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Acute respiratory distress syndrome (ARDS) is a multifactorial, inflammatory lung disease with significant morbidity and mortality that predominantly requires supportive care in its management. Although initially described in adult patients, the diagnostic definitions for ARDS have evolved over time to accurately describe this disease process in pediatric and, more recently, neonatal patients. The management of ARDS in each age demographic has converged in the application of lung-protective ventilatory strategies to mitigate the primary disease process and prevent its exacerbation by limiting ventilator-induced lung injury. However, differences arise in the preferred ventilatory strategies or adjunctive pulmonary therapies used to mitigate each type of ARDS. In this review, we compare and contrast the epidemiology, common etiologies, pathophysiology, diagnostic criteria, and outcomes of ARDS across the lifespan. Additionally, we discuss in detail the different management strategies used for each subtype of ARDS and spotlight how these strategies were applied to mitigate poor outcomes during the COVID-19 pandemic. This review is geared toward both clinicians and clinician-scientists as it not only summarizes the latest information on disease pathogenesis and patient management in ARDS across the lifespan but also highlights knowledge gaps for further investigative efforts. We conclude by projecting how future studies can fill these gaps in research and what improvements may be envisioned in the management of NARDS and PARDS based on the current breadth of literature on adult ARDS treatment strategies., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To determine whether Opto-Electronic Plethysmography (OEP) can distinguish Exercise-Induced Bronchoconstriction (EIB) breathing patterns by comparing individuals with and without EIB, and between broncho-constriction and recovery. Breathing pattern was quantified in terms of regional contribution, breathing timing, and the phase between chest sub-compartments which indicates the synchronization in movement of the different sub-compartments., Methods: Individuals ( n  = 47) reporting no respiratory symptoms and no history of any respiratory disease or disorder were assumed to have a healthy breathing pattern. Of 38 participants reporting respiratory symptoms during exercise, and/or a previous diagnosis of asthma or EIB, 10 participants had a positive result to the Eucapnic Voluntary Hyperpnea test, defined as a fall of at least 10% in FEV 1 from baseline at two consecutive time points and were classified into the EIB group. OEP data was obtained from 89 markers and an 11-camera motion capture system operating at 100 Hz as follows: pre- and post-EVH challenge, and post-inhaler in participants who experienced a bronchoconstriction, and 2) for the healthy group during tidal breathing., Results: RCpRCa-Phase (upper versus lower ribcage), RCaS-Phase (lower ribcage versus shoulders), and RCpS-Phase (upper ribcage versus shoulders) differed between bronchoconstriction and rest in athletes with EIB and rest in healthy participants ( p  < 0.05), in all cases indicating greater asynchrony post-bronchoconstriction, and later movement of the abdominal ribcage (RCa) post-bronchoconstriction. RCpS-Phase was different ( p  < 0.05) between all conditions (rest, post-bronchoconstriction, and post-inhaler) in EIB., Conclusions: OEP can characterize and distinguish EIB-associated breathing patterns compared to rest and individuals without EIB at rest.

Background: Restless legs syndrome (RLS) is a sensorimotor disorder that is prevalent in chronic inflammatory conditions. RLS prevalence, risk factors, and impact on sleep in CF have not been extensively characterized to date., Methods: An initial cohort was examined, including 75 persons with CF (PwCF) and 75 control subjects, to look at the prevalence and severity of RLS. A second validation cohort of 191 PwCF was then enrolled from two CF centers to examine risk factors for RLS. A diagnosis of RLS was made according to the International RLS Study Group (IRLSSG) criteria. Sleep quality was identified using the Pittsburgh sleep quality index (PSQI). Epworth sleepiness scale (ESS) was used to measure daytime sleepiness. We then analyzed laboratory and clinical risk factors and sleep symptoms for potential risk factors for RLS., Results: In the initial cohort, 36 % of PwCF had RLS, and 9 % of these had significant RLS. In contrast, only 15 % of controls had RLS, and none had significant RLS. In the second larger validation cohort with 191 subjects, a comparable prevalence of RLS was identified. Higher hemoglobin A1c, use of SSRI/SNRI medications, worse PSQI and ESS sleep quality scores, lower lung function, and higher antibiotic usage were significantly associated with a diagnosis of RLS. By multivariate multinominal logistic regression analysis, higher HbA1c and worse PSQI global sleep quality scores were independent predictors of significant RLS., Conclusions: RLS is highly prevalent in CF. Higher HbA1c and poor sleep quality, signified by higher PSQI, were each independent predictors of RLS., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo , the surfactant protein C protein (SPC) Cre + embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre + , MyD88 floxed, were also developed. Using an established protocol, mice were intranasally instilled with ODE or saline once or daily up to 3 weeks. Mice with MyD88-deficient SPC + lung epithelial cells exhibited decreased neutrophil influx following ODE exposure once and repetitively for 1 week without modulation of classic pro-inflammatory mediators including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and neutrophil chemoattractants. This protective response was lost after 3 weeks of repetitive exposure. ODE-induced Muc5ac mucin expression at 1 week was also reduced in MyD88-deficient SPC + cells. Acute ODE-induced IL-33 was reduced in MyD88-deficient SPC + cells whereas serum IgE levels were increased at one week. In contrast, mice with inducible MyD88-deficient CCSP + airway epithelial cells demonstrated no significant difference in experimental indices following ODE exposure. Collectively, these findings suggest that MyD88-dependent signaling targeted to all airway epithelial cells plays an important role in mediating neutrophil influx and mucin production in response to acute organic dust exposures.

Introduction: Exercise-induced bronchoconstriction (EIB) is not only highly prevalent in people with asthma, but can also occur independently, particularly in athletes. Fractional exhaled nitric oxide (FeNO) is an indirect biomarker of type 2 airway inflammation that has an established role in the assessment and management of asthma. The aim was to evaluate the value of FeNO in the assessment of EIB in athletes., Method: Multicenter retrospective analysis. In total, 488 athletes (male: 76%) performed baseline FeNO, and spirometry pre- and post-indirect bronchial provocation via eucapnic voluntary hyperpnea (EVH). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for established FeNO thresholds-that is, intermediate (≥25 ppb) and high FeNO (≥40 ppb and ≥ 50 ppb)-and were evaluated against objective evidence of EIB (≥10% fall in FEV 1 ). The diagnostic accuracy of FeNO was calculated using receiver operating characteristics area under the curve (ROC-AUC)., Results: Thirty-nine percent of the athletes had a post-EVH fall in FEV 1 consistent with EIB. FeNO values ≥25 ppb, ≥40 ppb, and ≥ 50 ppb were observed in 42%, 23%, and 17% of the cohort, respectively. The sensitivity of FeNO ≥25 ppb was 55%, which decreased to 37% and 27% at ≥40 ppb and ≥ 50 ppb, respectively. The specificity of FeNO ≥25 ppb, ≥40 ppb, and ≥ 50 ppb was 66%, 86%, and 89%, respectively. The ROC-AUC for FeNO was 0.656., Conclusions: FeNO ≥40 ppb provides good specificity, that is, the ability to rule-in a diagnosis of EIB. However, due to the poor sensitivity and predictive values, FeNO should not be employed as a replacement for indirect bronchial provocation in athletes., (© 2023 The Authors. Scandinavian Journal of Medicine & Science In Sports published by John Wiley & Sons Ltd.)

Importance: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis., Methods: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms., Discussion: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options., Registration: NCT05172024., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Helen Chu reported consulting for Merck, GSK, Pfizer, Ellume, Janssen, Vindico CME, and the Bill and Melinda Gates Foundation, and receiving research support from Gates Ventures, Ellume, and Sanofi Pasteur. She also serves as a co-investigator on studies funded by Pfizer, Novavax, and GSK. Maged Costantine reported receiving grant support for work not related to RECOVER work/publications from Baxter International and Siemens Healthcare and personal consulting fees not related to this paper from Progenity, Quidel Ortho, and Siemens Healthcare. Kristine Erlandson reported research funding from Gilead Sciences and consulting payments from Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to the University of Colorado. Emily Gallagher reported consulting for Novartis, Flare Therapeutics and Seagen. Edward Gardner reported research support (clinical trials) from Gilead Sciences, ViiV Healthcare, and Cepheid. Jason Goldman reported research support from Gilead, Eli Lilly and Regeneron; grants from Gilead, Merck (BARDA); personal fees for consulting from Gilead, Eli Lilly; and non-financial support from Adaptive Biotechnologies and Labcorp/Monogram Biosciences outside the submitted work. Timothy Heinrich reported grant support from Merck Inc. and consulting fees from Roche. Rachel Hess reported serving as Data Safety Monitoring Board member for Astellas Pharmaceuticals unrelated to the current work. Leora Horwitz reported being a member of the National Academy of Medicine Committee on the Long-Term Health Effects Stemming from COVID-19 and Implications for the Social Security Administration. Priscilla Hsue reported receiving honoraria from Gilead and Merck unrelated to study topic, receiving study drug from Regeneron unrelated to study topic, and receiving a research grant from Novartis. Judith James reported OMRF has licensed her IP to Progentec Biosciences, has received grant support from Progentec Biosciences, and serves on Advisory Committees to Glaxo Smith Klein, Merck and Novartis. Arthur Kim reports providing educational materials to Clinical Care Options and UpToDate and serving on a Data Safety Monitoring board for Kintor Pharmaceuticals, Ltd. Bruce Levy reported serving as a consultant for AstraZeneca, Entrinsic Biosciences, Gossamer Bio and Nocion Therapeutics and receiving research support from Amgen, Genentech, GlaxoSmithKline, Pieris Pharmaceuticals, SRA and Sanofi unrelated to the current work. Vincent Marconi reported receiving grants from NIH during the conduct of the study and grants from NIH, Veteran Affairs, and Centers for Disease Control and Prevention; grants, personal fees, nonfinancial support, and other from Lilly and Gilead; grants and personal fees from ViiV; and nonfinancial support from Bayer outside the submitted work. Grace McComsey reported serving as consultant for Merck, Gilead, ViiV, Janssen and have received research support from Pfizer, Vanda, Genentech, Roche, Redhill and Cognivue. Torri Metz reported being a site PI and a participant in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She also reported being a site PI for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Janet Mullington reported support for investigator-initiated research by "Open Medicine Foundation and the Patient-Led Research Collaborative" Princess Ogbogu reported research support from Astrazeneca, GSK, Blueprint medical; advisory board for Astrazeneca, GSK, Sanofi, Kalvista; and consulting for Astrazeneca, GSK Sairam Parthasarathy reported research funding to Institution from Sergey Brin foundation of COVID and Long-COVID research. Michael Peluso reported consulting fees from Gilead Sciences and AstraZeneca, and service on data safety monitoring board for American Gene Technologies. Sean Quigley reported service on speaker Board for Servier, Alnylam, Agios; service on advisory board for Recordati, Alexion. Franz Rischard reported research support from NIH/NHLBI, United Therapeutics, Acceleron/Merck, Janssen, Insmed, Aerovate, and Bayer; and consulting/advisory compensation from Acceleron and Bayer. Nadine Rouphael reported being a consultant for ICON and EMMES as a safety consultant for clinical trials; service on the advisory boards for Moderna; funds to institution from Sanofi, Lilly, Merck, Quidel and Pfizer. PJ Utz reported stock ownership of Gilead and PI of biomarker studies for Pfizer STOP-PASC paxlovid trial Juan Wisnivesky received receiving consulting honorarium from Sanofi, Banook, Prospero, PPD and Atea and research grants from Sanofi, Regeneron, Axella, and Arnold Consultants., (Copyright: © 2023 Horwitz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

There is no gold standard diagnostic method for breathing pattern disorders (BPD) which is commonly diagnosed through the exclusion of other pathologies. Optoelectronic plethysmography (OEP) is a 3D motion capture technique that provides a comprehensive noninvasive assessment of chest wall during rest and exercise. The purpose of this study was to determine if OEP can distinguish between active individuals classified with and without BPD at rest and during exercise. Forty-seven individuals with a healthy breathing pattern (HBP) and twenty-six individuals with a BPD performed a submaximal exercise challenge. OEP measured the movement of the chest wall through the calculation of timing, percentage contribution, and phase angle breathing pattern variables. A mixed model repeated measures ANOVA analysed the OEP variables between the groups classified as HBP and BPD at rest, during exercise, and after recovery. At rest, regional contribution variables including ribcage percentage contribution (HBP: 71% and BPD: 69%), abdominal ribcage contribution (HBP: 13% and BPD: 11%), abdomen percentage contribution (HBP: 29% and BPD: 31%), and ribcage and abdomen volume index (HPB: 2.5 and BPD: 2.2) were significantly ( p < 0.05) different between groups. During exercise, BPD displayed significantly ( p < 0.05) more asynchrony between various thoracic compartments including the ribcage and abdomen phase angle (HBP: -1.9 and BPD: -2.7), pulmonary ribcage and abdomen phase angle (HBP: -0.5 and BPD, 0.5), abdominal ribcage and shoulders phase angle (HBP: -0.3 and BPD: 0.6), and pulmonary ribcage and shoulders phase angle (HBP: 0.2 and BPD: 0.6). Additionally, the novel variables inhale deviation (HBP: 8.8% and BPD: 19.7%) and exhale deviation (HBP: -10.9% and BPD: -17.6%) were also significantly ( p < 0.05) different between the groups during high intensity exercise. Regional contribution and phase angles measured via OEP can distinguish BPD from HBP at rest and during exercise. Characteristics of BPD include asynchronous and thoracic dominant breathing patterns that could form part of future objective criteria for the diagnosis of BPD., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2022 Carol M. E. Smyth et al.)

An 82-year-old man presented to the emergency department with delirium, vomiting and an initial hyponatraemia of 112 mmol/L the day after successful transurethral vaporisation of the prostate. He had a tonic-clonic seizure in the acute surgical unit and was managed subsequently in the intensive care unit with a controlled rate of hypertonic saline. Initial work-up for the cause of hyponatraemia revealed a low urine osmolality, suggestive of relative excess water intake. Detailed examination of the operation notes revealed no discrepancy between intraoperative irrigating fluid input and output. Careful collateral history revealed that the patient had drunk 8 L of water in the 24 hours following the operation, after taking advice to 'drink plenty of water' literally. This case highlights the importance of conveying specific advice to patient, the lower incidence of transurethral resection syndrome in resections using saline as an irrigation fluid and outlines the pathway for investigation and management for hyponatraemia., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a plethora of positive health effects. Many UK children fail to meet the recommended level of PA, with an observed decline in CRF levels over recent decades. Second-hand tobacco smoke (SHS) is responsible for a significant proportion of the worldwide burden of disease, but little is understood regarding the impact of SHS exposure on CRF and PA in children. The aim of this study was to test the associations between SHS exposure and CRF, PA, and respiratory health in children., Method: Children (9-11 years) from UK primary schools in deprived areas participated (n = 104, 38 smoking households). Surveys determined household smoking, and exhaled carbon monoxide was used to indicate children's recent SHS exposure. CRF (VO 2peak ) was assessed via maximal treadmill protocol using breath-by-breath analysis. Fractional exhaled nitric oxide and spirometry were utilised as indicators of respiratory health., Results: Linear regression models demonstrated that SHS exposure was negatively associated with allometrically scaled VO 2peak ( B = -3.8, p = 0.030) but not PA or respiratory health., Conclusion: The results indicate that SHS is detrimental to children's CRF; given that approximately one-third of children are regularly exposed to SHS, this important finding has implications for both public health and the sport and exercise sciences.

The most common way to analyze the effect of aging on breathing is to divide subjects into age groups. However, in addition to the fact that there is no consensus in the literature regarding age group division, such design critically influences the interpretation of the effects attributed to aging. Thus, this study aimed to investigate the feasibility to distinguish different age groups from the 3D kinematic variables of breathing motion (i.e., markers' coordinate as a function of time allowing the calculation of compartmental volume variations) and to analyze whether the aging could influence these variables. Seventy-three physically active women aged 19-80 years performed quiet breathing and vital capacity maneuvers. To record the thoracoabdominal breathing motion, the 3D coordinates of 32 retroreflective markers positioned on the trunk were used to estimate the volume variation of the superior thorax, inferior thorax, and abdomen. The percentage of contribution and the correlation coefficient were calculated to analyze the breathing motion pattern from the estimated volumes. The k-means cluster analysis was performed to analyze the age group classification. Linear regression was performed to investigate whether age can predict changes in the breathing motion pattern. The results showed that physically active women could not be classified into age groups from breathing motion. Despite significant p values of the linear regression, the high variability of the data suggested that age itself is not enough to predict the changes in breathing motion pattern when non-sedentary women are considered., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There is a paucity of research examining hydration and nutrition behaviors in youth American football players. A potentially unique risk factor are league restrictions based on weight (WR) or age (AR). The purpose of this study was to examine hydration status between WR and AR leagues. The secondary purpose was to describe eating patterns in players. An observational cohort design with 63 youth football players (10 ± 1 yrs, 148.2 ± 9.4 cm, 44.9 ± 15.3 kg) was utilized. Independent variables were league (AR ( n = 36); WR ( n = 27)) and activity type (practice (PX = 8); game (GM = 3)). Dependent variables were hydration status (urine osmolality; percent change in body mass (%BM)), eating attitudes (Children's Eating Attitude Test (ChEAT-26)) and self-reported frequency of meals. On average, players arrived activity mildly hypohydrated (830 ± 296 mOsm/kg) and %BM was minimal (-0.1 ± 0.7%) during events. Players consumed 2 ± 1 meals and 1 ± 1 snack before events. The ChEAT-26 survey reported 21.6% ( n = 8) of players were at risk for abnormal eating attitudes. Among these players, eating binges, vomiting, excessive exercise and drastic weight loss were reported. Youth American football players arrived activity mildly hypohydrated and consumed enough fluid during activity to maintain euhydration. Abnormal eating attitudes and the use of unhealthy weight loss methods were reported by some youth American football players.

Background: Respiratory viral infections are one of the leading causes of need for emergency care and hospitalizations in asthmatic individuals, and airway-secreted cytokines are released within hours of viral infection to initiate these exacerbations. IL-33, specifically, contributes to these allergic exacerbations by amplifying type 2 inflammation. We hypothesized that blocking IL-33 in RSV-induced exacerbation would significantly reduce allergic inflammation., Methods: Sensitized BALB/c mice were challenged with aerosolized ovalbumin (OVA) to establish allergic inflammation, followed by RSV-A2 infection to yield four treatment groups: saline only (Saline), RSV-infected alone (RSV), OVA alone (OVA), and OVA-treated with RSV infection (OVA-RSV). Lung outcomes included lung mRNA and protein markers of allergic inflammation, histology for mucus cell metaplasia and lung immune cell influx by cytospin and flow cytometry., Results: While thymic stromal lymphopoietin (TSLP) and IL-33 were detected 6 h after RSV infection in the OVA-RSV mice, IL-23 protein was uniquely upregulated in RSV-infected mice alone. OVA-RSV animals varied from RSV- or OVA-treated mice as they had increased lung eosinophils, neutrophils, group 2 innate lymphoid cells (ILC2) and group 3 innate lymphoid cells (ILC3) detectable as early as 6 h after RSV infection. Neutralized IL-33 significantly reduced ILC2 and eosinophils, and the prototypical allergic proteins, IL-5, IL-13, CCL17 and CCL22 in OVA-RSV mice. Numbers of neutrophils and ILC3 were also reduced with anti-IL-33 treatment in both RSV and OVA-RSV treated animals as well., Conclusions: Taken together, our findings indicate a broad reduction in allergic-proinflammatory events mediated by IL-33 neutralization in RSV-induced asthma exacerbation., (© 2021. The Author(s).)

Dysfunctional breathing patterns (DBP) can have an impact on an individual's quality of life and/or exercise performance. Breathing retraining is considered to be the first line of treatment to correct breathing pattern, for example, reducing ribcage versus abdominal movement asynchrony. Optoelectronic plethysmography (OEP) is a non-invasive 3D motion capture technique that measures the movement of the chest wall. The purpose of this study was to investigate if the use of a newly developed real-time OEP phase angle and volume feedback system, as an acute breathing retraining intervention, could result in a greater reduction of phase angle values (i.e., an improvement in movement synchrony) when compared to real-time OEP volume feedback alone. Eighteen individuals with a DBP performed an incremental cycle test with OEP measuring chest wall movement. Participants were randomly assigned to either the control group, which included the volume-based OEP feedback or to the experimental group, which included both the volume-based and phase angle OEP feedback. Participants then repeated the same cycle test using the real-time OEP feedback. The phase angle between the ribcage versus abdomen (RcAbPhase), between the pulmonary ribcage and the combined abdominal ribcage and abdomen (RCpAbPhase), and between the abdomen and the shoulders (AbSPhase) were calculated during both cycle tests. Significant increases in RcAbPhase (pre: -2.89°, post: -1.39°, p < 0.01), RCpAbPhase (pre: -2.00°, post: -0.50°, p < 0.01), and AbSPhase (pre: -2.60°, post: -0.72°, p < 0.01) were found post-intervention in the experimental group. This indicates that the experimental group demonstrated improved synchrony in their breathing pattern and therefore, reverting towards a healthy breathing pattern. This study shows for the first time that dysfunctional breathing patterns can be acutely improved with real-time OEP phase angle feedback and provides interesting insight into the feasibility of using this novel feedback system for breathing pattern retraining in individuals with DBP.

Objective: To determine which intrinsic and extrinsic exertional heat illness (EHI) risk factors exist in youth American football players and observe perceptual and physiological responses of players during events (games and practices)., Methods: Cross-sectional cohort study observing 63 youth football players, varying in position. Independent variables were league (weight-restricted (WR, n = 27) and age-restricted (AR, n = 36)) and event type. Dependent variables were anthropometrics, work-to-rest ratio, and wet bulb globe temperature. Descriptive variables included preparticipation examination and uniform configuration. A subset of 16 players participated in physiological variables (heart rate and gastrointestinal temperature). Data collection occurred on 7 AR and 8 WR nonconsecutive practices and the first 3 games of the season., Results: Mean values for anthropometric variables were higher (p < 0.05) in the AR league than the WR league. Work time (χ 2 (1,111) = 4.232; p = 0.039) and rest time (χ 2 (1,111) = 43.41; p < 0.001) were significantly greater for games, but ratios were significantly higher for practices (χ 2 (1,111) = 40.62; p < 0.001). The majority of events (77%) observed were in black and red flag wet bulb globe temperature risk categories. A total of 57% of the players had a preparticipation examination, and up to 82% of events observed were in full uniforms. Individual gastrointestinal temperature and heart rate responses ranged widely and no players reached critical thresholds., Conclusion: Extrinsic (disproportionate work ratios, environmental conditions) and intrinsic (higher body mass index) EHI risk factors exist in youth football. Certain risk factors may be influenced by event and league type. National youth football organizations need to create thorough guidelines that address EHI risk factors for local leagues to adopt., (Copyright © 2019. Production and hosting by Elsevier B.V.)

Respiratory symptoms, including cough, are prevalent in individuals with asthma when exercising. This study investigates whether a heat and moisture exchanger (HME) face mask is effective in modulating exercise-induced bronchoconstriction (EIB) and post-exercise cough in a cold, dry environment in individuals with asthma. Twenty-six participants diagnosed with asthma (20 males, 6 females) completed three cycling exercise challenges at 8°C and 24% relative humidity in a randomised order. Participants wore either an HME mask (MASK), sham mask (SHAM), or no mask (CONT). Following a 3-min warm-up, participants completed 6-min cycling at 80% peak power output. Before and after exercise, maximal flow-volume loops were recorded. Post-exercise cough was monitored with a Leicester Cough Monitor (LCM) for 24 h. Results were analysed using repeated-measures ANOVA and Friedman's tests and data were presented as the mean±sd or median (interquartile range (IQR)). Eleven participants failed to demonstrate EIB ( i.e. >10% fall in forced expiratory volume in 1 s after exercise) and were removed from analysis. The percentage fall in forced expiratory volume in 1 s following exercise in CONT was greater than MASK (MASK: -6% (7%), SHAM: -11% (11%), CONT: -13% (9%); p<0.01). No difference was found between exercise in cough count per hour over the 24-h monitoring period or the number of coughs in the first hour after exercise. HME masks can attenuate EIB when exercising in cold, dry environments. The SHAM mask may not have been entirely inert, demonstrating the challenges of running randomised control trials utilising control and sham conditions., Competing Interests: Conflict of interest: A.R. Jackson has nothing to disclose. Conflict of interest: J.H. Hull has nothing to disclose. Conflict of interest: J.G. Hopker has nothing to disclose. Conflict of interest: H. Fletcher has nothing to disclose. Conflict of interest: W. Gowers has nothing to disclose. Conflict of interest: S.S. Birring reports grants and personal fees from Merck, and personal fees from Bayer, NeRRe and Sanofi, outside the submitted work. Conflict of interest: J.W. Dickinson has nothing to disclose., (Copyright ©ERS 2020.)

Weill-Marchesani syndrome (WMS) is a rare genetic disorder that affects the musculoskeletal system, the eye, and the cardiovascular system. Individuals with WMS present with short stature, joint contractures, thick skin, microspherophakia, small and dislocated lenses, and cardiac valve anomalies. WMS can be caused by recessive mutations in ADAMTS10 (WMS 1), ADAMTS17 (WMS 4), or LTBP2 (WMS 3), or by dominant mutations in fibrillin-1 (FBN1) (WMS 2); all genes encode secreted extracellular matrix (ECM) proteins. Individuals with WMS 4 due to ADAMTS17 mutations appear to have less severe cardiac involvement and present predominantly with the musculoskeletal and ocular features of WMS. ADAMTS17 is a member of the ADAMTS family of secreted proteases and directly binds to fibrillins. Here we report a novel pathogenic variant in ADAMTS17 that causes WMS 4 in an individual with short stature, brachydactyly, and small, spherical, and dislocated lenses. We provide biochemical and cell biological insights in the pathomechanisms of WMS 4, which also suggest potential biological functions for ADAMTS17. We show that the variant in ADAMTS17 prevents its secretion and we found intracellular accumulation of fibrillin-1 and collagen type I in patient-derived skin fibroblasts. In accordance, transmission electron microscopy revealed elastic fiber abnormalities, decreased collagen fibril diameters, and intracellular collagen accumulation in the dermis of the proband. Together, the data indicate a possible role for ADAMTS17 in the secretion of fibrillin-1 and collagen type I or in their early assembly in the pericellular matrix or the ECM., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Environmental organic dust exposures enriched in Toll-like receptor (TLR) agonists can reduce allergic asthma development but are associated with occupational asthma and chronic bronchitis. The TLR adaptor protein myeloid differentiation factor88 (MyD88) is fundamental in regulating acute inflammatory responses to organic dust extract (ODE), yet its role in repetitive exposures is unknown and could inform future strategies., Methods: Wild-type (WT) and MyD88 knockout (KO) mice were exposed intranasally to ODE or saline daily for 3 weeks (repetitive exposure). Repetitively exposed animals were also subsequently rested with no treatments for 4 weeks followed by single rechallenge with saline/ODE., Results: Repetitive ODE exposure induced neutrophil influx and release of pro-inflammatory cytokines and chemokines were profoundly reduced in MyD88 KO mice. In comparison, ODE-induced cellular aggregates, B cells, mast cell infiltrates and serum IgE levels remained elevated in KO mice and mucous cell metaplasia was increased. Expression of ODE-induced tight junction protein(s) was also MyD88-dependent. Following recovery and then rechallenge with ODE, inflammatory mediators, but not neutrophil influx, was reduced in WT mice pretreated with ODE coincident with increased expression of IL-33 and IL-10, suggesting an adaptation response. Repetitively exposed MyD88 KO mice lacked inflammatory responsiveness upon ODE rechallenge., Conclusions: MyD88 is essential in mediating the classic airway inflammatory response to repetitive ODE, but targeting MyD88 does not reduce mucous cell metaplasia, lymphocyte influx, or IgE responsiveness. TLR-enriched dust exposures induce a prolonged adaptation response that is largely MyD88-independent. These findings demonstrate the complex role of MyD88-dependent signaling during acute vs. chronic organic dust exposures.

Patients with cystic fibrosis (CF) experience multiple pulmonary exacerbations throughout their lifetime, resulting in repeated antibiotic exposure and hospital admissions. Reliable diagnostic markers to guide antibiotic treatment in patients with CF, however, are lacking. Given that the CF airway is characterized by persistent and frequent bacterial infection, our goal was to determine if procalcitonin (PCT) could be used as a severity and prognostic marker of CF exacerbation. We enrolled 40 participants at the time of diagnosis of CF pulmonary exacerbation. Inclusion criteria: age ≥19 years with exacerbation requiring antibiotics as determined by the treating physician. Exclusion criteria: antibiotics initiated more than 48 hours prior to enrollment, and pregnancy. Blood samples were collected on enrollment day and after 7-10 days of treatment. Of the 40 patients enrolled, 23 (57.5%) had detectable levels of PCT (≥0.05 ng/mL). PCT levels were significantly associated with pulmonary exacerbation scores (p=0.01) and per cent decrease in forced expiratory volume in 1 second (FEV 1 ) (p=0.01) compared with the best in the last 12 months. Those who had worsening PCT during treatment had less improvement in FEV 1 (p=0.001) and were more likely to be readmitted to the hospital sooner (p<0.0001). Likewise, those who had a detectable PCT at the time of admission were more likely to be readmitted sooner (p=0.03). PCT elevation during antibiotic treatment is associated with less improvement in FEV 1 and earlier readmission. A detectable PCT level occurs only in more severe CF exacerbations. Multicenter trials are needed to confirm whether PCT may play a role in the clinical care of patients with CF., Competing Interests: Competing interests: None declared., (© American Federation for Medical Research 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

The purpose of the study was to investigate the effect of inhaling 1600 μg of salbutamol (SAL) on 30 m sprint before and after the Yo-Yo Intermittent Recovery test. In a randomised cross over single blind study 13 male non-asthmatic, football players volunteered (mean ± SD; age 18.1 ± 0.9 years; weight 69.5 ± 8.3 kg; height 1.78 ± 0.07 m). Participants completed two visits and were randomly assigned to either (SAL) or (PLA) treatment and performed a set of three sprints of 30 m before and after the Yo-Yo Intermittent Recovery Test (Yo-Yo IRT). Best sprint and mean sprint were analysed in addition to the distance covered during the Yo-Yo IRT; rating of perceived exertion and heart rate were collected at the end of each level completed. Repeated measures ANOVA were performed to investigate changes in performance between groups. Following the inhalation of supra-therapeutic salbutamol dose (1600 μg) neither 30 m sprint time (PLA 4.43 ± 0.14 s; SAL 4.44 ± 0.15 s, p = 0.76) nor distance covered in the Yo-Yo IRT test reported significant variation between PLA conditions (1660 ± 217 m) and SAL (1610 ± 229 m, p = 0.16). Moreover, lactate values, heart rate and RPE did not differ significantly between groups. The inhalation of 1600 μg salbutamol does not enhance 30 m sprint performance in non-fatigued and fatigue conditions. Our findings suggest when football players acutely inhale double the permitted dose of salbutamol, as indicated in the World Anti-Doping Agency List of Prohibited Substances and Methods, they will not experience improvements in sprint or endurance performance., (© Journal of Sports Science and Medicine.)

Purpose: To investigate the impact of twice-daily inhalation of 100 µg of salmeterol (SAL) or 12 µg of formoterol (FOR) in addition to a strength- and power-training program over a 5-wk period on a 30-m sprint, strength, power, mood, stress, and skinfold thickness., Methods: In a randomized, single-blind study, 23 male and 15 female nonasthmatic, recreationally active individuals were recruited (mean [SD] age 26.3 [5.4] y, weight 76.2 [11.5] kg, height 176.9 [8.5] cm). Participants completed 3 standardized whole-body strength- and power-training sessions per week for 5 wk during which they were assigned to an SAL, FOR, or placebo group. Participants used their inhaler twice per day as instructed and completed assessments of sprint, strength, and power at baseline and 1 wk after cessation of the training program. The assessments included a 30-m sprint, vertical jump, 1-repetition-maximum (1RM) bench press, 1RM leg press, peak torque flexion and extension, anthropometric evaluation, and Rest-Q questionnaires., Results: After 5 wk of strength and power training, 30-m sprint time reduced in the FOR (0.29 [0.11] s, P = .049) and SAL (0.35 [0.05] s, P = .040) groups compared with placebo (+0.01 [0.11] s). No significant change was found in other assessments of strength, mood, or skinfold thickness., Conclusions: When strength and power training are combined with the inhalation of FOR or SAL over a 5-wk period, moderately trained individuals experience an improvement in 30-m sprint performance.

Background: Exogenous endophthalmitis is a potential complication of intraocular surgery and frequently results in visual impairment. Current treatment involves administration of intravitreal (IVT) antibiotics with or without vitrectomy surgery. Evidence for the use of adjunctive anti-inflammatory agents is conflicting. We set out to determine if bevacizumab, a humanized monoclonal IgG1 antibody targeted against vascular endothelial growth factor (VEGF), has anti-inflammatory properties in experimental models of Gram-positive and Gram-negative inflammation., Methods: BALB/c mice were subjected to lipopolysaccharide- (LPS) or peptidoglycan- (PGN) induced ocular inflammation and treated with IVT bevacizumab. Iris microvasculature was imaged 6 hours following irritant/treatment using intravital microscopy (IVM) before the mice were euthanized and the eyes were enucleated immediately post-mortem. Following enucleation, levels of VEGF and 23 cytokines and chemokines (IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17, TNF, KC, G-CSF, GM-CSF, Eotaxin, INF-γ, MCP-1, MIP-1α, MIP-1β, RANTES) were quantified using a multiplex assay., Results: Levels of VEGF were significantly increased during the inflammatory response, triggered by either PGN or LPS. Both the adherence of leukocytes to the iris vascular endothelium and the levels of pro-inflammatory cytokines and chemokines were significantly increased following administration of either irritant. Treatment with bevacizumab decreased levels of leukocyte adherence in LPS-treated eyes, however, not in PGN-treated eyes. Conversely, bevacizumab treatment decreased levels of cytokines and chemokines (TNF, IL-6, MCP-1, MIP-1α, MIP-1β, RANTES, KC) in PGN-treated eyes, however, not in LPS-treated eyes., Conclusions: Within a 6-hour window bevacizumab had anti-inflammatory actions that were distinct in both Gram-positive (PIU) and Gram-negative (EIU) models, respectively. Given our findings, this would suggest that bevacizumab may have utility as an adjunctive therapy to IVT antibiotics and vitrectomy in the management of exogenous endophthalmitis., (© 2018 Royal Australian and New Zealand College of Ophthalmologists.)

Terbutaline is a prohibited drug except for athletes with a therapeutic use exemption certificate; terbutaline's effects on endurance performance are relatively unknown. Purpose : To investigate the effects of 2 therapeutic (2 and 4 mg) inhaled doses of terbutaline on 3-km running time-trial performance. Methods : A total of 8 men (age 24.3 [2.4] y; weight 77.6 [8] kg; and height 179.5 [4.3] cm) and 8 women (age 22.4 [3] y; weight 58.6 [6] kg; and height 163 [9.2] cm) free from respiratory disease and illness provided written informed consent. Participants completed 3-km running time trials on a nonmotorized treadmill on 3 separate occasions following placebo and 2- and 4-mg inhaled terbutaline in a single-blind, repeated-measures design. Urine samples (15 min postexercise) were analyzed for terbutaline concentration. Data were analyzed using 1-way repeated-measures analysis of variance, and significance was set at P  < .05 for all analyses. Results : No differences were observed for completion times (1103 [201] s, 1106 [195] s, 1098 [165] s; P  = .913) for the placebo or 2- and 4-mg inhaled trials, respectively. Lactate values were higher ( P  = .02) after 4 mg terbutaline (10.7 [2.3] mmol·L -1 ) vs placebo (8.9 [1.8] mmol·L -1 ). Values of forced expiratory volume in the first second of expiration (FEV 1 ) were greater after inhalation of 2 mg (5.08 [0.2]; P  = .01) and 4 mg terbutaline (5.07 [0.2]; P  = .02) compared with placebo (4.83 [0.5] L) postinhalation. Urinary terbutaline concentrations were mean 306 (288) ng·mL -1 and 435 (410) ng·mL -1 ( P  = .2) and peak 956 ng·mL -1 and 1244 ng·mL -1 after 2 and 4 mg inhaled terbutaline, respectively. No differences were observed between the male and female participants. Conclusions : Therapeutic dosing of terbutaline does not lead to an improvement in 3-km running performance despite significantly increased FEV 1 . The findings suggest that athletes using inhaled terbutaline at high therapeutic doses to treat asthma will not gain an ergogenic advantage during 3-km running performance.

The original article [1] contained a minor error in Fig. 1.

Agriculture exposures are associated with reducing the risk of allergy and asthma in early life; yet, repeated exposures later in life are associated with chronic bronchitis and obstructive pulmonary diseases. The objective of this study was to investigate the airway inflammatory response to organic dust extract (ODE) in mice with established ovalbumin (OVA)-induced experimental asthma. C57BL/6 mice were either OVA sensitized/aerosol-exposed or saline (Sal) sensitized/aerosol-challenged. Both groups were then subsequently challenged once with intranasal saline or swine confinement ODE to obtain 4 treatment groups of Sal-Sal, Sal-ODE, OVA-Sal, and OVA-ODE. Airway hyper-responsiveness (AHR) to methacholine, bronchiolar lavage fluid, lung tissues, and serum were collected. Intranasal inhalation of ODE in OVA-treated (asthmatic) mice (OVA-ODE) increased AHR and total cellular influx marked by elevated neutrophil and eosinophil counts. Flow cytometry analysis further demonstrated that populations of CD11c hi dendritic cells (DC), CD3 + T cells, CD19 + B cells, and NKp46 + group 3 innate lymphoid cells (ILC3) were increased in lavage fluid of OVA-ODE mice as compared to ODE or OVA alone. Alveolar macrophages, DC, and T cells were significantly increased with co-exposure to OVA-ODE as compared to OVA alone. Lung ILC2 and ILC3 were only increased in OVA-Sal mice. Cytokine/chemokine levels varied with exposure to OVA-ODE reflecting an additive mixture of the pro- and allergic-inflammatory profiles. Collectively, ODE increased airway inflammatory cells and chemotactic mediator release in allergic (OVA) sensitized mice to suggest that persons with allergy/asthma be identified and warned prior to the occupational exposure of potentially worsening airway disease.

Inflammation from airborne microbes can overwhelm compensatory mucociliary clearance mechanisms, leading to mucous cell metaplasia. Toll-like receptor (TLR) activation via myeloid differentiation factor 88 (MyD88) signaling is central to pathogen responses. We have previously shown that agricultural organic dust extract (ODE), with abundant microbial component diversity, activates TLR-induced airway inflammation. With the use of an established model, C57BL/6J wild-type (WT) and global MyD88 knockout (KO) mice were treated with intranasal inhalation of ODE or saline, daily for 1 wk. ODE primarily increased mucin (Muc)5ac levels relative to Muc5b. Compared with ODE-challenged WT mice, ODE-challenged, MyD88-deficient mice demonstrated significantly increased Muc5ac immunostaining, protein levels by immunoblot, and expression by quantitative PCR. The enhanced Muc5ac levels in MyD88-deficient mice were not explained by differences in the differentiation program of airway secretory cells in naïve mice. Increased Muc5ac levels in MyD88-deficient mice were also not explained by augmented inflammation, IL-17A, or neutrophil elastase levels. Furthermore, the enhanced airway mucins in the MyD88-deficient mice were not due to defective secretion, as the mucin secretory capacity of MyD88-KO mice remained intact. Finally, ODE-induced Muc5ac levels were enhanced in MyD88-deficient airway epithelial cells in vitro. In conclusion, MyD88 deficiency enhances airway mucous cell metaplasia under environments with high TLR activation.

Background: Swimming-induced pulmonary oedema (SIPE) can affect people with no underlying health problems, but may be life threatening and is poorly understood. The aim of this systematic review was to synthesise the evidence on SIPE incidence, prevalence, risk factors, short- and long-term outcomes, recurrence and effectiveness of interventions to prevent recurrences., Methods: We carried out a literature search using bibliographic databases and reference lists. Risk of bias was assessed by adapting existing quality assessment tools including those developed by the National Heart Lung and Blood Institute., Results: Nine studies met the inclusion criteria. Quantitative synthesis was not possible because of study heterogeneity. Five studies, which differed from each other in case definition, swimming environment, population characteristics and denominators, reported an incidence of 0.01% of UK triathlons raced over 5 years in unspecified swimming environments (one study, not fully reported, of men and women of unspecified age); 0.5% of river races swum over 3 days in Sweden (one study, of men and women up to the age of 70); and 1.8-26.7% of time trials in the sea around Israel (three studies of male teenage military trainees). One study reported that 1.4% of triathletes in the USA had experienced SIPE. One study found that hypertension, female sex, fish oil use, long course distance and another lower initial lung volumes and flows were risk factors for SIPE. A third study reported that higher mean pulmonary artery pressures and pulmonary artery wedge pressures, and lower tidal volumes were associated with SIPE. Three studies suggested that SIPE symptoms usually resolve within 24 h, although a restrictive deficit in lung function persisted for a week in one small study. We found no studies that reported deaths from SIPE. The single small study of longer-term outcomes reported no difference between affected and unaffected swimmers. Two studies suggested that around 30% of people report recurrences of SIPE. Two very small uncontrolled studies of the effect of sildenafil for recurrence prevention were inconclusive., Conclusions: SIPE may be an important public health problem affecting the growing number of recreational open water swimmers. Further research should clarify the frequency of SIPE among recreational open water swimmers, confirm reported risk factors and explore others, explore long-term consequences and test interventions to prevent recurrences.

Respiratory assessment and the biomechanical analysis of chest and abdomen motion during breathing can be carried out using motion capture systems. An advantage of this methodology is that it allows analysis of compartmental breathing volumes, thoraco-abdominal patterns, percentage contribution of each compartment and the coordination between compartments. In the literature, mainly, two marker models are reported, a full marker model of 89 markers placed on the trunk and a reduced marker model with 32 markers. However, in practice, positioning and post-process a large number of markers on the trunk can be time-consuming. In this study, the full marker model was compared against the one that uses a reduced number of markers, in order to evaluate (i) their capability to obtain respiratory parameters (breath-by-breath tidal volumes) and thoracoabdominal motion pattern (compartmental percentage contributions, and coordination between compartments) during quiet breathing, and (ii) their response in different groups such as trained and untrained, male and female. Although tests revealed strong correlations of the tidal volume values in all the groups (R 2  > 0.93), the reduced model underestimated the trunk volume compared with the 89 marker model. The highest underestimation was found in trained males (bias of 0.43 L). The three-way ANOVA test showed that the model did not influence the evaluation of compartmental contributions and the 32 marker model was adequate to distinguish thoracoabdominal breathing pattern in the studied groups. Our findings showed that the reduced marker model could be used to analyse the thoracoabdominal motion in both trained and untrained populations but performs poorly in estimating tidal volume., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Chronic lower back pain is still regarded as a poorly understood multifactorial condition. Recently, the thoracolumbar fascia complex has been found to be a contributing factor. Ultrasound imaging has shown that people with chronic lower back pain demonstrate both a significant decrease in shear strain, and a 25% increase in thickness of the thoracolumbar fascia. There is sparse data on whether medical practitioners agree on the level of disorganisation in ultrasound images of thoracolumbar fascia. The purpose of this study was to establish inter-rater reliability of the ranking of architectural disorganisation of thoracolumbar fascia on a scale from 'very disorganised' to 'very organised'., Methods: An exploratory analysis was performed using a fully crossed design of inter-rater reliability. Thirty observers were recruited, consisting of 21 medical doctors, 7 physiotherapists and 2 radiologists, with an average of 13.03 ± 9.6 years of clinical experience. All 30 observers independently rated the architectural disorganisation of the thoracolumbar fascia in 30 ultrasound scans, on a Likert-type scale with rankings from 1 = very disorganised to 10 = very organised. Internal consistency was assessed using Cronbach's alpha. Krippendorff's alpha was used to calculate the overall inter-rater reliability., Results: The Krippendorf's alpha was .61, indicating a modest degree of agreement between observers on the different morphologies of thoracolumbar fascia.The Cronbach's alpha (0.98), indicated that there was a high degree of consistency between observers. Experience in ultrasound image analysis did not affect constancy between observers (Cronbach's range between experienced and inexperienced raters: 0.95 and 0.96 respectively)., Conclusions: Medical practitioners agree on morphological features such as levels of organisation and disorganisation in ultrasound images of thoracolumbar fascia, regardless of experience. Further analysis by an expert panel is required to develop specific classification criteria for thoracolumbar fascia.

Pharmacologic management of exercise-induced bronchoconstriction (EIB) is the mainstay of preventative therapy. There are some nonpharmacologic interventions, however, that may assist the management of EIB. This review discusses these nonpharmacologic interventions and how they may be applied to patients and athletes with EIB., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Our aim was to evaluate the prevalence of exercise-induced bronchoconstriction (EIB) in elite football players and assess subsequent impact of therapy on airway health and exercise performance. 97 male professional football players completed an airway health assessment with a eucapnic voluntary hyperpnoea (EVH) challenge to diagnose EIB. Players demonstrating a positive result (EVH + ) were prescribed inhaler therapy depending on severity, including inhaled corticosteroids and inhaled short-acting β 2 -agonists, and underwent repeat assessment after 9 weeks of treatment. Eight players (EVH + n=3, EVH - n=5) completed a peak oxygen uptake ( V ' O 2 peak ) test at initial and follow-up assessment. Out of the 97 players, 27 (28%) demonstrated a positive EVH result. Of these, 10 had no prior history (37%) of EIB or asthma. EVH outcome was not predictable by respiratory symptoms. Seven (24%) of the 27 EVH + players attended follow-up and demonstrated improved post-challenge spirometry (forced expiratory volume in 1 s pre-test -22.9±15.4%, post-test -9.0±1.6%; p=0.018). At follow-up V ' O 2 peak improved by 3.4±2.9 mL·kg -1 ·min -1 in EVH + players compared to 0.1±2.3 mL·kg -1 ·min -1 in EVH - players. Magnitude of inference analysis indicated treatment was possibly beneficial (74%) for exercise capacity. Elite football players have a high EIB prevalence. Treatment with inhaler therapy reduces EIB severity., Competing Interests: Conflict of interest: None declared.

The airway epithelium is a broad interface with the environment, mandating well-orchestrated responses to properly modulate inflammation. Classically, autophagy is a homeostatic pathway triggered in response to external cellular stresses, and is elevated in chronic airway diseases. Recent findings highlight the additional role of autophagy in vesicle trafficking and protein secretion, implicating autophagy pathways in complex cellular responses in disease. Th2 cytokines, IL-13 and IL-4, are increased in asthma and other airway diseases contributing to chronic inflammation. Previously, we observed that IL-13 increases reactive oxygen species (ROS) in airway epithelial cells in an autophagy-dependent fashion. Here, we tested our hypothesis that autophagy is required for IL-13-mediated superoxide production via the NADPH oxidase DUOX1. Using a mouse model of Th2-mediated inflammation induced by OVA-allergen, we observed elevated lung amounts of IL-13 and IL-4 accompanied by increased autophagosome levels, determined by LC3BII protein levels and immunostaining. ROS levels were elevated and DUOX1 expression was increased 70-fold in OVA-challenged lungs. To address the role of autophagy and ROS in the airway epithelium, we treated primary human tracheobronchial epithelial cells with IL-13 or IL-4. Prolonged, 7-day treatment increased autophagosome formation and degradation, while brief activation had no effect. Under parallel culture conditions, IL-13 and IL-4 increased intracellular superoxide levels as determined by electron paramagnetic resonance (EPR) spectroscopy. Prolonged IL-13 activation increased DUOX1, localized at the apical membrane. Silencing DUOX1 by siRNA attenuated IL-13-mediated increases in superoxide, but did not reduce autophagy activities. Notably, depletion of autophagy regulatory protein ATG5 significantly reduced superoxide without diminishing total DUOX1 levels. Depletion of ATG5, however, diminished DUOX1 localization at the apical membrane. The findings suggest non-canonical autophagy activity regulates DUOX1-dependent localization required for intracellular superoxide production during Th2 inflammation. Thus, in chronic Th2 inflammatory airway disease, autophagy proteins may be responsible for persistent intracellular superoxide production., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The Objectives of the study were to investigate whether 400 µg inhaled salbutamol influences 3 km running time-trial performance and lung function in eucapnic voluntary hyperpnoea positive (EVH+ve) and negative (EVH-ve) individuals. Fourteen male participants (22.4 ± 1.6yrs; 76.4 ± 8.7kg; 1.80 ± 0.07 m); (7 EVH+ve; 7 EVH-ve) were recruited following written informed consent. All participants undertook an EVH challenge to identify either EVH+ve (↓FEV 1 >10%) or EVH-ve (↓FEV 1 <10%). Participants performed three separate 3 km running time-trials in a low-humidity (20-25%) environment on a non-motorized treadmill, 15 minutes following inhalation of salbutamol (400 µg), placebo (non-active inhalant) or control (no inhalant), in a randomized, single-blind, repeated measures design. Forced vital capacity maneuvers were performed at baseline, 10 minutes post inhalation and post time-trial. Time to complete 3 km and lung function data were analyzed using mixed model repeated measures ANOVA. Significance was assumed at p < 0.05. All EVH+ve participants had FEV 1 falls from baseline between 10-25% post-challenge. There was no difference in performance time between trial conditions in EVH+ve (1012.7 ± 129.6s; 1002.4 ± 123.1s; 1015.9 ± 113.0s) (p = 0.774) and EVH-ve (962.1 ± 99.2s; 962.0 ± 76.2s; 950.8 ± 84.9s) (p = 0.401) groups for salbutamol, placebo and control trials, respectively. Exercising heart rate was significantly higher (p = 0.05) in the salbutamol trial (183 ± 8 beatsˑmin -1 ) compared to control (180 ± 9 beatsˑmin -1 ) with a trend towards significance (p=0.06) in the placebo trial (179 ± 9 beatsˑmin -1 ) for the pooled groups, no differences were seen between trials in groups individually. There was an increase in FEV 1 in both EVH+ve (4.01 ± 0.8L; 4.26 ± 0.7L; 4.25 ± 0.5L) and EVH-ve (4.81 ± 0.4L; 5.1 ± 0.4L; 5.1 ± 0.5L) groups which was significant post-inhalation (p = 0.01; p = 0.02), but not post-time-trial (p = 0.27; p = 0.06), respectively, following salbutamol. EVH+ve participants did not demonstrate significant falls (>10% from baseline) in FEV 1 following any time-trial. Administration of 400µg inhaled salbutamol does not improve 3 km time-trial performance in either mild EVH+ve or EVH-ve individuals despite significantly increased HR and FEV 1 .

Objective: Exogenous endophthalmitis is an ophthalmologic emergency defined by panocular inflammation. Vascular endothelial growth factor A (VEGF-A) contributes to inflammation by promoting chemotaxis of monocytes and granulocytes and by increasing vascular permeability. The purpose of this article is to determine if VEGF-A is elevated in the vitreous samples obtained from individuals with exogenous endophthalmitis., Methods: Vitreous samples from individuals with exogenous endophthalmitis (n = 18) were analyzed via Luminex assay and enzyme-linked immunosorbent assay for the cytokines VEGF-A, tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-8 (chemokine [CXCL]-8), IL-1β, IL-10, IL-12p70, IL-33, interferon (IFN)-γ, IFN-α, IFN-β, chemokine ligand (CCL)-3, IL-2, IL-5, IL-15, CXCL-10, CCL-2, IL-1Ra, CCL-5, IL-17, and CCL-11. Vitreous samples obtained at the time of macular hole surgery served as controls (n = 8)., Results: Concentrations of VEGF-A were significantly elevated in vitreous samples from individuals with exogenous endophthalmitis compared with macular hole (p < 0.001). VEGF-A was significantly upregulated in individuals with exogenous endophthalmitis after cataract surgery (p = 0.001), vitrectomy (p = 0.024), and intravitreal injection (p = 0.012). VEGF-A concentrations were similar in both culture-positive and culture-negative populations (p > 0.05). In a linear regression model, levels of VEGF-A correlated significantly with the chemokine CXCL-8 (p = 0.028)., Conclusions: We demonstrate that VEGF-A is potently upregulated in exogenous endophthalmitis. This observation provides a foundation for future studies of targeted VEGF-A blockade in the management of endophthalmitis., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Background: Optoelectronic plethysmography (OEP) is a non-invasive motion capture method to measure chest wall movements and estimate lung volumes., Objectives: To provide an overview of the clinical findings and research applications of OEP in the assessment of breathing mechanics across populations of healthy and diseased individuals., Methods: A bibliographic research was performed with the terms "opto-electronic plethysmography," "optoelectronic plethysmography," and "optoelectronic plethysmograph" in 50 digital library and bibliographic search databases resulting in the selection of 170 studies., Results: OEP has been extensively employed in studies looking at chest wall kinematics and volume changes in chest wall compartments in healthy subjects in relation to age, gender, weight, posture, and different physiological conditions. In infants, OEP has been demonstrated to be a tool to assess disease severity and the response to pharmacological interventions. In chronic obstructive pulmonary disease patients, OEP has been used to test if patients can dynamically hyperinflate or deflate their lungs during exercise. In neuromuscular patients, respiratory muscle strength and chest kinematics have been analyzed. A widespread application of OEP is in tailoring post-operative pulmonary rehabilitation as well as in monitoring volume increases and muscle contributions during exercise., Conclusions: OEP is an accurate and validated method of measuring lung volumes and chest wall movements. OEP is an appropriate alternative method to monitor and analyze respiratory patterns in children, adults, and patients with respiratory diseases. OEP may be used in the future to contribute to improvements in the therapeutic strategies for respiratory conditions., (© 2017 S. Karger AG, Basel.)

Background and Objective: Elite swimming and boxing require athletes to achieve relatively high minute ventilation. The combination of a sustained high ventilation and provocative training environment may impact the susceptibility of athletes to exercise-induced bronchoconstriction (EIB). The purpose of this study was to evaluate the prevalence of EIB in elite Great British (GB) boxers and swimmers., Methods: Boxers (n = 38, mean age: 22.1 ± 3.1 years) and swimmers (n = 44, mean age: 21.1 ± 2.6 years) volunteered for the study. Athletes completed an exercise-induced respiratory symptom questionnaire, baseline assessment of fraction of exhaled nitric oxide (FeNO), maximal spirometry manoeuvres and a eucapnic voluntary hyperpnoea (EVH) challenge. EIB was confirmed if forced expiratory volume in 1 s (FEV 1 ) reduced by ≥10% from baseline at two time points post-EVH challenge., Results: The prevalence of EIB was greater in elite swimmers (30 of 44; 68%) than in boxers (3 of 38; 8%) (P < 0.001). Twenty-two out of the 33 (67%) EVH-positive athletes had no prior diagnosis of asthma/EIB. Moreover, 12% (6 of 49) of the EVH-negative athletes had a previous diagnosis of asthma/EIB. We found a correlation between FeNO and FEV 1 change in lung function post-EVH challenge in swimmers (r = 0.32; P = 0.04) but not in boxers (r = 0.24; P = 0.15)., Conclusion: The prevalence of EIB was ninefold greater in swimmers when compared with boxers. Athletes who train and compete in provocative environments at sustained high ventilation may have an increased susceptibility to EIB. It is not entirely clear whether increased susceptibility to EIB affects elite sporting performance and long-term airway health in elite athletes., (© 2016 Asian Pacific Society of Respirology.)

Although chronic graft-versus-host disease (CGVHD) is the primary nonrelapse complication of allogeneic transplantation, understanding of its pathogenesis is limited. To identify the main operant pathways across the spectrum of CGVHD, we analyzed gene expression in circulating monocytes, chosen as in situ systemic reporter cells. Microarrays identified two interrelated pathways: 1) IFN-inducible genes, and 2) innate receptors for cellular damage. Corroborating these with multiplex RNA quantitation, we found that multiple IFN-inducible genes (affecting lymphocyte trafficking, differentiation, and Ag presentation) were concurrently upregulated in CGVHD monocytes compared with normal subjects and non-CGVHD control patients. IFN-inducible chemokines were elevated in both lichenoid and sclerotic CGHVD plasma and were linked to CXCR3 + lymphocyte trafficking. Furthermore, the levels of the IFN-inducible genes CXCL10 and TNFSF13B (BAFF) were correlated at both the gene and the plasma levels, implicating IFN induction as a factor in elevated BAFF levels in CGVHD. In the second pathway, damage-/pathogen-associated molecular pattern receptor genes capable of inducing type I IFN were upregulated. Type I IFN-inducible MxA was expressed in proportion to CGVHD activity in skin, mucosa, and glands, and expression of TLR7 and DDX58 receptor genes correlated with upregulation of type I IFN-inducible genes in monocytes. Finally, in serial analyses after transplant, IFN-inducible and damage-response genes were upregulated in monocytes at CGVHD onset and declined upon therapy and resolution in both lichenoid and sclerotic CGVHD patients. This interlocking analysis of IFN-inducible genes, plasma analytes, and tissue immunohistochemistry strongly supports a unifying hypothesis of induction of IFN by innate response to cellular damage as a mechanism for initiation and persistence of CGVHD.

In athletes, a secure diagnos is of exercise-induced bronchoconstriction (EIB) is dependent on objective testing. Evaluating spirometric indices of airflow before and following an exercise bout is intuitively the optimal means for the diagnosis; however, this approach is recognized as having several key limitations. Accordingly, alternative indirect bronchoprovocation tests have been recommended as surrogate means for obtaining a diagnosis of EIB. Of these tests, it is often argued that the eucapnic voluntary hyperpnea (EVH) challenge represents the 'gold standard'. This article provides a state-of-the-art review of EVH, including an overview of the test methodology and its interpretation. We also address the performance of EVH against the other functional and clinical approaches commonly adopted for the diagnosis of EIB. The published evidence supports a key role for EVH in the diagnostic algorithm for EIB testing in athletes. However, its wide sensitivity and specificity and poor repeatability preclude EVH from being termed a 'gold standard' test for EIB.

Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.

Objective: Investigate the effect of inhaling 1600 μg salbutamol for 6 weeks on endurance, strength, and power performances., Design: Randomized double-blind, mixed-model repeated measures., Participants: Sixteen male athletes (mean ± SD: age, 20.1 ± 1.6 years; height, 179.9 ± 8.2 cm; weight, 74.6 ± 9.1 kg)., Interventions: Participants were assigned to either a placebo inhaler (PLA) or inhaled 1600 μg salbutamol group (SAL). Over 6 weeks, participants inhaled PLA or SAL and completed 4 training sessions per week that focused on endurance, strength, and power., Main Outcome Measures: Participants completed the assessments of peak oxygen consumption (V[Combining Dot Above]O2peak), 3-km time trial, vertical jump height, 1 repetition maximum (1RM) bench and leg press, and peak torque knee flexion and extension. Assessments were undertaken at baseline, week 3, and week 6., Results: Over the 6 weeks, PLA and SAL groups improved V[Combining Dot Above]O2peak (51.7 ± 4.7 vs 56.8 ± 7.1 mL·min·kg; 53.1 ± 6.1 vs 55.0 ± 6.7 mL·min·kg); 3-km running time trial (988.6 ± 194.6 vs 947.5 ± 155.5 seconds; 1040.4 ± 187.4 vs 1004.2 ± 199.4 seconds); 1RM bench press (65.7 ± 15.4 vs 70.3 ± 13.8 kg; 64.3 ± 14.0 vs 72.5 ± 15.3 kg); and leg press (250.0 ± 76.4 vs 282.5 ± 63.6 kg; 217.9 ± 54.0 vs 282.8 ± 51.9 kg). The SAL group did not improve significantly greater in any endurance or strength and power measure when compared with the PLA group., Conclusions: Inhaling 1600 µg salbutamol daily over 6 weeks does not result in significant improvements in endurance, or strength and power performances., Clinical Relevance: Athletes using inhaled salbutamol to treat bronchoconstriction during exercise on a daily basis will not gain an advantage over nonasthmatic athletes not using inhaled salbutamol.

Objective: To examine the impact of dehydration, ethnicity, and gender on urinary concentrations of salbutamol in relation to the threshold stipulated by the World Anti-Doping Agency (WADA)., Design: Repeated measures open-label., Participants: Eighteen male and 14 female athletes (9 white males, 9 white females, 2 Afro-Caribbean males, 2 Afro-Caribbean females, 6 Asian [Indian subcontinent] males, and 4 Asian females) were recruited. All participants were nonasthmatic., Interventions: After inhalation of 800 μg or 1600 μg of salbutamol, athletes exercised in a hot controlled environment (35°C, 40% relative humidity) at a self-selected pace until a target weight loss (2% or 5%) was achieved., Main Outcome Measures: Urine concentration of free salbutamol., Results: After inhalation of 1600 μg salbutamol, 20 participants presented with a urine salbutamol concentrations above the current WADA limit (1000 ng/mL) and decision limit (1200 ng/mL) resulting in an adverse analytical finding. There were no differences according to gender or ethnic origin., Conclusions: Dehydration equivalent to a body mass loss greater than 2% concomitant to the acute inhalation of 1600 μg of salbutamol may result in a urine concentration above the current WADA limit and decision limit leading to a positive test finding independent of gender or ethnic origin., Clinical Relevance: Asthmatic athletes using salbutamol should receive clear dosing advise and education to minimize the risk of inhaling doses of salbutamol that may produce urine concentrations of salbutamol above 1200 ng/mL.