FactFinders for patient safety: Delaying epidural steroid injections: Infection and safe platelet cutoff.

This series of FactFinders presents a brief summary of the evidence and outlines recommendations to improve our understanding and management of patients with potential contraindications to epidural steroid injections.

Spatial transcriptomic validation of a biomimetic model of fibrosis enables re-evaluation of a therapeutic antibody targeting LOXL2.

Matrix stiffening by lysyl oxidase-like 2 (LOXL2)-mediated collagen cross-linking is proposed as a core feedforward mechanism that promotes fibrogenesis. Failure in clinical trials of simtuzumab (the humanized version of AB0023, a monoclonal antibody against human LOXL2) suggested that targeting LOXL2 may not have disease relevance; however, target engagement was not directly evaluated. We compare the spatial transcriptome of active human lung fibrogenesis sites with different human cell culture models to identify a disease-relevant model. Within the selected model, we then evaluate AB0023, identifying that it does not inhibit collagen cross-linking or reduce tissue stiffness, nor does it inhibit LOXL2 catalytic activity. In contrast, it does potently inhibit angiogenesis consistent with an alternative, non-enzymatic mechanism of action. Thus, AB0023 is anti-angiogenic but does not inhibit LOXL2 catalytic activity, collagen cross-linking, or tissue stiffening. These findings have implications for the interpretation of the lack of efficacy of simtuzumab in clinical trials of fibrotic diseases.

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.

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.

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.

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.

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 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.

Spatially resolved deconvolution of the fibrotic niche in lung fibrosis.

A defining pathological feature of human lung fibrosis is localized tissue heterogeneity, which challenges the interpretation of transcriptomic studies that typically lose spatial information. Here we investigate spatial gene expression in diagnostic tissue using digital profiling technology. We identify distinct, region-specific gene expression signatures as well as shared gene signatures. By integration with single-cell data, we spatially map the cellular composition within and distant from the fibrotic niche, demonstrating discrete changes in homeostatic and pathologic cell populations even in morphologically preserved lung, while through ligand-receptor analysis, we investigate cellular cross-talk within the fibrotic niche. We confirm findings through bioinformatic, tissue, and in vitro analyses, identifying that loss of NFKB inhibitor zeta in alveolar epithelial cells dysregulates the TGFß/IL-6 signaling axis, which may impair homeostatic responses to environmental stress. Thus, spatially resolved deconvolution advances understanding of cell composition and microenvironment in human lung fibrogenesis.

A scoping review of the application of motor learning principles to optimize myoelectric prosthetic hand control.

Although prosthetic hand rejection rates remain high, evidence suggests that effective training plays a major role in device acceptance. Receiving training early in the rehabilitation process also enhances functional prosthetic use, decreases the likelihood of developing an overreliance on the intact limb, and reduces amputation-related pain. Despite these obvious benefits, there is a current lack of evidence regarding the most effective training techniques to facilitate myoelectric prosthetic hand control, and it remains unknown whether training is effective in facilitating the acquisition and transfer of prosthetic skill. In this scoping review, we introduced and summarized key motor learning principles related to attentional focus, implicit motor learning, training eye-hand coordination, practice variability, motor imagery, and action observation, and virtual training and biofeedback. We then reviewed the existing literature that has applied these principles for training prosthetic hand control before outlining future avenues for further research. The importance of optimizing early and appropriate training cannot be overlooked. While the intuition and experience of clinicians holds enormous value, evidence-based guidelines based on well-established motor learning principles will also be crucial for training effective prosthetic hand control. While it is clear that more research is needed to form the basis of such guidelines, it is hoped that this review highlights the potential avenues for this work.

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.

Integrated transcriptomic analysis of human tuberculosis granulomas and a biomimetic model identifies therapeutic targets.

Tuberculosis (TB) is a persistent global pandemic, and standard treatment for it has not changed for 30 years. Mycobacterium tuberculosis (Mtb) has undergone prolonged coevolution with humans, and patients can control Mtb even after extensive infection, demonstrating the fine balance between protective and pathological host responses within infected granulomas. We hypothesized that whole transcriptome analysis of human TB granulomas isolated by laser capture microdissection could identify therapeutic targets, and that comparison with a noninfectious granulomatous disease, sarcoidosis, would identify disease-specific pathological mechanisms. Bioinformatic analysis of RNAseq data identified numerous shared pathways between TB and sarcoidosis lymph nodes, and also specific clusters demonstrating TB results from a dysregulated inflammatory immune response. To translate these insights, we compared 3 primary human cell culture models at the whole transcriptome level and demonstrated that the 3D collagen granuloma model most closely reflected human TB disease. We investigated shared signaling pathways with human disease and identified 12 intracellular enzymes as potential therapeutic targets. Sphingosine kinase 1 inhibition controlled Mtb growth, concurrently reducing intracellular pH in infected monocytes and suppressing inflammatory mediator secretion. Immunohistochemical staining confirmed that sphingosine kinase 1 is expressed in human lung TB granulomas, and therefore represents a host therapeutic target to improve TB outcomes.

Combined action observation and motor imagery: An intervention to combat the neural and behavioural deficits associated with developmental coordination disorder.

Action observation (AO) and motor imagery (MI) have been used separately across different populations to alleviate movement impairment. Recently these two forms of covert motor simulation have been combined (combined action observation and motor imagery; AOMI), resulting in greater neurophysiological activity in the motor system, and more favourable behavioural outcomes when compared to independent AO and MI. This review aims to outline how some of the neural deficits associated with developmental coordination disorder (DCD) are evident during AO and MI, and highlight how these motor simulation techniques have been used independently to improve motor skill learning in children in this population. The growing body of evidence indicating that AOMI is superior to the independent use of either AO and MI is then synthesised and discussed in the context of children with DCD. To conclude, recommendations to optimise the delivery of AOMI for children with DCD are provided and future avenues for research are highlighted.

Breathlessness and cough in the acute setting.

The symptom of breathlessness is well recognized as part of the presentation of a wide range of medical conditions. It can be a manifestation of a life-threatening emergency. In acute medical settings, the priority is to quickly recognize patients who are critically unwell and require emergency treatment. For these patients, rapid initial assessment and immediate treatment are essential. However, once symptoms have stabilized or in less acute settings, a more thorough assessment is required. Cough is a common respiratory symptom, often part of a symptom complex, which is troublesome for the patient. It is important to recognize worrying associated features to prompt further investigation. In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection emerged from a zoonotic source, resulting in many cases of infection, hospitalizations and deaths, and has since spread in a pandemic across every continent. A substantial percentage of patients with COVID-19 develop an acute respiratory illness requiring hospital care. Cough and acute breathlessness are two of the most prevalent symptoms in this infection; any patient presenting to an acute setting should currently be assumed to have this infection and immediately tested with a viral swab from the upper airway to guide management.

Acute Epiglottitis Due to COVID-19 Infection.

A 53-year-old man presented acutely to the Accident and Emergency department with a 2-day history of progressive odynophagia and shortness of breath. The patient had stridor at rest and acute epiglottitis was suspected. The patient was transferred urgently to theatre for intubation but due to a severely oedematous airway, this was unsuccessful and emergency tracheotomy was performed by the ENT team. Throughout admission the only positive microbiological sample was a nasopharyngeal swab for SARS-CoV-2 infection. In the absence of other positive microbiology, it is highly likely that COVID-19 was the aetiological cause of acute epiglottitis in this instance. LEARNING POINTS: COVID-19 infection is a novel disease with multiple presentations; it should be considered as a possible causative organism in patients presenting with acute epiglottitis.Due to the time delay in taking samples for microbiology and results being available, treatment should be commenced with antibiotics, nebulised adrenaline and steroids to cover bacterial infection.Presentation can occur following a delayed inflammatory response and treatment should target the organ system involved.