Medicine & Science in Sports & Exercise

Community-Level Sports Group Participation and the Risk of Cognitive Impairment Purpose Community-level group participation is a structural aspect of social capital that may have a contextual influence on individual health. We investigated the contextual effect of community-level prevalence of sports group participation on the risk of cognitive impairment among older individuals. Methods We analyzed prospective cohort data from the Japan Gerontological Evaluation Study (JAGES), a nationwide survey of 40,308 functionally independent older individuals from 346 communities. Cognitive impairment was assessed by the nationally standardized dementia scale proposed by the Ministry of Health, Labour and Welfare of Japan. Participation in a sports group ≥1 day/month was defined as “participation.” We applied a two-level multilevel survival analysis to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results The cumulative incidence of cognitive impairment during the 6-year follow-up period was 9.8%. The mean proportion of sports group participation was 25.2% (range: 0.0%–56.5%). Higher prevalence of community-level sports group participation was associated with a lower risk of cognitive impairment (HR: 0.92, 95% CI: 0.86–0.99, estimated by 10 percentage points of participation proportion) after adjusting for individual-level sports group participation, sex, age, disease, obesity, social isolation, alcohol, smoking, education, income, depression, daily walking time, population density, and sunlight hours. We found cross-level interaction between individual- and community-level sports group participation (HR: 0.87, 95% CI: 0.76–0.99). Conclusion We found a contextual preventive effect of community-level sports group participation on developing cognitive impairment among older individuals. Furthermore, the benefit may favor sports group participants. Therefore, promoting sports groups in a community setting may be effective as a population-based strategy for the prevention of dementia. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Corresponding author: Taishi Tsuji, Center for Preventive Medical Sciences, Chiba University, 1-8-1 Inohana, Chuo Ward, Chiba City, Chiba 260-8670 Japan, E-mail: tsuji.t@chiba-u.jp, Tel. +81.43.226.2803, Fax +81.43.226.2018 This study was supported by a grant of the Strategic Research Foundation Grant-aided Project for Private Universities from the Ministry of Education, Culture, Sport, Science, and Technology, Japan (MEXT), 2009–2013, for the Center for Well-being and Society, Nihon Fukushi University; a Health Labour Sciences Research Grant, Comprehensive Research on Aging and Health [grant numbers H22-Choju-Shitei-008, H24-Junkankitou-Ippan-007, H24-Chikyukibo-Ippan-009, H24-Choju-Wakate-009, H25-Kenki-Wakate-015, H25-Irryo-Shitei-003 (Fukkou), H26-Choju-Ippan-006, H28-Chouju-Ippan-02] from the Japanese Ministry of Health, Labour and Welfare; JSPS KAKENHI [grant numbers 22330172, 22390400, 23243070, 23590786, 23790710, 24390469, 24530698, 24653150, 24683018, 25253052, 25870573, 25870881, 22390400, 15K18174, 15KT0007, 15H01972, 16K16595, 17K15822] from the Japan Society for the Promotion of Science; a grant from the National Center for Geriatrics and Gerontology [grant numbers 24-17, 24-23]; the Research and Development Grants for Longevity Science from AMED; a grant from the Japan Foundation for Aging and Health; and also World Health Organization Centre for Health Development (WHO Kobe Centre) [grant number WHO APW 2017/713981]. The funding sources had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We declare that the results of the present study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation, and do not constitute endorsement by ACSM. None of the authors have a conflict of interest in relation to this manuscript. Accepted for Publication: 16 May 2019 © 2019 American College of Sports Medicine

Medical Tent Utilization at 10-km Road Races: Injury, Illness, and Influencing Factors Purpose To increase awareness of the need for coordinated medical care at 10-km races and to help direct future medical planning for these events. Methods We related medical encounter data from nineteen 10-km road races to runner, race and environmental characteristics. We quantified the most commonly used resources and described the disposition of runners in these encounters. Results Across the 19 races and 90,265 finishers, there were 562 medical events for a cumulative incidence of 6.2 events per 1000 finishers (95% CI 5.7, 6.8). Race size was associated with an increased incidence of medical events. Overall, the most common diagnosis was heat-related illness (1.6 per 1000 finishers), followed by musculoskeletal complaints (1.3 per 1000 finishers) and fluid/electrolyte imbalances (1.2 per 1000 finishers). For all diagnoses, runners with finishing times in the first performance quintile and in the fifth performance quintile had greater representation in the medical tent than mid-pack runners. Most runners were treated with supportive care, basic first aid, and oral rehydration. Ninety-four runners (1.0 per 1000 finishers) required ice water immersion for exertional heat stroke. There were low rates of hospital transport (0.2 per 1000 finishers), and no fatalities. Conclusions In 10-km road races, injury rates are low compared to longer races in similar weather conditions. Common medical issues can be managed with basic resources in the on-site medical tent. Green flag start race conditions may not predict race safety with regard to exertional heat stroke risk. There were no deaths in nearly 100,000 finishers. Corresponding Author information: Rebecca G. Breslow, MD, Division of Sports Medicine, Department of Orthopaedic Surgery, Brigham and Women’s Hospital, 45 Francis St., Boston, MA 02115. Tel: 617-525-7858. Fax: 617-730-2810. rbreslow@bwh.harvard.edu Supported in part by NIH-P30AR072577 (J.N.K.) and the Rheumatology Research Foundation (J.E.C.). The authors report no conflicts of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine. These results are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for publication: 4 June 2019. © 2019 American College of Sports Medicine

Area-level Socioeconomic Environment and Cardiorespiratory Fitness in Youth Introduction Cardiorespiratory fitness is one of the most important markers of cardiometabolic health and is a strong predictor of cardiovascular disease and all-cause mortality across the lifespan. However, little is known regarding the relationship of area-level socioeconomic environment on cardiorespiratory fitness during childhood and adolescence. Purpose To examine the relationship between area-level socioeconomic environment and cardiorespiratory fitness in a diverse sample of school-aged youth; and to determine the extent to which grade level, sex, race/ethnicity, and student poverty status moderate this relationship. Methods South Carolina FitnessGram data for school year 2015-2016 were obtained for 44,078 youth. Cardiorespiratory fitness was determined using PACER or 1-mile run/walk test. Area-level socioeconomic environment was expressed as a composite index score at the census tract level using data from the American Community Survey. Multilevel logistic regression analyses were conducted, controlling for individual-level characteristics and nesting within schools and districts. Interaction terms were then introduced to the model to examine their effect of multiple sociodemographic moderators. Results Approximately half of the sample had inadequate cardiorespiratory fitness for health. The odds of achieving the Healthy Fitness Zone for cardiorespiratory fitness decreased by approximately 25-34% with increasing deprivation of the area-level socioeconomic environment, after controlling for covariates. The association between area-level socioeconomic environment and cardiorespiratory fitness also varied significantly by sex, grade level, and race/ethnicity subgroups. Conclusions Cardiorespiratory fitness was positively associated with area-level socioeconomic environment, however, the relationship varied by demographic characteristics. These results highlight the importance of examining the influence of area-level socioeconomic environment on health across the life span. Additional research is needed to explore how area-level socioeconomic environment may impact evidence-based efforts to improve youth cardiorespiratory fitness levels. Please address all correspondence to Morgan Clennin, 921 Assembly Street, Suite 212, Columbia, SC 29208, Department of Exercise Science, University of South Carolina; clennin@email.sc.edu The authors acknowledge the South Carolina Department of Health and Environmental Control, the South Carolina Department of Education, and BlueCross BlueShield of South Carolina Foundation (funder). The authors have no conflicts of interest to report. The results of the present study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation; and these findings do not constitute endorsement by ACSM. Accepted for publication: 3 June 2019. © 2019 American College of Sports Medicine

High-Intensity Physical Exercise in a Glioblastoma Patient under Multimodal Treatment Introduction Glioblastoma multiforme (GBM) carries a strongly unfavorable prognosis despite intensive multidisciplinary therapy. Physical exercise is rarely offered to patients for fear of adverse events such as falls, epileptic seizures, or bleeding, despite little supporting evidence. Here, we report a study of high-level and long-term exercise in a GBM patient. Methods A 33-year-old male, diagnosed with a large cystic GBM, was included in our institution’s Personal Training Program after initial tumor resection and adjuvant radiochemotherapy. The program was designed to facilitate individual long-term high-intensity exercise. Supervised by a certified personal trainer, it consisted of at least four weekly training sessions and intermittent performance diagnostics. An activity tracker quantified training intensity. Results In this setting, the patient exercised at high intensity without adverse events for 87 continuous weeks (21 months). He averaged 43.7 metabolic equivalent of task hours per week (METh/week), well above the 75th percentile of healthy males the same age, while undergoing multiple surgeries, chemotherapy and radiation therapy regimens. The patient completed two marathons averaging less than 5 minutes/kilometer both times, despite tumor progression. Performance diagnostics indicated a gain of fitness even during continuous GBM treatment. Due to multiple intraventricular lesions and increasing intracranial pressure, training was stopped six weeks before the patient passed away two years after initial diagnosis. Conclusion This study demonstrates that high-intensity, long-term physical training regimens are feasible in GBM patients during full multidisciplinary therapy. In this patient, the exercise was pursued without adverse events and led to a gain of fitness despite tumor progression and intensive multiple therapies. We conclude that, in GBM patients, exercise regimens require further study instead of general discouragement. Corresponding Author: Fabian M. Troschel, cand. med., Department of Medicine, Münster University Hospital, Albert-Schweitzer-Campus 1, 48149 Münster, Germany. Phone: +49 251 83-48305. Fax: +49 251 83-47479. fabian.troschel@uni-muenster.de Acknowledgement section: The authors received no specific funding for this work. The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. The results of this study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by ACSM Accepted for publication: 21 May 2019. © 2019 American College of Sports Medicine

Individual Region- and Muscle-specific Hamstring Activity at Different Running Speeds Introduction Hamstring strain injuries typically occur in the proximal biceps femoris long head (BFlh) at high running speeds. Strain magnitude seems to be the primary determinant of strain injury, and may be regulated by muscle activation. In running, BFlh strain is largest in the proximal region, especially at high speeds. However, region-specific activity has not been examined. This study examined the proximal-distal and intermuscular activity of BFlh and semitendinosus (ST) as a function of increasing running speed. Methods Thirteen participants ran at steady speeds of 4.1 (slow), 5.4 (moderate), and 6.8 m·s-1 (fast) on a treadmill. Region- and muscle-specific electromyography (EMG) activity were recorded at each speed using high-density EMG, and were normalised to maximal voluntary isometric activity (MVIC). Muscle-tendon unit (MTU) lengths were calculated from kinematic recordings. Speed-effects, regional and intermuscular differences were tested with Statistical Parametric Mapping. Results With increasing running speed, EMG activity increased in all regions of both muscles to a similar extent in the clinically relevant late swing phase. Increases in MTU lengths in late swing as a function of running speed were comparatively small. In fast running, EMG activity was highest in late swing in all regions, and reached 115 ±20% (proximal region, mean ±95% confidence limit), 106 ±11% (middle), and 124 ±16% (distal) relative to MVIC in BFlh. Regional and intermuscular EMG patterns were highly individual, but each individual maintained similar proximal-distal and intermuscular EMG activity patterns across running speeds. Conclusion Running is associated with highly individual hamstring activity patterns, but these patterns are similar across speeds. It may thus be crucial to implement running at submaximal speeds early after hamstring injury for restoration of normal neuromuscular function. Corresponding author: András Hegyi, LL175, P.O. Box 35, FI-40014, Jyväskylä, Finland. E-mail: andras.a.hegyi@jyu.fi The authors have no professional relationships with companies or manufacturers who will benefit from the results of the present study. The results of the present study do not constitute endorsement by ACSM. The results of this unfunded study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for publication: 29 May 2019. © 2019 American College of Sports Medicine

No Benefit of Ingestion of a Ketone Monoester Supplement on 10-km Running Performance Purpose Pre-exercise ingestion of exogenous ketones alters the metabolic response to exercise, but effects on exercise performance have been equivocal. Methods On two occasions in a double-blind, randomized crossover design, eight endurance-trained runners performed 1 h of submaximal exercise at ~65% VO2max immediately followed by a 10-km self-paced TT on a motorized treadmill. An 8% carbohydrate-electrolyte solution was consumed before and during exercise, either alone (CHO+PLA), or with 573 mg.kg-1 of a ketone monoester supplement (CHO+KME). Expired air, heart rate (HR), and rating of perceived exertion (RPE) were monitored during submaximal exercise. Serial venous blood samples were assayed for plasma glucose, lactate and β-hydroxybutyrate concentrations. Results CHO+KME produced plasma β-hydroxybutyrate concentrations of ~1.0 to 1.3 mM during exercise (P < 0.001), but plasma glucose and lactate concentrations were similar during exercise in both trials. VO2, running economy, respiratory exchange ratio, HR and RPE were also similar between trials. Performance in the 10-km TT was not different (P = 0.483) between CHO+KME (mean = 2402 s; 95% confidence interval [CI] = 2204, 2600 s) and CHO+PLA (mean = 2422 s; 95% CI = 2217, 2628 s). Cognitive performance, measured by reaction time and a multi-tasking test, did not differ between trials. Conclusion Compared with carbohydrate alone, co-ingestion of KME by endurance-trained athletes elevated plasma β-hydroxybutyrate concentrations, but did not improve 10-km running TT or cognitive performance. CORRESPONDING AUTHOR: Brendan Egan, PhD, School of Health and Human Performance, Dublin City University, Glasnevin, Dublin 9, Ireland, e: brendan.egan@dcu.ie, t: +353 1 7008803, f: +353 1 7008888 This work was funded in part by an Irish Research Council Enterprise Partnership Postgraduate Fellowship (EPSPG2016177). The ketone monoester studied in this work was purchased from HVMN, Inc. (San Francisco, USA), and we thank Dr. Brianna Stubbs (HVMN, Inc.) for advice regarding the formulation and flavoring of the placebo condition. HVMN had no role in the implementation, interpretation, or dissemination of this work. No conflict of interest, financial or otherwise, is declared by the authors. The authors declare the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation and do not constitute endorsement by the American College of Sports Medicine. Accepted for Publication: 21 May 2019 © 2019 American College of Sports Medicine

Sedentarism, Physical Activity, Steps, and Neurotrophic Factors in Obese Children Purpose This study aimed to examine the associations of sedentary time, physical activity (PA) and step-related behaviors with neurotrophic growth factors. Methods A total of 97 children with overweight/obesity aged 8-11 years participated in this study. Sedentary time, PA, and steps were measured by GT3X+ accelerometers in hip and non-dominant wrist. Estimates of light, moderate, vigorous, and moderate-to-vigorous PA (MVPA) were obtained. Steps/daytime, peak 60-, 30-, and 1-min cadence were computed. The time accumulated (min/day) in different cadence bands of steps was also computed from hip accelerometer. Plasma levels of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), and insulin growth factor-1 (IGF-1) were determined by the XMap technology (Luminex IS 100/200 system, Luminex Corporation, Austin, TX). Results Light PA, moderate PA, MVPA and the peak 60-min cadence were positively related with BDNF concentrations (all P<0.05), and only light PA to VEGF (P=0.048). No association was observed for IGF-1 (P>0.05). The associations of light PA with BDNF and VEGF disappeared (all P>0.05) after performing analyses with non-dominant wrist-placement data. However, moderate PA and MVPA remained significantly associated with BDNF (both P<0.05). The time accumulated in cadence bands of 40-59 steps/min and 60-79 steps/min (i.e., walking at slow pace) was positively associated with plasma BDNF (all P<0.05). Conclusion In conclusion, PA is positively related to plasma BDNF, whereas no relationship was observed for VEGF or IGF-1. Higher amounts of time spent in slow walking cadence bands could increment BDNF levels. Exercise-based randomized controlled trials in children with overweight/obesity should be carried out to better understand the influence of PA behaviors on the neurotrophic factors. Corresponding author: Jose Mora-Gonzalez, Department of Physical and Sports Education, Faculty of Sports Science, University of Granada; Carretera de Alfacar, 21. Granada 18071, Spain; +(34) 958 24 66 51, fax: +(34) 958 24 94 28; email: jmorag@ugr.es The ActiveBrains project was funded by the Spanish Ministry of Economy and Competitiveness/FEDER (DEP2013-47540, DEP2016-79512-R, RYC-2011-09011). JM-G and JHM are supported by the Spanish Ministry of Education, Culture and Sport (FPU14/06837 and FPU15/02645, respectively). IE-C is supported by a grant from the Alicia Koplowitz Foundation. CC-S is supported by a grant from the Spanish Ministry of Economy and Competitiveness (BES-2014-068829). PM-G is supported by a grant from European Union’s Horizon 2020 research and innovation program (No 667302). Additional support was obtained from the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence, Unit of Excellence on Exercise and Health (UCEES); and by the Junta de Andalucía, Conserjería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ERDF) (Ref. SOMM17/6107/UGR). In addition, funding was provided by the SAMID III network, RETICS, funded by the PN I+D+I 2017-2021 (Spain), ISCIII- Sub-Directorate General for Research Assessment and Promotion, the European Regional Development Fund (ERDF) (Ref. RD16/0022) and the EXERNET Research Network on Exercise and Health in Special Populations (DEP2005-00046/ACTI). The results of the present study do not constitute endorsement by ACSM. We declare that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Accepted for publication: 26 May 2019. © 2019 American College of Sports Medicine

Horizontal Crank Position Affects Economy and Upper Limb Kinematics of Recumbent Handcyclists Purpose To determine the effects of horizontal crank position on economy and upper limb kinematics in recumbent handcycling. Methods Fifteen trained handcyclists performed trials at 50% and 70% of their peak aerobic power output (POPeak), determined during a maximal ramp test, in each horizontal crank position. Four horizontal crank positions, 94%, 97%, 100% and 103% of arm length, were investigated. Horizontal crank positions were defined as the distance between the acromion angle to the centre of the handgrip, while the crank arm was parallel to the floor and pointing away from the participant. Economy and upper limb kinematics were calculated during the final minute of each three-minute trial. Results Horizontal crank position significantly affected handcycling economy at 70% POPeak (P < 0.01) but not at 50% POPeak (P = 0.44). The 97% horizontal crank position (16.0 (1.5) mL·min-1·W-1) was significantly more economical than the 94% (16.7 (1.9) mL·min-1·W-1) (P = 0.04) and 103% (16.6 (1.7) mL·min-1·W-1) (P < 0.01) positions. The 100 % horizontal crank position (16.2 (1.7) mL·min-1·W-1) was significantly more economical than the 103% position (P < 0.01). Statistical parametric mapping indicated that an increase in horizontal crank position, from 94% to 103%, caused a significant increase in elbow extension, shoulder flexion, adduction, internal rotation, scapular internal rotation, wrist flexion, clavicle depression and clavicle protraction between 0 – 50 % (0° - 180°) of the cycle (P < 0.05). Conclusion Positioning the cranks at 97% to 100% of the athletes’ arm length improved handcycling economy at 70% POPeak as, potentially, the musculature surrounding the joints of the upper limb were in a more favourable position to produce force economically. Corresponding Author: V. L. Goosey-Tolfrey, NCSEM 1.26, Loughborough University Campus, Loughborough, LE11 3TU. E-mail: V.L.Tolfrey@lboro.ac.uk Telephone Number: +44 (0)1509 226386 This study was funded by the Engineering and Physical Sciences Research Council (grant no. EP/M507489/1) and supported by the English Institute of Sport, British Cycling and the Peter Harrison Centre for Disability Sport. The authors declare that the results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation, and statement that results of the present study do not constitute endorsement by American College of Sports Medicine. The authors report no conflict of interest. Accepted for publication: 3 June 2019. © 2019 American College of Sports Medicine

Assessment of Na+/K+ ATPase Activity in Small Rodent and Human Skeletal Muscle Samples Introduction In skeletal muscle, the Na+/K+ ATPase (NKA) plays essential roles in processes linked to muscle contraction, fatigue, and energy metabolism, however, very little information exists regarding the regulation of NKA activity. The scarcity of information regarding NKA function in skeletal muscle likely stems from methodological constraints, as NKA contributes minimally to total cellular ATP utilization, and therefore contamination from other ATPases prevents the assessment of NKA activity in muscle homogenates. Here we introduce a method that improves accuracy and feasibility for determination of NKA activity in small rodent muscle samples (5-10 mg) and in human skeletal muscle. Methods Skeletal muscle homogenates from mice (n = 6) and humans (n = 3) were used to measure NKA and sarcoplasmic reticulum Ca2+ ATPase (SERCA) activities with the addition of specific ATPase inhibitors to minimize ‘background noise’. Results We observed that myosin ATPase activity was the major interfering factor for estimation of NKA activity in skeletal muscle homogenates, as addition of 25 μM of blebbistatin (BLEB), a specific myosin ATPase inhibitor, considerably minimized ‘background noise’ (3-fold) and enabled the determination of NKA maximal activity with values three times higher than previously reported. Specificity of the assay was demonstrated after addition of 2 mM ouabain, which completely inhibited NKA. On the other hand, addition of BLEB did not affect the ability to measure SERCA function. The coefficient of variation for NKA and SERCA assays were 6.2% and 4.4%, respectively. Conclusion The present study has improved the methodology to determine NKA activity. We further show the feasibility of measuring NKA and SERCA activities from a common muscle homogenate. This methodology is expected to aid in our long-term understanding of how NKA affects skeletal muscle metabolic homeostasis and contractile function in diverse situations. Corresponding Author: Sebastian Jannas-Vela, Human Health & Nutritional Sciences, University of Guelph, 50 Stone Rd. East, Guelph, Canada, N1G 2W1. Phone: 519-824-4120 Ext 53907; Fax: 519-763-5902. Email: sjannas@uoguelph.ca This work was funded by The Natural Sciences and Engineering Research Council of Canada (NSERC; L.L.S and G.P.H.) and by CONICYT PFCHA/DOCTORADO BECAS CHILE/2013 – 72140421 (SJV). The authors do not have any conflicts to disclose. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation, and do not constitute endorsement by ACSM. Accepted for publication: 3 June 2019. © 2019 American College of Sports Medicine

Translational Medicine: Exercise Physiology Applied to Metabolic Myopathies The relevance of translational medicine (bringing basic science methods “to the bed of patients”) is universally recognized. Too often, however, the tools to be applied translationally are thought to derive only from the “-omics” (genomics, proteomics, transcriptomics, metabolomics, etc.) world. The failures of this “reductionist” approach are widely recognized. In the review we discuss studies demonstrating that scientifically sound mechanistic insights into diseases, relevant both in terms of basic science and clinically, and very well suited to be utilized within a translational medicine approach, can be obtained from the established field of exercise physiology. Methods originally aimed towards basic physiological mechanisms, and applied for the functional evaluation of athletes and sport performance, can have a valuable translational application in patients with metabolic myopathies; such as myophosphorylase deficiency (McArdle disease) or mitochondrial myopathies, diseases which share the common denominator of an impaired skeletal muscle oxidative metabolism. Several variables can yield pathophysiological insights, can identify and quantify the metabolic impairment and the effects on exercise tolerance (one of the main determinants of the patients’ clinical picture and quality of life), and can offer diagnostic clues: the impaired capacity of O2 extraction by skeletal muscle, evaluated by near-infrared spectroscopy; the “exaggerated” cardiovascular response to exercise; the slower speed of adjustment of oxidative metabolism during metabolic transitions; the “slow component” of pulmonary O2 uptake kinetics and the associated reduced efficiency and fatigue; the impaired intramuscular matching between O2 delivery and O2 utilization. The proposed methods are noninvasive, and therefore facilitate repeated or serial evaluations. They provide support for a simple message: physiology and physiological research remain the essential link between genes, molecules and clinical care. Correspondance to: Bruno Grassi, MD PhD, Department of Medicine, University of Udine, Piazzale M. Kolbe 4, I – 33100 Udine, Italy. Tel. +39-0432-494335. E-mail: bruno.grassi@uniud.it These studies were originally funded by Telethon-UILDM Grants n. GUP 030534 and GUP 08007. The authors have no conflict of interest to declare. The results of the present study do not constitute endorsement by ACSM. The results of the study are presented clearly, honestly, and without fabrication, falsification or inappropriate data manipulation. Accepted for publication: 23 May 2019. © 2019 American College of Sports Medicine