Author Correction: The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Developmental exposure to 17-α-hydroxyprogesterone caproate disrupts decision-making in adult female rats: A potential role for a dopaminergic mechanism.

The synthetic progestin, 17α-hydroxyprogesterone caproate (17-OHPC), is administered to pregnant individuals at risk for preterm birth and is likely transferred from mother to fetus. Yet, there is little information regarding the potential effects of 17-OHPC administration on behavioral and neural development in offspring. In rats, neonatal 17-OHPC exposure altered dopaminergic fiber distribution and density in the prelimbic medial prefrontal cortex (mPFC) in neonates and adolescents, respectively. Additionally, neonatal 17-OHPC exposure in male rats increased response omissions in a delay discounting task of impulsive decision-making. Because developmental 17-OHPC exposure has differential effects in males and females, investigating the effects of 17-OHPC on impulsive decision-making in female rats is necessary. The present study tested the effects of developmental 17-OHPC exposure (P1-P14) in a delay discounting task in which female rats chose between a small immediate reward and a larger delayed (0, 15 30, or 45 s) reward. 17-OHPC-exposed females made more omissions than controls. There was no effect of 17-OHPC on large reward preference nor on response time, and omissions were similar during both free- and forced-choice trials. The present study also aimed to investigate the neural mechanisms underlying omissions in 17-OHPC-exposed female rats. The dopamine transporter inhibitor, methylphenidate (MPH), was administered prior to delay discounting testing. MPH treatment did not reduce omissions in 17-OHPC-exposed females. If anything, MPH increased omissions in control females nearly fourfold during the longest delays. These results suggest that developmental 17-OHPC exposure increased omissions without affecting impulsivity or slowing decision-making. Furthermore, omissions may be regulated, at least in part, by dopaminergic mechanisms.

The honeycomb maze provides a novel test to study hippocampal-dependent spatial navigation.

Here we describe the honeycomb maze, a behavioural paradigm for the study of spatial navigation in rats. The maze consists of 37 platforms that can be raised or lowered independently. Place navigation requires an animal to go to a goal platform from any of several start platforms via a series of sequential choices. For each, the animal is confined to a raised platform and allowed to choose between two of the six adjacent platforms, the correct one being the platform with the smallest angle to the goal-heading direction. Rats learn rapidly and their choices are influenced by three factors: the angle between the two choice platforms, the distance from the goal, and the angle between the correct platform and the direction of the goal. Rats with hippocampal damage are impaired in learning and their performance is affected by all three factors. The honeycomb maze represents a marked improvement over current spatial navigation tests, such as the Morris water maze, because it controls the choices of the animal at each point in the maze, provides the ability to assess knowledge of the goal direction from any location, enables the identification of factors influencing task performance and provides the possibility for concomitant single-cell recording.

The Infant KIdney Dialysis and Utrafiltration (I-KID) Study: A Stepped-Wedge Cluster-Randomized Study in Infants, Comparing Peritoneal Dialysis, Continuous Venovenous Hemofiltration, and Newcastle Infant Dialysis Ultrafiltration System, a Novel Infant Hemodialysis Device.

OBJECTIVES: Renal replacement therapy (RRT) options are limited for small babies because of lack of available technology. We investigated the precision of ultrafiltration, biochemical clearances, clinical efficacy, outcomes, and safety profile for a novel non-Conformité Européenne-marked hemodialysis device for babies under 8 kg, the Newcastle Infant Dialysis Ultrafiltration System (NIDUS), compared with the current options of peritoneal dialysis (PD) or continuous venovenous hemofiltration (CVVH). DESIGN: Nonblinded cluster-randomized cross-sectional stepped-wedge design with four periods, three sequences, and two clusters per sequence. SETTING: Clusters were six U.K. PICUs. PATIENTS: Babies less than 8 kg requiring RRT for fluid overload or biochemical disturbance. INTERVENTIONS: In controls, RRT was delivered by PD or CVVH, and in interventions, NIDUS was used. The primary outcome was precision of ultrafiltration compared with prescription; secondary outcomes included biochemical clearances. MEASUREMENTS AND MAIN RESULTS: At closure, 97 participants were recruited from the six PICUs (62 control and 35 intervention). The primary outcome, obtained from 62 control and 21 intervention patients, showed that ultrafiltration with NIDUS was closer to that prescribed than with control: sd controls, 18.75, intervention, 2.95 (mL/hr); adjusted ratio, 0.13; 95% CI, 0.03-0.71; p = 0.018. Creatinine clearance was smallest and least variable for PD (mean, sd ) = (0.08, 0.03) mL/min/kg, larger for NIDUS (0.46, 0.30), and largest for CVVH (1.20, 0.72). Adverse events were reported in all groups. In this critically ill population with multiple organ failure, mortality was lowest for PD and highest for CVVH, with NIDUS in between. CONCLUSIONS: NIDUS delivers accurate, controllable fluid removal and adequate clearances, indicating that it has important potential alongside other modalities for infant RRT.

The impact of islet mass, number of transplants, and time between transplants on graft function in a national islet transplant program.

The UK islet allotransplant program is nationally funded to deliver one or two transplants over 12 months to individuals with type 1 diabetes and recurrent severe hypoglycemia. Analyses were undertaken 10 years after program inception to evaluate associations between transplanted mass; single versus two transplants; time between two transplants and graft survival (stimulated C-peptide >50 pmol/L) and function. In total, 84 islet transplant recipients were studied. Uninterrupted graft survival over 12 months was attained in 23 (68%) single and 47 (94%) (p = .002) two transplant recipients (separated by [median (IQR)] 6 (3-8) months). 64% recipients of one or two transplants with uninterrupted function at 12 months sustained graft function at 6 years. Total transplanted mass was associated with Mixed Meal Tolerance Test stimulated C-peptide at 12 months (p < .01). Despite 1.9-fold greater transplanted mass in recipients of two versus one islet infusion (12 218 [9291-15 417] vs. 6442 [5156-7639] IEQ/kg; p < .0001), stimulated C-peptide was not significantly higher. Shorter time between transplants was associated with greater insulin dose reduction at 12 months (beta -0.35; p = .02). Graft survival over the first 12 months was greater in recipients of two versus one islet transplant in the UK program, although function at 1 and 6 years was comparable. Minimizing the interval between 2 islet infusions may maximize cumulative impact on graft function.

Effort-based decision making in response to high-dose androgens: role of dopamine receptors.

INTRODUCTION: Anabolic-androgenic steroids (AAS) are performance-enhancing drugs used by both world-class and rank-and-file athletes. AAS abuse has been linked with risky decision-making, ranging from drunk driving to abusing multiple drugs. Our lab uses operant behavior in rats to test the effects of AAS (testosterone) on decision making. In our previous study, testosterone caused rats to work harder for food reward during an effort discounting (ED) task. ED is sensitive to dopamine in the nucleus accumbens, and AAS alter accumbens dopamine receptor expression. Accordingly, we determined if testosterone increases response to dopamine receptor antagonists during ED. METHODS: Rats were treated chronically with high-dose testosterone (7.5 mg/kg; n = 9) or vehicle (n = 9). We measured baseline preference for the large reward in an ED task, where rats choose between a small easy reward (one lever press for one sugar pellet) and a large difficult reward (2, 5, 10, or 15 presses for three pellets). Preference for the large reward was measured after administration of D1-like (SCH23390, 0.01 mg/kg) or D2-like (eticlopride, 0.06 mg/kg) receptor antagonists. RESULTS: At baseline, testosterone- and vehicle-treated rats showed similar preference for the large reward lever (FR5, testosterone: 68.6 ± 9.7% and vehicle: 85.7 ± 2.5%). SCH23390 reduced large reward preference significantly in both groups (FR5, testosterone: 41.3 ± 9.2%; vehicle: 49.1 ± 8.2%; F(1,16) = 17.7; P < 0.05). Eticlopride decreased large reward preference in both groups, but more strongly in testosterone-treated rats (FR5: testosterone: 37.0 ± 9.7%; vehicle: 56.3 ± 7.8%; F(1,16) = 35.3; P < 0.05). CONCLUSION: Testosterone increases response to dopamine D2-like receptor blockade, and this contributes to previously observed changes in decision-making behaviors.

Performance on a modified signal detection task of attention is impaired in male and female rats following developmental exposure to the synthetic progestin, 17α-hydroxyprogesterone caproate.

Based on evidence that the developing mesocortical dopamine pathway is sensitive to progestins, in the present study we tested the hypothesis that attention, a fundamental component of successful cognitive behavior, is disrupted by developmental exposure to the synthetic progestin, 17-α-hydroxyprogesterone caproate (17-OHPC). To assess attentional impairments, a modified signal detection task was utilized with three stimulus modalities: compound (light and tone), light alone, and tone alone, for four stimulus durations (2, 0.5, 0.25, 0.125 s). Adult rats were trained to push one lever if they detected the stimulus, and another lever if the stimulus was not presented. 17-OHPC animals were able to attend to the task, as evidenced by similar correct responses as controls. However, as the task became increasingly difficult at shorter durations, 17-OHPC animals made significantly more omissions compared to controls, suggesting that 17-OHPC treatment may disrupt attentional processes and/or delay response time. These findings add to the current body of literature demonstrating that exposure to 17-OHPC during development produces deficits in cognitive behavior in adulthood. These results may inform potential risks associated with 17-OHPC treatment in pregnant women with a history of preterm delivery who are commonly recipients of such treatment.

Anabolic-androgenic steroids and cognitive effort discounting in male rats.

Anabolic-androgenic steroids (AAS) are drugs of abuse that impair behavior and cognition. In a rodent model of AAS abuse, testosterone-treated male rats expend more physical effort, by repeatedly pressing a lever for a large reward in an operant discounting task. However, since modern society prioritizes cognitive over physical effort, it is important to determine if AAS limit cognitive effort. Here we tested the effects of AAS on a novel cognitive-effort discounting task. Each operant chamber had 3 nose-pokes, opposite 2 levers and a pellet dispenser. Rats pressed a lever to illuminate 1 nose-poke; they responded in the illuminated nose-poke to receive sugar pellets. For the 'easy' lever, the light remained on for 1 s, and a correct response earned 1 pellet. For the 'hard' lever, the light duration decreased from 1 s to 0.1 s across 5 blocks of trials, and a correct response earned 4 pellets. As the duration of the nose-poke light decreased, all rats decreased their choice of the hard lever in a modest discounting curve. Task accuracy also decreased significantly across the 5 blocks of trials. However, there was no effect of testosterone on choice of the hard lever or task accuracy. Antagonism of dopamine D1 or D2 receptors had no effect on lever choice or task accuracy. However, serotonin depletion significantly decreased preference for the hard lever, and impaired task accuracy. Thus, physical effort discounting depends on dopamine activity, while cognitive effort discounting task is sensitive to serotonin. AAS impair physical effort discounting, but not cognitive effort discounting.

Intensive versus standard physical rehabilitation therapy in the critically ill (EPICC): a multicentre, parallel-group, randomised controlled trial.

BACKGROUND: Early physical rehabilitation in the intensive care unit (ICU) has been shown to improve short-term clinical outcomes but long-term benefit has not been proven and the optimum intensity of rehabilitation is not known. METHODS: We conducted a randomised, parallel-group, allocation-concealed, assessor-blinded, controlled trial in patients who had received at least 48 hours of invasive or non-invasive ventilation. Participants were randomised in a 1:1 ratio, stratified by admitting ICU, admission type and level of independence. The intervention group had a target of 90 min physical rehabilitation per day, the control group a target of 30 min per day (both Monday to Friday). The primary outcome was the Physical Component Summary (PCS) measure of SF-36 at 6 months. RESULTS: We recruited 308 participants over 34 months: 150 assigned to the intervention and 158 to the control group. The intervention group received a median (IQR) of 161 (67-273) min of physical rehabilitation on ICU compared with 86 (31-139) min in the control group. At 6 months, 62 participants in the intervention group and 54 participants in the control group contributed primary outcome data. In the intervention group, 43 had died, 11 had withdrawn and 34 were lost to follow-up, while in the control group, 56 had died, 5 had withdrawn and 43 were lost to follow-up. There was no difference in the primary outcome at 6 months, mean (SD) PCS 37 (12.2) in the intervention group and 37 (11.3) in the control group. CONCLUSIONS: In this study, ICU-based physical rehabilitation did not appear to improve physical outcomes at 6 months compared with standard physical rehabilitation. TRIAL REGISTRATION NUMBER: ISRCTN 20436833.

A systems framework for national assessment of climate risks to infrastructure.

Extreme weather causes substantial adverse socio-economic impacts by damaging and disrupting the infrastructure services that underpin modern society. Globally, $2.5tn a year is spent on infrastructure which is typically designed to last decades, over which period projected changes in the climate will modify infrastructure performance. A systems approach has been developed to assess risks across all infrastructure sectors to guide national policy making and adaptation investment. The method analyses diverse evidence of climate risks and adaptation actions, to assess the urgency and extent of adaptation required. Application to the UK shows that despite recent adaptation efforts, risks to infrastructure outweigh opportunities. Flooding is the greatest risk to all infrastructure sectors: even if the Paris Agreement to limit global warming to 2°C is achieved, the number of users reliant on electricity infrastructure at risk of flooding would double, while a 4°C rise could triple UK flood damage. Other risks are significant, for example 5% and 20% of river catchments would be unable to meet water demand with 2°C and 4°C global warming respectively. Increased interdependence between infrastructure systems, especially from energy and information and communication technology (ICT), are amplifying risks, but adaptation action is limited by lack of clear responsibilities. A programme to build national capability is urgently required to improve infrastructure risk assessment.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'.

Prosocial effects of prolactin in male rats: Social recognition, social approach and social learning.

Prolactin (PRL) and oxytocin (OT) are pituitary hormones essential for lactation, but also promote sexual behavior. OT stimulates social behaviors, such as recognition, approach, and learning, but less is known about PRL in these behaviors. Since PRL and OT have complementary functions in reproduction, we hypothesized that PRL increases social recognition, approach, and learning. Male Long-Evans rats received ovine PRL (oPRL; 0.5, 2.0 or 5.0mg/kg), the PRL antagonist bromocriptine (0.1, 3.0 or 5.0mg/kg) or saline 20 mins before testing for recognition of familiar vs. unfamiliar stimulus males. Saline controls preferred the unfamiliar male (p<0.05), while bromocriptine blocked this preference. oPRL did not increase preference. To measure social approach, we determined if PRL restores approach 2h after defeat by an aggressive male. Defeated rats avoided the aggressive male. 2mg/kg oPRL, before or after defeat, restored approach towards the aggressive male (p<0.05). In non-defeated rats, oPRL or 3mg/kg bromocriptine had no effect. To determine if PRL increases social learning, we tested social transmission of food preference. Rats choose between two unfamiliar flavors, one of which they have previously been exposed to through interaction with a demonstrator rat. Vehicle controls preferred chow with the demonstrated flavor over the novel flavor. oPRL-treated rats were similar. Bromocriptine-treated rats failed to show a preference. When tested one week later, only oPRL-treated rats preferred the demonstrated flavor. The results suggest that PRL is required for social recognition and learning, and that increasing PRL enhances social memory and approach, similar to OT.

Using a meta-ethnographic approach to explore the nature of facilitation and teaching approaches employed in interprofessional education.

BACKGROUND: Interprofessional facilitators and teachers are regarded as central to the effective delivery of interprofessional education (IPE). As the IPE literature continues to expand, most studies have focused on reporting learner outcomes, with little attention paid to IPE facilitation. However, a number of studies have recently emerged reporting on this phenomenon. AIM: To present a synthesis of qualitative evidence on the facilitation of IPE, using a meta-ethnographic approach. METHODS: Electronic databases and journals were searched for the past 10 years. Of the 2164 abstracts initially found, 94 full papers were reviewed and subsequently 12 papers were included. Teams of two reviewers independently completed each step in the review process. The quality of these papers was assessed using a modified critical appraisal checklist. RESULTS: Seven key concepts embedded in the included studies were synthesized into three main factors which provided an insight into the nature of IPE facilitation. Specifically, the synthesis found that IPE facilitation is influenced by "contextual characteristics"; "facilitator experiences"; and the "use of different facilitation strategies". CONCLUSIONS: IPE facilitation is a complex activity affected by contextual, experiential and pedagogical factors. Further research is needed to explore the effects of these factors on the delivery of IPE.

Diagnostic differentiation of mild cognitive impairment due to Alzheimer's disease using a hippocampus-dependent test of spatial memory.

The hippocampus is one of the earliest brain regions affected in Alzheimer's disease (AD) and tests of hippocampal function have the potential to detect AD in its earliest stages. Given that the hippocampus is critically involved in allocentric spatial memory, this study applied a short test of spatial memory, the 4 Mountains Test (4MT), to determine whether test performance can differentiate mild cognitive impairment (MCI) patients with and without CSF biomarker evidence of underlying AD and whether the test can distinguish patients with MCI and mild AD dementia when applied in different cultural settings. Healthy controls (HC), patients with MCI, and mild AD dementia were recruited from study sites in UK and Italy. Study numbers were: HC (UK 20, Italy 10), MCI (UK 21, Italy 14), and AD (UK 11, Italy 9). Nineteen UK MCI patients were grouped into CSF biomarker-positive (MCI+, n = 10) and biomarker-negative (MCI-, n = 9) subgroups. Behavioral data were correlated with hippocampal volume and cortical thickness of the precuneus and posterior cingulate gyrus. Spatial memory was impaired in both UK and Italy MCI and AD patients. Test performance additionally differentiated between MCI+ and MCI- subgroups (P = 0.001). A 4MT score of ≤8/15 was associated with 100% sensitivity and 90% specificity for detection of early AD (MCI+ and mild AD dementia) in the UK population, and with 100% sensitivity and 50% specificity for detection of MCI and AD in the Italy sample. 4MT performance correlated with hippocampal volume in the UK population and cortical thickness of the precuneus in both study populations. In conclusion, performance on a hippocampus-sensitive test of spatial memory differentiates MCI due to AD with high diagnostic sensitivity and specificity. The observation that similar diagnostic sensitivity was obtained in two separate study populations, allied to the scalability and usability of the test in community memory clinics, supports future application of the 4MT in the diagnosis of pre-dementia due to AD.

Seasonal variation in Guillain-Barré syndrome: a systematic review, meta-analysis and Oxfordshire cohort study.

INTRODUCTION: Evidence for seasonal variation in incidence and subtype of Guillain-Barré syndrome (GBS) is contradictory, but has implications for provision of neurological services and understanding pathogenesis. METHODS: We searched PubMed and EMBASE between inception and January 2014, including all studies reporting seasonal incidence of GBS. We included a retrospective cohort study of patients with GBS at the John Radcliffe Hospital, Oxford 2001-2012 and determined the seasonal variation in GBS incidence and length of stay. The incidence rate ratio (IRR) for winter versus summer was pooled across studies by fixed and random effects meta-analysis weighted by inverse variance, stratified by geographical region, infectious prodrome and GBS subtype. RESULTS: Across 9836 patients from 42 studies there was a 14% increased risk of GBS in winter versus summer (IRR=1.14, 1.02-1.27, p=0.020), with significant heterogeneity between studies (I(2)=77%, p<0.0001), including significant seasonal variation in Oxford (n=140; p=0.037) for winter versus summer (IRR=1.92, 1.18-3.11, p=0.004) but a non-significantly reduced length of stay for winter versus other seasons (15 vs 21 days, p=0.08). Across all studies, there was greater seasonal variation with respiratory prodrome (IRR=3.06, 1.84-5.11, p<0.0001) than diarrhoeal prodrome (IRR=1.10, 0.60-2.00, p=0.76) and a greater incidence in winter in Western countries (IRR=1.28), the Far East (IRR=1.20) and Middle East (IRR=1.12), with a lower incidence in the Indian subcontinent (IRR=0.86) and Latin America (IRR=0.75). DISCUSSION: Incidence of GBS was greater in winter than summer, but this was not evident in all geographical regions. This is likely to be related to regional variation in prodromal illnesses.

Anabolic-androgenic steroids and appetitive sexual behavior in male rats.

Anabolic-androgenic steroids (AAS) increase libido and sexual behavior, but the underlying behavioral mechanisms are unclear. One way AAS may enhance expression of sexual behavior is by increasing the willingness to work for sex. In the present study, sexually-experienced male rats received daily injections of testosterone at supraphysiologic doses (7.5 mg/kg in water with 13% cyclodextrin) or vehicle and were tested for appetitive sexual behavior measured by operant responding for access to an estrous female. Initially, rats were trained in their home cage to respond on a nose-poke under a 10-min fixed-interval schedule for food reward. Once rats achieved stable response rates, the food was replaced by a female, followed by mating for 10 min. There was no effect of testosterone on operant responding for food (28.1 ± 4.4 responses/10 min for testosterone, 30.6 ± 4.3 for vehicle) or sex (35.0 ± 4.0 responses/10 min for testosterone, 37.3 ± 5.2 for vehicle). However, rats made significantly more responses for sex than for food (p < 0.05), and responses for food and sex were positively correlated among individuals (R(2) = 0.6). Additional groups of rats were trained to respond on a lever for the female under a 2nd-order schedule of reinforcement, where 5 responses opened a door to show the female for 5s. After 15 door openings, the male gained access to the female. There was no effect of testosterone on time to complete 75 responses: 38.4 ± 7.8 min for vehicle controls vs 43.3 ± 6.6 min for testosterone-treated rats (p > 0.05). These findings suggest that chronic high-dose testosterone does not enhance appetitive drive for sexual behavior.

Ethanol induces conditioned social preference in male mice.

BACKGROUND: Affiliative social interactions promote alcohol consumption, and alcohol also promotes affiliative behavior. Furthermore, for most species, moderate doses of ethanol (EtOH) and social affiliation are each rewarding. However, animal studies of drug and EtOH reward typically test individuals in isolation. To address social dimensions of EtOH reward, this study tested EtOH-induced conditioned social preference in male C57BL/6 mice with (ORCHX+T) and without (ORCHX) testosterone. METHODS: ORCHX+T males received EtOH (0, 1, 2, or 3 g/kg) intraperitoneally and were paired 4× for 30 minutes each with 1 of 2 stimulus males: with the CS- stimulus male after saline injection and with the CS+ male following EtOH. After pairing, time spent with CS+ and CS- males was measured in a 10-minute test. RESULTS: ORCHX+T test males showed conditioned preference for the CS+ male in response to 3 g/kg EtOH (change in preference: +71.3 ± 30.0 s/10 min, p < 0.05), but not for 0, 1, or 2 g/kg. By contrast, ORCHX males did not demonstrate conditioned preference for 3 g/kg EtOH (+16.0 ± 24.3 s/10 min, p > 0.05). In separate groups of mice, stimulus males (IS+) received EtOH during pairing to determine whether test mice prefer another intoxicated mouse. Both ORCHX+T and ORCHX test mice showed an increase in preference score for the IS+ mouse (ORCHX+T: +68.1 ± 24.0 seconds; ORCHX: +58.9 ± 19.6 seconds, p < 0.05). CONCLUSIONS: These data demonstrate that EtOH promotes social preference in male mice, as it does in females. Testosterone enhances this effect.

Chronic high-dose testosterone impairs economic decision making, but has no effect on memory in male rats.

The goal is to understand consequences of anabolic-androgenic steroid (AAS) abuse on cognitive function, using rats as a model. Economic decision making was evaluated in an operant test of effort value discounting, where subjects choose between 2 levers that deliver large and small rewards differing in maximum value and reward contrast. The hypothesis is that chronic high-dose testosterone increases preference for large rewards. Male rats were treated chronically with testosterone (7.5 mg/kg) or vehicle. Initially, all rats preferred the large reward lever when large and small rewards remained fixed at 3 and 1 sugar pellets, respectively. When different reward values were introduced, and with increasing response requirements, testosterone-treated rats made fewer responses for the large reward, and increased omissions. They earned fewer rewards overall. To determine if testosterone impairs memory, rats were tested for recognition memory with the novel object recognition and social transmission of food preference tasks, and for spatial memory with the radial arm maze and Morris water maze. There was not effect of chronic high-dose testosterone on any memory task. These results suggest that testosterone shifts economic decision making towards larger rewards even when they are disadvantageous, but does not alter memory in rats.

Defining predictors of responsiveness to advanced therapies in Crohn's disease and ulcerative colitis: protocol for the IBD-RESPONSE and nested CD-metaRESPONSE prospective, multicentre, observational cohort study in precision medicine.

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

Using the AR-V7 biomarker to determine treatment in metastatic castrate resistant prostate cancer, a feasibility randomised control trial, conclusions from the VARIANT trial [version 2; peer review: 2 approved].

Background: Prostate cancer is the most commonly diagnosed malignancy in the UK. Castrate resistant prostate cancer (CRPC) can be difficult to manage with response to next generation hormonal treatment variable. AR-V7 is a protein biomarker that can be used to predict response to treatment and potentially better inform management in these patients. Our aim was to establish the feasibility of conducting a definitive randomised controlled trial comparing the clinical utility of AR-V7 biomarker assay in personalising treatments for patients with metastatic CRPC within the United Kingdom (UK) National Health Service (NHS).  Due to a number of issues the trial was not completed successfully, we aim to discuss and share lessons learned herein. Methods: We conducted a randomised, open, feasibility trial, which aimed to recruit 70 adult men with metastatic CRPC within three secondary care NHS trusts in the UK to be run over an 18-month period. Participants were randomised to personalised treatment based on AR-V7 status (intervention) or standard care (control). The primary outcome was feasibility, which included: recruitment rate, retention and compliance. Additionally, a baseline prevalence of AR-V7 expression was to be estimated. Results: Fourteen participants were screened and 12 randomised with six into each arm over a nine-month period. Reliability issues with the AR-V7 assay meant prevalence was not estimated. Due to limited recruitment the study did not complete to target. Conclusions: Whilst the trial did not complete to target, we have ascertained that men with advanced cancer are willing to take part in trials utilising biomarker guided treatment. A number of issues were identified that serve as important learning points in future clinical trials.

Testosterone and sport: current perspectives.

Testosterone and other anabolic-androgenic steroids enhance athletic performance in men and women. As a result, exogenous androgen is banned from most competitive sports. However, due to variability in endogenous secretion, and similarities with exogenous testosterone, it has been challenging to establish allowable limits for testosterone in competition. Endogenous androgen production is dynamically regulated by both exercise and winning in competition. Furthermore, testosterone may promote athletic performance, not only through its long-term anabolic actions, but also through rapid effects on behavior. In women, excess production of endogenous testosterone due to inborn disorders of sexual development (DSD) may convey a competitive advantage. For many years, female competitors have been subject to tests of sexual genotype and phenotype known as gender verification. Although gender verification has not identified any normal man competing as a woman, this process has identified women athletes with DSD. As understanding of DSD has expanded in recent years, women with DSD are increasingly able to continue athletic competition.