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Biomedical Engineering Online Jan 2021This research has proved that mechanomyographic (MMG) signals can be used for evaluating muscle performance. Stimulation of the lost physiological functions of a muscle...
This research has proved that mechanomyographic (MMG) signals can be used for evaluating muscle performance. Stimulation of the lost physiological functions of a muscle using an electrical signal has been determined crucial in clinical and experimental settings in which voluntary contraction fails in stimulating specific muscles. Previous studies have already indicated that characterizing contractile properties of muscles using MMG through neuromuscular electrical stimulation (NMES) showed excellent reliability. Thus, this review highlights the use of MMG signals on evaluating skeletal muscles under electrical stimulation. In total, 336 original articles were identified from the Scopus and SpringerLink electronic databases using search keywords for studies published between 2000 and 2020, and their eligibility for inclusion in this review has been screened using various inclusion criteria. After screening, 62 studies remained for analysis, with two additional articles from the bibliography, were categorized into the following: (1) fatigue, (2) torque, (3) force, (4) stiffness, (5) electrode development, (6) reliability of MMG and NMES approaches, and (7) validation of these techniques in clinical monitoring. This review has found that MMG through NMES provides feature factors for muscle activity assessment, highlighting standardized electromyostimulation and MMG parameters from different experimental protocols. Despite the evidence of mathematical computations in quantifying MMG along with NMES, the requirement of the processing speed, and fluctuation of MMG signals influence the technique to be prone to errors. Interestingly, although this review does not focus on machine learning, there are only few studies that have adopted it as an alternative to statistical analysis in the assessment of muscle fatigue, torque, and force. The results confirm the need for further investigation on the use of sophisticated computations of features of MMG signals from electrically stimulated muscles in muscle function assessment and assistive technology such as prosthetics control.
Topics: Electric Stimulation; Humans; Mechanical Phenomena; Muscles; Myography
PubMed: 33390158
DOI: 10.1186/s12938-020-00840-w -
Archives of Academic Emergency Medicine 2022Knowledge of the safety of vaccines is crucial, both to prevent and cure them and to decrease the public hesitation in receiving vaccines. Therefore, this study aimed to... (Review)
Review
INTRODUCTION
Knowledge of the safety of vaccines is crucial, both to prevent and cure them and to decrease the public hesitation in receiving vaccines. Therefore, this study aimed to systematically review the adverse events reported for inactivated vaccines and Novavax.
METHODS
In this systematic review, the databases of PubMed, Scopus, Cochrane, and Web of Science were searched on September 15, 2021. Then we identified the eligible studies using a two-step title/abstract and full-text screening process. Data on the subjects, studies, and types of adverse events were extracted and entered in a word table, including serious, mild, local, and systemic adverse events as well as the timing of side effects' appearance.
RESULTS
Adverse effects of inactivated coronavirus vaccines side effects were reported from phases 1, 2, and 3 of the vaccine trials. The most common local side effects included injection site pain and swelling, redness, and pruritus. Meanwhile, fatigue, headache, muscle pain, fever, and gastrointestinal symptoms including abdominal pain and diarrhea were among the most common systemic adverse effects.
CONCLUSION
This systematic review indicates that inactivated COVID-19 vaccines, including Sinovac, Sinopharm, and Bharat Biotech, as well as the protein subunit vaccines (Novavax) can be considered as safe choices due to having milder side effects and fewer severe life-threatening adverse events.
PubMed: 36033990
DOI: 10.22037/aaem.v10i1.1585 -
Cognitive Neurodynamics Oct 2023Driving a vehicle is a complex, multidimensional, and potentially risky activity demanding full mobilization and utilization of physiological and cognitive abilities.... (Review)
Review
Driving a vehicle is a complex, multidimensional, and potentially risky activity demanding full mobilization and utilization of physiological and cognitive abilities. Drowsiness, often caused by stress, fatigue, and illness declines cognitive capabilities that affect drivers' capability and cause many accidents. Drowsiness-related road accidents are associated with trauma, physical injuries, and fatalities, and often accompany economic loss. Drowsy-related crashes are most common in young people and night shift workers. Real-time and accurate driver drowsiness detection is necessary to bring down the drowsy driving accident rate. Many researchers endeavored for systems to detect drowsiness using different features related to vehicles, and drivers' behavior, as well as, physiological measures. Keeping in view the rising trend in the use of physiological measures, this study presents a comprehensive and systematic review of the recent techniques to detect driver drowsiness using physiological signals. Different sensors augmented with machine learning are utilized which subsequently yield better results. These techniques are analyzed with respect to several aspects such as data collection sensor, environment consideration like controlled or dynamic, experimental set up like real traffic or driving simulators, etc. Similarly, by investigating the type of sensors involved in experiments, this study discusses the advantages and disadvantages of existing studies and points out the research gaps. Perceptions and conceptions are made to provide future research directions for drowsiness detection techniques based on physiological signals.
PubMed: 37786662
DOI: 10.1007/s11571-022-09898-9 -
The Cochrane Database of Systematic... May 2023The finding that exercise is inversely related to metabolic syndrome after transplantation is novel and suggests that exercise interventions might provide a means for... (Review)
Review
BACKGROUND
The finding that exercise is inversely related to metabolic syndrome after transplantation is novel and suggests that exercise interventions might provide a means for reducing metabolic syndrome complications in liver transplantation recipients. The use of exercise for increasing the physical activity daily levels by more frequent, higher intensity, and longer duration of training sessions, or the sum of these components may be necessary to counteract the effects of the pretransplant reduced activity, metabolic disturbances, and post-transplant immunosuppression, as well as improve physical function and aerobic capacity following liver transplantation. Regular physical activity has a long-term positive impact on recovery following various surgical procedures including transplantation, giving people the opportunity to return to an active life with their families, in society, and in their professional life. Likewise, specific muscle strength training may attenuate the loss of strength after liver transplantation.
OBJECTIVES
To evaluate the benefits and harms of exercise-based interventions in adults after liver transplantation compared to no exercise, sham interventions, or another type of exercise.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search date was 2 September 2022.
SELECTION CRITERIA
We included randomised clinical trials in liver transplantation recipients comparing any type of exercise with no exercise, sham interventions, or another type of exercise.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were 1. all-cause mortality; 2. serious adverse events; and 3. health-related quality of life. Our secondary outcomes were 4. a composite of cardiovascular mortality and cardiac disease; 5. aerobic capacity; 6. muscle strength; 7. morbidity; 8. non-serious adverse events; and 9. cardiovascular disease post-transplantation. We assessed risk of bias of the individual trials using RoB 1, described the interventions using the TIDieR checklist, and used GRADE to assess certainty of evidence.
MAIN RESULTS
We included three randomised clinical trials. The trials randomised 241 adults with liver transplantation, of which 199 participants completed the trials. The trials were conducted in the USA, Spain, and Turkey. They compared exercise versus usual care. The duration of the interventions ranged from two to 10 months. One trial reported that 69% of participants who received the exercise intervention were adherent to the exercise prescription. A second trial reported a 94% adherence to the exercise programme, with participants attending 45/48 sessions. The remaining trial reported a 96.8% adherence to the exercise intervention during the hospitalisation period. Two trials received funding; one from the National Center for Research Resources (US) and the other from Instituto de Salud Carlos III (Spain). The remaining trial did not receive funding. All trials were at an overall high risk of bias, derived from high risk of selective reporting bias and attrition bias in two trials. The results on all-cause mortality showed a higher risk of death in the exercise group versus the control group, but these results are very uncertain (risk ratio (RR) 3.14, 95% confidence interval (CI) 0.74 to 13.37; 2 trials, 165 participants; I² = 0%; very low-certainty evidence). The trials did not report data on serious adverse events excluding mortality or non-serious adverse events. However, all trials reported that there were no adverse effects associated with exercise. We are very uncertain on whether exercise compared with usual care has a beneficial or harmful effect on health-related quality of life assessed using the 36-item Short Form Physical Functioning subscale at the end of the intervention (mean difference (MD) 10.56, 95% CI -0.12 to 21.24; 2 trials, 169 participants; I² = 71%; very low-certainty evidence). None of the trials reported data on composite of cardiovascular mortality and cardiovascular disease, and cardiovascular disease post-transplantation. We are very uncertain if there are differences in aerobic capacity in terms of VO at the end of the intervention between groups (MD 0.80, 95% CI -0.80 to 2.39; 3 trials, 199 participants; I² = 0%; very low-certainty evidence). We are very uncertain if there are differences in muscle strength at end of the intervention between groups (MD 9.91, 95% CI -3.68 to 23.50; 3 trials, 199 participants; I² = 44%; very low-certainty evidence). One trial measured perceived fatigue using the Checklist Individual Strength (CIST). Participants in the exercise group showed a clinically important lower degree of fatigue perception than participants in the control group, with a mean reduction of 40 points in the CIST (95% CI 15.62 to 64.38; 1 trial, 30 participants). We identified three ongoing studies.
AUTHORS' CONCLUSIONS
Based on very low-certainty evidence in our systematic review, we are very uncertain of the role of exercise training (aerobic, resistance-based exercises, or both) in affecting mortality, health-related quality of life, and physical function (i.e. aerobic capacity and muscle strength) in liver transplant recipients. There were few data on the composite of cardiovascular mortality and cardiovascular disease, cardiovascular disease post-transplantation, and adverse event outcomes. We lack larger trials with blinded outcome assessment, designed according to the SPIRIT statement and reported according to the CONSORT statement.
Topics: Humans; Adult; Liver Transplantation; Quality of Life; Cardiovascular Diseases; Metabolic Syndrome; Exercise Therapy; Fatigue
PubMed: 37204002
DOI: 10.1002/14651858.CD013204.pub2 -
Neuropsychology Review Sep 2022Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic... (Meta-Analysis)
Meta-Analysis Review
Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (-22.74 ml; 95% CI: -37.72 to -7.76 ml; p = 0.003), grey matter (-18.81 ml; 95% CI: -29.60 to -8.03 ml; p < 0.001), putamen (-0.40 ml; 95% CI: -0.69 to -0.10 ml; p = 0.008) and acumbens (-0.09 ml; 95% CI: -0.15 to -0.03 ml; p = 0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p < 0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (-19.23 N; 95% CI: -35.93 to -2.53 N; p = 0.02) and an attenuation of upper-limb (-5.77%; 95% CI:-8.61 to -2.93%; p < 0.0001) and lower-limb (-2.16%; 95% CI:-4.24 to -0.07%; p = 0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (-5.61%; 95% CI: -9.57 to -1.65%; p = 0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation. Prospero registration Prospero registration number: CRD42016017934.
Topics: Brain; Cross-Sectional Studies; Fatigue; Humans; Multiple Sclerosis; Organ Size
PubMed: 33961198
DOI: 10.1007/s11065-021-09508-1 -
Sports Medicine (Auckland, N.Z.) Sep 2021The fatigue of a muscle or muscle group can produce global responses to a variety of systems (i.e., cardiovascular, endocrine, and others). There are also reported... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The fatigue of a muscle or muscle group can produce global responses to a variety of systems (i.e., cardiovascular, endocrine, and others). There are also reported strength and endurance impairments of non-exercised muscles following the fatigue of another muscle; however, the literature is inconsistent.
OBJECTIVE
To examine whether non-local muscle fatigue (NLMF) occurs following the performance of a fatiguing bout of exercise of a different muscle(s).
DESIGN
Systematic review and meta-analysis.
SEARCH AND INCLUSION
A systematic literature search using a Boolean search strategy was conducted with PubMed, SPORTDiscus, Web of Science, and Google Scholar in April 2020, and was supplemented with additional 'snowballing' searches up to September 2020. To be included in our analysis, studies had to include at least one intentional performance measure (i.e., strength, endurance, or power), which if reduced could be considered evidence of muscle fatigue, and also had to include the implementation of a fatiguing protocol to a location (i.e., limb or limbs) that differed to those for which performance was measured. We excluded studies that measured only mechanistic variables such as electromyographic activity, or spinal/supraspinal excitability. After search and screening, 52 studies were eligible for inclusion including 57 groups of participants (median sample = 11) and a total of 303 participants.
RESULTS
The main multilevel meta-analysis model including all effects sizes (278 across 50 clusters [median = 4, range = 1 to 18 effects per cluster) revealed a trivial point estimate with high precision for the interval estimate [- 0.02 (95% CIs = - 0.14 to 0.09)], yet with substantial heterogeneity (Q = 642.3, p < 0.01), I = 67.4%). Subgroup and meta-regression analyses showed that NLMF effects were not moderated by study design (between vs. within-participant), homologous vs. heterologous effects, upper or lower body effects, participant training status, sex, age, the time of post-fatigue protocol measurement, or the severity of the fatigue protocol. However, there did appear to be an effect of type of outcome measure where both strength [0.11 (95% CIs = 0.01-0.21)] and power outcomes had trivial effects [- 0.01 (95% CIs = - 0.24 to 0.22)], whereas endurance outcomes showed moderate albeit imprecise effects [- 0.54 (95% CIs = - 0.95 to - 0.14)].
CONCLUSIONS
Overall, the findings do not support the existence of a general NLMF effect; however, when examining specific types of performance outcomes, there may be an effect specifically upon endurance-based outcomes (i.e., time to task failure). However, there are relatively fewer studies that have examined endurance effects or mechanisms explaining this possible effect, in addition to fewer studies including women or younger and older participants, and considering causal effects of prior training history through the use of longitudinal intervention study designs. Thus, it seems pertinent that future research on NLMF effects should be redirected towards these still relatively unexplored areas.
Topics: Female; Health Status; Humans; Muscle Fatigue; Muscle Strength; Nutritional Status
PubMed: 33818751
DOI: 10.1007/s40279-021-01456-3 -
PeerJ 2019Fatigue in baseball pitchers is a process linked to lowered physical and mental performance, injury, and changes in kinematics. Numerous studies have associated fatigue...
BACKGROUND
Fatigue in baseball pitchers is a process linked to lowered physical and mental performance, injury, and changes in kinematics. Numerous studies have associated fatigue with overuse, high ball velocities, lack of rest time, poor mechanics, and degree of self-satisfaction. The aim of this study was to systematically review the literature to identify a theoretical framework for the relationship between outcomes and the manifestation of fatigue on baseball pitching. The synthesized data may identify areas requiring further research.
METHODOLOGY
This protocol was registered with PROSPERO (ID: CRD42018114194). SPORTDiscus, Medline, PubMed, Cochrane Database of Systematic Reviews, and Google Scholar were searched, using keywords such as fatigue in pitchers and changes in kinematics (e.g., pitching mechanics, valgus elbow torque), performance (e.g., pitch count, pitch type), and injury (e.g., pain, elbow, and shoulder soreness). Three reviewers independently screened the articles, selected relevant literature based on abstract eligibility, and assessed the methods described therein for final inclusion.
RESULTS
A total of 31,860 articles were screened for eligibility and 25 articles were included for the review. The selected articles included epidemiological, longitudinal, experimental, conference papers, and crossover laboratory studies. Evidence extracted from the 25 studies demonstrates a relationship between fatigue in baseball pitching, and three overarching outcomes: changes in kinematics, a decrease in performance, and an increase in injury risk.
CONCLUSIONS
Findings show that a co-dependence between changes in kinematics and a decrease in performance, which stems from central and peripheral fatigue, is a contributing factor of injury in baseball pitchers. A large percentage of baseball pitchers exhibit pain or soreness in either their elbow or shoulder, or both at some point in a season. Initially, kinematic changes occur that could maintain performance, but may increase joint and tissue loading. Performance decreased with elevated pitch counts and innings thrown, and pitching further into games or the season. Evidence was found to be consistent across all studies; however, more work is needed in the area of fatigue as an injury mechanism during pitching. With a proof of concept established, the prevention of negative outcomes associated with fatigue must be the focus of future research and performance should not be the only criteria.
PubMed: 31392098
DOI: 10.7717/peerj.7390 -
International Journal of Environmental... Sep 2022Recovery between efforts is critical to achieving optimal physical and sports performance. In this sense, many nutritional supplements that have been proven to improve... (Review)
Review
BACKGROUND
Recovery between efforts is critical to achieving optimal physical and sports performance. In this sense, many nutritional supplements that have been proven to improve recovery and physical and physiological performance are widely used. Supplements such as nitrates (NO), including organic foods such as beets, promote muscle recovery and relieve fatigue. This study aimed to comprehensively summarise the available literature on the effect of NO consumption on exercise-related fatigue and muscle damage.
METHODS
A systematic search was carried out based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) using electronic databases (e.g., PubMed, Scopus, and Web of Science). From a total of 1634 studies identified, 15 studies were included in this review.
RESULTS
Based on the review, NO intake provokes physiological and metabolic responses that could potentially boost exercise-related recovery. NO could improve recovery indicators related to strength, pain, inflammation, and muscle damage.
CONCLUSIONS
Despite the relative proven effectiveness of NO on recovery after aerobic and anaerobic efforts, based on the heterogeneity of the procedures (e.g., dosage, chronic vs. acute intake, participants' characteristics, variables and outcomes), it could be premature to suggest its extended use in sports.
Topics: Athletic Performance; Dietary Supplements; Exercise; Humans; Muscle Fatigue; Nitrates
PubMed: 36231323
DOI: 10.3390/ijerph191912021 -
Orthopaedic Journal of Sports Medicine Aug 2021Low-cycle fatigue damage accumulating to the point of structural failure has been recently reported at the origin of the human anterior cruciate ligament under strenuous... (Review)
Review
BACKGROUND
Low-cycle fatigue damage accumulating to the point of structural failure has been recently reported at the origin of the human anterior cruciate ligament under strenuous repetitive loading. If this can occur in a ligament, low-cycle fatigue damage may also occur in the connective tissue of muscle-tendon units. To this end, we reviewed what is known about how, when, and where injuries of muscle-tendon units occur throughout the body.
PURPOSE
To systematically review injuries in the muscle-tendon-bone complex; assess the site of injury (muscle belly, musculotendinous junction [MTJ], tendon/aponeurosis, tendon/aponeurosis-bone junction, and tendon/aponeurosis avulsion), incidence, muscles and tendons involved, mechanism of injury, and main symptoms; and consider the hypothesis that injury may often be consistent with the accumulation of multiscale material fatigue damage during repetitive submaximal loading regimens.
METHODS
PubMed, Web of Science, Scopus, and ProQuest were searched on July 24, 2019. Quality assessment was undertaken using ARRIVE, STROBE, and CARE (Animal Research: Reporting In Vivo Experiments, Strengthening the Reporting of Observational Studies in Epidemiology, and the Case Report Statement and Checklist, respectively).
RESULTS
Overall, 131 studies met the inclusion criteria, including 799 specimens and 2,823 patients who sustained 3,246 injuries. Laboratory studies showed a preponderance of failures at the MTJ, a viscoelastic behavior of muscle-tendon units, and damage accumulation at the MTJ with repetitive loading. Observational studies showed that 35% of injuries occurred in the tendon midsubstance; 28%, at the MTJ; 18%, at the tendon-bone junction; 13%, within the muscle belly and that 6% were tendon avulsions including a bone fragment. The biceps femoris was the most injured muscle (25%), followed by the supraspinatus (12%) and the Achilles tendon (9%). The most common symptoms were hematoma and/or swelling, tenderness, edema and muscle/tendon retraction. The onset of injury was consistent with tissue fatigue at all injury sites except for tendon avulsions, where 63% of the injuries were caused by an evident trauma.
CONCLUSION
Excluding traumatic tendon avulsions, most injuries were consistent with the hypothesis that material fatigue damage accumulated during repetitive submaximal loading regimens. If supported by data from better imaging modalities, this has implications for improving injury detection, prevention, and training regimens.
PubMed: 34395681
DOI: 10.1177/23259671211020731 -
Sports Medicine (Auckland, N.Z.) May 2022Proper design of resistance training (RT) variables is a key factor to reach the maximum potential of neuromuscular adaptations. Among those variables, the use of RT... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Proper design of resistance training (RT) variables is a key factor to reach the maximum potential of neuromuscular adaptations. Among those variables, the use of RT performed to failure (RTF) may lead to a different magnitude of acute fatigue compared with RT not performed to failure (RTNF). The fatigue response could interfere with acute adaptive changes, in turn regulating long-term adaptations. Considering that the level of fatigue affects long-term adaptations, it is important to determine how fatigue is affected by RTF versus RTNF.
OBJECTIVE
The aim of this systematic review and meta-analysis was to compare the effects of RTF versus RTNF on acute fatigue.
METHODS
The search was conducted in January 2021 in seven databases. Only studies with a crossover design that investigated the acute biomechanical properties (vertical jump height, velocity of movement, power output, or isometric strength), metabolic response (lactate or ammonia concentration), muscle damage (creatine kinase activity), and rating of perceived exertion (RPE) were selected. The data (mean ± standard deviation and sample size) were extracted from the included studies and were either converted into the standardized mean difference (SMD) or maintained in the raw mean difference (RMD) when the studies reported the results in the same scale. Random-effects meta-analyses were performed.
RESULTS
Twenty studies were included in the systematic review and 12 were included in the meta-analysis. The main meta-analyses indicated greater decrease of biomechanical properties for RTF compared with RTNF (SMD - 0.96, 95% confidence interval [CI] - 1.43 to - 0.49, p < 0.001). Furthermore, there was a larger increase in metabolic response (RMD 4.48 mmol·L, 95% CI 3.19-5.78, p < 0.001), muscle damage (SMD 0.76, 95% CI 0.31-1.21, p = 0.001), and RPE (SMD 1.93, 95% CI 0.87-3.00, p < 0.001) for RTF compared with RTNF. Further exploratory subgroup analyses showed that training status (p = 0.92), timepoint (p = 0.89), load (p = 0.10), and volume (p = 0.12) did not affect biomechanical properties; however, greater loss in the movement velocity test occurred on upper limbs compared with lower limbs (p < 0.001). Blood ammonia concentration was greater after RTF than RTNF (RMD 44.66 μmol·L, 95% CI 32.27-57.05, p < 0.001), as was 48 h post-exercise blood creatine kinase activity (SMD 0.86, 95% CI 0.33-1.42, p = 0.002). Furthermore, although there was considerable heterogeneity in the overall analysis (I = 83.72%; p < 0.01), a significant difference in RPE after RTF compared with RTNF was only found for studies that did not equalize training volumes.
CONCLUSIONS
In summary, RTF compared with RTNF led to a greater decrease in biomechanical properties and a simultaneous increase in metabolic response, higher muscle damage, and RPE. The exploratory analyses suggested a greater impairment in the velocity of movement test for the upper limbs, more pronounced muscle damage 48 h post-exercise, and a greater RPE in studies with non-equalized volume after the RTF session compared with RTNF. Therefore, it can be concluded that RTF leads to greater acute fatigue compared with RTNF. The higher acute fatigue after RTF can also have an important impact on chronic adaptive processes following RT; however, the greater acute fatigue following RTF can extend the time needed for recovery, which should be considered when RTF is used.
PROTOCOL REGISTRATION
The original protocol was prospectively registered (CRD42020192336) in the International Prospective Register of Systematic Reviews (PROSPERO).
Topics: Adaptation, Physiological; Ammonia; Creatine Kinase; Humans; Muscle Strength; Muscles; Resistance Training
PubMed: 34881412
DOI: 10.1007/s40279-021-01602-x