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Abstract Amyotrophic lateral sclerosis (ALS) patients lack effective treatments to maintain motor and neuromuscular function. This study aimed to evaluate the effect of a home-based exercise program on muscle strength, ALS scores, and transcriptome in ALS patients, Clinical Trials.gov #NCT03201991 (28/06/2017). An open-label, non-randomized pilot clinical trial was conducted in seven individuals with early-stage ALS. Participants were given 3 months of home-based resistance exercise focusing on the quadriceps muscles. The strength of exercised muscle was evaluated using bilateral quadriceps strength with manual muscle testing, handheld dynamometers, five times sit-to-stand, and Timed-Up-and-Go before and after the exercise program. In addition, changes in the Sickness Impact Profile ALS-19 (SIP/ALS-19) as the functional outcome measure and the transcriptome of exercised muscles were compared before and after the exercise. The primary outcome of muscle strength did not change significantly by the exercise program. The exercise program maintained the SIP/ALS-19 and the ALS Functional Rating Scale-Revised (ALSFRS-R). Transcriptome analysis revealed that exercise reverted the expression level of genes decreased in ALS, including parvalbumin. Three months of moderately intense strength and conditioning exercise maintained muscle strength of the exercised muscle and ALSFRS-R scores and had a positive effect on patients’ muscle transcriptome.

OBJECTIVES: This study aimed to quantify the duration of work participation and reasons for working years lost, according to gender and educational attainment, among a Norwegian population. METHODS: Register data on labor market attachment between 2000–2015 were obtained from Statistics Norway. We included five cohorts: individuals turning 20 (N=323 333), 30 (N=386 006), 40 (N=388 962), 50 (N=358 745), and 60 years (N=284 425) between 1 January 2000 and 31 December 2005. Individuals were followed for ten years. Data completeness allowed calculation of the average time spent in work and years lost to health-related absences and non-employment states per cohort. Changes in state probabilities over time were also depicted. Mean differences between genders and educational levels, and corresponding 95% confidence intervals were based on 1000 bootstrap samples. RESULTS: Both genders spent most time in work; however, per cohort, women worked approximately one year less than men. As cohorts aged, main reasons for working years lost changed from education and economic inactivity to sickness absence and disability pensioning; this trend was stronger for women than men. Individuals with a low education spent fewer years in work and more years in sickness absence and disability pensioning than highly educated peers. This difference tended to be larger for women and older cohorts. CONCLUSIONS: Per cohort, women participated one year less in work than men and, depending on age, spent more time in education, economic inactivity, sickness absence, and disability pensioning. Stronger educational gradients were seen for work and health-related absences for older cohorts and women.

Abstract Openness and transparency in the research process are a prerequisite to the production of high quality research outputs. Efforts to maximise these features have substantially accelerated in recent years, placing open and transparent research practices at the forefront of funding and related priorities, and encouraging investment in resources and infrastructure to enable such practices. Despite these efforts, there has been no systematic documentation of current practices, infrastructure, or training and resources that support open and transparent research in the UK. To address this gap, we developed and conducted the Open and Transparent Research Practices survey, a large-scale audit study completed by research-active staff in UK research institutions to better understand existing practices, needs, support, and barriers faced when implementing open and transparent research. The data presented here capture responses from over 2,500 research-active staff based at 15 institutions affiliated with the UK Reproducibility Network. The data provide a snapshot of open research practices that can be used to identify barriers, training needs, and areas that require greater investments.

Abstract Background Non-pharmacological interventions have proven effective at alleviating depression and anxiety symptoms in older adults. Methodological refinement and testing of these interventions in new contexts are needed on a small scale before their effectiveness and implementation can be evaluated. The purpose of this pilot study is to assess the feasibility of a future large-scale trial comparing an adapted mental health multi-component evidence-based intervention (VIDACTIVA) versus standard care for older adults experiencing depression symptoms in urban, resource-limited settings in Lima, Peru. Furthermore, this study will explore the acceptability, feasibility, and fidelity of implementing the intervention. Methods We will conduct an open-label, mixed methods pilot feasibility study with two parallel groups. A total of 64 older adults, stratified by sex, will be randomized at a 1:1 ratio to either the “intervention” or “control.” Participants will be followed for 22 weeks after enrollment. Those in the intervention group will receive eight VIDACTIVA sessions administered by community health workers (CHWs) over 14 weeks, with an additional eight weeks of follow-up. Participants in the control group will receive two psychoeducation sessions from a study fieldworker and will be directed to health care centers. Standard care does not involve CHWs. We will evaluate screening rates, recruitment strategies, retention rates, the acceptability of randomization, and assessments. Additionally, we will assess preliminary implementation outcomes—acceptability, feasibility, and fidelity—from the perspectives of CHWs (interventionists), older adults (main participants), older adults’ relatives, and healthcare professionals. Discussion If the findings from this feasibility trial are favorable, a fully powered randomized controlled trial will be conducted to evaluate `both the effectiveness and implementation of the intervention. This research will make a substantial contribution to the field of mental health in older adults, particularly by emphasizing a meticulous examination and documentation of the implementation process. By doing so, this study will offer valuable methodologies and metrics for adapting and assessing mental health interventions tailored to the unique needs of older adults in resource-constrained contexts and diverse cultural settings. Trial registration The current trial registration number is NCT06065020, which was registered on 26th September 2023.

Abstract Umbilical cord blood (UCB) is a rich source of beneficial stem and progenitor cells with known angiogenic, neuroregenerative and immune-modulatory properties. Preclinical studies have highlighted the benefit of UCB for a broad range of conditions including haematological conditions, metabolic disorders and neurological conditions, however clinical translation of UCB therapies is lacking. One barrier for clinical translation is inadequate cell numbers in some samples meaning that often a therapeutic dose cannot be achieved. This is particularly important when treating adults or when administering repeat doses of cells. To overcome this, UCB cell expansion is being explored to increase cell numbers. The current focus of UCB cell expansion is CD34+ haematopoietic stem cells (HSCs) for which the main application is treatment of haematological conditions. Currently there are 36 registered clinical trials that are examining the efficacy of expanded UCB cells with 31 of these being for haematological malignancies. Early data from these trials suggest that expanded UCB cells are a safe and feasible treatment option and show greater engraftment potential than unexpanded UCB. Outside of the haematology research space, expanded UCB has been trialled as a therapy in only two preclinical studies, one for spinal cord injury and one for hind limb ischemia. Proteomic analysis of expanded UCB cells in these studies showed that the cells were neuroprotective, anti-inflammatory and angiogenic. These findings are also supported by in vitro studies where expanded UCB CD34+ cells showed increased gene expression of neurotrophic and angiogenic factors compared to unexpanded CD34+ cells. Preclinical evidence demonstrates that unexpanded CD34+ cells are a promising therapy for neurological conditions where they have been shown to improve multiple indices of injury in rodent models of stroke, Parkinson’s disease and neonatal hypoxic ischemic brain injury. This review will highlight the current application of expanded UCB derived HSCs in transplant medicine, and also explore the potential use of expanded HSCs as a therapy for neurological conditions. It is proposed that expanded UCB derived CD34+ cells are an appropriate cellular therapy for a range of neurological conditions in children and adults.

Abstract The efficiency of global crop production is under threat from microbial pathogens which is likely to be worsened by climate change. Major contributors to plant disease are Pseudomonas syringae (P. syringae) pathovars which affect a variety of important crops. This opinion piece focuses on P. syringae pathovars actinidiae and syringae, which affect kiwifruit and stone fruits, respectively. We discuss some of the current control strategies for these pathogens and highlight recent research developments in combined biocontrol agents such as bacteriophages and combinations of bacteriophages with known anti‐microbials such as antibiotics and bacteriocins.

Abstract Fosfomycin has been used to treat carbapenem‐resistant Acinetobacter baumannii (CRAB) infections. However, there is insufficient information on dosage adjustment among critically ill patients with renal impairment. This study aims to evaluate the attainment of PK/PD targets for different dosage regimens of CRAB treatment in critically ill patients based on their renal function. Monte Carlo simulations were conducted to assess the probability of achieving time above the minimum inhibitory concentration (T > MIC) of 80% and 100% and to determine the cumulative fraction response (CFR) against institutional MICs. Our results demonstrated that administering fosfomycin 20–24 g/day to individuals with normal renal function (CrCl ≥60 mL/min) achieved the target at a MIC of ≤64 and ≤32 μg/mL during the first 24 h of treatment and at steady state, respectively. Notably, those with renal impairment achieved higher MIC values at a steady state despite dosage reduction. None of the regimens reached the target CFR. Our study suggested that administering fosfomycin at least 20 g/day to those with normal renal function provides sufficient exposure throughout the treatment course when the MIC value is ≤32 μg/mL. Less aggressive dosing regimens are advisable for patients with renal impairment. Additional clinical studies are necessary to verify our suggestions.

BACKGROUND: Maintaining physical activity throughout life is crucial for overall health and wellbeing. Yet the age-related decline in average physical activity, a natural phenomenon also observed in animals, poses a challenge. This study aimed to investigate whether participation in organised sports supported by the Swiss Youth+Sports (Y+S) programme is associated with sustaining or enhancing physical activity among children and adolescents during 5 years of follow-up. METHODS: The longitudinal study was nested in the population-based SOPHYA (Swiss children’s Objectively measured PHYsical Activity) cohort. Participants aged 6–16 years at SOPHYA1 (2014) with complete accelerometer data from baseline and follow-up assessment (SOPHYA2, 2019) were included. The primary exposure was participation in organised sport during the follow-up period, calculated by linkage with the Y+S database as the number of days with at least one activity in Y+S-offered programmes for ages 5 to 20 years. The primary outcome was the categorisation of participants into physical activity “improvers” or “worseners”. Improvers in the respective physical activity categories – total activity counts per minute (CPM), minutes in moderate-to-vigorous activity (MVPA), minutes in light activity (LPA) and minutes in sedentary behaviour (SB) – increased or maintained their active physical activity during the 5 follow-up years. Information on confounders and effect modifiers (sex, age, body mass index (BMI), language region, household income, education) was obtained by self-report at baseline. Logistic regressions examined the relationship between organised sport participation and the probability of being a physical activity improver in each physical activity intensity category separately. Covariates for the final models were selected through a stepwise procedure based on the Bayesian information criterion from a maximal model containing all covariates as well as all two-way interactions with organised sport and between them. All models were a priori adjusted for technical variables (season of measurement; wear time; duration of follow-up). RESULTS: The analysis included 432 participants. There was a strong CPM, MVPA and LPA decline from 2014 to 2019, but an increase in SB. Nevertheless, the prevalence of improvers was 22.5% for CPM, 9.5% for MVPA, 26.9% for LPA and 9.7% for SB. Engagement in organised sport between 2014 and 2019 was positively associated with CPM, MVPA and SB, but not with LPA improver status. For 30 additional days of participation in organised sport over the five years of the study, the odds of being an improver vs being a worsener increased by 4.0% for CPM (95% CI: 0.13–7.69), 6.2% for MVPA (95% CI: 0.82–11.54) and 6.0% for SB (95% CI:−1.49–13.97). CONCLUSION: The results provide supporting evidence that organised sport in the context of the Swiss Y+S programme may empower the young to maintain an active lifestyle and even offset the age-related decline in physical activity.

ABSTRACT Purpose: To create a nomogram to predict the absence of clinically significant prostate cancer (CSPCa) in males with non-suspicion multiparametric magnetic resonance imaging (mpMRI) undergoing prostate biopsy (PBx). Materials and Methods: We identified consecutive patients who underwent 3T mpMRI followed by PBx for suspicion of PCa or surveillance follow-up. All patients had Prostate Imaging Reporting and Data System score 1-2 (negative mpMRI). CSPCa was defined as Grade Group ≥2. Multivariate logistic regression analysis was performed via backward elimination. Discrimination was evaluated with area under the receiver operating characteristic (AUROC). Internal validation with 1,000x bootstrapping for estimating the optimism corrected AUROC. Results: Total 327 patients met inclusion criteria. The median (IQR) age and PSA density (PSAD) were 64 years (58-70) and 0.10 ng/mL2 (0.07-0.15), respectively. Biopsy history was as follows: 117 (36%) males were PBx-naive, 130 (40%) had previous negative PBx and 80 (24%) had previous positive PBx. The majority were White (65%); 6% of males self-reported Black. Overall, 44 (13%) patients were diagnosed with CSPCa on PBx. Black race, history of previous negative PBx and PSAD ≥0.15ng/mL2 were independent predictors for CSPCa on PBx and were included in the nomogram. The AUROC of the nomogram was 0.78 and the optimism corrected AUROC was 0.75. Conclusions: Our nomogram facilitates evaluating individual probability of CSPCa on PBx in males with PIRADS 1-2 mpMRI and may be used to identify those in whom PBx may be safely avoided. Black males have increased risk of CSPCa on PBx, even in the setting of PIRADS 1-2 mpMRI

Abstract Background Umbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury. Methods Preterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively. Results In VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls. Conclusions UCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.

Abstract There has been huge recent interest in the potential of making operational weather forecasts using machine learning techniques. As they become a part of the weather forecasting toolbox, there is a pressing need to understand how well current machine learning models can simulate high-impact weather events. We compare short to medium-range forecasts of Storm Ciarán, a European windstorm that caused sixteen deaths and extensive damage in Northern Europe, made by machine learning and numerical weather prediction models. The four machine learning models considered (FourCastNet, Pangu-Weather, GraphCast and FourCastNet-v2) produce forecasts that accurately capture the synoptic-scale structure of the cyclone including the position of the cloud head, shape of the warm sector and location of the warm conveyor belt jet, and the large-scale dynamical drivers important for the rapid storm development such as the position of the storm relative to the upper-level jet exit. However, their ability to resolve the more detailed structures important for issuing weather warnings is more mixed. All of the machine learning models underestimate the peak amplitude of winds associated with the storm, only some machine learning models resolve the warm core seclusion and none of the machine learning models capture the sharp bent-back warm frontal gradient. Our study shows there is a great deal about the performance and properties of machine learning weather forecasts that can be derived from case studies of high-impact weather events such as Storm Ciarán.

Abstract Background Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. Methods Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. Results While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. Conclusions This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs.

ABSTRACTBackground: Prior research has shown PTSD treatment leads to reductions in cardiovascular reactivity during trauma recall, but the extent to which such reductions are associated with changes in PTSD symptoms is less clear. Moreover, such relationships have not been investigated in a cognitively focused PTSD treatment.Objective: To examine changes in cardiovascular reactivity to the trauma memory in patients receiving cognitive processing therapy (CPT), CPT with a written trauma account, and a written account only condition. We also examined the association of such changes with symptom improvement.Method: 118 women with PTSD secondary to interpersonal violence completed pre- and post-treatment assessments of PTSD symptoms and cardiovascular reactivity during a script-driven imagery task.Results: Results indicated a significant but modest reduction in cardiovascular reactivity in CPT conditions. Changes in cardiovascular reactivity and reexperiencing symptoms were significantly associated among the whole sample. Among individuals with the greatest reactivity to the trauma memory at pretreatment, associations were also seen with changes in total PTSD, numbing, and trauma-related guilt.Conclusions: Results indicate that previous findings on the effect of PTSD treatment on cardiovascular reactivity during trauma recall extend to cognitively oriented treatment. Baseline cardiovascular reactivity may influence the extent to which reductions in PTSD symptoms and reactivity during trauma recall are related.

When initially introduced into a susceptible population, a disease may die out or result in a major outbreak. We present a Continuous-Time Markov Chain model for enzootic WNV transmission between two avian host species and a single vector, and use multitype branching process theory to determine the probability of disease extinction based upon the type of infected individual initially introducing the disease into the population – an exposed vector, infectious vector, or infectious host of either species. We explore how the likelihood of disease extinction depends on the ability of each host species to transmit WNV, vector biting rates on host species, and the relative abundance of host species, as well as vector abundance. Theoretical predictions are compared to the outcome of stochastic simulations. We find the community composition of hosts and vectors, as well as the means of disease introduction, can greatly affect the probability of disease extinction.

Summary: Background: The effectiveness of transforaminal lumbar interbody fusion (TLIF) compared to posterior lumbar interbody fusion (PLIF) in patients with single-level spondylolisthesis has not been substantiated. To address the evidence gap, a well-powered randomized controlled non-inferiority trial comparing the effectiveness of TLIF with PLIF, entitled the Lumbar Interbody Fusion Trial (LIFT), was conducted. Methods: In a multicenter randomized controlled non-inferiority trial among five Dutch hospitals, 161 patients were randomly allocated to either TLIF or PLIF (1:1), stratified according to study site. Patients and statisticians were blinded for group assignment. All patients were over 18 years old with symptomatic single-level degenerative, isthmic or iatrogenic lumbar spondylolisthesis, and eligible for lumbar interbody fusion surgery through a posterior approach. The primary outcome was change in disability measured with the Oswestry Disability Index (ODI) from preoperative to one year postoperative. The non-inferiority limit was set to 7.0 points based on the MCID of ODI. Secondary outcomes were change in quality-adjusted life years (QALY) assessed with EuroQol 5 Dimensions, 5 Levels (EQ-5D-5L) and Short Form Health Survey (SF-36), as well as back and leg pain (Numerical rating scale, NRS), anxiety and depression (Hospital Anxiety Depression Scale; HADS), perioperative blood loss, duration of surgery, duration of hospitalization, and complications. Trial registration: Netherlands Trial Registry, number 5722 (registration date March 30, 2016), Lumbar Interbody Fusion Trial (LIFT): A randomized controlled multicenter trial for surgical treatment of lumbar spondylolisthesis. Findings: Patients were included between August 2017 and November 2020. The total study population was 161 patients. Total loss-to-follow-up after one year was 16 patients. Per-protocol analysis included 66 patients in each group. In the TLIF group (mean age 61.6, 36 females), ODI improved from 46.7 to 20.7, whereas in the PLIF group (mean age 61.9, 41 females), it improved from 46.0 to 24.9. This difference (−4.9, 90% CI −12.2 to +2.4) did not reach the non-inferiority limit of 7.0 points in ODI. A significant difference in the secondary outcome measurement, QALY (SF-36), was observed in favor of TLIF (P

ABSTRACT The airway milieu of individuals with muco-obstructive airway diseases (MADs) is defined by the accumulation of dehydrated mucus due to hyperabsorption of airway surface liquid and defective mucociliary clearance. Pathological mucus becomes progressively more viscous with age and disease severity due to the concentration and overproduction of mucin and accumulation of host-derived extracellular DNA (eDNA). Respiratory mucus of MADs provides a niche for recurrent and persistent colonization by respiratory pathogens, including Pseudomonas aeruginosa, which is responsible for the majority of morbidity and mortality in MADs. Despite high concentration inhaled antibiotic therapies and the absence of antibiotic resistance, antipseudomonal treatment failure in MADs remains a significant clinical challenge. Understanding the drivers of antibiotic tolerance is essential for developing more effective treatments that eradicate persistent infections. The complex and dynamic environment of diseased airways makes it difficult to model antibiotic efficacy in vitro. We aimed to understand how mucin and eDNA concentrations, the two dominant polymers in respiratory mucus, alter the antibiotic tolerance of P. aeruginosa. Our results demonstrate that polymer concentration and molecular weight affect P. aeruginosa survival post antibiotic challenge. Polymer-driven antibiotic tolerance was not explicitly associated with reduced antibiotic diffusion. Lastly, we established a robust and standardized in vitro model for recapitulating the ex vivo antibiotic tolerance of P. aeruginosa observed in expectorated sputum across age, underlying MAD etiology, and disease severity, which revealed the inherent variability in intrinsic antibiotic tolerance of host-evolved P. aeruginosa populations.IMPORTANCEAntibiotic treatment failure in Pseudomonas aeruginosa chronic lung infections is associated with increased morbidity and mortality, illustrating the clinical challenge of bacterial infection control. Understanding the underlying infection environment, as well as the host and bacterial factors driving antibiotic tolerance and the ability to accurately recapitulate these factors in vitro, is crucial for improving antibiotic treatment outcomes. Here, we demonstrate that increasing concentration and molecular weight of mucin and host eDNA drive increased antibiotic tolerance to tobramycin. Through systematic testing and modeling, we identified a biologically relevant in vitro condition that recapitulates antibiotic tolerance observed in ex vivo treated sputum. Ultimately, this study revealed a dominant effect of in vivo evolved bacterial populations in defining inter-subject ex vivo antibiotic tolerance and establishes a robust and translatable in vitro model for therapeutic development.

The climate crisis has resulted in mental health challenges for varying demographic groups of all ages, but Indigenous youth are one of the most vulnerable populations impacted by the climate crisis. Conversations regarding Indigenous youth and the climate crisis are often held without their presence or input, identifying a gap in research and the literature. The findings from this review include the components of climate change regarding the mental health of Indigenous youth as being direct and indirect pathways of impact and resistance. Direct pathways include the more immediate and physical consequences of climate change associated with mental unwellness. Indirect pathways include less obvious consequences to those without lived experience, such as disruptions to culture and magnified social inequities, which also result in negative mental health consequences. The resistance component explores how Indigenous youth have been protesting and actively speaking out, which highlights the importance of the inclusion of Indigenous youth voices in decision-making spaces related to mental health service resources (i.e., funding) and policy in climate action. This review ends with a discussion on ways forward, the limitations herein, and how the uniqueness of the research may contribute to climate justice.

In recirculating aquaculture systems (RASs), ammonia excreted by fish must be converted to the less toxic nitrate before recirculation. Nitrifying microorganisms in biofilters used for this transformation can be sensitive to changes in salinity, which can present issues for systems that raise anadromous fish such as Atlantic salmon. Freshwater biofilters maintained at a low level of salinity (such as biofilters operated in coastal areas) may be better equipped to handle more drastic salinity shifts; therefore, experiments were performed on freshwater and low-salinity (3 ppt) biofilters to assess their ability to recover nitrification activity after an abrupt change in salinity (3, 20, and 33 ppt). Two-week tests showed full nitrification recovery in freshwater biofilters after a shift to 3 ppt but no ammonia oxidation in 20 or 33 ppt. Low-salinity-adapted filters (transitioned from 0 to 3 ppt) showed a small recovery (about 11%) after a shift to 20 ppt, and no activity when shifted to 33 ppt. Illumina sequencing revealed that, while nitrification was slowed or stopped with shifting salinities, the nitrifiers survived the salinity increases; conversely, the heterotrophic communities were more greatly affected and were reduced in proportion with increasing salinity. This work indicates that biofilters operated at low salinity may recover more quickly after large salinity changes, though this slight benefit may not outweigh the cost of low-level salinity maintenance. Further research into halotolerant heterotrophs in biofilms may increase the effectiveness of nitrifying biofilters under variable salinities.

Abstract Background Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid and is used to prevent acute gout flares in patients with gout. Observational and small interventional studies have suggested beneficial cardiovascular effects of allopurinol. Objective To determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Design Prospective, randomised, open-label, blinded endpoint multicentre clinical trial. Setting Four hundred and twenty-four UK primary care practices. Participants Aged 60 years and over with ischaemic heart disease but no gout. Interventions Participants were randomised (1 : 1) using a central web-based randomisation system to receive allopurinol up to 600 mg daily that was added to usual care or to continue usual care. Main outcome measures The primary outcome was the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes were non-fatal myocardial infarction, non-fatal stroke, cardiovascular death, all-cause mortality, hospitalisation for heart failure, hospitalisation for acute coronary syndrome, coronary revascularisation, hospitalisation for acute coronary syndrome or coronary revascularisation, all cardiovascular hospitalisations, quality of life and cost-effectiveness. The hazard ratio (allopurinol vs. usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis. Results From 7 February 2014 to 2 October 2017, 5937 participants were enrolled and randomised to the allopurinol arm (n = 2979) or the usual care arm (n = 2958). A total of 5721 randomised participants (2853 allopurinol; 2868 usual care) were included in the modified intention-to-treat analysis population (mean age 72.0 years; 75.5% male). There was no difference between the allopurinol and usual care arms in the primary endpoint, 314 (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years), hazard ratio 1.04 (95% confidence interval 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, hazard ratio 1.02 (95% confidence interval 0.87 to 1.20); p = 0.77. The pre-specified health economic analysis plan was to perform a ‘within trial’ cost-utility analysis if there was no statistically significant difference in the primary endpoint, so NHS costs and quality-adjusted life-years were estimated over a 5-year period. The difference in costs between treatment arms was +£115 higher for allopurinol (95% confidence interval £17 to £210) with no difference in quality-adjusted life-years (95% confidence interval −0.061 to +0.060). We conclude that there is no evidence that allopurinol used in line with the study protocol is cost-effective. Limitations The results may not be generalisable to younger populations, other ethnic groups or patients with more acute ischaemic heart disease. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment, but an on-treatment analysis gave similar results to the main analysis. Conclusions The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve cardiovascular outcomes compared to usual care in patients with ischaemic heart disease. We conclude that allopurinol should not be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease but no gout. Future work The effects of allopurinol on cardiovascular outcomes in patients with ischaemic heart disease and co-existing hyperuricaemia or clinical gout could be explored in future studies. Trial registration This trial is registered as EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? The purpose of the ALL-HEART study was to determine whether giving allopurinol to people with ischaemic heart disease (also commonly known as coronary heart disease) would reduce their risk of having a heart attack, stroke or of dying from cardiovascular disease. Allopurinol is a medication usually given to patients with gout to prevent acute gout flares. It is not currently used to treat ischaemic heart disease. What did we do? We randomly allocated people aged over 60 years with ischaemic heart disease to take up to 600 mg of allopurinol daily (in addition to their usual care) or to continue with their usual care. We then monitored participants for several years and recorded any major health events such as heart attacks, strokes and deaths. We obtained most of the follow-up data from centrally held electronic hospital admissions and death records, making the study easier for participants and more cost-efficient. We asked participants in both groups to complete questionnaires to assess their quality of life during the study. We also collected data to determine whether there was any economic benefit to the NHS of using allopurinol in patients with ischaemic heart disease. What did we find? There was no difference in the risk of heart attacks, strokes or death from cardiovascular disease between the participants given allopurinol and those in the group continuing their usual care. We also found no difference in the risks of other cardiovascular events, deaths from any cause or quality-of-life measurements between the allopurinol and usual care groups. What does this mean? The results of the ALL-HEART study suggest that we should not recommend that allopurinol be given to people with ischaemic heart disease to prevent further cardiovascular events or deaths. Scientific summary Background Allopurinol is a xanthine oxidase inhibitor that lowers serum uric acid (SUA) and is widely used in patients with gout to prevent acute gout flares. Xanthine oxidase promotes inflammation and atherosclerosis via the production of reactive oxygen species and xanthine oxidase levels are raised in several conditions including coronary artery disease. The role of SUA in cardiovascular (CV) disease is controversial, with some studies associating higher SUA levels with worse CV outcomes, but more recent genome-wide association studies suggest no major role of uric acid levels in determining CV outcomes. Some observational studies have suggested that allopurinol therapy may improve CV outcomes, while others have not found an association. Small interventional studies have shown that allopurinol therapy improves some CV parameters, including endothelial function, left ventricular hypertrophy, blood pressure, carotid intimal media thickness and arterial stiffness. Allopurinol therapy was also found to improve outcomes after acute coronary syndrome (ACS) in one study and to improve chest pain in patients with chronic stable angina with documented coronary artery disease in another. However, results have not been consistent across different studies. Before the ALL-HEART study, no large, randomised trial of the effects of allopurinol therapy on CV outcomes in patients with ischaemic heart disease (IHD) had been performed. Objectives Primary Does allopurinol therapy added to usual care improve major CV outcomes in patients aged over 60 years with IHD but no gout? Secondary Does allopurinol therapy added to usual care improve all-cause mortality or other CV outcomes in patients with IHD? What is the cost-effectiveness of adding allopurinol up to 600 mg daily to usual care in patients with IHD? Does allopurinol therapy added to usual care improve quality of life assessed by general health survey [EuroQol-5 Dimensions, five-level version (EQ-5D-5L)] or coronary heart disease-specific questionnaire (Seattle angina questionnaire)? Methods Design and participants The ALL-HEART study was a prospective, randomised, open-label, blinded endpoint (PROBE) multicentre trial undertaken in patients with IHD. Participants were primarily recruited from 424 primary care practices via 18 regional centres in the UK, with a small number also referred into the study from secondary care centres. Eligible patients were aged 60 years or over, with a history of IHD [myocardial infarction (MI), angina or other evidence of IHD]. Exclusion criteria were: history of gout; known severe renal impairment [estimated glomerular filtration rate (eGFR) < 30 ml/minute/1.73 m2]; moderate-to-severe heart failure (HF) [New York Heart Association (NYHA) III–IV]; significant hepatic disease [e.g. alanine transaminase (ALT) > 3 × upper limit of normal, cirrhosis, ascites] (investigator opinion); currently taking part in another interventional clinical trial of an investigational medicinal product or medical device (or taken part in one within the last 3 months); previous allergy to allopurinol; previous serious adverse cutaneous (skin) reaction to any drug (e.g. Stevens–Johnson syndrome, toxic epidermal necrolysis, hospitalisation due to skin reaction to drug) (investigator opinion); already taking urate-lowering therapy (including allopurinol, febuxostat, sulfinpyrazone, benzbromarone, probenecid, rasburicase); taking azathioprine, mercaptopurine, ciclosporin or theophylline; malignancy (except non-metastatic, non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 5 years (investigator opinion). The exclusion criterion relating to renal impairment was originally ‘known renal impairment eGFR < 60 ml/minute/1.73 m2’ for patients recruited from the start of the trial (7 February 2014) until 4 April 2016 when an updated version of the protocol was implemented at all study sites to allow the inclusion of patients with moderate renal impairment in the study with the purpose of making the study results more generalisable. Fifty-two per cent of the target number of patients had been randomised by this date. Randomisation At a single screening and randomisation visit usually held at the patient’s primary care practice by a research nurse, patients were consented, screened and randomised to receive allopurinol therapy or to continue their usual care. Baseline demographics, medical history, CV risk factors and concomitant medications were recorded. Blood pressure, height and weight were measured. Baseline blood tests were taken for urea, creatinine and electrolytes, full blood count and SUA. Participants were randomised before screening blood results were available. When the screening results were available, a nurse telephoned the patient to advise them to start taking randomised therapy. If the screening visit eGFR result was below the exclusion limit, the participant did not receive any allopurinol and was excluded from the modified intention-to-treat (mITT) analysis population, whichever arm of the study they had been randomised to. Randomisation was via a web-based randomisation facility located at the Robertson Centre for Biostatistics, University of Glasgow, accessed using a web-based application or an interactive voice response system. Randomisation was based on randomised permuted blocks of variable size, stratified by history of MI, history of stroke and primary care practice. Randomised intervention Allopurinol 100 or 300 mg tablets were prescribed to participants by their primary care physicians via the usual NHS prescription system. Participants with a screening eGFR result ≥ 60 ml/minute/1.73 m2 were prescribed allopurinol at 100 mg daily for 2 weeks, then 300 mg daily for 2 weeks then 600 mg daily (given as 300 mg twice daily) thereafter if tolerated for the duration of the study. After 4 April 2016, participants with a screening eGFR result 30–59 ml/minute/1.73 m2 were prescribed allopurinol at 100 mg daily for 2 weeks, then 300 mg daily thereafter if tolerated for the duration of the study. If there were tolerability issues, the dose could be decreased at the discretion of a physician. Participants who stopped randomised therapy were encouraged to continue with study follow-up. The comparison arm of the study was ‘usual care’; no placebo was given as this was a pragmatic open-label study. Randomised therapy was blinded to the endpoint adjudication committee, but not to participants, study staff or treating healthcare professionals. If allopurinol was started in participants randomised to the usual care group at any point in the study (e.g. for clinical reasons such as developing gout), this was recorded. Other study procedures At the screening visit, participants completed the EQ-5D-5L questionnaire to assess general health outcomes and the Seattle angina questionnaire to assess coronary artery disease-specific quality of life. Participants who had taken any allopurinol therapy attended a 6-week study visit. Blood samples were taken for urea, creatinine and electrolytes, full blood count and SUA. Participants were then followed up remotely by electronic record-linkage with centralised databases of hospitalisations, cancers and deaths held by Public Health Scotland (PHS) and NHS Digital and by annual questionnaires (online, by post or by telephone). Data on adverse events, skin rashes, gout flares and self-reported adherence to randomised therapy were collected at the 6-week visit, then by annual questionnaire (but could also be reported at any time by participants or health professionals). Participants completed the EQ-5D-5L and Seattle angina questionnaires again after 1 year and at the end of the trial. The trial recruitment period was extended once, and the trial follow-up period was extended twice. Recruitment exceeded the target of 5215 randomised participants to a final total of 5937 randomised participants due to an increase in recruitment rate in the last weeks of recruitment. The follow-up period of the trial ended on 30 September 2021. After this date, participants stopped randomised therapy and continued to receive their usual care. Study outcomes The primary and secondary outcomes were as follows. Primary outcome: Composite of non-fatal MI, non-fatal stroke or CV death. Secondary outcomes: Non-fatal MI. Non-fatal stroke. CV death. All-cause mortality. Hospitalisation for ACS. Coronary revascularisation. Hospitalisation for ACS or coronary revascularisation. Hospitalisation for HF. All CV hospitalisations. Quality of life. Cost-effectiveness. Adverse events Serious adverse events (SAEs) occurring during the study (until 30 September 2021) were recorded and any events ongoing at that time were followed up for a further 30 days, unless consent had been withdrawn. Treatment-related adverse events (adverse reactions), gout flares and rashes were also recorded. Allopurinol therapy was stopped if participants developed a rash that may have been due to allopurinol. For any SAEs that were potential study endpoints, detailed information was obtained from medical records and death certificates to support the production of an anonymised endpoint package that was adjudicated by an independent clinical endpoint adjudication committee, blinded to randomised therapy allocation. Statistical analysis The power calculation suggested that 5215 participants would need to be randomised 1 : 1 to give 80% power to detect a 20% reduction in the primary outcome for the intervention (allowing for a 4% dropout for withdrawal of consent and non-CV deaths). A primary event rate of 14% over an average of 4 years follow-up was estimated from other trials in similar patient groups. The study ended when 631 adjudicated first primary events had occurred. Baseline characteristics are presented by treatment group as means [standard deviation (SD)] and medians [interquartile range (IQR)] for continuous variables and as numbers (%) for categorical variables. Clinical outcomes were analysed on a time-to-first event basis using Cox proportional hazards models. Treatment effects (allopurinol vs. usual care) were estimated as hazard ratios (HR) and 95% confidence intervals (CIs) for the Cox models. Analyses were adjusted for the stratification variables history of MI and history of stroke and p-values were calculated from Wald statistics. The primary analysis was a mITT analysis. Health economic analysis A health economic analysis was planned to determine whether allopurinol was a cost-effective intervention in the context of the NHS setting in the UK in patients with IHD. The analysis plan was based around NHS costs and estimation of quality-adjusted life-years (QALYs) and was to include a ‘within trial’ cost–utility analysis if the primary outcome was not statistically different between randomised study arms. Trial approvals and committees The study was approved by an ethics committee, Medicines and Healthcare Products Regulatory Agency (MHRA) and Health Research Authority (HRA). An Independent Data Monitoring Committee oversaw trial safety. A Trial Steering Committee including independent and patient/lay members oversaw trial progress. Results From 7 February 2014 to 29 September 2017, 6134 patients consented to enrol in the trial and were assessed for eligibility. Also, 167 of the 6134 consented participants were not eligible and 30 others were not randomised. The final randomisation was completed on 2 October 2017. Of the 5937 randomised participants, 216 were excluded post randomisation from the mITT analysis population (184 did not meet the eGFR entry criteria once their screening blood results were available; 32 were later found to have not met all of the inclusion/exclusion criteria). Five thousand seven hundred and twenty-one participants (2853 in the allopurinol arm and 2868 in the usual care arm) were included in the mITT analysis population for the efficacy analysis. The population for safety analyses consisted of 2805 participants in the allopurinol arm (excluding the 48 participants in the allopurinol arm who never received any randomised therapy) and 2868 participants in the usual care arm. The mean duration of follow-up in the trial was 4.8 years. Two hundred and fifty-eight participants (9.0%) in the allopurinol group and 76 participants (2.6%) in the usual care group withdrew consent for all follow-up. One thousand six hundred and thirty-seven participants (57.4%) in the allopurinol arm withdrew from randomised treatment. Baseline characteristics were well balanced in the two groups. The mean age at study entry was 72.0 years (SD 6.8), 4321 participants (75.5%) were male, 5676 (99.2%) were white and 1241 (21.7%) had a history of diabetes mellitus. The median duration of IHD at study entry was 10.1 years (IQR 5.1–16.1). Three thousand four hundred and sixty-four (60.5%) participants were recruited in England and 2257 (39.5%) participants in Scotland. The most commonly taken dose of allopurinol was 600 mg daily. In the 2447 participants in the allopurinol arm with both a baseline and 6-week SUA result, SUA fell from a mean of 0.34 (SD 0.08) mmol/l at baseline to a mean of 0.18 (SD 0.09) mmol/l 6 weeks after randomisation. Forty-five participants in the usual care arm started allopurinol therapy during follow-up (for clinical reasons, mainly gout). Primary and secondary outcomes There was no significant difference between the randomised treatment groups in the rates of the primary outcome or any of the secondary time-to-event outcomes. Three hundred and fourteen (11.0%) participants in the allopurinol arm (2.47 events per 100 patient-years) and 325 (11.3%) in the usual care arm (2.37 events per 100 patient-years) experienced a primary outcome, HR 1.04 (95% CI 0.89 to 1.21); p = 0.65. Two hundred and eighty-eight (10.1%) participants in the allopurinol arm and 303 (10.6%) participants in the usual care arm died, HR 1.02 (95% CI 0.87 to 1.20); p = 0.77. Results for the primary outcome were consistent across all pre-specified subgroups. In a supporting on-treatment analysis, results for the time-to-event clinical outcomes were broadly similar to those in the mITT analysis. There was limited evidence of any effect of allopurinol on quality-of-life outcomes, with no differences in EQ-5D-5L outcomes or Seattle angina questionnaire outcomes at the end of the first year or at the final visit, except for a nominally significant but only slightly greater fall in the physical domain score of the Seattle angina questionnaire at the end of the first year [treatment difference = 1.219 (95% CI 0.027 to 2.410); p = 0.045] in the allopurinol arm. Health economic analysis There was strong evidence that allopurinol treatment was associated with incremental costs relative to usual care [incremental cost per patient £115.4, 95% CI (£17.0 to £210.2)], with little evidence of improvement in relation to incremental QALYs [incremental QALYs −0.000, 95% CI (−0.061 to 0.060)]. The cost-effectiveness acceptability curve asymptoted at a probability of 0.456, meaning that even with a willingness to pay of an infinite amount, the probability of cost-effectiveness was only 0.465. At a willingness to pay of £20,000 the probability of cost-effectiveness was 0.41. Adverse events There was no difference in SAE rates between treatment arms, except for the grouping of endocrine disorders where no events occurred in the allopurinol treatment group but 14 in the usual care group. However, these endocrine events included events with a spread of different types. Fifteen participants had SAEs that were considered potentially treatment related and none of these were fatal. There was no difference between treatment arms in the rates of incident cancers. Adjudicated causes of death were well balanced between the treatment groups, including deaths from COVID-19 and COVID-19 pneumonia. Conclusions The ALL-HEART study showed that treatment with allopurinol 600 mg daily did not improve CV outcomes compared to usual care in patients with IHD. There were also no benefits on quality of life. There was no evidence that allopurinol used in line with the study protocol is cost-effective within the NHS system. We conclude that allopurinol should not be recommended for the secondary prevention of CV events in patients with IHD but no gout. Recommendations for research Future research should explore other therapeutic options for the improvement of CV outcomes and quality of life in patients with IHD. Further exploration of the effects of allopurinol on CV outcomes in patients with co-existing IHD and clinical gout or hyperuricaemia could be considered (patients with gout were excluded from this study). Trial registration The ALL-HEART trial is registered with the EU Clinical Trials Register (EudraCT 2013-003559-39) and ISRCTN (ISRCTN 32017426). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 11/36/41) and is published in full in Health Technology Assessment; Vol. 28, No. 18. See the NIHR Funding and Awards website for further award information.

IntroductionFetal growth restriction (FGR) is a common pregnancy complication, caused by placental insufficiency, with serious adverse consequences for development in utero and postnatal wellbeing. There are no antenatal treatments to improve growth or organ development in FGR, and animal models are essential to mimic the physiological adaptations in FGR and to assess potential interventions. This study aimed to identify the temporal nature of reduced developmental trajectory in fetuses with FGR, and to examine the effects of common factors that may mediate differential growth such as glucocorticoid treatment. We hypothesised that the trajectory of growth would be adversely impacted by FGR.MethodsFGR was induced via surgical placental insufficiency in fetal sheep (89 days gestation/0.6 gestation; n=135) and compared to age-matched controls over the last third of gestation and into neonatal life (n=153).ResultsBody weight of FGR fetuses/lambs was significantly reduced compared to controls (p

OBJECTIVES: This study aimed to estimate the average individual effect of the company-level Norwegian Agreement on a More Inclusive Working Life (IA Agreement) on individuals’ (i) sustained return to work after a sickness absence (SA) episode, and (ii) recurrent SA. METHODS: Using register data, 79 253 men and 94 914 women born in Norway 1967–1976 were followed for one year between 2005 and 2010 after returning to work from an SA episode (>16 days). Weighted Cox proportional hazard models analysed time to first exit from work by companies’ IA status (IA/non-IA). Weighted cumulative incidence differences between IA and non-IA groups with 95% bootstrapped confidence intervals (CI) were calculated for the competing events of full SA, graded (

Abstract The objective of this study was to compare transperineal (TP) versus transrectal (TR) magnetic resonance imaging (MRI) and transrectal ultrasound (TRUS) fusion prostate biopsy (PBx). Consecutive men who underwent prostate MRI followed by a systematic biopsy. Additional target biopsies were performed from Prostate Imaging Reporting & Data System (PIRADS) 3–5 lesions. Men who underwent TP PBx were matched 1:2 with a synchronous cohort undergoing TR PBx by PSA, Prostate volume (PV) and PIRADS score. Endpoint of the study was the detection of clinically significant prostate cancer (CSPCa; Grade Group ≥ 2). Univariate and multivariable analyses were performed. Results were considered statistically significant if p

BackgroundPeople experiencing homelessness are more likely to experience poor health with physical functioning deficits and frailty commonly reported. It is not well known how strategies to target physical functioning deficits and frailty work in practice in this group. The primary aim of this study was to explore the feasibility of an exercise intervention with protein supplementation to target physical functioning and frailty in people experiencing homelessness evaluated by recruitment and retention rates, adherence to the exercise sessions and protein supplement, adverse effects, programme feedback and characteristics of non-returners, sporadic and frequent attenders. The secondary aim was to evaluate changes in effectiveness outcomes of grip strength, muscle mass, lower extremity physical function, pain, frailty, and risk of malnutrition.MethodThis prospective single-arm study evaluated the feasibility of a 16-week rolling, low-threshold, 'drop-in' once weekly exercise programme with protein supplementation. The main recruitment site was a day-service centre for people who are homeless. Feasibility was assessed by the recruitment and retention rates, adherence to the exercise sessions and protein supplement as well as adverse effects, programme feedback and evaluation of characteristics of non-returners, sporadic (≤50% of available sessions) and frequent attenders (≥50% of available sessions). Effectiveness outcomes included pain (Visual Analogue Scale), physical functioning and performance (hand-grip dynamometry, limb circumference, the Short Physical Performance Battery), frailty (SHARE-FI and Clinical Frailty Scale) and nutritional status (Mini Nutritional Assessment).ResultsThirty-one participants were recruited mean (SD) age 45(16) years. There was a recruitment rate of a median (IQR) of 2(1-3) new participants per week. The retention rate was 45% (n = 14) to the main recruitment site. Adherence to the exercise sessions and nutritional intervention was 90% and 100% respectively. Three adverse events were recorded during 74 interventions over the 16-week programme. The acceptability of the programme was highlighted in participant feedback. Characteristics of frequent returners (≥50%) were older age, female, more stably housed and more stable in addiction. The programme did not induce any changes in effectiveness outcomes.ConclusionThe feasibility of this programme was demonstrated. Overall, the programme was well received with higher retention rates in older participants, females, those more stably housed and those stable in addiction. A higher powered, more intense programme is needed to demonstrate programme effectiveness.

Background: Chronic, retracted proximal hamstring ruptures are a challenging problem and can be a significant cause of pain and disability if left untreated. Allograft augmentation is a viable surgical option with good clinical outcomes. Indications: Indications are symptomatic patients with chronic hamstring ruptures unable to be primarily repaired. Patients typically present with pain, instability, or lack of push of strength. Technique Description: An L-shaped extensile incision is made at the level of the gluteal crease. The gluteus maximus is retracted proximally. The sciatic nerve is identified, neurolysed, and tagged. Following the release of adhesions of the native tendon and confirmation of the inability to complete a primary repair, the Achilles tendon allograft is prepared. The allograft is incorporated with the native tendon and the subsequent hamstring construct is fixed and reduced to the ischial tuberosity with suture anchors. After copious irrigation, the incision is closed with Monocryl and Dermabond (Johnson and Johnson) and a sterile dressing is applied. The patient is placed in a hip brace locked in extension. Results: In a study by Rust et al, examining 72 patients with proximal hamstring ruptures, patients who underwent allograft reconstruction reported activities of daily living and postoperative sports activity equal to those of chronic repair, and inferior to those of acute repair. However, there were no significant differences between groups for patient-reported outcomes among acute and chronic repairs and allograft reconstruction. Moreover, a systematic review, by Van Der Made et al, published in the American Journal of Sports Medicine , included 13 studies that found that Achilles allograft repair for delayed proximal hamstring repair results in outcomes comparable to acute primary repair. Discussion/Conclusion: Although the literature on chronic proximal hamstring repair is fairly limited, studies have shown that proximal hamstring repair with allograft augmentation can be favorable in symptomatic patients. Allograft augmentation for chronic, retracted proximal hamstring ruptures provides increased functional outcomes in comparison with nonoperative management. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Summary: Microorganism communities can shape host phenotype evolution but are often comprised of thousands of taxa with varied impact on hosts. Identification of taxa influencing host evolution relies on first describing microorganism communities and acquisition routes. Keratinolytic (keratin-degrading) microorganisms are hypothesized to be abundant in saltmarsh sediments and to contribute to plumage evolution in saltmarsh-adapted sparrows. Metabarcoding was used to describe plumage bacterial (16S rRNA) and fungal (ITS) communities in three sparrow species endemic to North America’s Atlantic coast saltmarshes. Results describe limited within-species variability and moderate host species-level patterns in microorganism diversity and community composition. A small percentage of overall microorganism diversity was comprised of potentially keratinolytic microorganisms, warranting further functional studies. Distinctions between plumage and saltmarsh sediment bacteria, but not fungal, communities were detected, suggesting multiple bacterial acquisition routes and/or vertebrate host specialization. This research lays groundwork for future testing of causal links between microorganisms and avian host evolution.

ABSTRACT Social and economic inequities can have a profound impact on human health, particularly on the development and progression of chronic disease. For military veterans, exposure to unique environments and circumstances may further impact their health. There continues to be limited work regarding the influence of mental health within the context of socioeconomic inequities. In this cross-sectional study, we hypothesized that veterans residing in food deserts (e.g., places in which there is a lack of access to sufficient and/or nutritious food) would have decreased gut microbial species (α-diversity), different microbiome community compositions, and poorer quality of diet and mental health compared to non-food desert residents. The fecal microbiome of 342 military veterans was sequenced, and microbiome diversity and community composition were evaluated. Although dietary quality and α-diversity did not significantly differ by food desert status, resident status (food desert versus non-food desert) accounted for a moderate influence on β-diversity (2.4%). Factors such as race and psychiatric diagnoses accounted for greater proportions of β-diversity influence (7% and 10%, respectively). Moreover, more participants with current post-traumatic stress disorder lived in food deserts (P < 0.04), and there were significantly more participants in the non-food desert group diagnosed with substance use disorders (P = 0.002) and current alcohol use disorder (P = 0.04). These findings suggest that living in a food desert, in combination with additional associated risk factors, may influence gut microbial diversity and composition. To increase ecological validity, researchers investigating the influence of inter-related biopsychosocial factors over time may benefit from adopting a life-course perspective.IMPORTANCESocial and economic inequities can have a profound impact on human health. The inequities could result in alterations to the gut microbiome, an important factor that may have profound abilities to alter health outcomes. Moreover, the strong correlations between social and economic inequities have been long understood. However, to date, limited research regarding the microbiome and mental health within the context of socioeconomic inequities exists. One particular inequity that may influence both mental health and the gut microbiome is living in a food desert. Persons living in food deserts may lack access to sufficient and/or nutritious food and often experience other inequities, such as increased exposure to air pollution and poor access to healthcare. Together, these factors may confer a unique risk for microbial perturbation. Indeed, external factors beyond a food desert might compound over time to have a lasting effect on an individual’s gut microbiome. Therefore, adoption of a life-course approach is expected to increase the ecological validity of research related to social inequities, the gut microbiome, and physical and mental health.

ABSTRACT Crohn’s disease (CD) is a presentation of inflammatory bowel disease (IBD) that manifests in childhood and adolescence and involves chronic and severe enterocolitis, immune and gut microbial dysregulation, and other complications. Diet and gut-microbiota-produced metabolites are sources of anti-inflammatories that could ameliorate symptoms. However, questions remain on how IBD influences biogeographic patterns of microbial location and function in the gut, how early life transitional gut communities are affected by IBD and diet interventions, and how disruption to biogeography alters disease mediation by diet components or microbial metabolites. Many studies on diet and IBD use a chemically induced ulcerative colitis model, despite the availability of an immune-modulated CD model. Interleukin-10-knockout (IL-10-KO) mice on a C57BL/6 background, beginning at age 4 or 7 weeks, were fed a control diet or one containing 10% (wt/wt) raw broccoli sprouts, which was high in the sprout-sourced anti-inflammatory sulforaphane. Diets began 7 days prior to, and for 2 weeks after inoculation with Helicobacter hepaticus, which triggers Crohn’s-like symptoms in these immune-impaired mice. The broccoli sprout diet increased sulforaphane in plasma; decreased weight stagnation, fecal blood, and diarrhea associated; and increased microbiota richness in the gut, especially in younger mice. Sprout diets resulted in some anatomically specific bacteria in younger mice and reduced the prevalence and abundance of pathobiont bacteria which trigger inflammation in the IL-10-KO mouse, for example, Escherichia coli and Helicobacter. Overall, the IL-10-KO mouse model is responsive to a raw broccoli sprout diet and represents an opportunity for more diet-host-microbiome research.IMPORTANCETo our knowledge, IL-10-KO mice have not previously been used to investigate the interactions of host, microbiota, and broccoli, broccoli sprouts, or broccoli bioactives in resolving symptoms of CD. We showed that a diet containing 10% raw broccoli sprouts increased the plasma concentration of the anti-inflammatory compound sulforaphane and protected mice to varying degrees against disease symptoms, including weight loss or stagnation, fecal blood, and diarrhea. Younger mice responded more strongly to the diet, further reducing symptoms, as well as increased gut bacterial richness, increased bacterial community similarity to each other, and more location-specific communities than older mice on the diet intervention. Crohn’s disease disrupts the lives of patients and requires people to alter dietary and lifestyle habits to manage symptoms. The current medical treatment is expensive with significant side effects, and a dietary intervention represents an affordable, accessible, and simple strategy to reduce the burden of symptoms.

ABSTRACTFunctional effector T cells in the tumor microenvironment (TME) are critical for successful anti-tumor responses. T cell anti-tumor function is dependent on their ability to differentiate from a naïve state, infiltrate into the tumor site, and exert cytotoxic functions. The factors dictating whether a particular T cell can successfully undergo these processes during tumor challenge are not yet completely understood. Piezo1 is a mechanosensitive cation channel with high expression on both CD4+ and CD8+ T cells. Previous studies have demonstrated that Piezo1 optimizes T cell activation and restrains the CD4+ regulatory T cell (Treg) pool in vitro and under inflammatory conditions in vivo. However, little is known about the role Piezo1 plays on CD4+ and CD8+ T cells in cancer. We hypothesized that disruption of Piezo1 on T cells impairs anti-tumor immunity in vivo by hindering inflammatory T cell responses. We challenged mice with T cell Piezo1 deletion (P1KO) with tumor models dependent on T cells for immune rejection. P1KO mice had the more aggressive tumors, higher tumor growth rates and were unresponsive to immune-mediated therapeutic interventions. We observed a decreased CD4:CD8 ratio in both the secondary lymphoid organs and TME of P1KO mice that correlated inversely with tumor size. Poor CD4+ helper T cell responses underpinned the immunodeficient phenotype of P1KO mice. Wild type CD8+ T cells are sub-optimally activated in vivo with P1KO CD4+ T cells, taking on a CD25loPD-1hi phenotype. Together, our results suggest that Piezo1 optimizes T cell activation in the context of a tumor response.

Abstract Background Intact cognitive function is crucial for healthy aging. Functional social support is thought to protect against cognitive decline. We conducted a systematic review to investigate the association between functional social support and cognitive function in middle- and older-aged adults. Methods Articles were obtained from PubMed, PsycINFO, Sociological Abstracts, CINAHL, and Scopus. Eligible articles considered any form of functional social support and cognitive outcome. We narratively synthesized extracted data by following the Synthesis Without Meta-Analysis (SWiM) guidelines and assessed risk of bias using the Newcastle–Ottawa Scale (NOS). Results Eighty-five articles with mostly low risk-of-bias were included in the review. In general, functional social support—particularly overall and emotional support—was associated with higher cognitive function in middle- and older-aged adults. However, these associations were not all statistically significant. Substantial heterogeneity existed in the types of exposures and outcomes evaluated in the articles, as well as in the specific tools used to measure exposures and outcomes. Conclusions Our review highlights the role of functional social support in the preservation of healthy cognition in aging populations. This finding underscores the importance of maintaining substantive social connections in middle and later life. Systematic review registration Rutter EC, Tyas SL, Maxwell CJ, Law J, O'Connell ME, Konnert CA, Oremus M. Association between functional social support and cognitive function in middle-aged and older adults: a protocol for a systematic review. BMJ Open;10(4):e037301. https://doi.org/10.1136/bmjopen-2020-037301

Abstract Background Antenatal infection/inflammation is associated with disturbances in neuronal connectivity, impaired cortical growth and poor neurodevelopmental outcomes. The pathophysiological substrate that underpins these changes is poorly understood. We tested the hypothesis that progressive inflammation in late gestation fetal sheep would alter cortical neuronal microstructure and neural function assessed using electroencephalogram band power analysis. Methods Fetal sheep (0.85 of gestation) were surgically instrumented for continuous electroencephalogram (EEG) recording and randomly assigned to repeated saline (control; n = 9) or LPS (0 h = 300 ng, 24 h = 600 ng, 48 h = 1200 ng; n = 8) infusions to induce inflammation. Sheep were euthanised 4 days after the first LPS infusion for assessment of inflammatory gene expression, histopathology and neuronal dendritic morphology in the somatosensory cortex. Results LPS infusions increased delta power between 8 and 50 h, with reduced beta power from 18 to 96 h (P

Blood–brain barrier (BBB) dysfunction and neuroinflammation are key mechanisms of brain injury. We performed a time-course study following neonatal hypoxia–ischemia (HI) to characterize these events. HI brain injury was induced in postnatal day 10 rats by single carotid artery ligation followed by hypoxia (8% oxygen, 90 min). At 6, 12, 24, and 72 h (h) post-HI, brains were collected to assess neuropathology and BBB dysfunction. A significant breakdown of the BBB was observed in the HI injury group compared to the sham group from 6 h in the cortex and hippocampus (p < 0.001), including a significant increase in albumin extravasation (p < 0.0033) and decrease in basal lamina integrity and tight-junction proteins. There was a decrease in resting microglia (p < 0.0001) transitioning to an intermediate state from as early as 6 h post-HI, with the intermediate microglia peaking at 12 h (p < 0.0001), which significantly correlated to the peak of microbleeds. Neonatal HI insult leads to significant brain injury over the first 72 h that is mediated by BBB disruption within 6 h and a transitioning state of the resident microglia. Key BBB events coincide with the appearance of the intermediate microglial state and this relationship warrants further research and may be a key target for therapeutic intervention.

Background Heavy menstrual bleeding affects one in four women and negatively impacts quality of life. The levonorgestrel-releasing intrauterine system is an effective long-term treatment but is discontinued by many due to unpredictable bleeding, or adverse effects. The selective progesterone receptor modulator ulipristal acetate is used to treat symptomatic fibroids but long-term efficacy for the symptom of heavy menstrual bleeding, irrespective of presence of fibroids, is unknown. Objectives To determine whether ulipristal acetate is more effective at reducing the burden of heavy menstrual bleeding than levonorgestrel-releasing intrauterine system after 12 months of treatment in women with and without fibroids. We investigated mechanism of action of ulipristal acetate in a subset of 20 women. Design Randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Setting Ten UK hospitals. Participants Women with heavy menstrual bleeding aged 18 and over with no contraindications to levonorgestrel-releasing intrauterine system or ulipristal acetate. Interventions Three 12-week treatment cycles of 5 mg ulipristal acetate daily, separated by 4-week treatment-free intervals, or continuous levonorgestrel-releasing intrauterine system following allocation in a 1 : 1 ratio using a web-based minimisation procedure. Main trial outcome measures Primary outcome was quality-of-life measured by menorrhagia multi-attribute scale at 12 months. Secondary outcomes included menstrual bleeding and patient satisfaction. Impact on fibroid size, endometrial appearance and liver function was also collected. Mechanistic study outcome Cellular markers for endometrial cell structure and function, determined from endometrial biopsies; volume of uterus and fibroids and microcirculation parameters were determined from magnetic resonance images. Results Sample size was increased from 220 to 302 as a result of temporary halt to recruitment due to concerns of ulipristal acetate hepatoxicity. Subsequent withdrawal of ulipristal acetate and the COVID-19 pandemic led to a premature closure of recruitment, with 118 women randomised to each treatment and 103 women completing 12-month menorrhagia multi-attribute scale scores prior to this point. Primary outcome scores substantially improved in both arms, but at 12 months there was no evidence of a difference between those receiving three cycles of ulipristal acetate [median score category: 76–99, interquartile range (51–75 to 100), n = 53] and levonorgestrel-releasing intrauterine system [median score category: 76–99, interquartile range (51–75 to 100), n = 50; adjusted odds ratio 0.55, 95% confidence interval 0.26 to 1.17; p = 0.12]. Rates of amenorrhoea were much higher in those allocated ulipristal acetate compared with the levonorgestrel-releasing intrauterine system (12 months: 64% vs. 25%, adjusted odds ratio 7.12, 95% confidence interval 2.29 to 22.2). There was no evidence of a difference in other participant-reported outcomes. There were no cases of endometrial malignancy and no hepatotoxicity due to ulipristal acetate use. Mechanistic study results Ulipristal acetate produced a reversible reduction in endometrial cell proliferation, as well as reversible alteration of other endometrial cellular markers. Ulipristal acetate did not produce a reduction in the volume of the uterus irrespective of coexisting fibroids, nor an effect on uterine microvascular blood flow. Limitations The urgent safety measures and premature closure of recruitment impacted final sample size. Conclusions We found no evidence of a difference in quality of life between the two treatments, but ulipristal acetate was superior to levonorgestrel-releasing intrauterine system at inducing amenorrhoea. Ulipristal acetate currently has restricted availability due to concerns regarding hepatotoxicity. Future work There is a need to develop new, safe, effective and fertility-sparing medical treatments for heavy menstrual bleeding. The observed acceptability and effectiveness of ulipristal acetate warrants further research into the selective progesterone receptor modulator class of pharmacological agents. Study registration This trial is registered as ISRCTN 20426843. Plain language summary What is the problem? Heavy menstrual bleeding is a common condition that affects the lives of many women. A hormone-releasing coil, fitted inside the womb, is effective in making periods lighter but can make them less regular. A medicine called ulipristal acetate or UPA, taken as a pill, has been shown to reduce rapidly menstrual bleeding in women with large, non-cancerous tumours in the womb, known as fibroids. It was not known whether UPA is effective in women who have heavy periods but do not have fibroids of any significant size. What did we plan to do? To find out which treatment was better at controlling heavy periods, 236 women were enrolled in a clinical trial where they received either the hormone coil or UPA. The choice of treatment was made at random by a computer rather than the wishes of researchers or patients, to ensure a fair comparison. Participants completed questionnaires about their symptoms and life quality at intervals up to 1 year. Twice during the trial, medicines regulatory authorities raised safety concerns about UPA causing liver problems. This resulted in the introduction of regular blood tests. The second time, recruitment to the trial stopped early. What did we find? Both treatments improved the symptoms of heavy menstrual bleeding in the majority of women. We found no evidence that UPA was better overall after 1 year of treatment, compared with the hormone coil, although fewer women on UPA continued to have periods. Laboratory studies on samples taken from the lining of the womb showed temporary changes due to UPA, which disappeared after treatment stopped. What does this mean? Both treatments improve the symptoms of menstrual bleeding and general wellbeing. Because of safety concerns UPA is not available for all women with heavy menstrual bleeding and new, safer medical treatments are needed. Scientific summary Background Heavy menstrual bleeding (HMB) is the most common gynaecological problem in women of reproductive age, affecting one in four women, and has adverse profound impact on health-related quality of life. Common causes of HMB include structural abnormalities such as uterine fibroids, adenomyosis and dysfunction of the endometrium. The levonorgestrel-releasing intrauterine system (LNG-IUS) is a proven, effective long-term treatment but about one-third of women cease use by two years due to unpredictable bleeding, hormonal adverse effects or lack of effectiveness. Furthermore, fibroids can make the LNG-IUS less effective. Alternative medical options for HMB exist, but are either less effective or associated with unacceptable adverse effects. Surgical interventions are effective at inducing bleeding control and improving quality of life but are typically incompatible with future fertility. Effective long-term medical treatments for women with HMB are needed. A class of drugs called selective progesterone receptor modulators (SPRMs) have potential to provide an effective oral treatment for HMB. SPRMs bind with progesterone receptors, resulting in tissue-specific effects in both myometrial and overlying endometrial tissue as well as shrinking uterine fibroids. The SPRM ulipristal acetate (UPA) has been successfully used to treat fibroids, but we do not know how effective UPA is for the treatment of women with HMB who do not have fibroids. Furthermore, there are uncertainties regarding the mechanism and location of action of UPA, as well as its longer-term safety. SPRMs induce distinctive, non-physiological endometrial changes, which can be confused with endometrial hyperplasia. More recently there has been concern regarding the potential for UPA to cause drug-induced liver injury (DILI). Post marketing surveillance reports resulted in a temporary halt in UPA use in 2018 and 2020. Use of UPA has since been reinstated since January 2021, albeit in a restricted context, reflecting the paucity of existing alternatives for HMB. Given these uncertainties, we designed the UCON trial to evaluate the safety, tolerability and effectiveness of UPA on HMB and to understand its mechanism of action. Clinical objectives Primary objective: to determine whether UPA is more effective at reducing the burden of HMB symptoms than LNG-IUS after 12 months of treatment. Secondary objectives: Ascertain whether UPA use beyond 3 months’ and up to 12 months’ duration is associated with histological changes to the endometrium and, if so, whether this compromises safety. Ascertain whether UPA is more effective than LNG-IUS in relation to menstrual blood loss, sexual activity, generic quality of life, satisfaction with treatment, patient-reported adverse events, and compliance at 3, 6 and 12 months. Determine the response to UPA and LNG-IUS treatment difference in the presence of uterine fibroids in terms of (1) alleviation of HMB and (2) change in uterine/fibroid volume. Collect data on liver function in women taking UPA, once safety concerns were raised. Mechanism of action study objectives To understand how UPA causes a reduction in menstrual bleeding and uterine/fibroid volume in women with HMB, we determined whether UPA administration: Alters endometrial cell function (e.g., and not limited to, proliferation, apoptosis, expression of steroid receptors, tumour suppressors and inflammatory mediators). Reduces blood plasma flow in the endometrium, uterine myometrium and fibroid tissue. Alters the volume fraction of the extracellular matrix in these tissues. Reduces uterine and fibroid volume. Design This was a randomised, open-label, parallel group, multicentre trial with embedded mechanistic study. Methods Setting The trial recruited participants in 10 sites in NHS hospital settings across the UK between 2015 and 2020. The mechanism of action study was conducted solely at the Edinburgh site. Participants For the main trial, informed consent was sought from premenopausal women (aged 18–50 years) with self-reported HMB, no contraindications to LNG-IUS or UPA. Those with uterine size greater than equivalent 14-week size or with submucosal fibroids >2cm were excluded. Other exclusion criteria relating to use of other treatments and current health status were applied, including history of severe hepatic impairment. Screening and randomisation Participants were recruited in gynaecology clinics by research nurses who screened patient referral letters. Following consent, haemoglobin and circulating estradiol levels were assessed, clinical history elicited and transvaginal and/or abdominal ultrasound and endometrial biopsy were obtained if not previously performed. Following this, and confirmation of eligibility, randomisation was via a web-based central service based at Birmingham Clinical Trials Unit to allocate women in a 1 : 1 ratio using a minimisation algorithm. Screened patients in Edinburgh were offered the opportunity to participate in the mechanistic study. Interventions and follow-up Those allocated to UPA received three courses of treatment, each course comprising a daily 5-mg oral dose for 12 weeks followed by a four-week break. Those allocated to the LNG-IUS had it fitted in hospital or primary care. Participants allocated to UPA returned to hospital to collect their repeat prescription at 3 and 6 months, and may have been seen by a member of the care team if required. They were then seen in clinic at 12 months for ultrasound scan (USS) and haemoglobin/serum estradiol measurement. Those allocated to the LNG-IUS group attended USS at 12 months. Follow-up at interim time points was conducted by postal questionnaire. Those partaking in the mechanism of action study underwent magnetic resonance imaging (MRI) following randomisation and at the end of treatment cycles two and three. An additional endometrial biopsy was obtained at the end of treatment cycle two. Outcome measures Primary Condition-specific quality of life score as measured by the menorrhagia multi-attribute scale (MMAS) questionnaire at 12 months. Summary scores range from 0 (worst affected) to 100 (not affected). Secondary Condition-specific quality of life score as measured by MMAS at 3 and 6 months Menstrual bleeding (pictorial blood loss assessment chart)* Cycle regularity (ordinal four-point scale)* Duration of period (ordinal three option scale)* Pelvic pain during periods, intercourse and at other times (visual analogue scales; 0 = best outcome, 10 = worse outcome)* Uterine fibroid symptom and quality of life instrument (only given to women diagnosed with fibroids)* Sexual function (sexual activity questionnaire)* Generic quality of life (EQ-5D-5L)* Satisfaction with treatment outcome (five-point Likert scale) Participant rating of effect of treatment on HMB over 12 months (four-point Likert scale) Whether participant is willing to recommend the treatment to a friend (yes/no) Surgical intervention Adherence to trial treatments and reasons for changing treatment, as reported by the participant Serious adverse events and reactions Uterine volume, evidence of adenomyosis, presence of fibroids, largest fibroid volume, endometrial thickness, endometrial appearance, evidence of ovarian cysts at 12 months (USS) Endometrial biopsy at 12 months (UPA group only) Liver function tests, from 20 March 2018 every four weeks (UPA group only) Haemoglobin and serum estradiol at 12 months * assessed at 3, 6 and 12 months Mechanism of action A: Effects on cellular markers of endometrial steroid receptors and metabolising enzymes (governing local endometrial steroid [ligand] availability), cell proliferation, cell survival (apoptosis); detection of genes implicated in control of proliferation in endometrium; B: Effects on uterine/fibroid structure addressed by obtaining volume measurements for the whole uterus, and for the total volume of fibroids when present, by using high resolution structural MRI and stereology; and C: Uterine vascularity using dynamic contrast-enhanced MRI (DCE-MRI). Urgent safety measures In November 2017, the European Medicines Agency (EMA) issued an urgent drug alert for UPA due to a small number of reports of serious liver injury. A detailed investigation by the regulatory authorities was undertaken and it was found that eight reports of serious liver injury were reported in Europe from an estimated 740,000 women using UPA for uterine fibroids. Restrictions on prescribing UPA were subsequently issued and the trial sponsor implemented an urgent safety measure (USM) in February 2018, which halted recruitment. Those allocated UPA were allowed to complete their current course of UPA treatment but not commence any further outstanding courses. In addition, they commenced monthly assessment of LFTs (as well as a post treatment test approximately 2 weeks after the last course of UPA). In August 2018, the halt on UPA prescribing was lifted and recruitment to UCON resumed in October 2018 with additional safety measures in place, including exclusion of those with any history of liver disease [defined as levels of alanine transaminase (ALT) or aspartate aminotransferase (AST) of more than two times the upper limit of normal] and LFT monitoring as described above. UPA was stopped if women had an ALT or AST more than three times the upper limit of normal and a hepatology opinion was sought. In March 2020, the EMA temporarily suspended use of UPA a second time due to ongoing concerns regarding hepatotoxicity and a further USM was issued. All treatment courses of UPA were immediately stopped. In view of the second USM, the investigators, in discussion with the funder, chose premature closure of recruitment to the study but planned follow-up actions continued as per protocol. Statistical considerations The study was powered to detect a clinically useful difference in MMAS score (13 points) between the two groups at twelve months. To detect a difference of this size [0.5 standard deviations (SDs)] with 90% power (p = 0.05) would require 86 women in each group (172 in total). To allow for a 20% loss to follow-up or pregnancy, the sample size was inflated to 220 women. Following the initial USM, this figure was inflated to 302 women to ensure that there were adequate responses in the primary analysis population (defined below) to detect the same size of difference. The original planned primary analysis population comprised all participants, regardless of adherence to treatment, employing suitable regression models to estimate difference between groups. The enforced non-compliance as a result of the withdrawal of UPA had substantial implications for the validity of the data reported by participants. It was therefore necessary to redefine analysis populations, considering the restrictions that prevented women taking their courses of UPA might influence their responses and any other new potential biases that may be apparent in either group due to, for example, knowledge of the safety concerns around UPA. The primary analysis population would now comprise participants with questionnaire responses received prior to the first USM (12 February 2018), along with questionnaire responses from participants recruited following the study restart (18 October 2018) provided that the responses were returned before the second USM (17 March 2020). Results Main trial A total of 4471 women were approached for the study, with 236 consented and randomised, of whom 181 (77%) returned primary outcome data at 12 months (103 within the primary analysis population). Baseline data were comparable between groups; 92% were white, 34% had fibroids and 8% adenomyosis. In the primary analysis population, MMAS scores substantially improved in both arms, but at 12 months there was no evidence of a difference between the UPA [median score category: 76–99, IQR (51–75 to 100), n = 53] and LNG-IUS [median score category: 76–99, IQR (51–75 to 100), n = 50] groups (adjusted OR 0.55, 95% CI 0.26 to 1.17; p = 0.12). Rates of amenorrhoea where much higher in those allocated UPA compared with LNG-IUS at each time point (3 months: 56% vs. 5%, adjusted OR 29.3, 95% CI 7.37 to 116; 6 months 53% vs. 10%, adjusted OR 11.7 95% CI 3.78 to 36.0; 12 months: 64% vs. 25%, adjusted OR 7.12, 95% CI 2.29 to 22.2). There was no evidence of a difference in the other patient-reported outcomes although there was considerable uncertainty. In those with uterine fibroids, there were no changes in fibroid or uterine volume in either treatment group at 12 months. On endometrial biopsy, seven participants (8%) had evidence of progesterone receptor modulator associated endometrial changes (PAEC) at 12 months, although none was observed at a further 6 months post treatment; there were no cases of endometrial malignancy. Rates of serious adverse events were low, and no patients required admission to hospital for management of deranged liver function tests due to UPA use. Mechanism of action study Effects of UPA administration on the uterus: UPA produced a reduction in cell proliferation in the endometrium, as well as alteration of other local endometrial cellular markers (steroid receptor and steroid metabolising enzyme expression) creating a local endometrial oestrogenic environment. The effects on endometrial cellular markers were reversed upon withdrawal of UPA treatment. Stereological analysis in 19 patients showed that UPA did not produce a reduction in the volume of the uterus, irrespective of coexisting fibroids or adenomyosis. DCE-MRI in 15 patients showed that UPA appears not to have an effect on uterine blood flow. If adenomyosis was present in the uterus, there was a significant increase in plasma volume in the endometrium. However, one of the five women with adenomyosis also had fibroids. Effects of UPA administration on uterine fibroids: DCE-MRI studies showed that UPA produced an average reduction in plasma volume in 11 fibroids, which may be interpreted as being due to a reduction in extracellular matrix components. This finding was not supported by stereological analysis, which failed to show a reduction in the total volume of fibroids in eight patients. However, it should be noted that the number of subjects studied is small. Conclusions Both UPA and LNG-IUS alleviated the adverse impact of heavy menstrual bleeding on quality of life but we found no evidence of a difference between groups over 12 months. UPA was evidently superior to LNG-IUS in terms of inducing amenorrhoea. We observed no difference in reduction in the volume of the uterus, whether or not fibroids were present and no difference in change in the volume of fibroids was observed. Analysis of selected markers of endometrial cellular function demonstrated UPA modulation of the progesterone receptor, resulting in molecular and cellular alteration in steroid receptors within the endometrium, consistent with the development of a local (endometrial) oestrogenic microenvironment. Despite this, there is no evidence of pathological endometrial changes. We demonstrated that alteration in the endometrial microenvironment reverses on cessation of UPA treatment, a key factor for a medical treatment of HMB, particularly for those who wish to preserve fertility. UPA now has restricted availability due to concerns regarding hepatotoxicity. Findings from this study may offer insights into mechanism of action of other SPRM class members. New, effective and acceptable oral medical treatment options are needed to address an important unmet clinical need. Recommendations for research Further studies of medical treatments for HMB Developing other SPRMs, not associated with DILI Other hormonal/non-hormonal medical treatments for HMB Patient populations that encompass both the symptoms of HMB and underlying aetiologies, including structurally normal uterus, adenomyosis and small fibroids Study design with outcome measures impact on menstrual bleeding pattern, pelvic pain and impact on haemoglobin and iron-deficiency, as well as quality of life Qualitative studies to determine what are the most important outcomes to women who suffer HMB Study registration This trial is registered as ISRCTN 20426843. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme and will be published in full in Efficacy and Mechanism Evaluation; Vol. 10, No. 8. See the NIHR Journals Library website for further project information.

ABSTRACT Inflammatory bowel diseases (IBDs) are devastating conditions of the gastrointestinal tract with limited treatments, and dietary intervention may be effective and affordable for managing symptoms. Glucosinolate compounds are highly concentrated in broccoli sprouts, especially glucoraphanin (GLR), and can be metabolized by certain mammalian gut bacteria into anti-inflammatory isothiocyanates, such as sulforaphane. Gut microbiota exhibit biogeographic patterns, but it is unknown if colitis alters these or whether the location of glucoraphanin-metabolizing bacteria affects anti-inflammatory benefits. We fed specific pathogen-free C57BL/6 mice either a control diet or a 10% steamed broccoli sprout diet and gave a three-cycle regimen of 2.5% dextran sodium sulfate (DSS) in drinking water over a 34-day experiment to simulate chronic, relapsing ulcerative colitis (UC). We monitored body weight, fecal characteristics, lipocalin, serum cytokines, and bacterial communities from the luminal- and mucosal-associated populations in the jejunum, cecum, and colon. Mice fed the broccoli sprout diet with DSS treatment performed better than mice fed the control diet with DSS, and had significantly more weight gain, lower Disease Activity Index scores, lower plasma lipocalin and proinflammatory cytokines, and higher bacterial richness in all gut locations. Bacterial communities were assorted by gut location but were more homogenous across locations in the control diet + DSS mice. Importantly, our results showed that broccoli sprout feeding abrogated the effects of DSS on gut microbiota, as bacterial richness and biogeography were similar between mice receiving broccoli sprouts with and without DSS. Collectively, these results support the protective effect of steamed broccoli sprouts against dysbiosis and colitis induced by DSS. IMPORTANCE Evaluating bacterial communities across different locations in the gut provides a greater insight than fecal samples alone and provides an additional metric by which to evaluate beneficial host-microbe interactions. Here, we show that 10% steamed broccoli sprouts in the diet protects mice from the negative effects of dextran sodium sulfate-induced colitis, that colitis erases biogeographic patterns of bacterial communities in the gut, and that the cecum is not likely to be a significant contributor to colonic bacteria of interest in the DSS mouse model of ulcerative colitis. Mice fed the broccoli sprout diet during colitis performed better than mice fed the control diet while receiving DSS. The identification of accessible dietary components and concentrations that help maintain and correct the gut microbiome may provide universal and equitable approaches to IBD prevention and recovery, and broccoli sprouts represent a promising strategy.

Atlantic sea scallops, Placopecten magellanicus, are the most economically important marine bivalves along the northeastern coast of North America. Wild harvest landings generate hundreds of millions of dollars, and wild-caught adults and juvenile spat are increasingly being cultured in aquaculture facilities and coastal farms. However, the last two weeks of the larval maturation phase in hatcheries are often plagued by large mortality events. Research into other scallop- and aquacultured-species point to bacterial infections or altered functionality of microbial communities which associate with the host. Despite intense filtering and sterilization of seawater, and changing tank water every 48 h, harmful microbes can still persist in biofilms and mortality is still high. There are no previous studies of the bacterial communities associated with the biofilms growing in scallop hatchery tanks, nor studies with wild or hatchery sea scallops. We characterized the bacterial communities in veliger-stage wild or hatchery larvae, and tank biofilms using the 16 S rRNA gene V3-V4 region sequenced on the Illumina MiSeq platform. Hatchery larvae had lower bacterial richness (number of bacteria taxa present) than the wild larvae and tank biofilms, and hatchery larvae had a similar bacterial community (which taxa were present) to both wild larvae and tank biofilms. Bacterial richness and community similarity between tank samples fluctuated over the trial in repeated patterns of rise and fall, which showed some correlation to lunar cycle that may be a proxy for the effects of spring tides and trends in seawater bacteria and phages which are propagated into hatchery tanks. These results along with future work, will inform hatcheries on methods that will increase larval survival in these facilities, for example, implementing additional filtering or avoiding seawater collection during spring tides, to reduce bacterial taxa of concern or promote a more diverse microbial community which would compete against pathogens.

Abstract Background Fetal growth restriction (FGR) is associated with deficits in the developing brain, including neurovascular unit (NVU) dysfunction. Endothelial colony forming cells (ECFC) can mediate improved vascular stability, and have demonstrated potential to enhance vascular development and protection. This investigation examined whether ECFCs from human umbilical cord blood (UCB) enhanced NVU development in FGR and appropriate for gestational age (AGA) fetal sheep. Methods Twin-bearing ewes had surgery performed at 88–90 days’ gestation, inducing FGR in one fetus. At 113 days, ECFCs (1 × 107 cells) cultured from human UCB were administered intravenously to fetal sheep in utero. At 127 days, ewes and their fetuses were euthanised, fetal brains collected, and NVU components analysed by immunohistochemistry. Results Twenty-four fetal lambs, arranged in four groups: AGA (n = 7), FGR (n = 5), AGA + ECFC (n = 6), and FGR + ECFC (n = 6), were included in analyses. FGR resulted in lower body weight than AGA (P = 0.002) with higher brain/body weight ratio (P = 0.003). ECFC treatment was associated with increased vascular density throughout the brain in both AGA + ECFC and FGR + ECFC groups, as well as increased vascular–astrocyte coverage and VEGF expression in the cortex (P = 0.003, P = 0.0006, respectively) and in the subcortical white matter (P = 0.01, P = 0.0002, respectively) when compared with the untreated groups. Conclusions ECFC administration enhanced development of NVU components in both the AGA and FGR fetal brain. Further investigation is required to assess how to optimise the enhanced angiogenic capabilities of ECFCs to provide a therapeutic strategy to protect the developing NVU against vulnerabilities associated with FGR.

Abstract Background Neural stem cells (NSCs) have the potential to engraft and replace damaged brain tissue, repairing the damaged neonatal brain that causes cerebral palsy (CP). There are procedures that could increase engraftment of NSCs and may be critical for efficacy, but hold notable risks. Before clinical trials progress, it is important to engage with the CP community to understand their opinions. The aim of this study was to determine the acceptability of NSC therapy for CP in the CP community. Methods Australian residents with CP and parents/carers of those with CP completed a questionnaire to determine their willingness to use NSCs from three sources (fetal, embryonic and induced pluripotent stem cells) and their willingness to undergo accompanying procedures (neurosurgery, immunosuppression) that carry potential risks. To further explore their views, participants also answered free text questions about their ethical concerns regarding the source of NSCs and their perceptions of meaningful outcomes following NSC treatment. Results In total, 232 responses were analyzed. Participants were willing to use NSCs from all three cell sources and were willing to undergo NSC therapy despite the need for neurosurgery and immunosuppression. Participants identified a range of outcome domains considered important following NSC treatment including gross motor function, quality of life, independence and cognitive function. Conclusions Hypothetical NSC therapy was acceptable to the Australian CP community. This study has identified important findings from the CP community which can be used to inform future NSC research, including the design of clinical trials which may help to increase recruitment, compliance and participant satisfaction.

Abstract Background The prognosis for metastatic and recurrent tumors of the central nervous system (CNS) remains dismal, and the need for newer therapeutic targets and modalities is critical. The cell surface glycoprotein B7H3 is expressed on a range of solid tumors with a restricted expression on normal tissues. We hypothesized that compartmental radioimmunotherapy (cRIT) with the anti-B7H3 murine monoclonal antibody omburtamab injected intraventricularly could safely target CNS malignancies. Patients and methods We conducted a phase I trial of intraventricular 131I-omburtamab using a standard 3 + 3 design. Eligibility criteria included adequate cerebrospinal fluid (CSF) flow, no major organ toxicity, and for patients > dose level 6, availability of autologous stem cells. Patients initially received 74 MBq radioiodinated omburtamab to evaluate dosimetry and biodistribution followed by therapeutic 131I-omburtamab dose-escalated from 370 to 2960 MBq. Patients were monitored clinically and biochemically for toxicity graded using CTCAEv 3.0. Dosimetry was evaluated using serial CSF and blood sampling, and serial PET or gamma-camera scans. Patients could receive a second cycle in the absence of grade 3/4 non-hematologic toxicity or progressive disease. Results Thirty-eight patients received 100 radioiodinated omburtamab injections. Diagnoses included metastatic neuroblastoma (n = 16) and other B7H3-expressing solid tumors (n = 22). Thirty-five patients received at least 1 cycle of treatment with both dosimetry and therapy doses. Acute toxicities included

Background Despite its potential utility in delivering direct tumor killing and in situ whole-cell tumor vaccination, tumor cryoablation produces highly variable and unpredictable clinical response, limiting its clinical utility. The mechanism(s) driving cryoablation-induced local antitumor immunity and the associated abscopal effect is not well understood.Methods The aim of this study was to identify and explore a mechanism of action by which cryoablation enhances the therapeutic efficacy in metastatic tumor models. We used the subcutaneous mouse model of the rhabdomyosarcoma (RMS) cell lines RMS 76-9STINGwt or RMS 76-9STING-/-, along with other murine tumor models, in C57BL/6 or STING-/- (TMEM173-/-) mice to evaluate local tumor changes, lung metastasis, abscopal effect on distant tumors, and immune cell dynamics in the tumor microenvironment (TME).Results The results show that cryoablation efficacy is dependent on both adaptive immunity and the STING signaling pathway. Contrary to current literature dictating an essential role of host-derived STING activation as a driver of antitumor immunity in vivo, we show that local tumor control, lung metastasis, and the abscopal effect on distant tumor are all critically dependent on a functioning tumor cell-intrinsic STING signaling pathway, which induces inflammatory chemokine and cytokine responses in the cryoablated TME. This reliance extends beyond cryoablation to include intratumoral STING agonist therapy. Additionally, surveys of gene expression databases and tissue microarrays of clinical tumor samples revealed a wide spectrum of expressions among STING-related signaling components.Conclusions Tumor cell-intrinsic STING pathway is a critical component underlying the effectiveness of cryoablation and suggests that expression of STING-related signaling components may serve as a potential therapy response biomarker. Our data also highlight an urgent need to further characterize tumor cell-intrinsic STING pathways and the associated downstream inflammatory response evoked by cryoablation and other STING-dependent therapy approaches.

The nutritive role and ecology of gut-dwelling microbes in rainbow trout remain enigmatic. To improve our understanding of the rainbow trout gastrointestinal tract (GIT) microbiome, we performed whole shotgun metagenomic analyses on the assembled contigs from luminal contents from both mid- and hind-GIT regions for taxonomic and functional classifications of fish-fed animal and plant protein dietary sources. Our study revealed that trout respond well to the two diets containing animal and plant protein sources when supplemented with essential amino acids to meet the requirements of the fish. Microbes present were predominantly bacteria (89.9%) and mainly of the phyla Tenericutes, Firmicutes, Fusobacteria, and Proteobacteria. Eukaryotic (8.8%) microbes were mainly from phyla Ascomycota and Basidiomycota, while Archaea (

We report the discovery of a close-in ( P _orb = 3.349 days) warm Neptune with clear transit timing variations (TTVs) orbiting the nearby ( d = 47.3 pc) active M4 star, TOI-2015. We characterize the planet's properties using Transiting Exoplanet Survey Satellite (TESS) photometry, precise near-infrared radial velocities (RVs) with the Habitable-zone Planet Finder Spectrograph, ground-based photometry, and high-contrast imaging. A joint photometry and RV fit yields a radius ${R}_{p}={3.37}_{-0.20}^{+0.15}\ {R}_{\oplus }$ , mass ${m}_{p}={16.4}_{-4.1}^{+4.1}\ {M}_{\oplus }$ , and density ${\rho }_{p}\,={2.32}_{-0.37}^{+0.38}\ {\rm{g}}\ {\mathrm{cm}}^{-3}$ for TOI-2015 b, suggesting a likely volatile-rich planet. The young, active host star has a rotation period of P _rot = 8.7 ± 0.9 days and associated rotation-based age estimate of 1.1 ± 0.1 Gyr. Though no other transiting planets are seen in the TESS data, the system shows clear TTVs of super-period ${P}_{\sup }\approx 430\ \mathrm{days}$ and amplitude ∼100 minutes. After considering multiple likely period-ratio models, we show an outer planet candidate near a 2:1 resonance can explain the observed TTVs while offering a dynamically stable solution. However, other possible two-planet solutions—including 3:2 and 4:3 resonances—cannot be conclusively excluded without further observations. Assuming a 2:1 resonance in the joint TTV-RV modeling suggests a mass of ${m}_{b}={13.3}_{-4.5}^{+4.7}\ {M}_{\oplus }$ for TOI-2015 b and ${m}_{c}={6.8}_{-2.3}^{+3.5}\ {M}_{\oplus }$ for the outer candidate. Additional transit and RV observations will be beneficial to explicitly identify the resonance and further characterize the properties of the system.

We conducted the time-resolved simultaneous optical spectroscopic and photometric observations of mid-M-dwarf flare stars YZ CMi, EV Lac, and AD Leo. Spectroscopic observations were obtained using Apache Point Observatory 3.5 m and Small and Moderate Aperture Research Telescope System 1.5 m telescopes during 31 nights. Among the 41 detected flares, seven flares showed clear blue wing asymmetries in the H α line, with various correspondences in flare properties. The duration of the blue wing asymmetries range from 20 minutes to 2.5 hr, including a flare showing the shift from blue to red wing asymmetry. Blue wing asymmetries can be observed during both white-light and candidate non-white-light flares. All of the seven flares showed blue wing asymmetries also in the H β line, but there are large varieties on which other chromospheric lines showed blue wing asymmetries. One among the 7 flares was also observed with soft X-ray spectroscopy, which enabled us to estimate the flare magnetic field and length of the flare loop. The line-of-sight velocities of the blueshifted components range from –73 to –122 km s ^−1 . Assuming that the blueshifts were caused by prominence eruptions, the mass of upward-moving plasma was estimated to be 10 ^15 –10 ^19 g, which are roughly on the relation between flare energy and erupting mass expected from solar coronal mass ejections (CMEs). Although further investigations are necessary for understanding the observed various properties, these possible prominence eruptions on M-dwarfs could evolve into CMEs, assuming the similar acceleration mechanism with solar eruptions.

Abstract Objective Neonatal encephalopathy (NE) is an important cause of mortality and disability worldwide. Therapeutic hypothermia (HT) is an effective therapy, however not all babies benefit. Novel agents are urgently needed to improve outcomes. Melatonin in preclinical studies has promising neuroprotective properties. This meta‐analysis assessed the efficacy of melatonin in term animal models of NE on cerebral infarct size, neurobehavioural tests and cell death. Methods A literature search was carried out using Embase, MEDLINE and Web of Science (31 May 2021). We identified 14 studies and performed a meta‐analysis with a random effects model using standardised mean difference (SMD) as the effect size. The risk of bias was assessed using the Systematic Review Centre for Laboratory animal Experimentation tool and publication bias was assessed with funnel plots, and adjusted using trim and fill analysis. Subgroup and meta‐regression analyses were performed to assess the effects of study design variables. Results We observed significant reduction in brain infarct size (SMD −2.05, 95% CI [−2.93, −1.16]), improved neurobehavioural outcomes (SMD −0.86, 95% CI [−1.23, −0.53]) and reduction in cell death (SMD −0.60, 95% CI [−1.06, −0.14]) favouring treatment with melatonin. Neuroprotection was evident as a single therapy and combined with HT. Subgroup analysis showed greater efficacy with melatonin given before or immediately after injury and with ethanol excipients. The overall effect size remained robust even after adjustment for publication bias. Interpretation These studies demonstrate a significant neuroprotective efficacy of melatonin in term neonatal models of hypoxia‐ischaemia, and suggest melatonin is a strong candidate for translation to clinical trials in babies with moderate–severe NE.

Inflammation promotes adverse ventricular remodeling, a common antecedent of heart failure. Here, we set out to determine how inflammatory cells affect cardiomyocytes in the remodeling heart. Pathogenic cardiac macrophages induced an IFN response in cardiomyocytes, characterized by upregulation of the ubiquitin-like protein IFN-stimulated gene 15 (ISG15), which posttranslationally modifies its targets through a process termed ISGylation. Cardiac ISG15 is controlled by type I IFN signaling, and ISG15 or ISGylation is upregulated in mice with transverse aortic constriction or infused with angiotensin II; rats with uninephrectomy and DOCA-salt, or pulmonary artery banding; cardiomyocytes exposed to IFNs or CD4+ T cell–conditioned medium; and ventricular tissue of humans with nonischemic cardiomyopathy. By nanoscale liquid chromatography–tandem mass spectrometry, we identified the myofibrillar protein filamin-C as an ISGylation target. ISG15 deficiency preserved cardiac function in mice with transverse aortic constriction and led to improved recovery of mouse hearts ex vivo. Metabolomics revealed that ISG15 regulates cardiac amino acid metabolism, whereas ISG15 deficiency prevented misfolded filamin-C accumulation and induced cardiomyocyte autophagy. In sum, ISG15 upregulation is a feature of pathological ventricular remodeling, and protein ISGylation is an inflammation-induced posttranslational modification that may contribute to heart failure development by altering cardiomyocyte protein turnover.

In recent years, the scientific community has called for improvements in the credibility, robustness and reproducibility of research, characterized by increased interest and promotion of open and transparent research practices. While progress has been positive, there is a lack of consideration about how this approach can be embedded into undergraduate and postgraduate research training. Specifically, a critical overview of the literature which investigates how integrating open and reproducible science may influence student outcomes is needed. In this paper, we provide the first critical review of literature surrounding the integration of open and reproducible scholarship into teaching and learning and its associated outcomes in students. Our review highlighted how embedding open and reproducible scholarship appears to be associated with (i) students' scientific literacies (i.e. students’ understanding of open research, consumption of science and the development of transferable skills); (ii) student engagement (i.e. motivation and engagement with learning, collaboration and engagement in open research) and (iii) students' attitudes towards science (i.e. trust in science and confidence in research findings). However, our review also identified a need for more robust and rigorous methods within pedagogical research, including more interventional and experimental evaluations of teaching practice. We discuss implications for teaching and learning scholarship.

Summary: The American lobster, Homarus americanus, is an economically valuable and ecologically important crustacean along the North Atlantic coast of North America. Populations in southern locations have declined in recent decades due to increasing ocean temperatures and disease, and these circumstances are progressing northward. We monitored 57 adult female lobsters, healthy and shell diseased, under three seasonal temperature cycles for a year, to track shell bacterial communities using culturing and 16S rRNA gene sequencing, progression of epizootic shell disease using visual assessment, and antimicrobial activity of hemolymph. The richness of bacterial taxa present, evenness of abundance, and community similarity between lobsters was affected by water temperature at the time of sampling, water temperature over time based on seasonal temperature regimes, shell disease severity, and molt stage. Several bacteria were prevalent on healthy lobster shells but missing or less abundant on diseased shells, although some bacteria were found on all shells regardless of health status.

Abstract Accelerating ice loss from Thwaites Glacier is contributing approximately 5% of global sea‐level rise, and could add tens of centimeters to sea level over the coming centuries. We use an ocean model to calculate sub‐ice melting for a succession of Digital Elevation Models of the main trunk of Thwaites Glacier from 2011 to 2022. The ice evolution during this period induces a strong geometrical feedback onto melting. Ice thinning and retreat provides a larger melting area, thicker and better‐connected sub‐ice water column, and steeper ice base. This leads to stronger sub‐ice ocean currents, increasing melting by over 30% without any change in forcing from wider ocean conditions. This geometrical feedback over just 12 years is comparable to melting changes arising from plausible century‐scale changes in ocean conditions and subglacial meltwater inflow. These findings imply that ocean‐driven ice loss from Thwaites Glacier may only be weakly influenced by anthropogenic emissions mitigation.

Rationale & Objective: Kidney transplant recipients require frequent venipunctures. Microsampling methods that use a finger-prick draw of capillary blood, like volumetric absorptive microsamplers (VAMS), have the potential to reduce the pain, inconvenience, and volume of blood loss associated with venipuncture. This study aimed to provide diagnostic accuracy using VAMS for measurement of tacrolimus and creatinine compared to gold standard venous blood in adult kidney transplant recipients. Study Design: Diagnostic test study. Prospective blood samples for measurement of tacrolimus and creatinine were collected using Mitra VAMS and venipuncture immediately before and 2 hours after tacrolimus dosing. Setting & Participants: A convenience sample of 40 adult kidney transplant participants in the outpatient setting. Tests Compared: Method comparison was assessed by Passing-Bablok regression and Bland-Altman analysis. The predictive performance of VAMS measurement compared to venipuncture was also assessed through estimation of the median prediction error and median absolute percentage prediction error. Results: A total of 74 tacrolimus samples and 70 creatinine samples were analyzed from 40 participants. Passing-Bablok regression showed a systematic difference between VAMS and venipuncture when measuring tacrolimus and creatinine with a slope of 1.08 (95% CI, 1.03-1.13) and a slope of 0.65 (95% CI, 0.6-0.7), respectively. These values were then corrected for the systematic difference. When used for Bland-Altman analysis, corrected values of tacrolimus and creatinine showed a bias of -0.1 μg/L and 0.04 mg/dL, respectively. Tacrolimus (corrected) and creatinine (corrected) microsampling values when compared to corresponding venipuncture values met median prediction error and median absolute percentage prediction error predefined acceptability limits of