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Robert A Scott,1,2 Timothy J S Cross,3 Christopher Clarke,4 Shahid A Khan,5 Stephen D Ryder,1 James Franklin,6,* Aloysious D Aravinthan1,2,* 1NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK; 2Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, UK; 3Royal Liverpool and Broadgreen University Hospital NHS Trust, Liverpool, UK; 4Department of Radiology, Nottingham University Hospitals NHS Trust, Nottingham, UK; 5Division of Digestive Diseases, Imperial College London, London, UK; 6Institute of Medical Imaging and Visualisation, Bournemouth University, Bournemouth UK*These authors contributed equally to this workCorrespondence: James Franklin, Institute of Medical Imaging and Visualisation, Bournemouth University, Bournemouth Gateway Building, St Paul’s Lane, Bournemouth, BH8 8GP, UK, Email jfranklin@bournemouth.ac.uk Aloysious D Aravinthan, Nottingham Digestive Diseases Centre, Translational Medical Sciences, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, UK, Email aloysious.aravinthan@nottingham.ac.ukBackground & Aim: HCC has significantly improved outcomes when detected early. Guidelines recommend biannual surveillance with ultrasound (US) and/or AFP in at-risk individuals. This survey aimed to describe HCC surveillance adherence/practices amongst the NHS hospitals in the UK.Methods: An electronic survey was sent to 79 NHS hospitals via the British Association for the Study of the Liver distribution list. The responses were captured from July 2021 to January 2022. Centres were divided into hepato-pancreato-biliary (HPB) and non-HPB centres, depending on whether the hospital undertakes major liver surgeries.Results: A total of 39 (49.3%) centres responded: 15 HPB and 24 non-HPB centres from across the UK. HCC surveillance eligibility criteria were universally applied, but heterogeneous approaches occur outside these criteria. Eighty per cent of patients undergoing surveillance were estimated to have cirrhosis. Eighty-five per cent of centres do 6-monthly US and AFP requested by clinicians and liver clinical nurse specialists. Compliance was estimated at 80% but not routinely audited. In most centres, general sonographers and/or radiologists perform surveillance US scans without a standard reporting template, although structured reporting was viewed as desirable by the majority. Poor views on US are approached heterogeneously, with patients variably offered ongoing US, CT, or MRI with different protocols.Conclusion: Most responding NHS hospitals follow 6-monthly HCC surveillance guidance. Data recording is variable, with limited routine data collection regarding compliance, yield, and quality. Surveillance US is mostly performed by non-HPB specialists without standardised reporting. There is an inconsistent approach to poor views with US surveillance. Even in a universal healthcare system such as NHS, which is free at the point of care, delivery of HCC surveillance has not improved over the last decade and remains variable.Keywords: hepatocellular carcinoma, primary surveillance, ultrasound scan, cirrhosis, liver cancer

Mirashini Swaminathan,1 Mark Alexander Ellul,2 Timothy JS Cross1 1Department of Gastroenterology, Royal Liverpool University Hospital, 2Faculty of Health and Life Sciences, Institute of Infection and Global Health, University of Liverpool, Liverpool, UK Abstract: Hepatic encephalopathy (HE) is a common complication of liver dysfunction, including acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. It is a significant contributor of morbidity in patients with liver disease. HE is observed in acute liver failure, liver bypass procedures, for example, shunt surgery and transjugular intrahepatic portosystemic shunt, and cirrhosis. These are classified as Type A, B and C HE, respectively. HE can also be classified according to whether its presence is overt or covert. The pathogenesis is linked with ammonia and glutamine production, and treatment is based on mechanisms to reduce the formation and/or removal of these compounds. There is no specific diagnostic test for HE, and diagnosis is based on clinical suspicion, excluding other causes and use of clinical tests that may support its diagnosis. Many tests are used in trials and experimentally, but have not yet gained universal acceptance. This review focuses on the definitions, pathogenesis and treatment of HE. Consideration will be given to existing treatment, including avoidance of precipitating factors and novel therapies such as prebiotics, probiotics, antibiotics, laxatives, branched-chain amino acids, shunt embolization and the importance of considering liver transplant in appropriate cases. Keywords: hepatic encephalopathy, pathogenesis, treatment, lactulose, rifaximin, probiotics, covert hepatic encephalopathy

Competing Interests: Declaration of interests Thirteen of the authors (ZA, S-CH, LJ, AM, CO, MO, JP, YP-S, DS, LB-V, MRo, MW, and HW) were compensated for their time while drafting and developing the Lancet Countdown's report. LC was supported by a grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health. CD received funding from the European Research Council (FLORA, grant number 101039402). RD was supported by a grant from the High Tide Foundation and subcontracts on funds from the Wellcome Trust and US Centers for Disease Control and Prevention. GG-S received funding from the UK National Institute for Health and Care Research for the Global Health Research Group on Diet and Activity (NIHR133205, with sub-award contract number G109900-SJ1/171 with the University of Cambridge). SHG's research was supported by the National Research Foundation, Prime Minister's Office, Singapore, under its Campus for Research Excellence and Technological Enterprise programme (grant number NRF2019-THE001-0006). JJH was supported by two grants from the Wellcome Trust and a grant from the US National Science Foundation. RH, RK, and MSo acknowledge funding from Academy of Finland projects HEATCOST (grant 334798) and VFSP-WASE (grant 359421), together with EU Horizon projects FirEUrisk (grant number 101003890) and EXHAUSTION (grant number 820655). OJ was supported by grants from the National Health Medical Research Council (Heat and Health: building resilience to extreme heat in a warming world, GNT1147789); Wellcome Trust (Heat stress in ready-made garment factories in Bangladesh and the Heat inform pregnant study); and Resilience New South Wales (A new heat stress scale for general public); holds a patent for the Environmental Measurement Unit; and has received consulting fees from the National Institutes of Health. HM received funding from the Oak Foundation to support work on climate change through RealZero, is partly funded by the National Institute for Health Research's Comprehensive Biomedical Research Centre at University College London Hospitals, and received fees from Bayer Pharmaceuticals and Chiesl for sustainability consulting. JM-U was supported by grants PID2021-127107NB-I00 from Ministerio de Ciencia e Innovación (Spain) and 2021 SGR 00526 from Generalitat de Catalunya (Spain). JRo's work is supported by the Alexander von Humboldt foundation. RL, JRo, and MRo were supported by Horizon Europe through the IDAlert project (101057554) and UK Research and Innovation (reference number 10056533). RNS reports a contract with Massachusetts General Hospital. MSo and AU were supported by the Finnish Foreign Ministry project IBA-ILMA (grant number VN/13798/2023). MSp was supported by funding from the Wellcome Trust, through Our Planet Our Health (Livestock, Environment and People, award number 205212/Z/16/Z) and a Wellcome Career Development Award (Towards the full cost of diets, award number 225318/Z/22/Z). JDSh was supported by the Canadian Institutes of Health Research, the Commonwealth Fund, and the Emergency Care Research Institute and has received consulting fees from the Institute for Healthcare Research. JT was supported by the Research Council of Finland (T-Winning Spaces 2035 project), the UK Medical Research Council (PICNIC project), and the Finnish Ministry of the Environment (SEASON project). JB is employed as a consultant by the Global Climate and Health Alliance. ML received consulting fees from YarCom for advisory services and was supported by general use gifts awarded to the Center on Global Energy Policy at Columbia University, USA. JMil acknowledges consulting fees from the C40 Climate Leadership Group. CZ-C received a consultancy from the University of Alberta and was supported by contracts with her university (Universidad Peruana Cayetano Heredia), University of Leeds, WHO, and the Wellcome Trust; she was also supported by a letter of agreement between her university and the Food and Agriculture Organization's Indigenous Peoples Unit. MD was supported by the Wellcome Trust via the Complex Urban Systems for Sustainability and Health project (grants 205207/Z/16/Z and 209387/Z/17/Z). IH, S-CH, MRo, CT, and RL were supported by the Horizon Europe CATALYSE project (CATALYSE grant number 101057131, HORIZON-HLTH-2021-ENVHLTH-02, with UK Research and Innovation reference number 10041512). The work of YH, YL, DT, and QZ was supported by the National Aeronautics and Space Administration's Earth Action programme (grant number 80NSSC21K0507). AJP was supported by the Bezos Earth Fund and the Schmidt Family Foundation. ER and SD were supported by a Process-based models for climate impact attribution across sectors (PROCLIAS) grant (COST Action PROCLIAS grant CA19139), funded by European Cooperation in Science and Technology. All other authors declare no competing interests.

INTRODUCTION: While there are numerous factors that may affect pilot attentional performance, we hypothesize that an increased expiratory work of breathing experienced by fighter pilots may impose a "distraction stimulus" by creating an increased expiratory effort sensation. Therefore, the purpose of this study was to determine the extent to which increasing expiratory pressure time product or expiratory effort sensation impacts attentional performance. METHODS: Data was collected on 10 healthy participants (age: 29 ± 6 yr). Participants completed six repetitions of a modified Masked Conjunctive Continuous Performance Task protocol while breathing against four different expiratory threshold loads. Repeated measures analysis of variances and generalized additive mixed effects models were used to investigate the effects of expiratory threshold load conditions on expiratory pressure time product, expiratory effort sensation, and the influence of altered end tidal gases on Masked Conjunctive Continuous Performance Task scores. RESULTS: The overall median hit reaction times were significantly longer as the expiratory threshold loads increased. Specific shape-conjunctive and non-conjunctive median hit reaction times were longer with increased expiratory effort sensation. Additionally, increased expiratory effort sensation did not significantly change commission error rates, but did significantly increase omission error rates. DISCUSSION: The findings of our work suggest that both progressively greater expiratory threshold loads during spontaneous breathing and expiratory effort sensation may impair subjects' attentional performance due to longer reaction times and increased stimuli recognition error rates. Kelley EF, Cross TJ, Johnson BD. Expiratory threshold loading and attentional performance . Aerosp Med Hum Perform. 2024; 95(7):367-374.

We investigated the effect of exercise intensity and tolerable duration on the development of exercise-induced diaphragm and expiratory muscle fatigue. Ten healthy adults (25 ± 5 yr; 2 females) cycled to intolerance on three separate occasions: 1 ) 5% below critical power (tw ) and gastric (Pga tw ) twitch pressures, respectively. Exercise time was 34.5 ± 6.2 min, 10.2 ± 2.6 min, and 4.9 ± 0.7 min for 2 ) at end-exercise was lower during 2peak ) relative to Δ25 (97 ± 4% V̇o 2peak ) and Δ50 (99 ± 4% V̇o 2peak ) ( P < 0.001). The pre- to postexercise decrease in Pdi tw was greater after Δ25 (-22 ± 12%) versus tw from pre- to postexercise was not different between trials ( 0.05). In conclusion, the magnitude of exercise-induced diaphragm fatigue was greater after longer-duration severe exercise than after shorter-duration severe and heavy exercise. By contrast, the magnitude of exercise-induced expiratory muscle fatigue was unaffected by exercise intensity and tolerable duration. NEW & NOTEWORTHY Exercise-induced respiratory muscle fatigue contributes to limiting exercise tolerance. Accordingly, better understanding the exercise conditions under which respiratory muscle fatigue occurs is warranted. Although heavy-intensity as well as short- and long-duration severe-intensity exercise performed to intolerance elicit diaphragm and expiratory muscle fatigue, we find, for the first time, that the relationship between exercise intensity, exercise duration, and the magnitude of exercise-induced fatigue is different for the diaphragm compared with the expiratory muscles.

The MJA-Lancet Countdown on health and climate change in Australia was established in 2017 and produced its first national assessment in 2018 and annual updates in 2019, 2020, 2021 and 2022. It examines five broad domains: health hazards, exposures and impacts; adaptation, planning and resilience for health; mitigation actions and health co-benefits; economics and finance; and public and political engagement. In this, the sixth report of the MJA-Lancet Countdown, we track progress on an extensive suite of indicators across these five domains, accessing and presenting the latest data and further refining and developing our analyses. Our results highlight the health and economic costs of inaction on health and climate change. A series of major flood events across the four eastern states of Australia in 2022 was the main contributor to insured losses from climate-related catastrophes of $7.168 billion - the highest amount on record. The floods also directly caused 23 deaths and resulted in the displacement of tens of thousands of people. High red meat and processed meat consumption and insufficient consumption of fruit and vegetables accounted for about half of the 87 166 diet-related deaths in Australia in 2021. Correction of this imbalance would both save lives and reduce the heavy carbon footprint associated with meat production. We find signs of progress on health and climate change. Importantly, the Australian Government released Australia's first National Health and Climate Strategy, and the Government of Western Australia is preparing a Health Sector Adaptation Plan. We also find increasing action on, and engagement with, health and climate change at a community level, with the number of electric vehicle sales almost doubling in 2022 compared with 2021, and with a 65% increase in coverage of health and climate change in the media in 2022 compared with 2021. Overall, the urgency of substantial enhancements in Australia's mitigation and adaptation responses to the enormous health and climate change challenge cannot be overstated. Australia's energy system, and its health care sector, currently emit an unreasonable and unjust proportion of greenhouse gases into the atmosphere. As the Lancet Countdown enters its second and most critical phase in the leadup to 2030, the depth and breadth of our assessment of health and climate change will be augmented to increasingly examine Australia in its regional context, and to better measure and track key issues in Australia such as mental health and Aboriginal and Torres Strait Islander health and wellbeing., (© 2024 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Competing Interests: Declaration of interests 14 of the authors (MRo, MWa, LJ, MBO'H, CO, HW, CdN, HK, PL, DS, CG, ZA, MY-G, and KRvD) were compensated for their time while drafting and developing the Lancet Countdown's report. OG was supported by the EU Horizon Grant: Climate Action To Advance Healthy Societies in Europe (Project 101057131–CATALYSE), for which there is overlap of data collection and preprocessing with the materials submitted in this report. MSp was supported by the Wellcome Trust Livestock, Environment and People (grant number 205212/Z/16/Z) and Wellcome Trust (grant number 225318/Z/22/Z). JT was supported by the Academy of Finland grants for the T-Winning (grant number 353327). CD was supported by the UK Natural Environment Research Council Independent Research Fellowship (grant number NE/N01524X/1), which ended in 2021, and by the European Research Council starting grant FLORA (grant number 101039402). OJ was supported by the NHMRC Investigator Grant entitled Heat and Health: Building resilience to extreme heat in a warming world (GNT20009507), the Wellcome Trust grant Heat stress in ready-made garment factories in Bangladesh (216059/Z/19/Z), and the Resilience New South Wales grant A new heat stress scale for general public (PJ-0000850). YL was supported by funding from the National Aeronautics and Space Administration (grant number: 80NSSC21K0507) for the wildfire population exposure and fire danger indicators. TO and IH were supported by the UK Research and Innovation Engineering and Physical Sciences Research Council Centre for Research in Energy Demand Solutions (grant number EP/R035288/1). MRo was supported by funding from IDAlert project (UK Research and Innovation project reference number 10056533). KB was supported by funding from the National Institute for Health and Care Research (NIHR) Centre on Non-communicable Diseases and Environmental Change (NIHR203247). All other authors declare no competing interests. The authors alone are responsible for the views expressed in this Commission, and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated.

Introduction: Measurement of the work of breathing (Wb) during exercise provides useful insights into the energetics and mechanics of the respiratory muscles across a wide range of minute ventilations. The methods and analytical procedures used to calculate the Wb during exercise have yet to be critically appraised in the literature., Purpose: The aim of this systematic review was to evaluate the quality of methods used to measure the Wb during exercise in the available literature., Methods: We conducted an extensive search of three databases for studies that measured the Wb during exercise in adult humans. Data were extracted on participant characteristics, flow/volume and pressure devices, esophageal pressure (P oes ) catheters, and methods of Wb analysis., Results: A total of 120 articles were included. Flow/volume sensors used were primarily pneumotachographs ( n = 85, 70.8%), whereas the most common pressure transducer was of the variable reluctance type ( n = 63, 52.5%). Esophageal pressure was frequently obtained via balloon-tipped catheters ( n = 114, 95.0%). Few studies mentioned calibration, frequency responses, and dynamic compensation of their measurement devices. The most popular method of measuring the Wb was pressure-volume integration ( n = 51, 42.5%), followed by the modified Campbell ( n = 28, 23.3%) and Dean & Visscher diagrams ( n = 26, 21.7%). Over one-third of studies did not report the methods used to process their pressure-volume data, and the majority (60.8%) of studies used the incorrect Wb units and/or failed to discuss the limitations of their Wb measurements., Conclusions: The findings of this systematic review highlight the need for the development of a standardized approach for measuring Wb, which is informative, practical, and accessible for future researchers., (Copyright © 2023 by the American College of Sports Medicine.)

The main protease of SARS-CoV-2 (M pro ) plays a critical role in viral replication; although it is relatively conserved, M pro has nevertheless evolved over the course of the COVID-19 pandemic. Here, we examine phenotypic changes in clinically observed variants of M pro , relative to the originally reported wild-type enzyme. Using atomistic molecular dynamics simulations, we examine effects of mutation on protein structure and dynamics. In addition to basic structural properties such as variation in surface area and torsion angles, we use protein structure networks and active site networks to evaluate functionally relevant characters related to global cohesion and active site constraint. Substitution analysis shows a continuing trend toward more hydrophobic residues that are dependent on the location of the residue in primary, secondary, tertiary, and quaternary structures. Phylogenetic analysis provides additional evidence for the impact of selective pressure on mutation of M pro . Overall, these analyses suggest evolutionary adaptation of M pro toward more hydrophobicity and a less-constrained active site in response to the selective pressures of a novel host environment.

Objectives: The frequency of bushfires in Australia is increasing and it is expected bushfire smoke will become a more prevalent phenomenon impacting air quality. The objective of this position statement is to provide guidance to the sport sector regarding exercise in air affected by bushfire smoke., Design: This is position statement from the Australian Institute of Sport, based on a narrative review of the literature regarding bushfire smoke and its effects on health and exercise performance., Methods: A narrative review of scientific publications regarding the effects of bushfire smoke on health and exercise performance., Results: Bushfire smoke has negative impacts on health and performance. Athletes exercising at high intensity over a prolonged duration will increase their exposure to air pollutants. Athletes with a history of elevated airway responsiveness are likely to be at increased risk of an adverse response to bushfire smoke exposure., Conclusions: Athletes, coaches, support staff and sport organisations should monitor air quality (PM2.5 concentration) and make appropriate adjustments to training duration and intensity., Competing Interests: Declaration of interest statement We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2023. Published by Elsevier Ltd.)

Rationale: There are growing concerns over the occurrence of adverse physiologic events (PEs) occurring in pilots during operation of United States Air Force and Navy high-performance aircraft. We hypothesize that a heightened inspiratory work of breathing experienced by jet pilots by virtue of the on-board life support system may constitute a "distraction stimulus" consequent to an increased sensation of respiratory muscle effort. As such, the purpose of this study was to determine whether increasing inspiratory muscle effort adversely impacts on attentional performance., Methods: Twelve, healthy participants (age: 29 ± 6 years) were recruited for this study. Participants completed six repetitions of a modified Masked Conjunctive Continuous Performance Task (MCCPT) protocol while breathing against four different inspiratory threshold loads to assess median reaction times (RTs). A computer-controlled threshold loading device was used to set the inspiratory threshold loads. Repeated measures analysis of variances (ANOVAs) were performed to examine: (i) the efficacy of the threshold loading device to impose significantly higher loading at each loading condition; (ii) the effects of loading condition on respiratory muscle effort sensation; and (iii) the influence of hypercapnia on MCCPT scores during inspiratory threshold loading. Generalized additive mixed effects models (GAMMs) were used to examine the potential non-linear effects of respiratory muscular effort sensation, device loading, and hypercapnia, on MCCPT scores during inspiratory threshold loading., Results: Inspiratory threshold loading significantly augmented ( P < 0.05) inspiratory effort sensation and the inspiratory pressure-time product (PTP). Our analyses also revealed that median hit RT was positively associated with inspiratory effort sensation during inspiratory loading trials., Conclusion: The findings of this work suggest that it was not increasing inspiratory muscle effort (i.e., PTP) per se , but rather participant's subjective perception of inspiratory "load" that impacts negatively on attentional performance; i.e., as the degree of inspiratory effort sensation increased, sotoo did median hit RT. As such, it is reasonable to suggest that minimizing inspiratory effort sensation (independent of the mechanical output of the inspiratory muscles) during high-performance flight operations may prove useful in reducing pilot RTs during complex behavioral tasks., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kelley, Cross and Johnson.)

The purpose of this study was to determine whether the longitudinal progression of decline in left ventricular ejection fraction (LVEF) in Duchenne muscular dystrophy (DMD) patients is moderated by ADRB1 genotype and whether the efficacy of ß-blocker therapy is influenced by genotype status. About 147 DMD patients (6-34 years.) were analyzed with a focus on β 1 adrenergic receptor (ADRB1) genotype variants. Patients were grouped by ADRB1 genotype resulting in Gly389 patients and Arg389 patients. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of LVEF across patient ages between genotype groups and for ß-blocker use. Both genotype groups displayed a progressive decline in LVEF starting around the mean age of ambulation loss (~12 years). However, there was no difference between genotype groups in the progression of decline in LVEF. There was a significant effect of ß-blocker use on longitudinal LVEF, wherein patients on ß-blockers had systematically lower LVEF when compared to patients not on ß-blockers. However, the effect of ß-blocker therapy on LVEF was not affected by ADRB1 genotype. The current study did not demonstrate an influence of patient ADRB1 genotype on longitudinal LVEF in our cohort. Despite previous literature suggesting a positive influence of ß-blocker use on cardiac function in DMD patients and of an ADRB1 genotypic difference in responsiveness to ß-blocker use, we did not observe this in our cohort. Interestingly, our cohort did not demonstrate a positive influence of ß-blocker use on LVEF measures., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Asthma with irreversible or fixed airflow obstruction (FAO) is a severe clinical phenotype that is difficult to treat and is associated with an accelerated decline in lung function and excess morbidity. There are no current treatments to reverse or prevent this excessive decline in lung function in these patients, due to a lack of understanding of the underlying pathophysiology. The current paradigm is that FAO in asthma is due to airway remodeling driven by chronic inflammation. However, emerging evidence indicates significant and critical structural and functional changes to the lung parenchyma and its lung elastic properties in asthma with FAO, suggesting that FAO is a 'whole lung' problem and not just of the airways. In this Perspective we draw upon what is known thus far on the pathophysiological mechanisms contributing to FAO in asthma, and focus on recent advances and future directions. We propose the view that structural and functional changes in parenchymal tissue, are just as (if not more) important than airway remodeling in causing persistent lung function decline in asthma. We believe this paradigm of FAO should be considered when developing novel treatments., Competing Interests: GK reports that during the last 5 years and conduct of the study; grants, personal fees and other from AstraZeneca, Boehringer Ingelheim, CycloPharm, GlaxoSmithKline, Novartis, Menarini, MundiPharma, Chiesi, Cipla, grants from National Health & Medical Research Council, Asthma Foundation, Philanthropic donations via Sydney University, other from ATS and ERS, non-financial support and other from Restech, outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rutting, Thamrin, Cross, King and Tonga.)

The progression of decline in forced vital capacity as percent predicated (FVC%p) is a strong indicator of worsening prognosis in patients with Duchenne muscular dystrophy (DMD). Evidence suggests that ß 2 adrenergic (ADRB2) receptors may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function. The purpose of this study was to determine the influence of ADRB2 genotype on longitudinal measures of FVC%p as a function of age in DMD patients. Data from the CINRG Duchenne Natural History Study including 169 DMD patients (5-25 yrs) were analyzed. A generalized additive mixed effects model was used to examine differences in the nonlinear trend of FVC%p across patient ages between genotype groups after controlling for patient demographics, corticosteroid-use, and ambulatory status. Both genotype groups displayed a progressive, maturational decline in FVC%p. Notwithstanding this decline, patients expressing the Gly16 polymorphism demonstrated systematically lower FVC%p values at any given age compared with patients expressing the Arg16 polymorphism (P < 0.01). Therefore, expressing the Gly16 polymorphism may prove detrimental to respiratory function in DMD patients. These data suggest maybe ADRB2 genotyping should be considered in the clinical management of DMD patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Published by Elsevier B.V.)

Background: The COVID-19 pandemic has arguably facilitated a shift toward increased sedentariness and reduced physical activity. Moreover, there is mounting evidence that mental health has also declined during the pandemic. However, it remains unknown to what extent social distancing (SD) behaviors and mental health have affected the physical activity levels of the general population., Objective: The purpose of this study was to determine the influence of SD behaviors and prevailing mental health on the odds of being physically active during the early COVID-19 pandemic response., Methods: A total of 4819 adults (2474/4819, 51.3%, female) from the US population with a median age of 46 (IQR 35-59) completed an online survey during the early pandemic response (April-June 2020). The survey included questions on adherence to 11 SD behaviors, and validated questionnaires which assessed self-reported physical activity, depression, anxiety, and mental well-being. Respondents were categorized into 2 physical activity groups: inactive (0-599 metabolic equivalent of task [MET]-minutes/week) and active (≥600 MET-minutes/week). A logistic generalized additive model (GAM) was used to determine which SD factors and mental health outcomes were associated with physical activity level., Results: The GAM analysis revealed that wearing a facemask in public (odds ratio [OR] 1.46, 95% CI 1.14-1.79; P=.003), limiting the use of public transport (OR 1.47, 95% CI 1.19-1.83; P=.001), and restricting travel outside the house (OR 1.56, 95% CI 1.19-2.05; P=.002) were SD behaviors associated with higher odds of being more physically active. Conversely, avoiding physical activity outside the house was associated with higher odds of being inactive (OR 0.52, 95% CI 0.46-0.63; P<.001). Leaving the house more frequently, and a higher mental well-being were associated with increasing odds of being physically active (P<.001). Engaging with a moderate number of SD behaviors (3-7 total) was positively associated with physical activity, whereas a very high SD vigilance (ie, engaging with ≥10 total behaviors) decreased the odds of being active during the early pandemic response., Conclusions: Based on the findings of our study, we suggest that future public health messaging of SD guidelines should include (1) a clear portrayal of the benefits of regular exercise on mental health; and (2) a specific focus on how to be physically active outdoors in a COVID-safe manner., (©Troy J Cross, Jennifer M J Isautier, Sarah J Morris, Bruce D Johnson, Courtney M Wheatley-Guy, Bryan J Taylor. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 24.09.2021.)

Stewart, Glenn M., Troy J. Cross, Michael J. Joyner, Steven C. Chase, Timothy Curry, Josh Lehrer-Graiwer, Kobina Dufu, Nicholas E. Vlahakis, and Bruce D. Johnson. Impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve on arterial blood gases and pulmonary gas exchange during maximal exercise in hypoxia. High Alt Med Biol . 22:249-262, 2021. Introduction: Physiological and pathological conditions, which reduce the loading of oxygen onto hemoglobin (Hb), can impair exercise capacity and cause debilitating symptoms. Accordingly, this study examined the impact of pharmacologically left shifting the oxygen-hemoglobin dissociation curve (ODC) on arterial oxygen saturation (SaO 2 ) and exercise capacity. Methods: Eight healthy subjects completed a maximal incremental exercise test in hypoxia (F I O 2 : 0.125) and normoxia (F I O 2 : 0.21) before (Day 1) and after (Day 15) daily ingestion of 900 mg of voxelotor (an oxygen/Hb affinity modulator). Pulmonary gas exchange and arterial blood gases were assessed throughout exercise and at peak. Data for a 1,500 mg daily drug dose are reported in a limited cohort ( n  = 3). Results: Fourteen days of drug administration left shifted the ODC (p50 measured under standard conditions, Day 1: 28.0 ± 2.1 mmHg vs. Day 15: 26.1 ± 1.8 mmHg, p  < 0.05). Throughout incremental exercise in hypoxia, SaO 2 was systematically higher after drug (peak exercise SaO 2 on Day 1: 71 ± 2 vs. Day 15: 81% ± 2%, p  < 0.001), whereas oxygen extraction (Ca-vO 2 diff) and consumption (VO 2 ) were similar (peak exercise Ca-vO 2 diff on Day 1: 11.5 ± 1.7 vs. Day 15: 11.0 ± 1.8 ml/100 ml blood, p  = 0.417; peak VO 2 on Day 1: 2.59 ± 0.39 vs. Day 15: 2.47 ± 0.43 l/min, p  = 0.127). Throughout incremental exercise in normoxia, SaO 2 was systematically higher after drug, whereas peak VO 2 was reduced (peak exercise SaO 2 on Day 1: 93.9 ± 1.8 vs. Day 15: 95.8% ± 1.0%, p  = 0.008; peak VO 2 on Day 1: 3.62 ± 0.55 vs. Day 15: 3.26 ± 52 l/min, p  = 0.001). Conclusion: Pharmacologically increasing the affinity of Hb for oxygen improved SaO 2 during hypoxia without impacting exercise capacity; however, left shifting the ODC in healthy individuals appears detrimental to exercise capacity in normoxia. Left shifting the ODC to different magnitudes and under more chronic forms of hypoxia warrants further study.

The mechanical work of breathing (Wb) is an insightful tool used to assess respiratory mechanics during exercise. There are several different methods used to calculate the Wb, however, each approach having its own distinct advantages/disadvantages. To date, a comprehensive assessment of the differences in the components of Wb between these methods is lacking. We therefore sought to compare the values of Wb during graded exercise as determined via the four most popular methods: 1 ) pressure-volume integration; 2 ) the Hedstrand diagram; 3 ) the Otis diagram; and the 4 ) modified Campbell diagram. Forty-two participants (30 ± 15 yr; 16 women) performed graded cycling to volitional exhaustion. Esophageal pressure-volume loops were obtained throughout exercise. These data were used to calculate the total Wb and, where possible, its subcomponents of inspiratory and expiratory, resistive and elastic Wb, using each of the four methods. Our results demonstrate that the components of Wb were indeed different between methods across the minute ventilations engendered by graded exercise. Importantly, however, no systematic pattern in these differences could be observed. Our findings indicate that the values of Wb obtained during exercise are uniquely determined by the specific method chosen to compute its value-no two methods yield identical results. Because there is currently no "gold-standard" for measuring the Wb, it is emphasized that future investigators be cognizant of the limitations incurred by their chosen method, such that observations made by others may be interpreted with greater context, and transparency. NEW & NOTEWORTHY The measurement of the work of breathing (Wb) during exercise provides us with deep insights into respiratory (patho)physiology, and sheds light on the putative factors which lead to respiratory muscle fatigue. There are 4 popular methods available to determine the Wb. Our study demonstrates that no two of these methods produce identical values of Wb during exercise. This paper also discusses the practical and theoretical limitations of each method.

Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

There are growing concerns that the COVID-19 pandemic has facilitated a sedentary shift in our physical activity habits. A reduction in physical activity during the pandemic may be secondary to restrictive policies implemented at the government-level, typically those policies which limit interpersonal contact; for example, physical/social distancing. It is without question that social distancing is a necessary measure to mitigate community transmission of the novel virus; however, these policies often limit the public's opportunities to engage in physical activity. The strictest enforcement of social distancing occurs during an authority-mandated 'lockdown' (also known as a 'shelter-in-place' or 'stay-at-home' order). This Viewpoint focuses on the current evidence demonstrating that physical activity declines during a COVID-19 'lockdown'. We highlight the point that most of the available evidence stems from investigations using non-validated, self-reported measures of physical activity and discuss the caveats therewith. This Viewpoint explores whether current evidence reflects an 'actual' or rather a 'perceived' reduction in physical activity, and raises the question of whether this distinction matters in the end., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The modified Campbell diagram provides one of the most comprehensive assessments of the work of breathing (Wb) during exercise, wherein the resistive and elastic work of inspiration and expiration are quantified. Importantly, a necessary step in constructing the modified Campbell diagram is to obtain a value for chest wall compliance (C CW ). To date, it remains unknown whether estimating or directly measuring C CW impacts the Wb, as determined by the modified Campbell diagram. Therefore, the purpose of this study was to evaluate whether the components of the Wb differ when the modified Campbell diagram is constructed using an estimated versus measured value of C CW . Forty-two participants ( n = 26 men, 16 women) performed graded exercise to volitional exhaustion on a cycle ergometer. C CW was measured directly at rest via quasistatic relaxation. Estimated values of C CW were taken from prior literature. The measured value of C CW was greater than that obtained via estimation (214 ± 52 mL/cmH 2 O vs. 189 ± 18 mL/cmH 2 O; P < 0.05). At modest-to-high minute ventilations (i.e., 50-200 L/min), the inspiratory elastic Wb was greater and expiratory resistive Wb was lower, when modified Campbell diagrams were constructed using estimated compared with measured values of C CW ( P = 0.001). These differences were however small and never exceeded ±5%. Thus, although our findings demonstrate that estimating C CW has a measurable impact on the determination of the Wb, its effect appears relatively small within a cohort of healthy adults during graded exercise.

We describe here a novel protocol that sequentially combines venous followed by arterial occlusions to determine muscle blood flow and O 2 uptake from a single measurement point using near-infrared spectroscopy (NIRS) during handgrip exercise. NIRS data were obtained from the flexor digitorum superficialis (FDS) muscle on the dominant arm of 15 young, healthy adults (3 women; 26 ± 7 years; 78.6 ± 9.1 kg). Participants completed a series of 15-s static handgrip contractions at 20, 40 and 60% of maximal voluntary contraction (MVC) immediately followed by either a: (i) venous occlusion (VO); (ii); arterial occlusion (AO); or venous then arterial occlusion (COMBO). Each condition was repeated 3 times for each exercise-intensity. The concordance correlation coefficient (CCC) and robust linear mixed effects modeling were used to determine measurement agreement between vascular occlusion conditions. FDS muscle blood flow ([Formula: see text]) and conductance ([Formula: see text]) demonstrated strong absolute agreement between VO and COMBO trials from rest up to 60%MVC, as evidenced by high values for CCC (> 0.82) and a linear relationship between conditions that closely approximated the line-of-identity (perfect agreement). Conversely, although FDS muscle O 2 uptake ([Formula: see text]) displayed "substantial" to "near perfect" agreement between methods across exercise intensities (i.e., CCC > 0.80), there was a tendency for COMBO trials to underestimate [Formula: see text] by up to 7%. These findings indicate that the COMBO method provides valid estimates of [Formula: see text] and, to a slightly lesser extent, [Formula: see text] at rest and during static handgrip exercise up to 60%MVC. Practical implications and suggested improvements of the method are discussed.

The SARS-CoV-2 main protease (M pro ) is essential to viral replication and cleaves highly specific substrate sequences, making it an obvious target for inhibitor design. However, as for any virus, SARS-CoV-2 is subject to constant neutral drift and selection pressure, with new M pro mutations arising over time. Identification and structural characterization of M pro variants is thus critical for robust inhibitor design. Here we report sequence analysis, structure predictions, and molecular modeling for seventy-nine M pro variants, constituting all clinically observed mutations in this protein as of April 29, 2020. Residue substitution is widely distributed, with some tendency toward larger and more hydrophobic residues. Modeling and protein structure network analysis suggest differences in cohesion and active site flexibility, revealing patterns in viral evolution that have relevance for drug discovery.

Numerous pathophysiological conditions induce hypoxemia-related cardiopulmonary perturbations, decrements in exercise capacity, and debilitating symptoms. Accordingly, this study investigated the efficacy of an allosteric hemoglobin modulator (voxelotor) to enhance arterial oxygen saturation during low-intensity exercise in hypoxia. Eight normal healthy subjects (36 ± 7 yr; 73.8 ± 9.5 kg; 3 women) completed a submaximal cycling test (60 W) under normoxic ([Formula: see text]: 0.21; O 2 partial pressure: 144 mmHg) and hypoxic ([Formula: see text]: 0.125; O 2 partial pressure: 82 mmHg) conditions before ( day 1 ) and after ( day 15 ) 14 days of oral drug administration. While stationary on a cycle ergometer and during exercise, ratings of perceived exertion (RPE) and dyspnea, oxygen consumption (V̇o 2 ), and cardiac output (Q) were measured noninvasively, while arterial blood pressure (MAP) and blood gases ([Formula: see text], [Formula: see text], and [Formula: see text]) were measured invasively. The 14-day drug administration left shifted the oxygen-hemoglobin dissociation curve (ODC; p50 measured at standard pH and Pco 2 ; day 1 : 28.0 ± 2.1 mmHg vs. day 15 : 26.1 ± 1.8 mmHg, P < 0.05). RPE, dyspnea, V̇o 2 , Q, and MAP were not different between day 1 and day 15 . [Formula: see text] was similar during normoxia on day 1 and day 15 while stationary but higher during exercise ( day 1 : 95.2 ± 0.4% vs. day 15 : 96.6 ± 0.3%, P < 0.05). [Formula: see text] was higher during hypoxia on day 15 while stationary ( day 1 : 82.9 ± 3.4% vs. day 15 : 90.9 ± 1.8%, P < 0.05) and during exercise ( day 1 : 73.6 ± 2.5% vs. day 15 : 84.8 ± 2.7%, P < 0.01). [Formula: see text] and [Formula: see text]were systematically higher and lower, respectively, after drug ( P < 0.01), while the alveolar-arterial oxygen difference was unchanged suggesting hyperventilation contributed to the rise in [Formula: see text]. Oral administration of voxelotor left shifted the ODC and stimulated a mild hyperventilation, leading to improved arterial oxygen saturation without altering V̇o 2 and central hemodynamics during rest and low-intensity exercise. This effect was more pronounced during submaximal hypoxic exercise, when arterial desaturation was more evident. Additional studies are needed to determine the effects of voxelotor during maximal exercise and under chronic forms of hypoxia. NEW & NOTEWORTHY In humans, a novel allosteric hemoglobin-oxygen affinity modulator was administered to comprehensively examine the cardiopulmonary consequences of stabilizing a portion of the available hemoglobin in a high-oxygen affinity state during submaximal exercise in normoxia and hypoxia. Oral administration of voxelotor enhanced arterial oxygen saturation during submaximal exercise without altering oxygen consumption and central hemodynamics; however, the partial pressure of arterial carbon dioxide was reduced and the partial pressure of arterial oxygen was increased implying that hyperventilation also contributed to the increase in oxygen saturation. The preservation of arterial oxygen saturation and content was particularly evident during hypoxic submaximal exercise, when arterial desaturation typically occurs, but this did not influence arterial-venous oxygen difference.

Intrapleural pressure during a forced vital capacity (VC) maneuver is often in excess of that required to generate maximal expiratory airflow. This excess pressure compresses alveolar gas (i.e., thoracic gas compression [TGC]), resulting in underestimated forced expiratory flows (FEFs) at a given lung volume. It is unknown if TGC is influenced by sex; however, because men have larger lungs and stronger respiratory muscles, we hypothesized that men would have greater TGC. We examined TGC across the "effort-dependent" region of VC in healthy young men (n = 11) and women (n = 12). Subjects performed VC maneuvers at varying efforts while airflow, volume, and esophageal pressure (P OES ) were measured. Quasistatic expiratory deflation curves were used to obtain lung recoil (P LUNG ) and alveolar pressures (i.e., P ALV  = P OES -P LUNG ). The raw maximal expiratory flow-volume (MEFV raw ) curve was obtained from the "maximum effort" VC maneuver. The TGC-corrected curve was obtained by constructing a "maximal perimeter" curve from all VC efforts (MEFV corr ). TGC was examined via differences between curves in FEFs (∆FEF), area under the expiratory curves (∆A EX ), and estimated compressed gas volume (∆VGC) across the VC range. Men displayed greater total ∆A EX (5.4 ± 2.0 vs. 2.0 ± 1.5 L 2 ·s -1 ; p < .001). ∆FEF was greater in men at 25% of exhaled volume only (p < .05), whereas ∆VGC was systematically greater in men across the entire VC (main effect; p < .05). P ALV was also greater in men throughout forced expiration (p < .01). Taken together, these findings demonstrate that men display more TGC, occurring early in forced expiration, likely due to greater expiratory pressures throughout the forced VC maneuver., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Introduction: Long-term use of continuous-flow left ventricular assist devices may have negative consequences for autonomic, cardiovascular and gastrointestinal function. It has thus been suggested that non-invasive monitoring of arterial pulsatility in patients with a left ventricular assist device is highly important for ensuring patient safety and longevity. We have developed a novel, semi-automated frequency-domain-based index of arterial pulsatility that is obtained during suprasystolic occlusions of the upper arm: the 'cuff pulsatility index'., Purpose: The purpose of this study was to evaluate the relationship between the cuff pulsatility index and invasively determined arterial pulsatility in patients with a left ventricular assist device., Methods: Twenty-three patients with a left ventricular assist device with end-stage heart failure (six females: age = 65 ± 9 years; body mass index = 30.5 ± 3.7 kg m -2 ) were recruited for this study. Suprasystolic occlusions were performed on the upper arm of the patient's dominant side, from which the cuff pressure waveform was obtained. Arterial blood pressure was obtained from the radial artery on the contralateral arm. Measurements were obtained in triplicate. The relationship between the cuff pressure and arterial blood pressure waveforms was assessed in the frequency-domain using coherence analysis. A mixed-effects approach was used to assess the relationship between cuff pulsatility index and invasively determined arterial pulsatility (i.e. pulse pressure)., Results: The cuff pressure and arterial blood pressure waveforms demonstrated a high coherence up to the fifth harmonic of the cardiac frequency (heart rate). The cuff pulsatility index accurately tracked changes in arterial pulse pressure within a given patient across repeated measurements., Conclusions: The cuff pulsatility index shows promise as a non-invasive index for monitoring residual arterial pulsatility in patients with a left ventricular assist device across time.

Heart failure (HF) is a complex and multifaceted disease. The disease affects multiple organ systems, including the respiratory system. This review provides three unique examples illustrating how the cardiovascular and respiratory systems interrelate because of the pathology of HF. Specifically, these examples outline the impact of HF pathophysiology on 1 ) respiratory mechanics and the mechanical "cost" of breathing; 2 ) mechanical interactions of the heart and lungs; and on 3 ) abnormalities of pulmonary gas exchange during exercise, and how this may be applied to treatment. The goal of this review is to, therefore, raise the awareness that HF, though primarily a disease of the heart, is accompanied by marked pathology of the respiratory system.

We propose that abnormalities of the pulmonary system contribute significantly to the exertional dyspnea and exercise intolerance observed in patients with chronic heart failure. Interventions designed to address the deleterious pulmonary manifestations of heart failure may, therefore, yield promising improvements in exercise tolerance in this population.

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease resulting in severe respiratory derangements. As such, DMD patients are at a high risk of nocturnal hypoventilation, thereby requiring nocturnal ventilation (NV). To this end, NV is an important clinical milestone in the management of DMD. Emerging evidence suggests that ß 2 adrenergic receptors (ADRB2) may play a role in determining respiratory function, whereby more functional ADRB2 genotype variants (e.g., Gly16) are associated with improved pulmonary function and respiratory muscle strength. These findings suggest that the more functional ADRB2 genotype may help to preserve respiratory function in patients with DMD. The purpose of this study was to identify the influence of ADRB2 genotype on the risk of NV use in DMD. Data from the CINRG Duchenne Natural History Study including 175 DMD patients (3-25 yrs) were analyzed focusing on ADRB2 genotype variants. Time-to-event analyses were used to examine differences in the age at prescription of full-time NV use between genotypes. There were no differences between genotype groups in age, height, weight, corticosteroid use, proportion of ambulatory patients, or age at loss of ambulation. DMD patients expressing the Gly16 polymorphism had a significantly (P < 0.05) lower mean age at NV prescription compared with those patients expressing the Arg16 polymorphism (21.80 ± 0.59 yrs. vs 25.91 ± 1.31 yrs., respectively). In addition, a covariate-adjusted Cox model revealed that the Gly16 variant group possessed a 6.52-fold higher risk of full-time NV use at any given age compared with the Arg16 polymorphism group. These data suggest that genetic variations in the ADRB2 gene may influence the age at which DMD patients are first prescribed NV, whereby patients with the Gly16 polymorphism are more likely to require NV assistance at an earlier age than their Arg16 counterparts.

The purpose of this report was to 1 ) detail the construction of a low-cost device that provides a "reference" flow waveform for pneumotachograph (PNT) calibration, i.e., the "syringe potentiometer" (SP), and to compare the 2 ) accuracy and 3 ) practical performance of "calibration curves" obtained with the SP device to other more established methods of PNT calibration, i.e., the weighted averaging (WA) and polynomial least-squares (PolyLS) methods. Volume and flow waveforms obtained via the SP device were validated against a motion capture system and were deemed accurate surrogates of actual syringe volume and flows. The SP device was used to construct a calibration curve of a PNT by dividing the flow waveform of the SP by the analog output of the PNT amplifier. A total of 187 inspiratory and 187 expiratory strokes were collected. When the entire data set of expiratory strokes was used, the SP, WA, and PolyLS methods together demonstrated acceptable volume and flow errors as per American Thoracic Society/European Respiratory Society recommendations (less than ±3.5% and less than ±5.0% errors, respectively). The "practical" performance of each method was assessed with a nested subsampling procedure, whereby volume and flow errors were evaluated as the number of strokes was increased (in blocks of 5 strokes). To this end, the SP method demonstrated practical performance superior to that of the WA and PolyLS approaches, whereby acceptable volume and flow errors were achieved after only 5 calibration strokes; the WA and PolyLS methods required 15 and 20 strokes, respectively, to achieve the same level of volume and flow accuracy. NEW & NOTEWORTHY This report describes the construction and validation of a low-cost device for the purposes of pneumotachograph (PNT) calibration: the "syringe potentiometer" (SP). Calibration of a PNT with the SP device yielded acceptable volume and flow errors (<3.5% and 5%, respectively) across a wide range of flows (<0.5 to 15 L/s). The SP device offered superior "practical performance" over other established PNT calibration methods, whereby acceptable volume and flow errors were achieved after only five calibration strokes.

Airway luminal area is the major determinant of resistance to airflow in the tracheobronchial tree. Women may have smaller central conducting airways than men; however, previous evidence is confounded by an indirect assessment of airway geometry and by subjects with prior smoking history. The purpose of this study was to examine the effect of sex on airway size in healthy nonsmokers. Using low-dose high-resolution computed tomography, we retrospectively assessed airway luminal area in healthy men ( n = 51) and women ( n = 73) of varying ages (19-86 yr). Subjects with a positive smoking history, cardiopulmonary disease, or a body mass index > 40 kg/m 2 were excluded. Luminal areas of the trachea, right and left main bronchus, bronchus intermediate, left and right upper lobes, and the left lower lobe were analyzed at three discrete points. The luminal areas of the conducting airways were ~26%-35% smaller in women. The trachea had the largest differences in luminal area between men and women (298 ± 47 vs. 195 ± 28 mm 2 or 35% smaller for men and women, respectively), whereas the left lower lobe had the smallest differences (57 ± 15 vs. 42 ± 9 mm 2 or 26% smaller for men and women, respectively). When a subset of subjects was matched for height, the sex differences in airway luminal area persisted, with women being ~20%-30% smaller. With all subjects, there were modest relationships between height and airway luminal area ( r = 0.73-0.53, P < 0.05). Although there was considerable overlap between sexes, the luminal areas of the large conducting airways were smaller in healthy women than in men. NEW & NOTEWORTHY Previous evidence for sex differences in airway size has been confounded by indirect measures and/or cohorts with significant smoking histories or pathologies. We found that central airways in healthy women were significantly smaller (~26%-35%) than men. The significant sex-difference in airway size was attenuated (20%-30% smaller) but preserved in a subset of subjects matched for height. Over a range of ages, healthy women have smaller central airways than men.

It is unknown whether the greater total work of breathing (WOB) with aging is due to greater elastic and/or resistive WOB. We hypothesized that older compared with younger adults would exhibit a greater total WOB at matched ventilations (V̇e) during graded exercise, secondary to greater inspiratory resistive and elastic as well as expiratory resistive WOB. Older (OA: 60 ± 8 yr; n = 9) and younger (YA: 38 ± 7 yr; n = 9) adults performed an incremental cycling test to volitional fatigue. Esophageal pressure, inspiratory (IRV) and expiratory reserve volumes (ERV), expiratory flow limitation (EFL), and ventilatory variables were measured at matched V̇e (i.e., 25, 50, and 75 l/min) during exercise. The inspiratory resistive and elastic as well as expiratory resistive WOB were quantified using the Otis method. At V̇e of 75 l/min, older adults had greater %EFL and larger tidal volumes to inspiratory capacity but smaller relative IRV ( P ≤ 0.03) than younger adults. Older compared with younger adults had greater total WOB at V̇ E of 50 and 75 l/min (OA: 90 ± 43 vs. YA: 49 ± 21 J/min; P < 0.04 for both). At V̇e of 75 l/min, older adults had greater inspiratory elastic and resistive WOB (OA: 44 ± 27 vs. YA: 24 ± 22 and OA: 23 ± 15 vs. YA: 11 ± 3 J/min, respectively, P < 0.03 for both) and expiratory resistive WOB (OA: 23 ± 19 vs. YA: 14 ± 9 J/min, P = 0.02) than younger adults. These data demonstrate that aging-induced pulmonary alterations result in greater inspiratory elastic and resistive as well as expiratory resistive WOB, which may have implications for the integrated response during exercise. NEW & NOTEWORTHY Aging-induced changes to the pulmonary system result in increased work of breathing (WOB) during exercise. However, it is not known whether this higher WOB with aging is due to differences in elastic and/or resistive WOB. Herein, we demonstrate that older adults exhibited greater inspiratory elastic and resistive as well as expiratory resistive WOB during exercise.

The purpose of this report was to illustrate how thoracic gas compression (TGC) artifact, and differences in air density, may together conflate the interpretation of changes in the forced expiratory flows (FEFs) at high altitude (>2400 m). Twenty-four adults (10 women; 44 ± 15 year) with normal baseline pulmonary function (>90% predicted) completed a 12-day sojourn at Mt. Kilimanjaro. Participants were assessed at Moshi (Day 0, 853 m) and at Barafu Camp (Day 9, 4837 m). Typical maximal expiratory flow-volume (MEFV) curves were obtained in accordance with ATS/ERS guidelines, and were either: (1) left unadjusted; (2) adjusted for TGC by constructing a "maximal perimeter" MEFV curve; or (3) adjusted for both TGC and differences in air density between altitudes. Forced vital capacity (FVC) was lower at Barafu compared with Moshi camp (5.19 ± 1.29 L vs. 5.40 ± 1.45 L, P < 0.05). Unadjusted data indicated no difference in the mid-expiratory flows (FEF 25-75% ) between altitudes (∆ + 0.03 ± 0.53 L sec -1 ; ∆ + 1.2 ± 11.9%). Conversely, TGC-adjusted data revealed that FEF 25-75% was significantly improved by sojourning at high altitude (∆ + 0.58 ± 0.78 L sec -1 ; ∆ + 12.9 ± 16.5%, P < 0.05). Finally, when data were adjusted for TGC and air density, FEFs were "less than expected" due to the lower air density at Barafu compared with Moshi camp (∆-0.54 ± 0.68 L sec -1 ; ∆-10.9 ± 13.0%, P < 0.05), indicating a mild obstructive defect had developed on ascent to high altitude. These findings clearly demonstrate the influence that TGC artifact, and differences in air density, bear on flow-volume data; consequently, it is imperative that future investigators adjust for, or at least acknowledge, these confounding factors when comparing FEFs between altitudes., (© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Introduction: Ectopic or heterotopic pancreas is a congenital disorder defined as abnormally located pancreatic tissue found outside the pancreatic frame. It is a rare entity that occasionally causes symptoms depending on its location., Presentation of Case: We present the case of an incidental finding of proximal jejunal ectopic pancreas in a middle-aged woman presenting with appendicitis., Discussion and Conclusion: Although rare it is necessary to be aware that jejunal ectopic pancreas can lead to jejunojejunal intussusception. Although diagnostic tools are emerging, pre operative diagnosis is difficult and resection is the management of choice of the incidentally found lesion., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Pulmonary congestion is a common finding of heart failure (HF), but it remains unclear how pulmonary and heart blood volumes (V p and V h , respectively) and extravascular lung water (EVLW) change in stable HF and affect lung function., Methods: Fourteen patients with HF (age 68 ± 11 y, LVEF 33 ± 8%) and 12 control subjects (age 65 ± 9 y) were recruited. A pulmonary function test, thoracic computerized tomographic (CT) scan, and contrast perfusion scan were performed. From the thoracic scan, a histogram of CT attenuation of lung tissue was generated and skew, kurtosis, and full-width half-max (FWHM) calculated as surrogates of EVLW. Blood volumes were calculated from the transit time of the contrast through the great vessels of the heart., Results: Patients with HF had greater V p and V h (V p 0.55 ± 0.21 L vs 0.41 ± 0.13 L; V h 0.53 ± 0.33 L vs 0.40 ± 0.15 L) and EVLW (skew 3.2 ± 0.5 vs 3.7 ± 0.7; kurtosis 19.4 ± 6.6 vs 25.9 ± 9.4; FWHM 73 ± 13 HU vs 59 ± 9 HU). Spirometric measures were decreased in HF (percentage of predicted: forced vital capacity 86 ± 17% vs 104 ± 9%; forced expiratory volume in 1 second 83 ± 20% vs 105 ± 11%; maximal mid-expiratory flow 82 ± 42% vs 115 ± 43%). V p was associated with decreased expiratory flows, and EVLW was associated with decreased lung volumes., Conclusions: Congestion in stable patients with HF includes expanded V p and V h and increased EVLW associated with reductions in lung volumes and expiratory flows., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: It is unclear whether the respiratory compensation point (RCP) may be used as a valid surrogate for critical power (CP). Accordingly, we sought to determine the measurement agreement between the CP and the RCP obtained during incremental cycling of varying ramp slopes., Methods: Eleven recreationally active men completed three separate ramp-incremental cycling protocols, where the work rate increment was slow (SR, 15 W·min), medium (MR, 30 W·min), or fast (FR, 45 W·min). The RCP was obtained using the ventilatory equivalent for CO2 output method. The CP was determined via Morton's model for ramp-incremental exercise. The assumption that the RCP and the CP occur at equivalent external work rates was assessed by one-way repeated-measures ANOVA and by evaluating the concordance correlation coefficient (CCC) and typical error (root-mean-square error [RMSE]) for each ramp protocol, separately., Results: The external work rate corresponding to the RCP increased with increases in the ramp-incremental slope (P < 0.05). The RCP values in MR (268 ± 37 W) and FR (292 ± 41 W), but not SR (243 ± 35 W), were different (P < 0.05) from CP (247 ± 43 W). The degree to which the relationship between the CP and the RCP approximated the line of identity was relatively poor for SR (CCC = 0.73 and RMSE = 28 W), MR (CCC = 0.63 and RMSE = 36 W), and FR (CCC = 0.42 and RMSE = 55 W)., Conclusions: Our data confirm that the external work rate associated with the RCP is labile and that these power outputs display poor measurement agreement with the CP. Taken together, these findings indicate that the RCP does not provide an accurate estimation of CP.

Chest wall strapping has been used to assess mechanisms of dyspnea with restrictive lung disease. This study examined the hypothesis that dyspnea with restriction depends principally on the degree of reflex ventilatory stimulation. We compared dyspnea at the same (iso)ventilation when added dead space provided a component of the ventilatory stimulus during exercise. Eleven healthy men undertook a randomized controlled crossover trial that compared four constant work exercise conditions: 1 ) control (CTRL): unrestricted breathing at 90% gas exchange threshold (GET); 2 ) CTRL+dead space (DS): unrestricted breathing with 0.6-l dead space, at isoventilation to CTRL due to reduced exercise intensity; 3 ) CWS: chest wall strapping at 90% GET; and 4 ) CWS+DS: chest strapping with 0.6-l dead space, at isoventilation to CWS with reduced exercise intensity. Chest strapping reduced forced vital capacity by 30.4 ± 2.2% (mean ± SE). Dyspnea at isoventilation was unchanged with CTRL+DS compared with CTRL (1.93 ± 0.49 and 2.17 ± 0.43, 0-10 numeric rating scale, respectively; P = 0.244). Dyspnea was lower with CWS+DS compared with CWS (3.40 ± 0.52 and 4.51 ± 0.53, respectively; P = 0.003). Perceived leg fatigue was reduced with CTRL+DS compared with CTRL (2.36 ± 0.48 and 2.86 ± 0.59, respectively; P = 0.049) and lower with CWS+DS compared with CWS (1.86 ± 0.30 and 4.00 ± 0.79, respectively; P = 0.006). With unrestricted breathing, dead space did not change dyspnea at isoventilation, suggesting that dyspnea does not depend on the mode of reflex ventilatory stimulation in healthy individuals. With chest strapping, dead space presented a less potent stimulus to dyspnea, raising the possibility that leg muscle work contributes to dyspnea perception independent of the ventilatory stimulus. NEW & NOTEWORTHY Chest wall strapping was applied to healthy humans to simulate restrictive lung disease. With chest wall strapping, dyspnea was reduced when dead space substituted for part of a constant exercise stimulus to ventilation. Dyspnea associated with chest wall strapping depended on the contribution of leg muscle work to ventilatory stimulation. Chest wall strapping might not be a clinically relevant model to determine whether an alternative reflex ventilatory stimulus mimics the intensity of exertional dyspnea., (Copyright © 2017 the American Physiological Society.)

The purpose of this study was to examine the effect of venous occlusion per se on forearm muscle blood flow, as determined by the near-infrared spectroscopy (NIRS) venous occlusion technique (NIRS-VOT). NIRS data were obtained from the flexor digitorum superficialis (FDS) muscle on the dominant arm of 16 young, ostensibly healthy participants (14 men and two women; 30 ± 6 year; 73 ± 7 kg). Participants completed a series of five venous occlusion trials while seated at rest, and a series of 12 venous occlusion trials during a reactive hyperaemia induced by 5 min of forearm arterial occlusion. The NIRS-VOT was used to assess FDS muscle blood flow (Q˙mus), beat-by-beat, over the first four cardiac beats during venous occlusions. Q˙mus was also reported as a cumulative value, wherein the first two, first three and first four cardiac beats were used to calculate muscle blood flow. We observed that Q˙mus was highest when calculated over the first cardiac beat during venous occlusions performed at rest and throughout reactive hyperaemia (P<0·05). Moreover, the inclusion of more than one cardiac beat in the calculation of Q˙mus underestimated muscle blood flows, irrespective of the prevailing level of arterial inflow. These findings support the idea that venous occlusion per se affects the measurement of Q˙mus via the NIRS-VOT. Accordingly, it is recommended that Q˙mus is determined over the first cardiac beat when using the NIRS-VOT to assess microvascular blood flow of human forearm muscles., (© 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)