Class B1 GPCRs: Insights into Multi-Receptor Pharmacology for the Treatment of Metabolic Disease.

The secretin-like, class B1 sub-family of seven transmembrane-spanning G protein coupled receptors (GPCRs) consists of 15 members that coordinate important physiological processes. These receptors bind peptide ligands and utilize a distinct mechanism of activation that is driven by evolutionarily conserved structural features. For the class B1 receptors, the C-terminus of the cognate ligand is initially recognized by the receptor via a large N-terminal extracellular domain that forms a hydrophobic ligand binding groove. This binding enables the N-terminus of the ligand to engage deep into a large volume, open transmembrane pocket of the receptor. Importantly, the phylogenetic basis of this ligand-receptor activation mechanism has provided opportunities to engineer analogues of several class B1 ligands for therapeutic use. Among the most successful of these are drugs targeting the glucagon-like peptide-1 (GLP-1) receptor for the treatment of type 2 diabetes and obesity. Recently, multi-functional agonists possessing activity at the GLP-1 receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, such as tirzepatide, and others that also contain glucagon receptor activity, have been developed. In this article, we review members of the class B1 GPCR family with focus on receptors for GLP-1, GIP, and glucagon, including their signal transduction and receptor trafficking characteristics. The metabolic importance of these receptors is also highlighted, along with the benefit of poly-pharmacologic ligands. Further, key structural features and comparative analyses of high-resolution cryogenic electron microscopy structures for these receptors in active-state complex with either native ligands or multi-functional agonists are provided, supporting the pharmacological basis of such therapeutic agents.

Abolishing ß-arrestin recruitment is necessary for the full metabolic benefits of G protein-biased glucagon-like peptide-1 receptor agonists.

AIM: Earlier studies have shown that peptide glucagon-like peptide-1 receptor (GLP-1R) agonists with reduced ß-arrestin recruitment show enhanced anti-hyperglycaemic efficacy through avoidance of GLP-1R desensitization. However, the ligand modifications needed to decrease ß-arrestin recruitment usually also reduces GLP-1R affinity, therefore higher doses are needed. Here we aimed to develop new, long-acting, G protein-biased GLP-1R agonists with acute signalling potency comparable with semaglutide, to provide insights into specific experimental and therapeutic scenarios. MATERIALS AND METHODS: New GLP-1R agonist peptides were assessed using a variety of in vitro and in vivo assays. RESULTS: First, we show that very substantial reductions in ß-arrestin recruitment efficacy are required to realize fully the benefits of GLP-1R agonism on blood glucose lowering in mice, with more moderate reductions being less effective. Secondly, our lead compound (SRB107) performs substantially better than semaglutide for effects on blood glucose and weight loss, which may be jointly attributable to its biased agonist action and protracted pharmacokinetics. Thirdly, we show that biased agonist-specific GLP-1R internalization profiles occur at clinically relevant pharmacological concentrations. Finally, we show that SRB107 cAMP signalling is differentially modulated by single and double GLP1R coding variants seen in human populations, with implications for GLP-1R agonist pharmacogenomics. CONCLUSIONS: Completely abolishing ß-arrestin recruitment improves the anti-hyperglycaemic effects of GLP-1R agonists in mice.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

Collaborative care approaches for people with severe mental illness.

BACKGROUND: Collaborative care for severe mental illness (SMI) is a community-based intervention that promotes interdisciplinary working across primary and secondary care. Collaborative care interventions aim to improve the physical and/or mental health care of individuals with SMI. This is an update of a 2013 Cochrane review, based on new searches of the literature, which includes an additional seven studies. OBJECTIVES: To assess the effectiveness of collaborative care approaches in comparison with standard care (or other non-collaborative care interventions) for people with diagnoses of SMI who are living in the community. SEARCH METHODS: We searched the Cochrane Schizophrenia Study-Based Register of Trials (10 February 2021). We searched the Cochrane Common Mental Disorders (CCMD) controlled trials register (all available years to 6 June 2016). Subsequent searches on Ovid MEDLINE, Embase and PsycINFO together with the Cochrane Central Register of Controlled Trials (with an overlap) were run on 17 December 2021. SELECTION CRITERIA: Randomised controlled trials (RCTs) where interventions described as 'collaborative care' were compared with 'standard care' for adults (18+ years) living in the community with a diagnosis of SMI. SMI was defined as schizophrenia, other types of schizophrenia-like psychosis or bipolar affective disorder. The primary outcomes of interest were: quality of life, mental state and psychiatric admissions at 12 months follow-up. DATA COLLECTION AND ANALYSIS: Pairs of authors independently extracted data. We assessed the quality and certainty of the evidence using RoB 2 (for the primary outcomes) and GRADE. We compared treatment effects between collaborative care and standard care. We divided outcomes into short-term (up to six months), medium-term (seven to 12 months) and long-term (over 12 months). For dichotomous data we calculated the risk ratio (RR) and for continuous data we calculated the standardised mean difference (SMD), with 95% confidence intervals (CIs). We used random-effects meta-analyses due to substantial levels of heterogeneity across trials. We created a summary of findings table using GRADEpro. MAIN RESULTS: Eight RCTs (1165 participants) are included in this review. Two met the criteria for type A collaborative care (intervention comprised of the four core components). The remaining six met the criteria for type B (described as collaborative care by the trialists, but not comprised of the four core components). The composition and purpose of the interventions varied across studies. For most outcomes there was low- or very low-certainty evidence. We found three studies that assessed the quality of life of participants at 12 months. Quality of life was measured using the SF-12 and the WHOQOL-BREF and the mean endpoint mental health component scores were reported at 12 months. Very low-certainty evidence did not show a difference in quality of life (mental health domain) between collaborative care and standard care in the medium term (at 12 months) (SMD 0.03, 95% CI -0.26 to 0.32; 3 RCTs, 227 participants). Very low-certainty evidence did not show a difference in quality of life (physical health domain) between collaborative care and standard care in the medium term (at 12 months) (SMD 0.08, 95% CI -0.18 to 0.33; 3 RCTs, 237 participants). Furthermore, in the medium term (at 12 months) low-certainty evidence did not show a difference between collaborative care and standard care in mental state (binary) (RR 0.99, 95% CI 0.77 to 1.28; 1 RCT, 253 participants) or in the risk of being admitted to a psychiatric hospital at 12 months (RR 5.15, 95% CI 0.67 to 39.57; 1 RCT, 253 participants). One study indicated an improvement in disability (proxy for social functioning) at 12 months in the collaborative care arm compared to usual care (RR 1.38, 95% CI 0.97 to 1.95; 1 RCT, 253 participants); we deemed this low-certainty evidence. Personal recovery and satisfaction/experience of care outcomes were not reported in any of the included studies. The data from one study indicated that the collaborative care treatment was more expensive than standard care (mean difference (MD) international dollars (Int$) 493.00, 95% CI 345.41 to 640.59) in the short term. Another study found the collaborative care intervention to be slightly less expensive at three years. AUTHORS' CONCLUSIONS: This review does not provide evidence to indicate that collaborative care is more effective than standard care in the medium term (at 12 months) in relation to our primary outcomes (quality of life, mental state and psychiatric admissions). The evidence would be improved by better reporting, higher-quality RCTs and the assessment of underlying mechanisms of collaborative care. We advise caution in utilising the information in this review to assess the effectiveness of collaborative care.

Non-reporting of sport-related concussion symptoms: a cross-sectional study of community rugby league players in the UK.

Recognising and removing players with suspected sport-related concussions is crucial for community sports. OBJECTIVES: Quantify rates and factors associated with non-reporting of concussion symptoms in community rugby league. METHODS: Overall, 484 community rugby league players aged ≥18 years and 965 parents of rugby league players aged <18 years completed an online survey, regarding concussion history, knowledge, prevalence and reasons for non-reporting of concussion, long-term implications and perceptions of concussion. RESULTS: Thirty-five percent of players aged ≥18 years and 22% of parents of players aged <18 years reported at least one concussion in the last two seasons. Forty-three percent of players aged ≥18 years and 5% of parents of players aged<18 years surveyed stated they did not report concussion-related symptoms sustained during 2020 and 2021 seasons. The two most common reasons for non-reporting of concussion symptoms were 'didn't want to be ruled out of a match' and 'didn't want to let down the team'. Players aged ≥18 years who received external coaching pressures around concussion were more likely to not report concussion symptoms. Over 40% of parents and players were concerned about the potential long-term implications. Ten percent of players aged ≥18 years and 7% of parents of players aged <18 years would encourage their family members/children to not play rugby league. CONCLUSIONS: Non-reporting rates of suspected concussion symptoms in adult community players were twice as high as in professional rugby league, with similar reasons (wanting to play and not letting the team down). Engaging coaches to prioritise brain health and providing broader and appropriate education on concussion should be focused on, given the concerns reported by community players and parents.

Head Acceleration Events During Tackle, Ball-Carry, and Ruck Events in Professional Southern Hemisphere Men's Rugby Union Matches: A Study Using Instrumented Mouthguards.

OBJECTIVES: Describe head acceleration events (HAEs) experienced by professional male rugby union players during tackle, ball-carry, and ruck events using instrumented mouthguards (iMGs). DESIGN: Prospective observational cohort. METHODS: Players competing in the 2023 Currie Cup (141 players) and Super Rugby (66 players) seasons wore iMGs. The iMG-recorded peak linear acceleration (PLA) and peak angular acceleration (PAA) were used as in vivo HAE approximations and linked to contact-event data captured using video analysis. Using the maximum PLA and PAA per contact event (HAEmax), ordinal mixed-effects regression models estimated the probabilities of HAEmax magnitude ranges occurring, while accounting for the multilevel data structure. RESULTS: As HAEmax magnitude increased the probability of occurrence decreased. The probability of a HAEmax ≥15g was 0.461 (0.435-0.488) (approximately 1 in every 2) and ≥45g was 0.031 (0.025-0.037) (1 in every 32) during ball carries. The probability of a HAEmax >15g was 0.381 (0.360-0.404) (1 in every 3) and >45g 0.019 (0.015-0.023) (1 in every 53) during tackles. The probability of higher magnitude HAEmax occurring was greatest during ball carries, followed by tackles, defensive rucks and attacking rucks, with some ruck types having similar profiles to tackles and ball carries. No clear differences between positions were observed. CONCLUSION: Higher magnitude HAEmax were relatively infrequent in professional men's rugby union players. Contact events appear different, but no differences were found between positions. The occurrence of HAEmax was associated with roles players performed within contact events, not their actual playing position. Defending rucks may warrant greater consideration in injury prevention research.

The Frequency and Severity of Gastrointestinal Symptoms in Rugby Players.

This study aimed to assess the self-reported frequency and severity of gastrointestinal symptoms (GIS) at rest and around rugby training and match play in male and female rugby union players. An online questionnaire was sent to registered rugby union players (sevens or fifteens). Thirteen GIS were assessed alongside perceptions of appetite around rugby and rest using Likert and visual analog scales. Questions investigating a range of medical and dietary factors were included. Three hundred and twenty-five players (male n=271, female n=54) participated in the study. More frequent GIS (at least one GIS experienced weekly/more often) was reported by players at rest (n=203; 62%) compared to around rugby (n=154; 47%). The overall severity of GIS was low (mild discomfort), but a portion of players (33%) did report symptoms of moderate severity around rugby. Female players reported more frequent and severe symptoms compared to male counterparts (p<0.001). Self-reported appetite was significantly lower after matches compared to training. There were no dietary or medical factors associated with GIS severity scores. This study describes GIS characteristics in male and female rugby union players. Half of the players assessed experienced some form of GIS that may affect nutrition, training, or performance, and should thus be a consideration for practitioners supporting this cohort.

Computational modelling of dynamic cAMP responses to GPCR agonists for exploration of GLP-1R ligand effects in pancreatic ß-cells and neurons.

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) which plays important physiological roles in insulin release and promoting fullness. GLP-1R agonists initiate cellular responses by cyclic AMP (cAMP) pathway signal transduction. Understanding of the potential of GLP-1R agonists in the treatment of type 2 diabetes may be advanced by considering the cAMP dynamics for agonists at GLP-1R in both pancreatic ß-cells (important in insulin release) and neurons (important in appetite regulation). Receptor desensitisation in the cAMP pathway is known to be an important regulatory mechanism, with different ligands differentially promoting G protein activation and desensitisation. Here, we use mathematical modelling to quantify and understand experimentally obtained cAMP timecourses for two GLP-1R agonists, exendin-F1 (ExF1) and exendin-D3 (ExD3), which give markedly different signals in ß-cells and neurons. We formulate an ordinary differential equation (ODE) model for the dynamics of cAMP signalling in response to G protein-coupled receptor (GPCR) ligands, encompassing ligand binding, receptor activation, G protein activation, desensitisation and second messenger generation. We validate our model initially by fitting to timecourse data for HEK293 cells, then proceed to parameterise the model for ß-cells and neurons. Through numerical simulation and sensitivity studies, our analysis adds support to the hypothesis that ExF1 offers more potential glucose regulation benefit than ExD3 over long timescales via signalling in pancreatic ß-cells, but that there is little difference between the two ligands in the potential appetite suppression effects offered via long-time signalling in neurons on the same timescales.

Innovation in sport medicine and science: a global social network analysis of stakeholder collaboration in rugby union.

Objectives: To investigate the network of stakeholders involved in rugby union research across the globe. Methods: Using author affiliations listed on scientific publications, we identified the organisations that contributed to rugby union research from 1977 to 2022 and examine collaboration through coauthorship indicators. We determined the locations and sectors of identified organisations and constructed a collaboration network. Network metrics, including degree centrality and betweenness centrality, are computed to identify influential organisations and measure intersector collaboration. Results: There is an increase in scientific knowledge creation and collaboration between organisations for rugby union research over time. Among the sectors, the university, professional sports team and sports governing body sectors exhibit the highest intersectoral and intrasectoral density. Predominantly, influential actors are located in England, Australia, France, New Zealand, Ireland and South Africa. Australian Catholic University, Leeds Beckett University, Stellenbosch University, Swansea University, University College London and the University of Cape Town emerge as influential actors between 2016 and 2022. Conclusions: Our study underscores the ongoing growth of scientific knowledge generation in rugby union, primarily led by organisations in tier 1 rugby-playing nations within the university sector. Intersectoral collaboration with sports governing bodies plays a crucial role, acting as a broker between sectors. However, the overall collaboration landscape between and within sectors is low. These results highlight an opportunity for improved collaboration opportunities, as the organisations driving knowledge creation have been identified.

Identification of pattern mining algorithm for rugby league players positional groups separation based on movement patterns.

The application of pattern mining algorithms to extract movement patterns from sports big data can improve training specificity by facilitating a more granular evaluation of movement. Since movement patterns can only occur as consecutive, non-consecutive, or non-sequential, this study aimed to identify the best set of movement patterns for player movement profiling in professional rugby league and quantify the similarity among distinct movement patterns. Three pattern mining algorithms (l-length Closed Contiguous [LCCspm], Longest Common Subsequence [LCS] and AprioriClose) were used to extract patterns to profile elite rugby football league hookers (n = 22 players) and wingers (n = 28 players) match-games movements across 319 matches. Jaccard similarity score was used to quantify the similarity between algorithms' movement patterns and machine learning classification modelling identified the best algorithm's movement patterns to separate playing positions. LCCspm and LCS movement patterns shared a 0.19 Jaccard similarity score. AprioriClose movement patterns shared no significant Jaccard similarity with LCCspm (0.008) and LCS (0.009) patterns. The closed contiguous movement patterns profiled by LCCspm best-separated players into playing positions. Multi-layered Perceptron classification algorithm achieved the highest accuracy of 91.02% and precision, recall and F1 scores of 0.91 respectively. Therefore, we recommend the extraction of closed contiguous (consecutive) over non-consecutive and non-sequential movement patterns for separating groups of players.

Injury Profile in Youth Female Athletes: A Systematic Review and Meta-Analysis.

BACKGROUND: An increasing number of epidemiological studies assessing the incidence, prevalence and severity of injury in youth female sport are available. However, no study has sought to synthesise the current evidence base across all youth female sport. As such, a systematic review and meta-analysis of injury in this cohort is necessary to understand the diversity of injury and its associated burden between sports in addition to identifying the density of research available. OBJECTIVE: To conduct a systematic review and meta-analysis of epidemiological data of injuries in youth female athletes with particular attention to injury incidence, mean days lost and injury burden. METHODS: Searches were performed in PubMed, EBSCO (SPORTDiscus with Full Text MEDLINE, APA PsycINFO, CINAHL, Academic Search Complete) and Cochrane databases. Studies were considered if they reported time-loss injury incidence or prevalence in youth female (≤ 19 years old) athletes. Study quality and risk of bias were assessed using STROBE-SIIS extension, Newcastle-Ottawa Scale, and funnel plots, respectively. Injury incidence and burden rate data were modelled using a mixed-effect Poisson regression model. Days lost data were modelled using a generalised linear mixed model. RESULTS: Thirty-two studies were included. The overall incidence rate, mean days lost per injury, and burden rate were 4.4 injuries per 1000 h (95% CI 3.3-5.9), 10 days (95% CI 6-15), and 46 days per 1000 h (95% CI 23-92), respectively. Forty percent of athletes sustained at least one time-loss injury. Competitive level was a significant moderator of match and training injury incidence, with elite youth athletes presenting greater pooled injury incidence estimates than non-elite athletes (p = 0.0315 and p = 0.0047, respectively). The influence of moderators on days lost and injury burden could not be determined due to an insufficient number of studies for analysis. CONCLUSION: Despite a broad inclusion criterion, there is limited injury surveillance research available across youth female sport. Outside of soccer, little research density is evidenced with single studies available in popular team sports such as Australian football and rugby union. Insufficient study numbers reporting mean days lost and injury burden data were available for analysis, and pooled days lost data could only be estimated for soccer. This highlights a need for future research to report days lost data alongside injury number and exposure so burden can be calculated and the full risk of injury to youth female athletes can be identified.

The effects of rule changes in football-code team sports: a systematic review.

Rule changes within football-code team sports aim to improve performance, enhance player welfare, increase competitiveness, and provide player development opportunities. This manuscript aimed to review research investigating the effects of rule changes in football-code team sports. A systematic search of electronic databases (PubMed, ScienceDirect, CINAHL, MEDLINE, and SPORTDiscus) was performed to August 2023; keywords related to rule changes, football-code team sports, and activity type. Studies were excluded if they failed to investigate a football-code team sport, did not quantify the change of rule, or were review articles. Forty-six studies met the eligibility criteria. Four different football codes were reported: Australian rules football (n = 4), rugby league (n = 6), rugby union (n = 16), soccer (n = 20). The most common category was physical performance and match-play characteristics (n = 22). Evidence appears at a high risk of bias partly due to the quasi-experimental nature of included studies, which are inherently non-randomised, but also due to the lack of control for confounding factors within most studies included. Rule changes can result in unintended consequences to performance (e.g., longer breaks in play) and effect player behaviour (i.e., reduce tackler height in rugby) but might not achieve desired outcome (i.e., unchanged concussion incidence). Coaches and governing bodies should regularly and systematically investigate the effects of rule changes to understand their influence on performance and injury risk. It is imperative that future studies analysing rule changes within football codes account for confounding factors by implementing suitable study designs and statistical analysis techniques.

Review article: Emergency medical services transfer of severe traumatic brain injured patients to a neuroscience centre: A systematic review.

Patients with severe traumatic brain injuries require urgent medical attention at a hospital. We evaluated whether transporting adult patients with a severe traumatic brain injury (TBI) to a Neuroscience Centre is associated with reduced mortality. We reviewed studies published between 2010 and 2023 on severe TBI in adults (>18 years) using Medline, CINAHL, Google Scholar and Cochrane databases. We focused on mortality rates and the impact of transferring patients to a Neuroscience Centre, delays to neurosurgery and EMS triage accuracy. This review analysed seven studies consisting of 53 365 patients. When patients were directly transported to a Neuroscience Centre, no improvement in survivability was demonstrated. Subsequently, transferring patients from a local hospital to a Neuroscience Centre was significantly associated with reduced mortality in one study (adjusted odds ratio: 0.79, 95% confidence interval: 0.64-0.96), and 24-h (relative risk [RR]: 0.31, 0.11-0.83) and 30-day (RR: 0.66, 0.46-0.96) mortality in another. Patients directly transported to a Neuroscience Centre were more unwell than those taken to a local hospital. Subsequent transfers increased time to CT scanning and neurosurgery in several studies, although these were not statistically significant. Additionally, EMS could accurately triage. None of the included studies demonstrated statistically significant findings indicating that direct transportation to a Neuroscience Centre increased survivability for patients with severe traumatic brain injuries. Subsequent transfers from a non-Neuroscience Centre to a Neuroscience Centre reduced mortality rates at 24 h and 30 days. Further research is required to understand the differences between direct transport and subsequent transfers to Neuroscience Centres.

Validity, reliability, and the contributing physical characteristics of a modified 15m prone Yo-Yo Intermittent Recovery Test Level-1 test in elite female rugby league players.

This study aims to establish the validity and reliability of the prone Yo-YoIRL1 in elite female rugby league players (part one) and determine the anthropometric and physical characteristics contributing to 15m prone Yo-YoIRL1 performance (part two). Part one, 21 subjects completed one Yo-YoIRL1, one 20m and two 15m prone Yo-YoIRL1 tests over four sessions, with 7-14 days in-between. Part two, ten subjects completed a testing battery, including body mass, height, dual-energy x-ray absorptiometry, isometric mid-thigh pull, isometric bench-press, 10m and 20m sprints and an incremental treadmill test ([Formula: see text]). The 15m prone YoYoIRL1 demonstrated poor reliability with a typical error of 68m (21%) and a smallest worthwhile change of 54m (9%). Validity analysis found the prone versions of the YoYoIRL1 were not sensitive measures of intermittent running performance. Both prone YoYoIRL1 test distances demonstrated large mean bias (76% and -37% respectively) and typical error of the estimate (19% and 21%, respectively) in comparison to the YoYoIRL1. Body mass (r = -0.89), lean mass (r = -0.64), body fat % (r = -0.68), [Formula: see text] (l∙min-1) (r = -0.64), IMTP (r = -0.69), IBP (r = -0.15), 10m (r = -0.77) and 20m (r = -0.72) momentum displayed large negative relationships with 15m prone Yo-YoIRL1 performance. Due to the poor validity of the 20m prone YoYoIRL1, the poor validity and reliability of the 15m prone YoYoIRL1, and the anthropometric and physical characteristics which negatively impact performance, practitioners should reconsider the use of the prone YoYoIRL1 test to monitor high intensity intermittent running performance.

Paving the path for injury prevention in rugby-7s: A systematic review and meta-analysis.

This review and meta-analysis aimed to describe the current rugby-7s injury epidemiological literature by examining injury data from both sexes, all levels of play, and their associated risk factors. Studies published up until March 2024 were included. These studies were retrieved from six databases using search terms related to rugby-7s or sevens, tackle, collision, collision sport, injury, athlete, incidence rate, mechanism, and risk factor. Only peer-reviewed original studies using prospective or retrospective cohort designs with a clearly defined rugby-7s sample were considered. Included studies needed to report one injury outcome variable. Non-English and qualitative studies; reviews, conference papers, and abstracts were excluded. Twenty studies were included. The meta-analysis used the DerSimonian-Laird continuous random-effects method to calculate the pooled estimated means and 95% confidence interval. The estimated mean injury incidence rate for men was 108.5/1000 player-hours (95% CI: 85.9-131.0) and 76.1/1000 player-hours (95% CI: 48.7-103.5) for women. The estimated mean severity for men was 33.9 days (95% CI: 20.7-47.0) and 44.2 days (95% CI: 32.1-56.3) for women. Significantly more match injuries occurred in the second half of matches, were acute, located at the lower limb, diagnosed as joint/ligament, and resulted from being tackled. Fatigue, player fitness, and previous injuries were associated with an increased risk of injury. There were no statistically significant differences between women's and men's injury profiles. However, the inherent cultural and gendered factors which divide the two sports should not be ignored. The findings from this review will help pave the way forward beyond the foundational stages of injury prevention research in rugby-7s.

Lipid regulation of the glucagon receptor family.

The glucagon receptor family are typical class B1 G protein-coupled receptors (GPCRs) with important roles in metabolism, including the control of pancreas, brain, and liver function. As proteins with seven transmembrane domains, GPCRs are intimately in contact with lipid bilayers and therefore can be putatively regulated by interactions with their lipidic components, including cholesterol, sphingolipids, and other lipid species. Additionally, these receptors, as well as the agonists they bind to, can undergo lipid modifications, which can influence their binding capacity and/or elicit modified or biased signalling profiles. While the effect of lipids, and in particular cholesterol, has been widely studied for other GPCR classes, information about their role in regulating the glucagon receptor family is only beginning to emerge. Here we summarise our current knowledge on the effects of cholesterol modulation of glucagon receptor family signalling and trafficking profiles, as well as existing evidence for specific lipid-receptor binding and indirect effects of lipids via lipid modification of cognate agonists. Finally, we discuss the different methodologies that can be employed to study lipid-receptor interactions and summarise the importance of this area of investigation to increase our understanding of the biology of this family of metabolically relevant receptors.

Sequences Related to Chimay Rhabdovirus Are Widely Distributed in Ixodes ricinus Ticks across England and Wales.

Ticks are the main arthropod vector of pathogens to humans and livestock in the British Isles. Despite their role as a vector of disease, many aspects of tick biology, ecology, and microbial association are poorly understood. To address this, we investigated the composition of the microbiome of adult and nymphal Ixodes ricinus ticks. The ticks were collected on a dairy farm in Southwest England and RNA extracted for whole genome sequencing. Sequences were detected from a range of microorganisms, particularly tick-associated viruses, bacteria, and nematodes. A majority of the viruses were attributed to phlebo-like and nairo-like virus groups, demonstrating a high degree of homology with the sequences present in I. ricinus from mainland Europe. A virus sharing a high sequence identity with Chimay rhabdovirus, previously identified in ticks from Belgium, was detected. Further investigations of I. ricinus ticks collected from additional sites in England and Wales also identified Chimay rhabdovirus viral RNA with varying prevalence in all tick populations. This suggests that Chimay rhabdovirus has a wide distribution and highlights the need for an extended exploration of the tick microbiome in the United Kingdom (UK).

Player Activity and Load Profiling with Hidden Markov Models: A Novel Application in Rugby League.

Player movement in rugby league is complex, being spatiotemporal and multifaceted. Modeling this complexity to provide robust measures of player activity and load has proved difficult, with important aspects of player movement yet to be considered. These include the influence of time-varying covariates on player activity and the combination of different dimensions of player movement. Few studies have simultaneously categorized player activity into different activity states and investigated factors influencing the transition between states, or compared player activity and load profiles between matches and training. This study applied hidden Markov models (HMMs)-a data-driven, multivariate approach-to rugby league training and match GPS data to i) demonstrate how HMMs can combine multiple variables in a data-driven way to effectively categorize player movement states, ii) investigate the influence of two time-varying covariates, score difference and elapsed match time on player activity states, and iii) compare player activity and load profiles within and between training and match modalities. HMMs were fitted to player GPS, accelerometer and heart rate data of one English Super League team across 60 training sessions and 35 matches. Distinct activity states were detected for both matches and training, with transitions between states in matches influenced by score difference and elapsed time and clear differences in activity and load profiles between training and matches. HMMs can model the complexity of player movement to effectively profile player activity and load in rugby league and have the potential to facilitate new research across several sports.

We successfully derived player activity and load profiles in both training and match contexts in a data-driven and multivariate way using hidden Markov models.HMMs can be used to investigate the probability of changing between activity states as a function of time-varying covariates, augmenting current activity profiling practice.We discovered key differences between the activity and load profiles between training and matches in rugby league. In particular, a very directed high-speed running state in training that is seldom accessed by players in matches.We demonstrated how visualizing the output of HMMs can provide decision support by facilitating comparisons of activity and load profiles within and between players in matches and training.We posit that the methodology detailed in this paper can become a standardized approach to player activity and load profiling based on player movement data across multiple sports because it is flexible, data-driven, multivariate and statistically robust.

ENERGY EXPENDITURE OF INTERNATIONAL FEMALE RUGBY UNION PLAYERS DURING A MAJOR INTERNATIONAL TOURNAMENT: A DOUBLY LABELLED WATER STUDY.

The purpose of this study was to quantify the total energy expenditure (TEE) of international female rugby union players. Fifteen players were assessed over 14-days throughout an international multi-game tournament, which represented two consecutive one-match microcycles. Resting metabolic rate (RMR) and TEE were assessed by indirect calorimetry and doubly labelled water, respectively. Physical activity level (PAL) was estimated (TEE:RMR). Mean RMR, TEE, and PAL were 6.60 ± 0.93 MJ.day-1, 13.51 ± 2.28 MJ.day-1 and 2.0 ± 0.3 AU, respectively. There was no difference in TEE (13.74 ± 2.31 vs. 13.92 ± 2.10 MJ.day-1; p = 0.754), or PAL (2.06 ± 0.26 AU vs. 2.09 ± 0.23 AU; p = 0.735) across microcycles, despite substantial decreases in training load (total distance: -8088 m, collisions: -20 n, training duration: -252 min). After correcting for body composition, there was no difference in TEE (13.80 ± 1.74 vs. 13.16 ± 1.97 adj. MJ.day-1, p = 0.190), RMR (6.49 ± 0.81 vs. 6.73 ± 0.83 adj. MJ.day-1, p = 0.633) or PAL (2.15 ± 0.14 vs 1.87 ± 0.26 AU, p = 0.090) between forwards and backs. For an injured participant (n = 1), TEE reduced by 1.7 MJ.day-1 from pre-injury. For participants with illness (n = 3), TEE was similar to pre-illness (+0.49 MJ.day-1). The energy requirements of international female rugby players were consistent across one-match microcycles. Forwards and backs had similar adjusted energy requirements. These findings are critical to inform the dietary guidance provided to female rugby players.