Prospective cohort study of long-term neurological outcomes in retired elite athletes: the Advanced BiomaRker, Advanced Imaging and Neurocognitive (BRAIN) Health Study protocol.

INTRODUCTION: Although limited, recent research suggests that contact sport participation might have an adverse long-term effect on brain health. Further work is required to determine whether this includes an increased risk of neurodegenerative disease and/or subsequent changes in cognition and behaviour. The Advanced BiomaRker, Advanced Imaging and Neurocognitive Health Study will prospectively examine the neurological, psychiatric, psychological and general health of retired elite-level rugby union and association football/soccer players. METHODS AND ANALYSIS: 400 retired athletes will be recruited (200 rugby union and 200 association football players, male and female). Athletes will undergo a detailed clinical assessment, advanced neuroimaging, blood testing for a range of brain health outcomes and neuropsychological assessment longitudinally. Follow-up assessments will be completed at 2 and 4 years after baseline visit. 60 healthy volunteers will be recruited and undergo an aligned assessment protocol including advanced neuroimaging, blood testing and neuropsychological assessment. We will describe the previous exposure to head injuries across the cohort and investigate relationships between biomarkers of brain injury and clinical outcomes including cognitive performance, clinical diagnoses and psychiatric symptom burden. ETHICS AND DISSEMINATION: Relevant ethical approvals have been granted by the Camberwell St Giles Research Ethics Committee (Ref: 17/LO/2066). The study findings will be disseminated through manuscripts in clinical/academic journals, presentations at professional conferences and through participant and stakeholder communications.

Generation of the NeoThy mouse model for human immune system studies.

Humanized mouse models, created via transplantation of human hematopoietic tissues into immune-deficient mice, support a number of research applications, including transplantation immunology, virology and oncology studies. As an alternative to the bone marrow, liver, thymus humanized mouse, which uses fetal tissues for generating a chimeric human immune system, the NeoThy humanized mouse uses nonfetal tissue sources. Specifically, the NeoThy model incorporates hematopoietic stem and progenitor cells from umbilical cord blood (UCB) as well as thymus tissue that is typically discarded as medical waste during neonatal cardiac surgeries. Compared with fetal thymus tissue, the abundant quantity of neonatal thymus tissue offers the opportunity to prepare over 1,000 NeoThy mice from an individual thymus donor. Here we describe a protocol for processing of the neonatal tissues (thymus and UCB) and hematopoietic stem and progenitor cell separation, human leukocyte antigen typing and matching of allogenic thymus and UCB tissues, creation of NeoThy mice, assessment of human immune cell reconstitution and all experimental steps from planning and design to data analysis. This entire protocol takes a total of ~19 h to complete, with steps broken up into multiple sessions of 4 h or less that can be paused and completed over multiple days. The protocol can be completed, after practice, by individuals with intermediate laboratory and animal handling skills, enabling researchers to make effective use of this promising in vivo model of human immune function.

Sporadic Metastatic Malignant Peripheral Nerve Sheath Tumour with an NF1 Mutation Responding to Trametinib: A Case Report.

Sporadically occurring malignant peripheral nerve sheath tumours (MPNSTs) can have a variety of genomic alterations including altered NF1, leading to activation of the RAS-RAF-MEK-ERK signalling pathway. Trametinib is an inhibitor of MEK1 and MEK2. Here we present a case of a patient diagnosed with sporadic MPNST with an identified NF1 gene treated successfully with trametinib.

The influence of match exposure on injury risk in elite men's rugby union.

OBJECTIVES: To investigate the influence of previous season match exposure on injury incidence and burden in elite men's rugby union. DESIGN: A three-season (2016-17 to 2018-19) retrospective cohort design was used to collect and analyse injury and exposure data across English Premiership rugby union teams. METHODS: Generalised linear mixed-effects models were used to model the influence of match exposure (all match involvements, match involvements of ≥20 mins, and full-game equivalents) upon match and training injury incidence and burden in the following season. RESULTS: Involvement in ≥31 matches within a season was associated with substantially increased match and training injury burden in the following season. Match exposure was not clearly associated with injury incidence in the following season. The increased match injury burden associated with higher match involvements appeared to be driven by an increased risk for older (>26 y) Forwards, whilst the increased training injury burden associated with higher match involvements appeared to be driven by an increased risk for older (>26 y) Backs. CONCLUSIONS: The present study demonstrates that all match involvements, regardless of duration, should be considered when exploring associations between match exposure and injury risk. High match involvements (≥ 31 matches) are associated with elevated injury burden, in both matches and training, in the following season. The physical and psychological load of players with high previous-season match exposure should be carefully managed.

Development of a distributed international patient data registry for hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand access to patients across the globe. This international PDR will enable researchers to study outcomes in HCL in ways not previously possible due to the rarity of the disease and will serve as a platform for future prospective research.

Concussion and long-term cognitive function among rugby players-The BRAIN Study.

OBJECTIVE: The BRAIN Study was established to assess the associations between self-reported concussions and cognitive function among retired rugby players. METHODS: Former elite-level male rugby union players (50+ years) in England were recruited. Exposure to rugby-related concussion was collected using the BRAIN-Q tool. The primary outcome measure was the Preclinical Alzheimer Cognitive Composite (PACC). Linear regressions were conducted for the association between concussion and PACC score, adjusting for confounders. RESULTS: A total of 146 participants were recruited. The mean (standard deviation) length of playing career was 15.8 (5.4) years. A total of 79.5% reported rugby-related concussion(s). No association was found between concussion and PACC (ß -0.03 [95% confidence interval (CI): -1.31, 0.26]). However, participants aged 80+ years reporting 3+ concussions had worse cognitive function than those without concussion (ß -1.04 [95% CI: -1.62, -0.47]). CONCLUSIONS: Overall there was no association between concussion and cognitive function; however, a significant interaction with age revealed an association in older participants.

Trends in match concussion incidence and return-to-play time in male professional Rugby Union: A 16-season prospective cohort study.

AIM: To describe trends in the incidence of match concussions and time to return-to-play in professional rugby union. METHODS: Match concussion incidence (injuries per 1000 player-match-hours) and time to return-to-play (mean and median days absence) were recorded in 3006 male professional rugby union players over 16 seasons (2002/03 - 2018/19). RESULTS: From 2002/03 to 2009/10, incidence of concussions was stable at 4.3/1000 player-match-hours. From 2009/10 to 2018/19, there was an increase in concussion incidence, with the highest incidence in 2016/17 at 20.9/1000 player-match-hours (95% CI: 17.9-24.3). Annual prevalence of concussion also increased, suggesting more players were concussed rather than the same players sustaining more concussions. Before the introduction of standardized graduated return-to-play (GRTP) guidelines in 2011, 27% of players returned to play in <6 days. After the introduction of the GRTP, this decreased to 7%, with no players returning in <6 days after 2014/15. Between 2002/03 and 2018/19, incidence of all other injuries remained stable. CONCLUSIONS: From 2009/10 onwards, the incidence of diagnosed concussions increased. Since the introduction of the GRTP, there has been a dramatic reduction in the number of players returning in <6 days.

Hairy cell leukemia and COVID-19 adaptation of treatment guidelines.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Measuring Psychological Load in Sport.

Monitoring the physical load undertaken by athletes and examining the subsequent relationship with performance and injury and illness risk is common practice in high performance sport. Less attention has been paid to the psychological factors contributing to the overall load experienced and the impact upon health status and performance. This paper discusses considerations for the conceptualization and measurement of psychological load in sport. First, we outline the importance of ensuring conceptual clarity is adopted in the measurement of psychological load. Next, we discuss the challenges to measuring psychological load in a comparable manner to which physical load is currently evaluated, including use of subjective assessment, adoption of specific and global approaches, and development of measurement instrumentation, techniques, and expertise. We then offer recommendations for practitioners when undertaking assessment of psychological load in sport. We conclude with future research directions to advance the study and measurement of the construct, including the interaction between psychological and physical load, the appraisal of the load faced, and personal and social resources available to successfully cope. We also highlight the need to consider groups of athletes (e. g., transitioning athlete, long-term injured) at greater risk from threats to mental and physical health from increased psychological load.

Robotic surgery for colorectal cancer in the Octogenarians.

BACKGROUND: We evaluated the short-term outcomes of robotic colorectal cancer surgery in octogenarian patients, focussing on postoperative morbidity and survival. METHODS: All patients ≥80 years in a prospective colorectal cancer database undergoing robotic curative colorectal cancer resection were included. Patient demographics, intraoperative findings, postoperative and oncological outcomes were recorded. Patients were further subdivided into two groups named: old (OG 80-85 years) and very old (VOG ≥ 86 years). RESULTS: Fifty-eight consecutive patients were included (median age, 83 years; male, 53.4%; median BMI, 26.5). Median total operative time was 230 min, median blood loss 20 ml, median length of stay 7 days. Major complications were seen in 12% of patients; and the 90-day mortality rate was 1.7%. Complete R0 resection achieved in 93% of cases, average lymph node harvest was 22. Overall and disease-free survival was 81% and 87.3%, respectively (median follow-up 24.5 months). We noticed a trend towards more advanced lesion staging in the VOG, but only N2 stage was significant (p = 0.03). There was a statistically significant difference in overall survival in favour of the OG (p = 0.024). CONCLUSIONS: Robotic surgery is feasible in octogenarian patients undergoing curative colorectal cancer resection and is associated with good post-operative outcomes and overall survival.

Unique diagnostic signatures of concussion in the saliva of male athletes: the Study of Concussion in Rugby Union through MicroRNAs (SCRUM).

OBJECTIVE: To investigate the role of salivary small non-coding RNAs (sncRNAs) in the diagnosis of sport-related concussion. METHODS: Saliva was obtained from male professional players in the top two tiers of England's elite rugby union competition across two seasons (2017-2019). Samples were collected preseason from 1028 players, and during standardised head injury assessments (HIAs) at three time points (in-game, post-game, and 36-48 hours post-game) from 156 of these. Samples were also collected from controls (102 uninjured players and 66 players sustaining a musculoskeletal injury). Diagnostic sncRNAs were identified with next generation sequencing and validated using quantitative PCR in 702 samples. A predictive logistic regression model was built on 2017-2018 data (training dataset) and prospectively validated the following season (test dataset). RESULTS: The HIA process confirmed concussion in 106 players (HIA+) and excluded this in 50 (HIA-). 32 sncRNAs were significantly differentially expressed across these two groups, with let-7f-5p showing the highest area under the curve (AUC) at 36-48 hours. Additionally, a combined panel of 14 sncRNAs (let-7a-5p, miR-143-3p, miR-103a-3p, miR-34b-3p, RNU6-7, RNU6-45, Snora57, snoU13.120, tRNA18Arg-CCT, U6-168, U6-428, U6-1249, Uco22cjg1,YRNA_255) could differentiate concussed subjects from all other groups, including players who were HIA- and controls, immediately after the game (AUC 0.91, 95% CI 0.81 to 1) and 36-48 hours later (AUC 0.94, 95% CI 0.86 to 1). When prospectively tested, the panel confirmed high predictive accuracy (AUC 0.96, 95% CI 0.92 to 1 post-game and AUC 0.93, 95% CI 0.86 to 1 at 36-48 hours). CONCLUSIONS: SCRUM, a large prospective observational study of non-invasive concussion biomarkers, has identified unique signatures of concussion in saliva of male athletes diagnosed with concussion.

Padded Headgear does not Reduce the Incidence of Match Concussions in Professional Men's Rugby Union: A Case-control Study of 417 Cases.

Concussion is the most common match injury in rugby union. Some players wear padded headgear, but whether this protects against concussion is unclear. In professional male rugby union players, we examined: (i) the association between the use of headgear and match concussion injury incidence, and (ii) whether wearing headgear influenced time to return to play following concussion. Using a nested case-control within a cohort study, four seasons (2013-2017) of injury data from 1117 players at the highest level of rugby union in England were included. Cases were physician-diagnosed concussion injuries. Controls were other contact injuries (excluding all head injuries). We determined headgear use by viewing video footage. Sixteen percent of cases and controls wore headgear. Headgear use had no significant effect on concussion injury incidence (adjusted odds ratio=1.05, 95% CI: 0.71-1.56). Median number of days absent for concussion whilst wearing headgear was 8 days, compared with 7 days without headgear. Having sustained a concussion in the current or previous season increased the odds of concussion more than four-fold (odds ratio=4.55, 95% CI: 3.77-5.49). Wearing headgear was not associated with lower odds of concussions or a reduced number of days' absence following a concussion.

SARS-CoV-2 transmission during rugby league matches: do players become infected after participating with SARS-CoV-2 positive players?

OBJECTIVES: To examine the interactions between SARS-CoV-2 positive players and other players during rugby league matches and determine within-match SARS-CoV-2 transmission risk. METHODS: Four Super League matches in which SARS-CoV-2 positive players were subsequently found to have participated were analysed. Players were identified as increased-risk contacts, and player interactions and proximities were analysed by video footage and global positioning system (GPS) data. The primary outcome was new positive cases of SARS-CoV-2 within 14 days of the match in increased-risk contacts and other players participating in the matches. RESULTS: Out of 136 total players, there were 8 SARS-CoV-2 positive players, 28 players identified as increased-risk contacts and 100 other players in the matches. Increased-risk contacts and other players were involved in 11.4±9.0 (maximum 32) and 4.0±5.2 (maximum 23) tackles, respectively. From GPS data, increased-risk contacts and other players were within 2 m of SARS-CoV-2 positive players on 10.4±18.0 (maximum 88) and 12.5±20.7 (maximum 121) occasions, totalling 65.7±137.7 (maximum 689) and 89.5±169.4 (maximum 1003) s, respectively. Within 14 days of the match, one increased-risk contact and five players returned positive SARS-CoV-2 reverse transcriptase PCR (RT-PCR) tests, and 27 increased-risk contacts and 95 other participants returned negative SARS-CoV-2 RT-PCR tests. Positive cases were most likely traced to social interactions, car sharing and wider community transmission and not linked to in-match transmission. CONCLUSION: Despite tackle involvements and close proximity interactions with SARS-CoV-2 positive players, in-match SARS-CoV-2 transmission was not confirmed. While larger datasets are needed, these findings suggest rugby presents a lower risk of viral transmission than previously predicted.

TISSUE CHANGES OBSERVED IN EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA) FOLLOWING A PRESCRIBED FIRE.

Necropsies were performed on five eastern box turtles (Terrapene carolina carolina), found in an area recently subjected to an early-season prescribed fire, to determine whether mortality was burn related. External injuries primarily consisted of burns to exposed extremities and carapacial scutes which ranged from two burned scales to >80% of the shell. Internally, there was no evidence of smoke inhalation, but multiorgan and multifocal inflammation may have contributed to mortality.

Whole body-diffusion weighted imaging for the assessment of treatment response in hairy cell leukaemia: A positive first step.

We present the case of a patient diagnosed with hairy cell leukaemia (HCL) who subsequently developed biopsy confirmed bone lesions and underwent multiple lines of therapy. The reported incidence of bone lesions in HCL is 3%, and bony involvement can be associated with high tumour burden and aggressive disease. The commonly lytic bone lesions in HCL are difficult to accurately assess for response. Whole body diffusion weighted imaging (WB-DWI) has been used clinically in multiple myeloma; we postulate clinical utility in HCL, where hypercellularity also applies. In our case, WB-DWI appears to discriminate sites of active disease from bone response. We present the salient radiological and pathological images. To our knowledge, this is the first description of WB-DWI in HCL; we support research of WB-DWI in the staging, prognostication and response assessment of HCL.

Lower limb force-production capacities in alpine skiing disciplines.

Specific force capacities might be a limiting factor for alpine skiing performance, yet there is little consensus on the capabilities in question, and whether they differ between disciplines. We aimed to test discipline (speed and technical) and performance (event-specific world standing) effects on lower limb force-production qualities. National-level skiers (N = 31) performed loaded squat jumps and isometric mid-thigh pulls to detect dynamic force output at extremely low and high velocities and maximum isometric force and rate of force development, respectively. Discipline differences were assessed via a general linear model including performance and allowing for interaction effects, with performance associations further characterized via distinct Pearson's correlations. Jump height did not differentiate disciplines, with absolute power slightly higher in speed athletes (F(1,27)  = 4.42, P = .045, ω2  = 0.10), and neither variables were related to performance. Speed athletes possessed greater dynamic force at low velocities (F0 ; F(1,27)  = 13.8, P < .001, ω2  = 0.17), and greater relative and absolute maximum isometric force (F(1,25)  = 11.19-20.70, ω2  = 0.16-0.22, P < .003). Overall, higher ranked athletes possessed more force-dominant profiles (F(1,27)  = 16.28, ω2  = 0.34; r = 0.60 to 0.67, P < .001) and increased rate of force development characteristics (average and maximum, r = -0.50 to -0.82, P < .048). Very robust associations existed between maximum isometric force and speed performance (r = -0.88, P < .001), but only a trend for higher absolute isometric force in technical athletes (r = -0.49, P = .052). Alpine skiers display a preponderance for dynamic force output at low velocities, and isometric force for speed athletes, which highlights the interest in specific assessment and conditioning practices for ski athletes.

Training Load and Injury Risk in Elite Rugby Union: The Largest Investigation to Date.

Training load monitoring has grown in recent years with the acute:chronic workload ratio (ACWR) widely used to aggregate data to inform decision-making on injury risk. Several methods have been described to calculate the ACWR and numerous methodological issues have been raised. Therefore, this study examined the relationship between the ACWR and injury in a sample of 696 players from 13 professional rugby clubs over two seasons for 1718 injuries of all types and a further analysis of 383 soft tissue injuries specifically. Of the 192 comparisons undertaken for both injury groups, 40% (all injury) and 31% (soft tissue injury) were significant. Furthermore, there appeared to be no calculation method that consistently demonstrated a relationship with injury. Some calculation methods supported previous work for a "sweet spot" in injury risk, while a substantial number of methods displayed no such relationship. This study is the largest to date to have investigated the relationship between the ACWR and injury risk and demonstrates that there appears to be no consistent association between the two. This suggests that alternative methods of training load aggregation may provide more useful information, but these should be considered in the wider context of other established risk factors.