AIM:Indoles are tryptophan (Trp)-derived metabolites that are produced by the gut microbiota and may influence the gut-microbiota-brain axis in multiple sclerosis (MS). Indole-3-lactate (ILA) is reduced in persons with MS and improves MS clinical scores in animal models via its anti-inflammatory remyelinating properties. The ILA/indole-3-acetate (IAA) (ILA/AA) index is considered a neuroprotection index. Physical exercise and diet can modify gut microbiota and indole metabolism. METHODS:This secondary analysis of a randomized control trial aimed to assess the effects of acute and chronic exercise on serum indoles in relapsing-remitting MS (RRMS). Thirty-one RRMS patients (≥ 70% session attendance) completed a 10 week multimodal functional training (60 min, 3×/week) vs. a waitlist control group. Blood samples were collected at baseline and compared to a matched healthy control group, and after 10 weeks for the assessment of chronic effects. Additionally, acute effects of a single bout of exercise were assessed with a blood sample before, during, and immediately after one interim training session. Serum indole concentrations were measured using LC-MS/MS. RESULTS:Baseline indole levels in RRMS patients differed from those of matched healthy controls, and reduced ILA levels were observed. The 10 week intervention increased the ILA/IAA index, while a single exercise bout induced an increase in both ILA and ILA/IAA. CONCLUSION:Multimodal functional training over 10 weeks led to an improved ILA/IAA index suggesting a neuroprotective shift in gut microbiota composition, and a single bout acutely increases the circulating level of ILA. STUDY REGISTRATION NUMBER:DRKS00017091.

This study examines enablers and barriers to integrating biological maturation into talent identification and development processes within German football academies. Biological maturation significantly influences physical performance, selection decisions, and injury risk in youth football. Early maturing players are often favoured during talent identification, leading to premature deselection of talented late-maturing athletes. Using the COM-B framework (Capability, Opportunity, Motivation - Behaviour), we investigated stakeholders perceived barriers and enablers to implementing maturation strategies. An adapted COM-B-Qv1 questionnaire was distributed to 990 stakeholders across 56 elite academies and 344 regional training centres (June - July 2025), yielding 142 complete responses (14.3% completion rate). Internal consistency of the adapted scales was acceptable to good (Cronbach's α = 0.67-0.84). Results showed that 78% of participants conduct maturation assessments, while 24% rarely or never considered it in player development and 51% did so only occasionally. Regional-affiliated stakeholders reported significantly higher barriers than league-affiliated participants (p < 0.05). Opportunity, expressed through the perceived lack of tools, time, and incentives, emerged as the strongest barrier (mean = 3.38 ± 1.30). These findings suggest that targeted training, enablement, and environmental restructuring may be particularly effective for improving the systematic integration of biological maturation in German football academies, especially in regional settings.

Elite football clubs rely heavily on medical and performance units to optimise players' health care and performance. Despite their growing importance, little is known about how these departments are structured and managed. This study investigates the organisational structure and operational processes within medical and performance departments in elite European football clubs. An online survey was distributed to 193 professional football clubs in 29 European countries, with 66 complete responses (34% response rate). Descriptive quantitative analyses and descriptive analyses of open-ended items explored leadership models, communication, data management, and return-to-play (RTP) procedures. Organisational structures varied, with flat (30%), functional (21%), and matrix (23%) models most common. Regional differences in leadership configurations were observed, though not statistically significant between European regions. Most departments reported to a Sports Director (42%) and operated with established communication pathways, with 89% agreeing that information was effectively transferred. Data were primarily stored centrally within the medical department or the club. Return-to-play practices almost exclusively followed a phased model, with physiotherapists central across all stages. Team doctors were heavily involved in early stages but less so during return to performance, where sport scientists and rehab coaches became more prominent reflecting current multidisciplinary RTP frameworks. High levels of external engagement (91%) and research involvement (62%) highlight a growing emphasis on evidence-based practice. These findings describe substantial structural heterogeneity and increasing professionalisation of medical and performance departments in European elite football. Regional variability and differences in leadership, data management, and decision-making processes warrant further investigation rather than direct comparison.

In vitro modelling of distinct chamber-specific human cardiac physiology is crucial for predictive drug safety and translational pharmacology. Existing models, though powerful seem to lack scalable resolution to distinguish atrial and ventricular responses and might not be compatible with high-throughput workflows, limiting their utility for next-generation preclinical testing. This study aimed to establish a scalable and flexible platform for generating high-purity atrial and ventricular induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and to validate their functional, electrophysiological, and transcriptomic identities. Our aim was to demonstrate direct integration of these models into high-throughput electrophysiology and contraction tracking assays relevant for scalable drug testing. iPSCs were differentiated into atrial and ventricular cardiomyocytes using subtype-directed differentiation protocols. iPSC-CM identity and purity were confirmed by flow cytometry and immunofluorescence microscopy (>99% cTnT-positive). Functional phenotyping included motion tracking of cardiomyocyte monolayers and three-dimensional engineered heart muscle (EHM) using the myrImager system (Synentech/myriamed). Automated patch-clamp experiments assessed sodium (INa), L-type calcium (ICa,L), and inward rectifier potassium (IK1) currents, as well as cellular membrane capacitance. Transcriptomic profiling was performed on three iPSC lines, each in three independent differentiation batches, to identify chamber-specific gene expression profiles. Both atrial and ventricular iPSC-CMs demonstrated high purity and reproducible chamber-specific differences. Atrial cells exhibited faster spontaneous contractile phenotype and shorter contraction cycles, whereas ventricular cells showed stronger and lower frequency of spontaneous contractions. Electrophysiological screening using automated patch-clamp system confirmed higher peak INa density (pA/pF) in atrial cells, while ventricular cells showed greater ICa,L, IK1, and membrane capacitance, consistent with native cardiomyocyte physiology. Transcriptomic analysis revealed distinct atrial phenotype, with enriched atrial expression of NR2F1, NR2F2, TBX5, KCNA5, KCNK3, KCNQ2, CACNA1D, HOXA3, NPPA and others. Importantly, all functional and electrophysiological assays were fully compatible with scalable high-throughput platforms, enabling direct application into drug screening workflows. Subtype-directed differentiation of iPSCs generates reproducible, chamber-specific cardiomyocytes that can be integrated with high-throughput electrophysiology and contractility assays. This scalable and flexible platform provides a human-relevant model for predictive cardiac safety assessment and pharmacological testing aligning with innovative approaches in preclinical drug development.

In elite football, injury risk is considerable, especially in the weeks after return-to-play (RTP). Consequently, optimal rehabilitation and well-informed decisions regarding the timepoint of RTP are crucial. Arguably, experiential knowledge as well as data-driven analyses may provide meaningful insights. This work leverages their synergies to identify and scrutinize promising options for reducing injury risk. A mixed-methods approach is implemented as sequential problem-solving pipeline. Semi-structured interviews were conducted with 14 experienced practitioners in elite European football. Areas of overlap in the interview data were identified by thematic analysis. Subsequently, media-based injury data was used to scrutinize expert judgement. In total 4 themes were identified concerning 1) time between index injury and RTP (rehab time), 2) rehabilitation strategy, 3) psychosocial factors, and 4) team structure. Most prominently, it was suspected that injury risk post-RTP would be lower with longer rehab times. Data analytics confirmed lower injury risk after longer rehab time (for the respective index injury diagnosis) if expressed per calendar day but not if expressed per unit of football exposure post-RTP. Hazard ratios for pooled episodes were 0.886 (0.834-0.937) for calendar time in days and 1.046 (1.005 - 1.087) for football exposure in weighted hours. Taken together, our results indicate options for improvement which are simple (at least logistically) and largely consistent with the literature. However, quantitative results don't provide direct support to the experts judgement that delaying RTP would reduce injury risk. Importantly, these findings are likely context specific and pertain only to elite players who sustained a subsequent injury.

Abstract Background Swimmers often fail to achieve recommended sleep durations. Early morning training, common in swimming, is associated with shorter sleep. Sleep extension through later wake-up times appears to be an appropriate measure to counteract this. Therefore, this study investigated whether delaying early morning training has an effect on sleep, recovery and performance, and whether changes in sleep mediate eventual effects on recovery and performance. Methods Using cross-over design, 27 national-level swimmers (13 females, 14 males; age: 15.6 ± 1.0 years) completed two 8-day training camps in January and October 2023 in Saarbrücken, Germany. Morning sessions started at 07:00 AM (early) or 09:00 AM (late), with conditions randomized between camps. Sleep and recovery were assessed using actigraphy, sleep diaries, and the Short Recovery and Stress Scale. Performance was evaluated using 100 m main stroke and 800 m freestyle time-trials pre- and post-camp. Linear mixed-effects models and repeated measures analysis of variance were employed to assess the effect of training time on sleep, recovery and performance. Regression-based mediation analysis tested whether changes in sleep and recovery mediated the effects of training timepoint on recovery and performance. Results Sleep duration per night was significantly longer in the late compared to the early condition (1.0 ± 0.5 h; t = 14.0, p < .001). However, there was no significant effect on measures of recovery ( p > .080), and 100 m and 800 m performance ( p > .204). Mediation analysis showed no indirect effects of sleep duration on mental capacity or of mental capacity on performance ( p > .05). Conclusion Delaying early morning training from 07:00 AM to 09:00 AM increased sleep duration by one hour on average, but this did not significantly affect recovery or performance in elite swimmers. Nevertheless, the study provides evidence that early morning training is associated with reduced sleep duration and highlights the persistent sleep challenges faced by adolescent swimmers. Trial registration DRKS, DRKS00039267 . Registered 17 February 2026—Retrospectively registered, https://www.drks.de/DRKS00039267 .

Background: Injuries to the upper extremity account for nearly half of the overall injury burden in professional football (soccer), with incidence rates differing across major muscle groups under both acute and overuse conditions. Importantly, they are commonly associated with an increased susceptibility to subsequent injury, especially in the weeks after return to play (RTP). However, the specific post-RTP risk trajectories after different lower-extremity muscle injuries remain insufficiently characterized. Purpose: To investigate the risk trajectory for noncontact subsequent injury after returning from major lower-extremity muscle injuries in professional football players, differentiating acute from overuse index injuries. Study Design: Descriptive epidemiology study. Methods: Prospectively collected injury data from clubs in the first and second German Bundesliga over 3 seasons (2022-2023 to 2024-2025) were used for time-to-event analysis. Index injuries (ie, injuries from which players returned to play during the study period) of interest included hamstring, quadriceps, adductor, and calf injuries. Acute and overuse index muscle injuries were analyzed separately across these locations. Noncontact time-loss subsequent injuries occurring in the same season as RTP were considered the event of interest. Built upon previously published methodology, the Kaplan-Meier survival function was used to estimate the cumulative hazard function, from which the continuous hazard function was derived. Results: During the 3 analyzed seasons, 374 acute and 304 overuse index injuries were identified at the 4 lower-extremity muscle groups. Observed noncontact subsequent-injury rates were 27.9%, 26.2%, 39.3%, and 21.2% after acute hamstring, quadriceps, adductor, and calf index injuries, respectively, and 28.1%, 27.7%, 27.2%, and 27.4% for overuse index injuries. While the time course of noncontact subsequent injury risk globally aligned with previous findings, differences between muscle groups were observed. Players returning from acute hamstring and adductor injuries showed elevated risk, which diminished within approximately 12 and 4 weeks, respectively, and leveled off thereafter. By contrast, a delayed risk peak around 3 weeks after RTP was found for overuse calf index injuries. Conclusion: This descriptive study further confirms the time-varying nature of subsequent injury risk for specific lower-extremity muscle injuries. The observed differences in risk trajectories across muscle groups highlighted the need for careful RTP decision-making based on each index injury.

Abstract The erythrocyte sedimentation rate (ESR) is one of the most widely used laboratory diagnostic parameters in the preliminary assessment of inflammation; indeed, every reader of this work has likely received an ESR assessment in their lifetime. A rapid ESR is a non-specific parameter that provides information about the inflammatory process. Although the origins of this methodology date back to antiquity, the prevailing view that ESR simply reflected particle settling of erythrocytes has recently undergone a paradigm shift: once cell aggregates form a system-spanning network, gravitational collapse of a weak and percolating gel reveals a more complex process reflecting the failure. The apparent non-specific nature of the cells and proteins involved also called into question the medical utility of ESR, at least in well-resourced environments. Here we show a new experimentally derived and physically modelled approach (“supraESR”) that enhances the value and accuracy of ESR for a variety of conditions that exhibit abnormally slow ESR (e.g., sickle cell disease, neuroacanthocytosis syndromes, chronic mountain sickness). We introduce a completely new diagnostic parameter that is based on an established and easily automated measurement method that promises low-cost screening for neuroacanthocytosis syndrome, a group of rare neurodegenerative diseases that are currently detectable only through integration of complex multimodal findings.

BACKGROUND AND OBJECTIVES:Kynurenine pathway (KP) metabolites modulate inflammatory activity and neuronal viability. The consequences of KP imbalance partly resemble the molecular mechanisms of multiple sclerosis (MS). An improved understanding of KP imbalance and its relevance in MS requires holistic approaches beyond single-metabolite investigations. Thus, we aimed to explore the presence of KP metabolite patterns in MS and to evaluate their relevance in relation to participant characteristics and clinical measures. METHODS:In this multinational cross-sectional analysis, we determined serum concentrations of KP metabolites in persons with MS and healthy individuals using targeted metabolomics (LC-MS/MS). Analyses were conducted between March 24, 2022, and August 9, 2024. The source studies were conducted in Denmark, Germany, and Switzerland. All participants were aged 18 years or older and free of acute or chronic diseases besides MS. Persons with MS had mild to moderate disease severity (Expanded Disability Status Scale [EDSS] score ≤6.5). Following the investigation of individual metabolites, we explored KP metabolite patterns using exploratory factor analysis. Associations between KP metabolite patterns and participant characteristics, MS symptoms, and MRI metrics were investigated using correlation analyses, proportional odds regression, and multiple linear regression. RESULTS:The MS cohort included 353 participants (67.1% female) with a mean (SD) age of 46.1 (12.4) years. The mean (SD) EDSS score was 3.1 (1.8). The healthy control (HC) cohort included 111 participants (53.2% female) with a mean (SD) age of 45.7 (16.6) years. Persons with MS showed 2 distinct KP metabolite patterns: an inflammation-driven neurotoxic pattern (NeuroTox) and a neuroprotective pattern (NeuroPro). Greater NeuroTox was associated with a higher EDSS score, older age, and higher body fat percentage. Greater NeuroPro was associated with a lower EDSS score and higher cardiorespiratory fitness. DISCUSSION:Using a data-driven approach, we demonstrate the presence of 2 KP metabolite patterns, NeuroTox and NeuroPro, in MS. Greater NeuroTox and lower NeuroPro were both associated with greater disease severity. Future studies need to investigate the KP metabolite patterns across the MS disability spectrum and may use comparable approaches to investigate whether KP imbalance follows similar or disease-specific patterns in diseases other than MS. TRIAL REGISTRATION INFORMATION:NCT03322761, NCT02661555, NCT04762342, NCT04356248, DRKS00017091, DRKS00031445, DRKS00028792, DRKS00029105.

Repetitive heading of the ball is a distinctive feature of professional football (soccer) and has been discussed as a potential long-term risk factor for neurodegenerative disease. Epidemiologic investigation is limited by the absence of valid methods to quantify heading exposure across a player's career. To provide a tool for estimating the heading frequency in male professional football players for epidemiological studies where detailed career histories exist but sufficient individual heading exposure data are lacking. Detailed career histories of former male football players were combined with position-specific heading rates derived from two systematic video analyses spanning multiple decades and league levels in Germany. Season-specific heading rates were estimated using natural cubic splines by position, league level, seasons, and combined with playing time to calculate cumulative exposure. Heading rates varied substantially by position and changed markedly over time. In the absence of a gold standard, the plausibility of the match-heading index was evaluated in the SoccHealth project using negative control outcomes. The cumulative heading index showed no association with negative control outcomes (body mass index and handgrip strength), while expected age-related associations remained, which may be interpreted as consistent with the index's plausibility. We present a novel match-heading index that can be combined with objective career-history data to estimate cumulative career-long match-heading exposure in former male football players. By integrating objective video-based data with detailed career histories and accounting for temporal and positional variation, this approach substantially improves exposure assessment for future epidemiologic studies of long-term neurological outcomes in football players.

The Men’s 2026 Fédération Internationale de Football Association (FIFA) Football World Cup (FWC) will take place across the USA, Mexico and Canada, with host cities spanning 4300 km east–west and 4000 km north–south. The geographical distribution exposes players to environmental challenges that can negatively impact their health and performance, including: (i) extreme heat; (ii) altitude; (iii) air pollution and seasonal allergens; and (iv) travel. FWCs have never presented this combination of extreme environmental factors. Extreme heat is expected in 14 out of the 16 host cities, with historical maximum wet-bulb globe temperatures ranging from 21 to 35 °C (mean ambient temperatures: 19.1–32.7 °C). Matches in Guadalajara (1566 m) and Mexico City (2240 m) will take place at altitude. Travel requirements and increased human activities during mega-events increase the susceptibility of players/athletes to, and risk and spread of, airborne illnesses. Changes in air pollution and allergens from players’ domestic club locations and between host cities will also impact player health. Circadian misalignment (up to 19 time zones may be crossed to reach team base camps) and travel fatigue (up to 3 time zones crossed and a 7-h in-tournament flight time) may impact players’ mental and physical health, decrementing athletic performance. Teams adopting evidence-based guidelines to mitigate the impact of these environmental challenges will be best prepared to protect player health and performance during the tournament. Therefore, this review presents the predicted environmental challenges using the best available data and models and provides evidence-based long- and short-term strategies to best mitigate their impact. Relevant clinical considerations for each challenge are also outlined.

OBJECTIVES:This review primarily aimed to compare the incidence rate of head injuries, and of sport-related concussions only, between football and rugby players, according to sex, age, level of participation, and setting. A secondary aim was to examine within-sport differences in incidence rates, considering the same independent variables. DESIGN:Systematic review and meta-analysis. METHODS:Three electronic databases (EBSCOhost, Web of Science, PubMed) were searched for studies published between 2001 and August 2025. Studies reporting the incidence of head injuries and/or sport-related concussions per 1000 h in players aged 12 years and older, were included. Four authors independently evaluated the studies' eligibility and quality. Data on head injuries and sport-related concussions were pooled in two meta-analyses. RESULTS:The search yielded 6848 results, with 43 rugby and 26 football studies included. Overall, rugby players showed significantly higher incidence rates than football players for sport-related concussions (6.8 vs. 0.3; p < 0.001), a finding consistent across subgroups (sex, age, and level of participation). Only sport-related concussion training incidence rates were not significantly different between sports (0.2 vs. 0.1). The sole significant difference in incidence rate ratios of sport-related concussions, within sports, was the match/training ratio: rugby (47; 95% confidence interval: 18-123) and football (10; 95% confidence interval: 8-13). CONCLUSION:A considerably higher rate of head injuries and sport-related concussions in rugby compared to football has been shown overall and for all investigated subgroups of the sports. This difference is most likely due to the different injury mechanisms and frequency of contact events between the two sports.

The Men’s 2026 Fédération Internationale de Football Association (FIFA) World Cup (Canada, Mexico and the USA) will expose teams to an unprecedented combination of environmental challenges (heat, altitude, air pollution, allergens and travel). Conditions will vary significantly between host cities, creating a significant threat to player health and performance. These unique stressors may require teams to adopt and adapt strategies to best protect player health and performance. A related open access Sports Medicine review outlines these environmental challenges and the evidence-based guidelines to prepare for and mitigate their effects. Motivation for the present review stems from the unique practical and logistical complexities of ‘tournament football’—especially at the expanded 2026 FIFA World Cup—alongside the limitations of previous football-facing reviews, where ‘evidence-informed practice’ is often not underpinned by football-specific research and thus limits external/ecological validity. Building on the recommendations of the main review, this partner review focuses on integrating those guidelines into practice. It aims to provide teams with a practice-compatible framework to implement evidence-based strategies to protect player health and optimise performance at the 2026 FIFA World Cup.