universities: OHSU 31%, PSU 19%, OSU 27%, UO 23%. 38% of all graduate student trainees are in behavioral or social science. Key precepts behind success include: concentration on specific graduate programs at each university; implementing a common curriculum based on the MCR curriculum; interinstitutional mentor teams; leadership team that spans universities; required core TL1 activities; and a competitive application process with an interinstitutional review committee. Applicants are required to identify how translational science education enhances their research career. DISCUSSION/SIGNIFICANCE: Creating a statewide resource for TL1 translational science training has increased opportunities to expand translational research throughout Oregon through providing new opportunities to enhance excellence through disseminating resources and training across the universities.

Abstract Gummy stem blight (GSB) is a fungal disease affecting cucurbit crops, including watermelon (Citrullus lanatus), leading to significant yield losses. The disease is caused by three Stagonosporopsis species, of which Stagonosporopsis citrulli is the most common in the southeastern United States. Currently no gummy stem blight-resistant watermelon cultivars are available to growers. In this study, QTL-seq in an interspecific population developed from Sugar Baby × PI 189225 (Citrullus amarus) identified QTL on chromosomes 2, 5, 9 and 11. A novel QTL on chromosome 5 (Qgsb5.2) associated with resistance to S. citrulli (PVE = 13.3%) was confirmed by genetic mapping. KASP marker assays were developed for selection of Qgsb5.2 to allow breeders to track the allele contributing resistance to GSB, reducing the need for laborious phenotyping. Pyramiding different GSB resistance QTL could be a useful strategy to develop GSB resistant watermelon cultivars.

Background People with pulmonary hypertension (PH) are not routinely referred for exercise rehabilitation despite the potential for reducing breathlessness and improving quality of life. We describe the development of a supervised pulmonary hypertension exercise rehabilitation (SPHERe) programme for people with PH.Methods Development was completed in three phases: (1) systematic review, (2) stakeholder engagement with consensus from patients and experts and (3) prepilot intervention acceptability testing. We completed systematic reviews to identify international cardiopulmonary rehabilitation guidance and trials of exercise-based interventions for people with PH. Evidence from systematic reviews and stakeholder consensus shaped the SPHERe intervention, including addition of individual behavioural support sessions to promote exercise adherence. The draft SPHERe intervention was ratified through discussions with multidisciplinary professionals and people living with PH. We acceptability tested the centre-based intervention with eight participants in a prepilot development phase which identified a number of condition-specific issues relating to safety and fear avoidance of activity. Comprehensive intervention practitioner training manuals were produced to ensure standardised delivery. Participant workbooks were developed and piloted. Trial recruitment began in January 2020 but was subsequently suspended in March 2020 further to COVID-19 pandemic ‘lockdowns’. In response to the pandemic, we undertook further development work to redesign the intervention to be suitable for exclusively home-based online delivery. Recruitment to the revised protocol began in June 2021.Discussion The final SPHERe intervention incorporated weekly home-based online group exercise and behavioural support ‘coaching’ sessions supervised by trained practitioners, with a personalised home exercise plan and the optional loan of a stationary exercise bike. The intervention was fully manualised with clear pathways for assessment and individualised exercise prescription. The clinical and cost-effectiveness of the SPHERe online rehabilitation intervention is currently being tested in a UK multicentre randomised controlled trial.Trial registration number ISCRTN10608766.

Objective Insomnia is the most prevalent sleep disorder, with few effective pharmacotherapies. Anecdotal reports and recent preclinical research suggest that cannabinol (CBN), a constituent of Cannabis sativa derived from delta-9-tetrahydrocannabinol, could be an effective treatment. Despite this, the isolated effects of CBN on sleep have yet to be systematically studied in humans.Methods The present protocol paper describes a randomised, double-blind, placebo-controlled, single-dose, three-arm, cross-over, proof-of-concept study which investigates the effects of CBN on sleep and next-day function in 20 participants with clinician-diagnosed insomnia disorder and an Insomnia Severity Index Score ≥15. Participants receive a single fixed oral liquid dose of 30 mg CBN, 300 mg CBN and matched placebo, in random order on three treatment nights; each separated by a 2-week wash-out period. Participants undergo overnight sleep assessment using in-laboratory polysomnography and next-day neurobehavioural function tests. The primary outcome is wake after sleep onset minutes. Secondary outcomes include changes to traditional sleep staging, sleep-onset latency and absolute spectral power during non-rapid eye movement (NREM) sleep. Tertiary outcomes include changes to sleep spindles during NREM sleep, arousal indices, absolute spectral power during REM sleep and subjective sleep quality. Safety-related and exploratory outcomes include changes to next-day simulated driving performance, subjective mood and drug effects, postural sway, alertness and reaction time, overnight memory consolidation, pre and post-sleep subjective and objective sleepiness; and plasma, urinary, and salivary cannabinoid concentrations. The study will provide novel preliminary data on CBN efficacy and safety in insomnia disorder, which will inform larger clinical trials.Ethics and dissemination Human Research Ethics Committee approval has been granted by Bellberry (2021-08-907). Study findings will be disseminated in a peer-reviewed journal and at academic conferences.Trial registration number NCT05344170.

Background: Up to half of people hospitalised with COVID-19 report diverse and persistent symptoms affecting quality of life for months and sometimes years after discharge (long-COVID). We describe the development of an online group exercise and behavioural support intervention for people who continue to experience such physical and/or emotional health problems more than three months after hospital discharge. Methods: Intervention development was informed by the Medical Research Council framework for complex interventions. Our multidisciplinary team of academics, clinicians, and people with long-COVID, had collective expertise in the development and testing of complex interventions. We integrated a bio-psycho-social model of care drawing on rehabilitation literature for long-term health conditions and experiences from our pre-pilot study. Multiple stakeholder meetings were held to refine the intervention which was designed to be deliverable within the UK National Health Service. We adhere to TIDieR guidance for transparent and explicit reporting of telehealth interventions. Results: The final REGAIN online exercise and behavioural support intervention consisted of an initial 1:1 consultation with a trained practitioner, followed by eight online group exercise, and six group support, sessions delivered over eight weeks. Participants could also access an online library of on-demand exercise and support videos. Conclusions: The final REGAIN intervention, combining exercise and behavioural support, is fully manualised with clear pathways to delivery and implementation. It is currently being tested in a randomised controlled trial. The intervention, developed with extensive patient and stakeholder engagement, could be incorporated into existing NHS rehabilitation programmes, should it prove to be clinically and cost-effective for people with long-COVID. Trial registration: International Standard Randomised Controlled Trial Number (ISRCTN) 11466448: Rehabilitation exercise and psychological support after COVID-19 infection: REGAIN.

Bupropion had been in use since the late 1980s as an unconventional treatment for depression. Unlike other antidepressants, bupropion has no serotonergic activity and inhibits the reuptake of norepinephrine and dopamine. The drug has been used to treat depression, Attention Deficit Hyperactivity Disorder (ADHD), and smoking cessation. This investigation reviews the pharmacokinetic and pharmacodynamic effects of bupropion and its mechanisms of action and interactions with other drugs. We evaluated the efficacy of major on and off-label uses of bupropion, focusing on the indications, benefits, and adverse effects. Our review demonstrates that bupropion is superior to placebo and non-inferior to SSRIs such as escitalopram in treating major depressive disorder. More research is needed to determine positive patient-centered outcomes such as increases in quality of life. In the case of ADHD, the evidence for efficacy is mixed with poorly conducted randomized clinical trials, small sample sizes, and a lack of long-term assessments. The same is true in the case of bipolar disorder in which there is still limited and controversial data available on bupropion's safety and efficacy. In the case of smoking cessation, bupropion is found to be an effective anti-smoking drug with synergistic benefits when used as a combination therapy. We conclude that bupropion has the potential to provide benefit for a subset of patients who do not tolerate other typical antidepressants or anti-smoking therapies or for those whose treatment goals align with bupropion's unique side effect profile, such as smokers who wish to quit and lose weight. Additional research is needed to determine the drug's full clinical potential, particularly in the areas of adolescent depression and combination therapy with varenicline or dextromethorphan. Clinicians should use this review to understand the varied uses of the drug and identify the situations and patient populations in which bupropion can lend its greatest benefit.

Abstract Background The IO Score is a 27-gene immuno-oncology (IO) classifier that has previously predicted benefit to immune checkpoint inhibitor (ICI) therapy in triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC). It generates both a continuous score and a binary result using a defined threshold that is conserved between breast and lung. Herein, we aimed to evaluate the IO Score’s binary threshold in ICI-naïve TCGA bladder cancer patients (TCGA-BLCA) and assess its clinical utility in metastatic urothelial cancer (mUC) using the IMvigor210 clinical trial treated with the ICI, atezolizumab. Methods We identified a list of tumor immune microenvironment (TIME) related genes expressed across the TCGA breast, lung squamous and lung adenocarcinoma cohorts (TCGA-BRCA, TCGA-LUSQ, and TCGA-LUAD, 939 genes total) and then examined the expression of these 939 genes in TCGA-BLCA, to identify patients as having high inflammatory gene expression. Using this as a test of classification, we assessed the previously established threshold of IO Score. We then evaluated the IO Score with this threshold in the IMvigor210 cohort for its association with overall survival (OS). Results In TCGA-BLCA, IO Score positive patients had a strong concordance with high inflammatory gene expression (p

Abstract Humans are exposed to extreme environmental stressors during spaceflight and return with alterations in brain structure and shifts in intracranial fluids. To date, no studies have evaluated the effects of spaceflight on perivascular spaces (PVSs) within the brain, which are believed to facilitate fluid drainage and brain homeostasis. Here, we examined how the number and morphology of magnetic resonance imaging (MRI)-visible PVSs are affected by spaceflight, including prior spaceflight experience. Fifteen astronauts underwent six T 1-weighted 3 T MRI scans, twice prior to launch and four times following their return to Earth after ~ 6-month missions to the International Space Station. White matter MRI-visible PVS number and morphology were calculated using an established, automated segmentation algorithm. We validated our automated segmentation algorithm by comparing algorithm PVS counts with those identified by two trained raters in 50 randomly selected slices from this cohort; the automated algorithm performed similarly to visual ratings (r(48) = 0.77, p 0.50). Among the astronaut cohort, we found that novice astronauts showed an increase in total PVS volume from pre- to post-flight, whereas experienced crewmembers did not (p = 0.020), suggesting that experienced astronauts may exhibit holdover effects from prior spaceflight(s). Greater pre-flight PVS load was associated with more prior flight experience (r = 0.60–0.71), though these relationships did not reach statistical significance (p > 0.05). Pre- to post-flight changes in ventricular volume were not significantly associated with changes in PVS characteristics, and the presence of spaceflight associated neuro-ocular syndrome (SANS) was not associated with PVS number or morphology. Together, these findings demonstrate that PVSs can be consistently identified on T 1-weighted MRI scans, and that spaceflight is associated with PVS changes. Specifically, prior spaceflight experience may be an important factor in determining PVS characteristics.

Abstract The study assessed chronic myocardial, coronary and systemic effects of intracoronary supersaturated oxygen (SSO2) therapy. Left anterior descending coronary arteries of 40 swine were stented and randomized to 90-min selective intracoronary infusion of SSO2 (pO2 760–1000 mmHg) or normoxemic saline. In 20 out of 40 animals, SSO2 delivery followed a 60-min balloon occlusion to induce myocardial infarction (MI). In both normal and MI models, intracoronary treatment with hyperoxemic SSO2 therapy showed no evidence of coronary thrombosis. There were no biologically relevant differences between treatments at either time point in regard to coronary intervention site healing and neointimal growth. No signs of any myocardial or systemic toxicity were observed after 7 or 30 days. A trend was observed toward reduced incidence of microscopic MI scars and reduced infarct size in histopathology, as well as toward better recovery of echocardiographically evaluated global and regional contractility at 30 days. No treatment related infarcts or thromboemboli were observed in the downstream organs.

BackgroundLaw enforcement officers are routinely exposed to hazardous, disturbing events that can impose severe stress and long-term psychological trauma. As a result, police and other public safety personnel (PSP) are at increased risk of developing posttraumatic stress injuries (PTSIs) and disruptions to the autonomic nervous system (ANS). ANS functioning can be objectively and noninvasively measured by heart rate (HR), heart rate variability (HRV), and respiratory sinus arrhythmia (RSA). Traditional interventions aimed at building resilience among PSP have not adequately addressed the physiological ANS dysregulations that lead to mental and physical health conditions, as well as burnout and fatigue following potential psychological trauma. ObjectiveIn this study, we will investigate the efficacy of a web-based Autonomic Modulation Training (AMT) intervention on the following outcomes: (1) reducing self-reported symptoms of PTSI, (2) strengthening ANS physiological resilience and wellness capacity, and (3) exploring how sex and gender are related to baseline differences in psychological and biological PTSI symptoms and response to the AMT intervention. MethodsThe study is comprised of 2 phases. Phase 1 involves the development of the web-based AMT intervention, which includes 1 session of baseline survey measures, 6 weekly sessions that integrate HRV biofeedback (HRVBF) training with meta-cognitive skill practice, and 1 session of follow-up survey measures. Phase 2 will use a cluster randomized control design to test the effectiveness of AMT on the following prepost outcomes: (1) self-report symptoms of PTSI and other wellness measures; (2) physiological indicators of health and resilience including resting HR, HRV, and RSA; and (3) the influence of sex and gender on other outcomes. Participants will be recruited for an 8-week study across Canada in rolling cohorts. ResultsThe study received grant funding in March 2020 and ethics approval in February 2021. Due to delays related to COVID-19, phase 1 was completed in December 2022, and phase 2 pilot testing began in February 2023. Cohorts of 10 participants in the experimental (AMT) and control (prepost assessment only) groups will continue until a total of 250 participants are tested. Data collection from all phases is expected to conclude in December 2025 but may be extended until the intended sample size is reached. Quantitative analyses of psychological and physiological data will be conducted in conjunction with expert coinvestigators. ConclusionsThere is an urgent need to provide police and PSP with effective training that improves physical and psychological functioning. Given that help-seeking for PTSI is reduced among these occupational groups, AMT is a promising intervention that can be completed in the privacy of one’s home. Importantly, AMT is a novel program that uniquely addresses the underlying physiological mechanisms that support resilience and wellness promotion and is tailored to the occupational demands of PSP. Trial RegistrationClinicalTrials.gov NCT05521360; https://clinicaltrials.gov/ct2/show/NCT05521360 International Registered Report Identifier (IRRID)PRR1-10.2196/33492

Objectives Flash glucose monitoring for patients with T1 diabetes avoids frequent painful finger-prick testing, thus potentially improving frequency of glucose self-monitoring. Our study aimed to explore experiences of young people using Freestyle Libre sensors and their parents, and to identify benefits and challenges to National Health Service (NHS) staff of its adoption in their care provision.Participants Young people with T1 diabetes, their parents and healthcare professionals were interviewed between February and December 2021. Participants were recruited via social media and through NHS diabetes clinic staff.Design Semistructured interviews were conducted online and analysed using thematic methods. Staff themes were mapped onto normalisation process theory (NPT) constructs.Results Thirty-four participants were interviewed: 10 young people, 14 parents and 10 healthcare professionals. Young people reported that life was much easier since changing to flash glucose monitoring, increasing confidence and independence to manage their condition. Parents’ quality of life improved and they appreciated access to real-time data. Using the NPT concepts to understand how technology was integrated into routine care proved useful; health professionals were very enthusiastic about flash glucose monitoring and coped with the extra data load to facilitate more tailored patient support within and between clinic visits.Conclusion This technology empowers young people and their parents to understand their diabetes adherence more completely; to feel more confident about adjusting their own care between clinic appointments; and provides an improved interactive experience in clinic. Healthcare teams appear committed to delivering improving technologies, acknowledging the challenge for them to assimilate new information required to provide expert advice.

Introduction Public health responses to the COVID-19 pandemic have reaped adverse physical, psychological, social and economic effects, with older adults disproportionally affected. Psychological consequences of the pandemic include fear, worry and anxiety. COVID-19 fear may impact individuals’ mitigation behaviours, influencing their willingness to (re)engage in health, social and economic behaviours. This study seeks (1) to develop a robust and evidence-based questionnaire to measure the prevalence of COVID-19 fear among older adults (aged ≥50) in Scotland and (2) to examine the impact of COVID-19 fear on the willingness of older adults to (re)engage across health, social and economic domains as society adjusts to the ‘new normal’ and inform policy and practice.Methods and analysis This mixed-method study includes a large-scale multimodal survey, focus groups and interviews with older adults (aged ≥50) living in Scotland, and an email-based ‘e-Delphi’ consultation with professionals working with older adults. The COVID-19 fear scale was developed and validated using exploratory and confirmatory factor analyses. Survey data will be analysed using descriptive and inferential statistics. Thematic analysis will be used to analyse qualitative data. Survey and qualitative findings will be triangulated and used as the starting point for an ‘e-Delphi’ consensus consultation with expert stakeholders.Ethics and dissemination Ethical approval has been obtained from the University of Stirling for multimodal survey development, fieldwork methodology and data management. Anonymised survey data will be deposited with the UK Data Service, with a link provided via the Gateway to Global Ageing. Qualitative data will be deposited with the University of Stirling online digital repository—DataSTORRE. A dedicated work package will oversee dissemination via a coproduced project website, conference presentations, rapid reports and national and international peer-reviewed journal articles. There is planned engagement with Scottish and UK policy makers to contribute to the UK government’s COVID-19 recovery strategy.

Bacteria produce a variety of polysaccharides with functional roles in cell surface coating, surface and host interactions, and biofilms. We have identified an 'Orphan' bacterial cellulose synthase catalytic subunit (BcsA)-like protein found in four model pseudomonads, P. aeruginosa PA01, P. fluorescens SBW25, P. putida KT2440 and P. syringae pv. tomato DC3000. Pairwise alignments indicated that the Orphan and BcsA proteins shared less than 41% sequence identity suggesting they may not have the same structural folds or function. We identified 112 Orphans among soil and plant-associated pseudomonads as well as in phytopathogenic and human opportunistic pathogenic strains. The wide distribution of these highly conserved proteins suggest they form a novel family of synthases producing a different polysaccharide. In silico analysis, including sequence comparisons, secondary structure and topology predictions, and protein structural modelling, revealed a two-domain transmembrane ovoid-like structure for the Orphan protein with a periplasmic glycosyl hydrolase family GH17 domain linked via a transmembrane region to a cytoplasmic glycosyltransferase family GT2 domain. We suggest the GT2 domain synthesises β-(1,3)-glucan that is transferred to the GH17 domain where it is cleaved and cyclised to produce cyclic-β-(1,3)-glucan (CβG). Our structural models are consistent with enzymatic characterisation and recent molecular simulations of the PaPA01 and PpKT2440 GH17 domains. It also provides a functional explanation linking PaPAK and PaPA14 Orphan (also known as NdvB) transposon mutants with CβG production and biofilm-associated antibiotic resistance. Importantly, cyclic glucans are also involved in osmoregulation, plant infection and induced systemic suppression, and our findings suggest this novel family of CβG synthases may provide similar range of adaptive responses for pseudomonads.

Abstract Background and Aims Single‐use electrocardiography (ECG) leads have been developed to reduce healthcare‐associated infection. This study compared the validity and reliability of short‐term heart rate variability (HRV) obtained from single‐use disposable ECG leads. Methods Thirty healthy subjects (33 ± 10 years; 9 females) underwent 5‐min resting HRV assessments using disposable (single use) ECG cable and wire system (Kendall DL™ Cardinal Health) and a standard, reusable ECG leads (CardioExpress, Spacelabs Healthcare). Results Intraclass correlation coefficient (ICC) with 95% confidence interval (CI) between disposable and reusable ECG leads was for the time domain [R‐R interval (ms); 0.99 (0.91, 1.00)], the root mean square of successive normal R‐R interval differences (RMSSD) (ms); 0.91 (0.76, 0.96), the SD of normal‐to‐normal R‐R intervals (SDNN) (ms); 0.91 (0.68, 0.97) and frequency domain [low‐frequency (LF) normalized units (nu); 0.90 (0.79, 0.95), high frequency (HF) nu; 0.91 (0.80, 0.96), LF power (ms2); 0.89 (0.62, 0.96), HF power (ms2); 0.90 (0.72, 0.96)] variables. The mean difference and upper and lower limits of agreement between disposable and reusable leads for time‐ and frequency‐domain variables were acceptable. Analysis of repeated measures using disposable leads demonstrated excellent reproducibility (ICC 95% CI) for R‐R interval (ms); 0.93 (0.85, 0.97), RMSSD (ms); 0.93 (0.85, 0.97), SDNN (ms); 0.88 (0.75, 0.95), LF power (ms2); 0.87 (0.72, 0.94), and HF power (ms2); 0.88 (0.73, 0.94) with coefficient of variation ranging from 2.2% to 5% (p > 0.37 for all variables). Conclusion Single‐use Kendall DL™ ECG leads demonstrate a valid and reproducible tool for the assessment of HRV.

Abstract Arteriovenous fistula (AVF) is the preferred type of vascular access for maintenance haemodialysis but it may contribute to maladaptive cardiovascular remodelling. We studied the effect of AVF creation on cardiac structure and function in patients with chronic kidney disease (CKD). In this prospective cohort study patients with CKD listed for first AVF creation underwent cardiac magnetic resonance (CMR) imaging at baseline and at 6 weeks. All participants had ultrasound measurements of fistula blood flow at 6 weeks. The primary outcome was the change in left ventricular (LV) mass. Secondary outcomes included changes in LV volumes, LV ejection fraction, cardiac output, LV global longitudinal strain and N-terminal-pro B-type natriuretic peptide (NT-proBNP). A total of 55 participants were enrolled, of whom 40 (mean age 59 years) had AVF creation and completed both scans. On the second CMR scan, a mean increase of 7.4 g (95% CI 1.1–13.7, p = 0.02) was observed in LV mass. Significant increases in LV end-diastolic volumes (p = 0.04) and cardiac output (p = 0.02) were also seen after AVF creation. No significant changes were observed in LV end-systolic volumes, LV ejection fraction, NT-proBNP and LV global longitudinal strain. In participants with fistula blood flows ≥ 600 mL/min (n = 22) the mean increase in LV mass was 15.5 g (95% CI 7.3–23.8) compared with a small decrease of 2.5 g (95% CI − 10.6 to 5.6) in participants with blood flows

Songbirds and humans share the ability to adaptively modify their vocalizations based on sensory feedback. Prior studies have focused primarily on the role that auditory feedback plays in shaping vocal output throughout life. In contrast, it is unclear how non-auditory information drives vocal plasticity. Here, we first used a reinforcement learning paradigm to establish that somatosensory feedback (cutaneous electrical stimulation) can drive vocal learning in adult songbirds. We then assessed the role of a songbird basal ganglia thalamocortical pathway critical to auditory vocal learning in this novel form of vocal plasticity. We found that both this circuit and its dopaminergic inputs are necessary for non-auditory vocal learning, demonstrating that this pathway is critical for guiding adaptive vocal changes based on both auditory and somatosensory signals. The ability of this circuit to use both auditory and somatosensory information to guide vocal learning may reflect a general principle for the neural systems that support vocal plasticity across species.

Abstract Loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and incompletely penetrant craniosynostosis. The impact of LOF in IL11 has not been characterized. We generated IL11 knockout (Il11 −/−) mice that are born in expected ratios and have normal hematological profiles. Lung fibroblasts from Il11 −/− mice are resistant to pro-fibrotic stimulation with TGFβ1. Following bleomycin-induced lung injury, Il11 −/− mice are protected from pulmonary fibrosis and exhibit lesser ERK, STAT3 and NF-kB activation, reduced Il1b, Timp1, Ccl2 and diminished IL6 expression, both at baseline and after injury: placing Il11 activity upstream of IL6 in this model. Il11 −/− female mice are infertile. Unlike Il11ra1 −/− mice, Il11 −/− mice do not have craniosynostosis, have normal long bone mass and reduced body weights. These data further establish the role of IL11 signaling in lung fibrosis while suggesting that bone development abnormalities can be associated with mutation of IL11RA but not IL11, which may have implications for therapeutic targeting of IL11 signaling.

Abstract Shortly after the enactment of restrictions aimed at limiting the spread of COVID-19, various local government and public health authorities around the world reported an increased sighting of rats. Such reports have yet to be empirically validated. Here we combined data from multi-catch rodent stations (providing data on rodent captures), rodent bait stations (providing data on rodent activity) and residents’ complaints to explore the effects of a six week lockdown period on rodent populations within the City of Sydney, Australia. The sampling interval encompassed October 2019 to July 2020 with lockdown defined as the interval from April 1st to May 15th, 2020. Rodent captures and activity (visits to bait stations) were stable prior to lockdown. Captures showed a rapid increase and then decline during the lockdown, while rodent visits to bait stations declined throughout this period. There were no changes in the frequency of complaints during lockdown relative to before and after lockdown. There was a non-directional change in the geographical distribution of indices of rodent abundance suggesting that rodents redistributed in response to resource scarcity. We hypothesize that lockdown measures initially resulted in increased rodent captures due to sudden shortage of human-derived food resources. Rodent visits to bait stations might not show this pattern due to the nature of the binary data collected, namely the presence or absence of a visit. Relocation of bait stations driven by pest management goals may also have affected the detection of any directional spatial effect. We conclude that the onset of COVID-19 may have disrupted commensal rodent populations, with possible implications for the future management of these ubiquitous urban indicator species.

Prospective serosurveillance of severe acute respiratory syndrome coronavirus 2 in 1,069 healthcare workers in London, UK, demonstrated that nucleocapsid antibody titers were stable and sustained for

High-parameter single-cell phenotyping has enabled in-depth classification and interrogation of immune cells, but to date has not allowed for glycan characterization. Here, we develop CyTOF-Lec as an approach to simultaneously characterize many protein and glycan features of human immune cells at the single-cell level. We implemented CyTOF-Lec to compare glycan features between different immune subsets from blood and multiple tissue compartments, and to characterize HIV-infected cell cultures. Using bioinformatics approaches to distinguish preferential infection of cellular subsets from viral-induced remodeling, we demonstrate that HIV upregulates the levels of cell-surface fucose and sialic acid in a cell-intrinsic manner, and that memory CD4+ T cells co-expressing high levels of fucose and sialic acid are highly susceptible to HIV infection. Sialic acid levels were found to distinguish memory CD4+ T cell subsets expressing different amounts of viral entry receptors, pro-survival factors, homing receptors, and activation markers, and to play a direct role in memory CD4+ T cells’ susceptibility to HIV infection. The ability of sialic acid to distinguish memory CD4+ T cells with different susceptibilities to HIV infection was experimentally validated through sorting experiments. Together, these results suggest that HIV remodels not only cellular proteins but also glycans, and that glycan expression can differentiate memory CD4+ T cells with vastly different susceptibility to HIV infection.