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.

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.

Engineered mini-G proteins block the internalization of cognate GPCRs and disrupt downstream intracellular signaling.

Mini-G proteins are engineered, thermostable variants of Gα subunits designed to stabilize G protein-coupled receptors (GPCRs) in their active conformations. Because of their small size and ease of use, they are popular tools for assessing GPCR behaviors in cells, both as reporters of receptor coupling to Gα subtypes and for cellular assays to quantify compartmentalized signaling at various subcellular locations. Here, we report that overexpression of mini-G proteins with their cognate GPCRs disrupted GPCR endocytic trafficking and associated intracellular signaling. In cells expressing the Gαs-coupled GPCR glucagon-like peptide 1 receptor (GLP-1R), coexpression of mini-Gs, a mini-G protein derived from Gαs, blocked ß-arrestin 2 recruitment and receptor internalization and disrupted endosomal GLP-1R signaling. These effects did not involve changes in receptor phosphorylation or lipid nanodomain segregation. Moreover, we found that mini-G proteins derived from Gαi and Gαq also inhibited the internalization of GPCRs that couple to them. Finally, we developed an alternative intracellular signaling assay for GLP-1R using a nanobody specific for active Gαs:GPCR complexes (Nb37) that did not affect GLP-1R internalization. Our results have important implications for designing methods to assess intracellular GPCR signaling.

Training injuries in elite men's senior and academy (Super League) rugby league; an analysis of 224,000 exposure-hours.

OBJECTIVES: Report two-years of training injury data in senior and academy professional rugby league. DESIGN: Prospective cohort study. METHODS: Match and training time-loss injuries and exposure data were recorded from two-seasons of the European Super League competition. Eleven/12 (2021) and 12/12 (2022) senior and 8/12 (2021) and 12/12 (2022) academy teams participated. Training injuries are described in detail and overall match injuries referred to for comparison only. RESULTS: 224,000 training exposure hours were recorded with 293 injuries at the senior (mean [95 % confidence interval]; 3 [2-3] per 1000 h) and 268 academy level (2 [2-3] per 1000 h), accounting for 31 % and 40 % of all injuries (i.e., matches and training). The severity of training injuries (senior: 35 [30-39], academy: 36 [30-42] days-lost) was similar to match injuries. Lower-limb injuries had the greatest injury incidence at both levels (senior: 1.85 [1.61-2.12], academy: 1.28 [1.08-1.51] per 1000 h). Head injuries at the academy level had greater severity (35 [25-45] vs. 18 [12-14] days-lost; p < 0.01) and burden (17 [16-18] vs. 4 [4-5] days-lost per 1000 h; p = 0.02) than senior level. At the senior level, the incidence of contact injuries was lower than non-contact injuries (risk ratio: 0.29 [0.09-0.88], p = 0.02). CONCLUSIONS: Training injuries accounted for about a third of injuries, with similar injury severity to match-play. Within training there is a higher rate of non-contact vs. contact injuries. Whilst current injury prevention interventions target matches, these data highlight the importance of collecting high quality training injury data to develop and evaluate injury prevention strategies in training.

Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity.

OBJECTIVES: Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice. METHODS: Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice. RESULTS: Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance. CONCLUSIONS: Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.

Embracing the impact from instrumented mouthguards (iMGs): A survey of iMG managers' perceptions of staff and player interest into the technology, data and barriers to use.

Instrumented mouthguards (iMGs) are a novel technology being used within rugby to quantify head acceleration events. Understanding practitioners' perceptions of the barriers and facilitators to their use is important to support implementation and adoption. This study assessed men's and women's rugby union and league iMG managers' perceptions of staff and player interest in the technology, data and barriers to use. Forty-six iMG managers (men's rugby union and league n = 20 and n = 9 and women's rugby union and league n = 7 and n = 10) completed an 18-question survey. Perceived interest in data varied across staff roles with medical staff being reported as having the most interest. The iMG devices were perceived as easy to use but uncomfortable. Several uses of data were identified, including medical applications, player monitoring and player welfare. The comfort, size and fit of the iMG were reported as the major barriers to player use. Time constraints and a lack of understanding of data were barriers to engagement with the data. Continued education on how iMG data can be used is required to increase player and staff buy-in, alongside improving comfort of the devices. Studies undertaken with iMGs investigating player performance and welfare outcomes will make data more useful and increase engagement.

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 Incidence and Propensity of Head Acceleration Events in a Season of Men's and Women's English Elite-Level Club Rugby Union Matches.

OBJECTIVES: To describe and compare the incidence and propensity of head acceleration events (HAEs) using instrumented mouthguards (iMG) by playing position in a season of English elite-level men's and women's rugby union matches. METHODS: iMG data were collected for 255 men and 133 women from 1,865 and 807 player-matches, respectively, and synchronised to video-coded match footage. Head peak resultant linear acceleration (PLA) and peak resultant angular acceleration (PAA) were extracted from each HAE. Mean incidence and propensity values were calculated across different recording thresholds for forwards and backs in addition to positional groups (front row, second row, back row, half backs, centres, back three) with 95% confidence intervals (CI) estimated. Significance was determined based on 95% CI not overlapping across recording thresholds. RESULTS: For both men and women, HAE incidence was twice as high for forwards than backs across the majority of recording thresholds. HAE incidence and propensity were significantly lower in the women's game compared to the men's game. Back-row and front-row players had the highest incidence across all HAE thresholds for men's forwards, while women's forward positional groups and men's and women's back positional groups were similar. Tackles and carries exhibited a greater propensity to result in HAE for forward positional groups and the back three in the men's game, and back row in the women's game. CONCLUSION: These data offer valuable benchmark and comparative data for future research, HAE mitigation strategies, and management of HAE exposure in elite rugby players. Positional-specific differences in HAE incidence and propensity should be considered in future mitigation strategies.

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.

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.

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.

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.

Worldwide absence of canonical benzimidazole resistance-associated mutations within ß-tubulin genes from Ascaris.

BACKGROUND: The giant roundworm Ascaris is an intestinal nematode, causing ascariasis by infecting humans and pigs worldwide. Recent estimates suggest that Ascaris infects over half a billion people, with chronic infections leading to reduced growth and cognitive ability. Ascariasis affects innumerable pigs worldwide and is known to reduce production yields via decreased growth and condemnation of livers. The predominant anthelminthic drugs used to treat ascariasis are the benzimidazoles. Benzimidazoles interact with ß-tubulins and block their function, and several benzimidazole resistance-associated mutations have been described in the ß-tubulins of ruminant nematodes. Recent research on ascarids has shown that these canonical benzimidazole resistance-associated mutations are likely not present in the ß-tubulins of Ascaris, Ascaridia or Parascaris, even in phenotypically resistant populations. METHODS: To further determine the putative absence of key ß-tubulin polymorphisms, we screened two ß-tubulin isotypes of Ascaris, highly expressed in adult worms. Using adult and egg samples of Ascaris obtained from pigs and humans worldwide, we performed deep amplicon sequencing to look for canonical resistance-associated mutations in Ascaris ß-tubulins. Subsequently, we examined these data in closer detail to study the population dynamics of Ascaris and genetic diversity within the two isotypes and tested whether genotypes appeared to partition across human and pig hosts. RESULTS: In the 187 isolates, 69 genotypes were found, made up of eight haplotypes of ß-tubulin isotype A and 20 haplotypes of isotype B. Single nucleotide polymorphisms were seen at 14 and 37 positions for ß-tubulin isotype A and isotype B, respectively. No evidence of any canonical benzimidazole resistance-associated mutations was found in either human- or pig-derived Ascaris isolates. There was, however, a difference in the genetic diversity of each isotype and distribution of ß-tubulin genotypes between human- and pig-derived Ascaris. Statistical tests of population differentiation show significant differences (p < 0.001) between pig- and human-derived worms; however, more diversity was seen between worms from different populations than worms from different hosts. CONCLUSIONS: Our work suggests an absence of canonical ß-tubulin mutations within Ascaris, but alternative modes of anthelminthic resistance may emerge necessitating continued genetic scrutiny alongside monitoring of drug efficacy.

Longitudinal changes in anthropometric, physiological, and physical qualities of international women's rugby league players.

This is the first study to assess longitudinal changes in anthropometric, physiological, and physical qualities of international women's rugby league players. Thirteen forwards and 11 backs were tested three times over a 10-month period. Assessments included: standing height and body mass, body composition measured by dual x-ray absorptiometry (DXA), a blood panel, resting metabolic rate (RMR) assessed by indirect calorimetry, aerobic capacity (i.e.,[Formula: see text]) evaluated by an incremental treadmill test, and isometric force production measured by a force plate. During the pre-season phase, lean mass increased significantly by ~2% for backs (testing point 1: 47 kg; testing point 2: 48 kg) and forwards (testing point 1: 50 kg; testing point 2: 51 kg) (p = ≤ 0.05). Backs significantly increased their [Formula: see text] by 22% from testing point 1 (40 ml kg-1 min-1) to testing point 3 (49 ml kg-1 min-1) (p = ≤ 0.04). The [Formula: see text] of forwards increased by 10% from testing point 1 (41 ml kg-1 min-1) to testing point 3 (45 ml kg-1 min-1), however this change was not significant (p = ≥ 0.05). Body mass (values represent the range of means across the three testing points) (backs: 68 kg; forwards: 77-78 kg), fat mass percentage (backs: 25-26%; forwards: 30-31%), resting metabolic rate (backs: 7 MJ day-1; forwards: 7 MJ day-1), isometric mid-thigh pull (backs: 2106-2180 N; forwards: 2155-2241 N), isometric bench press (backs: 799-822 N; forwards: 999-1024 N), isometric prone row (backs: 625-628 N; forwards: 667-678 N) and bloods (backs: ferritin 21-29 ug/L, haemoglobin 137-140 g/L, iron 17-21 umol/L, transferrin 3 g/L, transferring saturation 23-28%; forwards: ferritin 31-33 ug/L, haemoglobin 141-145 g/L, iron 20-23 umol/L, transferrin 3 g/L, transferrin saturation 26-31%) did not change (p = ≥ 0.05). This study provides novel longitudinal data which can be used to better prepare women rugby league players for the unique demands of their sport, underpinning female athlete health.

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).

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.

When to Pull the Trigger: Conceptual Considerations for Approximating Head Acceleration Events Using Instrumented Mouthguards.

Head acceleration events (HAEs) are acceleration responses of the head following external short-duration collisions. The potential risk of brain injury from a single high-magnitude HAE or repeated occurrences makes them a significant concern in sport. Instrumented mouthguards (iMGs) can approximate HAEs. The distinction between sensor acceleration events, the iMG datum for approximating HAEs and HAEs themselves, which have been defined as the in vivo event, is made to highlight limitations of approximating HAEs using iMGs. This article explores the technical limitations of iMGs that constrain the approximation of HAEs and discusses important conceptual considerations for stakeholders interpreting iMG data. The approximation of HAEs by sensor acceleration events is constrained by false positives and false negatives. False positives occur when a sensor acceleration event is recorded despite no (in vivo) HAE occurring, while false negatives occur when a sensor acceleration event is not recorded after an (in vivo) HAE has occurred. Various mechanisms contribute to false positives and false negatives. Video verification and post-processing algorithms offer effective means for eradicating most false positives, but mitigation for false negatives is less comprehensive. Consequently, current iMG research is likely to underestimate HAE exposures, especially at lower magnitudes. Future research should aim to mitigate false negatives, while current iMG datasets should be interpreted with consideration for false negatives when inferring athlete HAE exposure.

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.