Caffeine Gum Improves Reaction Time but Reduces Composure Versus Placebo During the Extra-Time Period of Simulated Soccer Match-Play in Male Semiprofessional Players.

This study aimed to determine whether caffeine gum influenced perceptual-cognitive and physical performance during the extra-time period of simulated soccer match-play. Semiprofessional male soccer players (n = 12, age: 22 ± 3 years, stature: 1.78 ± 0.06 m, mass: 75 ± 9 kg) performed 120-min soccer-specific exercise on two occasions. In a triple-blind, randomized, crossover design, players chewed caffeinated (200 mg; caffeine) or control (0 mg; placebo) gum for 5 min following 90 min of soccer-specific exercise. Perceptual-cognitive skills (i.e., passing accuracy, reaction time, composure, and adaptability) were assessed using a soccer-specific virtual reality simulator, collected pre- and posttrial. Neuromuscular performance (reactive-strength index, vertical jump height, absolute and relative peak power output, and negative vertical displacement) and sprint performance (15 and 30 m) were measured at pretrial, half-time, 90 min, and posttrial. Caffeine gum attenuated declines in reaction time (pre: 90.8 ± 0.8 AU to post: 90.7 ± 0.8 AU) by a further 4.2% than placebo (pre: 92.1 ± 0.8 AU to post: 88.2 ± 0.8 AU; p < .01). Caffeine gum reduced composure by 4.7% (pre: 69.1 ± 0.8 AU to post: 65.9 ± 0.8 AU) versus placebo (pre: 68.8 ± 0.8 AU to post: 68.3 ± 0.8 AU; p < .01). Caffeine gum did not influence any other variables (p > .05). Where caffeine gum is consumed by players prior to extra-time, reaction time increases but composure may be compromised, and neuromuscular and sprint performance remain unchanged. Future work should assess caffeine gum mixes with substances like L-theanine that promote a relaxed state under stressful conditions.

Development and Validation of the Combined Action Observation and Motor Imagery Ability Questionnaire.

Combined use of action observation and motor imagery (AOMI) is an increasingly popular motor-simulation intervention, which involves observing movements on video while simultaneously imagining the feeling of movement execution. Measuring and reporting participant imagery-ability characteristics are essential in motor-simulation research, but no measure of AOMI ability currently exists. Accordingly, the AOMI Ability Questionnaire (AOMI-AQ) was developed to address this gap in the literature. In Study 1, two hundred eleven participants completed the AOMI-AQ and the kinesthetic imagery subscales of the Movement Imagery Questionnaire-3 and Vividness of Motor Imagery Questionnaire-2. Following exploratory factor analysis, an 8-item AOMI-AQ was found to correlate positively with existing motor-imagery measures. In Study 2, one hundred seventy-four participants completed the AOMI-AQ for a second time after a period of 7-10 days. Results indicate a good test-retest reliability for the AOMI-AQ. The new AOMI-AQ measure provides a valid and reliable tool for researchers and practitioners wishing to assess AOMI ability.

Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that zinc finger E-box-binding homeobox 1-mediated epithelial-mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-ß-induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial-mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1-tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-ß-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor-like repeats. Together, these data identify that aberrant bidirectional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals.

CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains.

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in TB granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells.

Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells.

Cluster of differentiation 1c (CD1c)-dependent self-reactive T cells are abundant in human blood, but self-antigens presented by CD1c to the T-cell receptors of these cells are poorly understood. Here we present a crystal structure of CD1c determined at 2.4 Å revealing an extended ligand binding potential of the antigen groove and a substantially different conformation compared with known CD1c structures. Computational simulations exploring different occupancy states of the groove reenacted these different CD1c conformations and suggested cholesteryl esters (CE) and acylated steryl glycosides (ASG) as new ligand classes for CD1c. Confirming this, we show that binding of CE and ASG to CD1c enables the binding of human CD1c self-reactive T-cell receptors. Hence, human CD1c adopts different conformations dependent on ligand occupancy of its groove, with CE and ASG stabilizing CD1c conformations that provide a footprint for binding of CD1c self-reactive T-cell receptors.

A new approach to OSCE preparation - PrOSCEs.

BACKGROUND: Objectively structured clinical examinations (OSCEs) are a stressful experience for many health care students and professionals in training. Mock OSCEs have been shown to be beneficial for student OSCE preparation. However, due to their expense and administrative burden students may only get a few opportunities to partake in these. To address this gap in student preparation a series of regularly run totally peer led multi-role practice OSCEs (PrOSCEs) was developed. METHODS: Fifteen PrOSCEs were run over five-months. A total of 32 second year medical students took part, all of whom were enrolled on the graduate-entry programme at the University of Southampton. In each PrOSCE, 18 participants rotated through the roles of 'student', 'examiner' and 'patient' in six simulated stations designed by their peers. Peer feedback was provided after each station. At the end of the series of PrOSCEs students were asked to fill in an anonymous online feedback survey to assess the usefulness of the PrOSCEs in exam preparation. RESULTS: Twenty-two students responded to the survey. 100% of respondents deemed routine participation either 'very useful' or 'useful' in preparing for their exam. PrOSCEs were found to improve confidence (mean = 7.9/10, 95% CI 7.4-8.3), expected performance (mean = 7.5/10, 95% CI 6.8-8.2) and help guide revision (mean = 8.3/10, 95% CI 7.6-9.0). Self-perceived teaching performance and confidence in providing feedback was also positively associated with participation. The most beneficial roles were 'student' and 'station creator'. Free-text feedback suggests that the informal setting and regular practice were particularly beneficial. CONCLUSION: The peer-led nature of the PrOSCEs allows for a low cost, low administrative burden and easy to replicate adjunct or alternative to large scale mock OSCEs. In addition the multi-role aspect of this approach could enhance exam preparation and may also improve aptitude as a clinical teacher. Further studies are required to understand if repeated practice has beneficial implications on OSCE performance.

Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Tracking and responding to an outbreak of tuberculosis using MIRU-VNTR genotyping and whole genome sequencing as epidemiological tools.

Background: We describe an outbreak that contributed to a near doubling of the incidence of tuberculosis in Southampton, UK. We examine the importance of 24 locus mycobacterial interspersed repetitive unit variable number tandem repeat (MIRU-VNTR) genotyping in its identification and management and the role of whole genome sequencing (WGS) in tracing the spread of the strain. Methods: Outbreak cases were defined as those diagnosed between January and December 2011 with indistinguishable 24 locus-MIRU-VNTR genotypes or, cases linked epidemiologically. A cluster questionnaire was administered by TB nurses to identify contacts and social settings. Results: Overall, 25 patients fulfilled the case definition. No cases with this MIRU-VNTR genotype had been detected in the UK previously. Connections were found between all cases through household contacts or social venues including a football club, Internet cafe and barber's shop. Public health actions included extended contact tracing, venue screening and TB awareness-raising. The outbreak resulted in a high rate of transmission and high incidence of clinical disease among contacts. Conclusions: This outbreak illustrates the value of combining active case-finding with prospective MIRU-VNTR genotyping to identify settings to undertake public health action. In addition WGS revealed that the VNTR-defined cluster was a single outbreak and that active TB transmission not reactivation was responsible for this outbreak in non-UK born individuals.

Corticosteroids and infliximab impair the performance of interferon-γ release assays used for diagnosis of latent tuberculosis.

The impact of immunosuppression on interferon-γ release assays and novel cytokine biomarkers of TB infection, mycobacteria-specific IL-2, IP-10 and TNF-α responses was investigated in an ex vivo model. Cytokine responses in standard QuantiFERON-TB Gold in-Tube (QFT-GIT) assays were compared with duplicate assays containing dexamethasone or infliximab. Dexamethasone converted QFT-GIT results from positive to negative in 30% of participants. Antigen-stimulated interferon-γ, IL-2 and TNF-α responses were markedly reduced, but IP-10 responses were preserved. Infliximab caused QFT-GIT result conversion in up to 30% of participants and substantial reductions in all cytokine responses. Therefore, corticosteroids and anti-TNF-α agents significantly impair interferon-γ release assay performance. IP-10 may be a more robust TB biomarker than interferon-γ in patients receiving corticosteroids.

'The worm that got away': parainfectious atypical optic neuritis associated with schistosomiasis infection.

Although optic neuritis is commonly associated with multiple sclerosis, patients with atypical optic neuritis require further investigations to exclude other associated conditions. We report a woman presenting with cough, fatigue, atypical optic neuritis with chiasmitis. She responded partially to corticosteroids and we subsequently found she had a ground-glass lung nodule. Follow-up CT scan of thorax at 12 months showed new parenchymal lung lesions that suggested schistosomiasis. Further questioning by a respiratory physician identified, in retrospect, a previous exposure history; serological testing confirmed schistosoma infection. She was treated with praziquantel and slowly improved clinically, with radiological improvement in the optic chiasm, regression of the parenchymal lung lesions but with the ground glass nodule unchanged. We diagnosed parainfectious optic neuritis associated with schistosomiasis, based upon exposure history, serological confirmation and radiological features, together with the response to treatment, and having excluded other causes of an atypical optic neuritis.

Extremes of age are associated with indeterminate QuantiFERON-TB gold assay results.

Results from 3,263 QuantiFERON-TB Gold in-tube (QFT-GIT) assays were analyzed to determine the impact of age on test performance. The proportion of indeterminate results was significantly higher in pediatric and elderly (9.1% and 7.4%, respectively) than in adult (2.6%; chi-square test, P < 0.0001) patients. A detailed analysis of indeterminate QFT-GIT assay results is presented.

LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis.

The factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signalling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells inhibits autophagy and induces EMT as a consequence. In IPF lungs, this is caused by downregulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and MRC5 lung fibroblasts coupled with RNA sequencing (RNA-seq) confirmed that paracrine signalling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

Soccer heading immediately alters brain function and brain-muscle communication.

Introduction: There is growing evidence of a link between repetitive soccer heading and the increased incidence of neurodegenerative disease. Even a short bout of soccer heading has been shown to impair cognitive performance and disrupt movement control. However, a greater understanding of the mechanisms behind these immediate impairments is needed. The current study attempted to identify how a short bout of soccer heading alters brain function and brain-muscle communication during a movement task. Methods: Sixty soccer players were exposed to either an acute bout (i.e., 20 balls thrown underarm) of soccer heading (n = 30) or a control condition where participants (n = 30) headed soccer balls in virtual reality (VR). Before and after heading, we measured cognitive performance on the King-Devick test, as well as electromyography (EMG), electroencephalography (EEG) and brain-muscle communication (i.e., corticomuscular coherence; CMC) during a force precision task. Results: Following the heading protocol, the VR group improved their cognitive performance whereas the Heading group showed no change. Both groups displayed more precise force contractions at post-test. However, the VR group displayed elevated frontal theta activity and global increases in alpha and beta activity during the contraction task, whereas the Heading group did not. Contrary to our expectations, the Heading group displayed elevated CMC, whereas the VR group showed no change. Discussion: Our findings indicate a short bout of soccer heading may impair cognitive function and disrupt the organization of efficient neural processes that typically accompany motor skill proficiency. Soccer heading also induced corticomuscular hyperconnectivity, which could represent compensatory brain-muscle communication and an inefficient allocation of increased task-related neuromuscular resources. These initial findings offer insights to the mechanisms behind the impairments experienced after a short bout of repetitive soccer heading.

A Qualitative Study of Medical Students' Perspectives on Distance Learning During COVID-19.

Introduction: With the Coronavirus disease 2019 [COVID-19] pandemic, changes were undertaken out of necessity to allow medical students to continue their education. The aim of this study is to create key themes for educators to consider when implementing distance learning strategies into the curriculum based on 2nd year graduate entry medical students experience of learning and engagement with the use of distance learning during the COVID-19 pandemic. Materials and Methods: A qualitative study with a phenomenological methodology was set within a constructivist paradigm. A volunteer sampling strategy was used to recruit participants. Nine semi-structured, audio-recorded interviews were undertaken and transcribed verbatim. A thematic analysis was undertaken of the transcripts using the Braun and Clarke framework with an open-coded approach. Results: Exploration of the student experience generated an understanding of the learning process. The concept of adaptability emerged based on the themes of technology, environment, study skills and human interaction. Discussion: Necessary changes to the formal curriculum affected medical students learning and experience that demanded adaptability. The 'new normal' generated a context within which students were communicating and interacting in ways creating individual challenges for students and educators. Conclusion: With the advancements in information, communication and technology, distance learning is likely to be further incorporated in undergraduate training long term. Its position should be one that is harmonious within the wider educational realm that engages and meets the needs of the students. The rich understanding exposes adaptations and considerations for educators to improve the student experience.

Combined action observation and motor imagery improves learning of activities of daily living in children with Developmental Coordination Disorder.

Developmental coordination disorder (DCD) is characterised by poor motor coordination, which interferes with the ability to execute activities of daily living (ADLs). Combined action observation and motor imagery (AOMI) involves observing movement videos whilst imagining simultaneously the sensations of executing the same movement. Laboratory-based research indicates that AOMI can help improve movement coordination in children with DCD, but no previous research had investigated the efficacy of AOMI interventions for learning ADLs. This study investigated the efficacy of a home-based, parent-led, AOMI intervention for learning ADLs in children with DCD. Children with confirmed (n = 23) or suspected (n = 5) DCD (total sample n = 28), aged 7-12 years, were assigned to either an AOMI intervention or a control intervention (both n = 14). Participants attempted the following ADLs at pre-test (week 1), post-test (week 4), and retention test (week 6): shoelace tying, cutlery use, shirt buttoning, and cup stacking. Task completion times and movement techniques were recorded. The AOMI intervention produced significantly faster task completion times than the control intervention at post-test for shoelace tying, and significantly improved movement techniques for shoelace tying and cup stacking. Importantly, for children who could not tie shoelaces at pre-test (n = 9 per group), 89% of those following the AOMI intervention learnt the skill successfully by the end of the study, compared to only 44% of those following the control intervention. The findings indicate that home-based, parent-led, AOMI interventions can aid the learning of complex ADLs in children with DCD, and may be particularly effective for facilitating the learning of motor skills that do not currently exist within these children's motor repertoire.

A tool for measuring mental workload during prosthesis use: The Prosthesis Task Load Index (PROS-TLX).

When using a upper-limb prosthesis, mental, emotional, and physical effort is often experienced. These have been linked to high rates of device dissatisfaction and rejection. Therefore, understanding and quantifying the complex nature of workload experienced when using, or learning to use, a upper-limb prosthesis has practical and clinical importance for researchers and applied professionals. The aim of this paper was to design and validate a self-report measure of mental workload specific to prosthesis use (The Prosthesis Task Load Index; PROS-TLX) that encapsulates the array of mental, physical, and emotional demands often experienced by users of these devices. We first surveyed upper-limb prosthetic limb users who confirmed the importance of eight workload constructs taken from published literature and previous workload measures. These constructs were mental demands, physical demands, visual demands, conscious processing, frustration, situational stress, time pressure and device uncertainty. To validate the importance of these constructs during initial prosthesis learning, we then asked able-bodied participants to complete a coin-placement task using their anatomical hand and then using a myoelectric prosthesis simulator under low and high mental workload. As expected, using a prosthetic hand resulted in slower movements, more errors, and a greater tendency to visually fixate the hand (indexed using eye-tracking equipment). These changes in performance were accompanied by significant increases in PROS-TLX workload subscales. The scale was also found to have good convergent and divergent validity. Further work is required to validate whether the PROS-TLX can provide meaningful clinical insights to the workload experienced by clinical users of prosthetic devices.

Genetic and geographic influence on phenotypic variation in European sarcoidosis patients.

Introduction: Sarcoidosis is a highly variable disease in terms of organ involvement, type of onset and course. Associations of genetic polymorphisms with sarcoidosis phenotypes have been observed and suggest genetic signatures. Methods: After obtaining a positive vote of the competent ethics committee we genotyped 1909 patients of the deeply phenotyped Genetic-Phenotype Relationship in Sarcoidosis (GenPhenReSa) cohort of 31 European centers in 12 countries with 116 potentially disease-relevant single-nucleotide polymorphisms (SNPs). Using a meta-analysis, we investigated the association of relevant phenotypes (acute vs. sub-acute onset, phenotypes of organ involvement, specific organ involvements, and specific symptoms) with genetic markers. Subgroups were built on the basis of geographical, clinical and hospital provision considerations. Results: In the meta-analysis of the full cohort, there was no significant genetic association with any considered phenotype after correcting for multiple testing. In the largest sub-cohort (Serbia), we confirmed the known association of acute onset with TNF and reported a new association of acute onset an HLA polymorphism. Multi-locus models with sets of three SNPs in different genes showed strong associations with the acute onset phenotype in Serbia and Lublin (Poland) demonstrating potential region-specific genetic links with clinical features, including recently described phenotypes of organ involvement. Discussion: The observed associations between genetic variants and sarcoidosis phenotypes in subgroups suggest that gene-environment-interactions may influence the clinical phenotype. In addition, we show that two different sets of genetic variants are permissive for the same phenotype of acute disease only in two geographic subcohorts pointing to interactions of genetic signatures with different local environmental factors. Our results represent an important step towards understanding the genetic architecture of sarcoidosis.