Potential Diaphragm Muscle Weakness-related Dyspnea Persists 2 Years after COVID-19 and Could Be Improved by Inspiratory Muscle Training: Results of an Observational and an Interventional Clinical Trial.

Rationale: Diaphragm muscle weakness might underlie persistent exertional dyspnea, despite normal lung and cardiac function in individuals who were previously hospitalized for acute coronavirus disease (COVID-19) illness. Objectives: The authors sought, first, to determine the persistence and pathophysiological nature of diaphragm muscle weakness and its association with exertional dyspnea 2 years after hospitalization for COVID-19 and, second, to investigate the impact of inspiratory muscle training (IMT) on diaphragm and inspiratory muscle weakness and exertional dyspnea in individuals with long COVID. Methods: Approximately 2 years after hospitalization for COVID-19, 30 individuals (11 women, 19 men; median age, 58 years; interquartile range [IQR] = 51-63) underwent comprehensive (invasive) respiratory muscle assessment and evaluation of dyspnea. Eighteen with persistent diaphragm muscle weakness and exertional dyspnea were randomized to 6 weeks of IMT or sham training; assessments were repeated immediately after and 6 weeks after IMT completion. The primary endpoint was change in inspiratory muscle fatiguability immediately after IMT. Measurements and Main Results: At a median of 31 months (IQR = 23-32) after hospitalization, 21 of 30 individuals reported relevant persistent exertional dyspnea. Diaphragm muscle weakness on exertion and reduced diaphragm cortical activation were potentially related to exertional dyspnea. Compared with sham control, IMT improved diaphragm and inspiratory muscle function (sniff transdiaphragmatic pressure, 83 cm H2O [IQR = 75-91] vs. 100 cm H2O [IQR = 81-113], P = 0.02), inspiratory muscle fatiguability (time to task failure, 365 s [IQR = 284-701] vs. 983 s [IQR = 551-1,494], P = 0.05), diaphragm voluntary activation index (79% [IQR = 63-92] vs. 89% [IQR = 75-94], P = 0.03), and dyspnea (Borg score, 7 [IQR = 5.5-8] vs. 6 [IQR = 4-7], P = 0.03). Improvements persisted for 6 weeks after IMT completion. Conclusions: To the best of the authors' knowledge, this study is the first to identify a potential treatment for persisting exertional dyspnea in long COVID and provide a possible pathophysiological explanation for the treatment benefit. Clinical trial registered with www.clinicaltrials.gov (NCT04854863, NCT05582642).

Ventilator-induced diaphragm dysfunction: phenomenology and mechanism(s) of pathogenesis.

Mechanical ventilation (MV) is used to support ventilation and pulmonary gas exchange in patients during critical illness and surgery. Although MV is a life-saving intervention for patients in respiratory failure, an unintended side-effect of MV is the rapid development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is labelled as 'ventilator-induced diaphragm dysfunction' (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a risk factor for the failure to wean patients from MV. Indeed, the inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. The pathogenesis of VIDD has been extensively investigated, revealing that increased mitochondrial production of reactive oxygen species within diaphragm muscle fibres promotes a cascade of redox-regulated signalling events leading to both accelerated proteolysis and depressed protein synthesis. Together, these events promote the rapid development of diaphragmatic atrophy and contractile dysfunction. This review highlights the MV-induced changes in the structure/function of diaphragm muscle and discusses the cell-signalling mechanisms responsible for the pathogenesis of VIDD. This report concludes with a discussion of potential therapeutic opportunities to prevent VIDD and suggestions for future research in this exciting field.

Inspiratory muscle endurance is similarly reduced in the early and late stages of chronic Chagas heart disease.

OBJECTIVE: Inspiratory muscle strength (IMS) appears to be reduced in subjects with chronic Chagas heart disease (CHD), especially in the presence of heart failure (HF). However, only one study about IMS and inspiratory muscle endurance (IME) in those with CHD without heart failure is available. This study aimed to compare IMS and IME in subjects with CHD in the presence and absence of HF. METHODS: This is a cross-sectional study in which 30 CHD adult patients were divided into CHD-CC group (initial phase of CHD, without HF; n = 15) and CHD-HF group (advanced phase of CHD, with HF; n = 15). We assessed IMS by maximum inspiratory pressure (MIP) and IME by incremental (Pthmax) and constant load (TLim) tests. Reduced IMS and IME were considered by predicted MIP values <70% and Pthmax/MIP <75%, respectively. RESULTS: Inspiratory muscle weakness (IMW) was more frequent in CHD-HF than in CHD-CC (46.7% vs. 13.3%; p = 0.05), and both groups had high frequencies of reduced IME (93.3% CHD-CC vs. 100.0% CHD-HF; p = 0.95). Age-adjusted logistic regression analysis using HF as a dependent variable showed that HF was associated with an increased chance of IMW compared with the CHD-CC group (OR = 7.47; p = 0.03; 95% CI 1.20-46.19). CONCLUSION: This study suggests that, in patients with CHD, HF is associated with IMW, and that reduction of IME is already present in the initial phase, similar to the advanced phase with HF.

Evaluation of the applicability of weak shoulder and arm sparing signs in amyotrophic lateral sclerosis by multiple neurologists and neurology residents: A single-center study.

INTRODUCTION/AIMS: Amyotrophic lateral sclerosis (ALS) exhibits selective muscle weakness. The weak shoulder and arm sparing signs, assessed by a single experienced neurologist, have been reported to be superior to previous signs in sensitivity and specificity. However, it is unknown whether the same results are observed when assessed by multiple neurologists. METHODS: Subjects were retrospectively identified from our department's inpatient database from 2014 to 2023. Medical Research Council (MRC) scores of the deltoid (Del), biceps brachii (BB), triceps brachii (TB), and first dorsal interosseous (FDI) muscles were evaluated. The weak shoulder sign was defined as positive when Del was weaker than BB and TB. The arm sparing sign was defined as positive when both Del and FDI were weaker than BB and TB. Sensitivity was analyzed in all ALS patients and in subgroups based on the region of symptom onset, presence or absence of upper motor neuron (UMN) signs, and the Japanese ALS Severity Classification. RESULTS: Seventy-one patients with ALS were identified. Eight neurologists and three neurology residents evaluated each patient's MRC scores. The weak shoulder and arm sparing signs were observed in 72% and 48% of patients, respectively, with no significant difference in sensitivity across patient subgroups. DISCUSSION: The weak shoulder and arm sparing signs showed high and moderate sensitivity, respectively, consistent with a previous report, even when evaluated by multiple examiners. This expands the clinical utility and increases the reliability of these signs, potentially contributing to accurate ALS diagnosis when combined with other clinical features and objective assessments.

The other face of facioscapulohumeral muscular dystrophy: Exploring orofacial weakness using muscle ultrasound.

INTRODUCTION/AIMS: One of the most distinct clinical features of facioscapulohumeral muscular dystrophy (FSHD) is facial weakness. It leads to diminished facial expression and functional impairments. Despite its clinical relevance, little else is known about orofacial muscle involvement. We therefore evaluated orofacial muscle involvement in a sizeable cohort of FSHD participants with muscle ultrasound. METHODS: Muscle ultrasound images of the following orofacial muscles were scored visually and quantitatively: depressor anguli oris (DAO), orbicularis oris (OO), buccinator, temporalis, masseter, digastric, zygomaticus major and minor bilaterally, and the geniohyoid. Reliability analyses of both visual and quantitative evaluations were performed. Ultrasound results were correlated with other measures: the FSHD clinical score, facial weakness score, and facial function scale. RESULTS: We included 107 FSHD participants (male 54%; age 52 ± 14 years), of whom 92% showed signs of facial weakness. The reliability of visual ultrasound analysis varied widely (κ 0.0-1.0). Quantitative ultrasound reliability was high (intraclass correlation analysis ≥ 0.96). The DAO, buccinator, OO, temporalis, and zygomaticus minor muscles were affected most often (15%-39%). The digastric, geniohyoid, zygomaticus major, and masseter muscles were least often affected (<5%). The ultrasound compound score correlated weakly to moderately with other outcome measures used (ρ = 0.3-0.7). DISCUSSION: This study adds to the understanding of orofacial weakness in FSHD, confirming the involvement of the muscles of facial expression in FSHD using ultrasound. We showed that orofacial muscle ultrasound is feasible and reliable when quantitatively assessed. Future studies should evaluate orofacial muscle ultrasound longitudinally, alongside clinical and patient-reported facial weakness outcome measures, to assess their potential as outcome measures.

Association of chronic liver disease with bone diseases and muscle weakness.

The liver is a vital organ involved in nutrient metabolism, hormone regulation, immunity, cytokine production, and gut homeostasis. Impairment in liver function can result in malnutrition, chronic inflammation, decreased anabolic hormone levels, and dysbiosis. These conditions eventually cause an imbalance in osteoblast and osteoclast activities, resulting in bone loss. Osteoporosis is a frequent complication of chronic liver disease (CLD) that adversely affects quality of life and increases early mortality. Sarcopenia is another common complication of CLD characterized by progressive loss of skeletal muscle mass and function. Assessment criteria for sarcopenia specific to liver disease have been established, and sarcopenia has been reported to be associated with an increase in the risk of liver disease-related events and mortality in patients with CLD. Owing to their similar risk factors and underlying pathophysiological mechanisms, osteoporosis and sarcopenia often coexist (termed osteosarcopenia), progress in parallel, and further exacerbate the conditions mentioned above. Therefore, comprehensive management of these musculoskeletal disorders is imperative. This review summarizes the clinical implications and characteristics of osteoporosis, extending to sarcopenia and osteosarcopenia, in patients with CLD caused by different etiologies.

Clinical characteristics and impairment of activities of daily living among patients with myasthenia gravis with differing degrees of muscle weakness: a real-world study of patients in the US and five European countries.

BACKGROUND: Real-world data were employed to determine clinical characteristics of patients with myasthenia gravis (MG) with differing degrees of muscle weakness, as defined using the Myasthenia Gravis Foundation of America (MGFA) classification system. METHODS: Data were drawn from the Adelphi MG Disease Specific Programme (DSP)™, a multinational (United States, France, Germany, Italy, Spain, United Kingdom) survey completed by physicians and their patients with MG in 2020. The association between MGFA class and impairment in activities of daily living (ADL) was tested using linear regression adjusting for sex and Charlson Comorbidity Index. Bivariate comparisons were performed for each individual item. A range of other clinical characteristics were also explored according to MGFA class. RESULTS: Among 1232 patients, those in MGFA class I had significantly lower ADL impairment versus class II or III/IV (adjusted for sex and Charlson Comorbidity Index) (p < 0.01). However, heterogeneity occurred within each MGFA class. Bulbar symptoms (impaired speech, difficulty swallowing, and/or difficulty chewing/choking on food) were reported in some class I patients (mild in 1.1-1.9% and moderate in 0.3-1.1% of patients) and class II patients (mild in 8.5-16.4%, moderate in 4.7-7.4%, and severe in 0.3-0.9% of patients), and shortness of breath was reported in some class I (mild in 0.5% of patients) and class II patients (mild in 9.8%, moderate in 4.8%, and severe in 0.3% of patients). Conversely, in 11.2-19.2% of class III/IV patients, bulbar symptoms and shortness of breath reported were only mild in severity. In line with this finding, despite significant correlations between MGFA class and several clinical characteristics, patients across every class were at risk of experiencing myasthenic crisis or hospitalization, experiencing comorbidities including anxiety and depression, and not being in remission. CONCLUSIONS: Although MGFA class correlates with greater ADL impairment and presence of other clinical characteristics, there is variability between patients in each class in terms of symptoms experienced, overall disease burden, and the precise nature of ADL impairment.

Characteristics of Skeletal Muscle Strength in Subjects With Interstitial Lung Disease.

OBJECTIVES: To investigate muscle strength and the prevalence of muscle weakness in adults with interstitial lung diseases (ILDs) compared to healthy subjects. DESIGN: Cross-sectional (description of clinical features). SETTING: Public referral center (University Hospital). PARTICIPANTS: One hundred and twelve adults with ILD (n=48, 60±10yr, 68% female) and healthy counterparts (control group, n=64, 57±10yr, 58% female) (N=112). INTERVENTION: Not applicable. MAIN OUTCOME MEASURE(S): Muscle strength and prevalence of muscle weakness in adults with ILD. Muscle strength was assessed via maximal isometric voluntary contraction of dominant upper and lower limb muscle groups. Data from the control group were used to generate reference equations. Muscle weakness was defined as a muscle strength value below the lower limit of normal calculated using data from the control group. Data were expressed as mean ± SD or median [interquartile range] according to the data distribution. RESULTS: Compared to the control group, adults with ILD had lower muscle strength for all muscle groups assessed (values presented as %predicted: pectoralis major 75[57-86]%; quadriceps 72[58-87]%; latissimus dorsi 76[57-103]%; deltoid 74[64-98]%; biceps brachii 78[64-91]%; triceps brachii 84[62-101]%; P≤.001 for all). Prevalence of muscle weakness in people with ILD was 40% for pectoralis major, 25% for latissimus dorsi, 16% for triceps brachii, 20% for biceps brachii, 27% for deltoid and 46% for quadriceps. CONCLUSIONS: Adults with ILD present a generalised reduction in peripheral Muscle strength, ranging between 20% to 46% of people depending on the muscle group assessed. and it was more prevalent in lower limb muscles.

Patient-reported difficulty in activities of daily living and corresponding muscle weakness in elderly patients undergoing haemodialysis.

AIM: Patients undergoing haemodialysis have reduced muscle strength and impaired activities of daily living (ADL). We examined possible relationship between difficult ADL and corresponding muscle weakness in elderly haemodialysis patients. METHODS: This was a single-centre, cross-sectional study. Patient-reported ADL difficulty was examined using a questionnaire in six ADL using upper limbs (eating, grooming and dressing) and lower limbs (bathing, toileting and locomotion). We measured six muscle strengths by dynamometers of shoulder flexion, shoulder abduction, elbow flexion, handgrip, hip abduction and knee extension. The muscle strength with the lowest Z-score was considered as the weakest muscle strength for the patient. RESULTS: The six scores of ADL difficulty were all inversely associated with the six muscle strengths in the 81 total participants of whom 71 individuals (87.7%) had any ADL difficulty. Among the six measurements of muscle strength, handgrip strength showed the highest associations with all ADL difficulties. In 25 patients who perceived that the most difficult ADL was an activity using upper limbs, the common weakest muscle strengths were the hip abduction, handgrip and elbow flexion. In 44 patients who perceived that the most difficult ADL was an activity using lower limbs, knee extension was the most prevalent weakest muscle strength. CONCLUSION: This study suggested preferential relationship between the most difficult ADL and corresponding muscle weakness in elderly haemodialysis patients. This finding may be useful in prevention and treatment.

Resistance training effects on pubertal children with a risk of developing pediatric dynapenia.

PURPOSE: Many modern-day children are at risk of pediatric dynapenia (muscle weakness). We examined the effects of a 12-week resistance training (RT) program on neuromuscular function and body composition parameters in pubertal children with a risk of dynapenia. METHODS: Twelve children (13.4 ± 0.9 y) with dynapenia performed a progressive RT program consisting of knee extension and flexion, bench press, abdominal crunch, back extension, lateral pull-down, elbow flexion, and upright row (1-2 sets of 10-15 repetitions/exercise) twice/week for 12 weeks. Outcome measures included one-repetition maximum (1-RM) strength, maximal voluntary isometric contraction (MVIC) torque, rate of torque development (RTD), electromyographic (EMG) activity, muscle thickness (MT), muscle quality (MQ) assessed by echo intensity (MQEI) of the knee extensors and specific tension of MVIC torque to thigh fat-free mass (MQST), and total and regional body and bone composition assessed by dual-energy X-ray absorptiometry. Changes in the measures before and after the 12-week RT and associations among the measures were analyzed by linear mixed models. RESULTS: Significant (p < 0.05) increases in 1-RM (63.9 ± 4.5%), MVIC torque (16.3 ± 17.8%), MT (18.8 ± 5.5%) and MQ (MQEI: -25.9 ± 15.2%; MQST: 15.1 ± 18.8%;) were evident from pre- to post-training. Total fat-free mass (FFM) increased by 2.3 ± 3.2% from baseline (p = 0.01), but no changes (p > 0.05) in the other measures were observed. Significant (p < 0.05) associations between the changes in 1-RM and/or MVIC torque and the changes in quadriceps MT, MQEI, MQST and total body FFM were evident. CONCLUSIONS: The 12-week RT was effective for improving neuromuscular and body composition parameters, and thereby reversed the risk of pediatric dynapenia.

No sign of weakness: a systematic review and meta-analysis of hip and calf muscle strength after anterior cruciate ligament injury.

OBJECTIVE: We aimed to determine hip and lower-leg muscle strength in people after ACL injury compared with an uninjured control group (between people) and the uninjured contralateral limb (between limbs). DESIGN: Systematic review with meta-analysis. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Scopus, Cochrane CENTRAL and SportDiscus to 28 February 2023. ELIGIBILITY CRITERIA: Primary ACL injury with mean age 18-40 years at time of injury. Studies had to measure hip and/or lower-leg muscle strength quantitatively (eg, dynamometer) and report muscle strength for the ACL-injured limb compared with: (i) an uninjured control group and/or (ii) the uninjured contralateral limb. Risk of bias was assessed according to Cochrane Collaboration domains. RESULTS: Twenty-eight studies were included (n=23 measured strength ≤12 months post-ACL reconstruction). Most examined hip abduction (16 studies), hip extension (12 studies) and hip external rotation (7 studies) strength. We found no meaningful difference in muscle strength between people or between limbs for hip abduction, extension, internal rotation, flexion or ankle plantarflexion, dorsiflexion (estimates ranged from -9% to +9% of comparator). The only non-zero differences identified were in hip adduction (24% stronger on ACL limb (95% CI 8% to 42%)) and hip external rotation strength (12% deficit on ACL limb (95% CI 6% to 18%)) compared with uninjured controls at follow-ups >12 months, however both results stemmed from only two studies. Certainty of evidence was very low for all outcomes and comparisons, and drawn primarily from the first year post-ACL reconstruction. CONCLUSION: Our results do not show widespread or substantial muscle weakness of the hip and lower-leg muscles after ACL injury, contrasting deficits of 10%-20% commonly reported for knee extensors and flexors. As it is unclear if deficits in hip and lower-leg muscle strength resolve with appropriate rehabilitation or no postinjury or postoperative weakness occurs, individualised assessment should guide training of hip and lower-leg strength following ACL injury. PROSPERO REGISTRATION NUMBER: CRD42020216793.

Using Physiological Markers to Assess Comfort during Neuromuscular Electrical Stimulation Induced Muscle Contraction in a Virtually Guided Environment: Pilot Study for a Path toward Combating ICU-Acquired Weakness.

We assessed the feasibility of implementing a virtually guided Neuromuscular Electrical Stimulation (NMES) protocol over the tibialis anterior (TA) muscle while collecting heart rate (HR), Numeric Pain Rating Scale (NPRS), and quality of contraction (QoC) data. We investigated if HR, NPRS, and QoC differ ON and OFF the TA motor point and explored potential relationships between heart rate variability (HRV) and the NPRS. Twelve healthy adults participated in this cross-sectional study. Three NMES trials were delivered ON and OFF the TA motor point. HR, QoC, and NPRS data were collected. There was no significant difference in HRV ON and OFF the motor point (p > 0.05). The NPRS was significantly greater OFF the motor point (p < 0.05). The QoC was significantly different between motor point configurations (p < 0.05). There was no correlation between the NPRS and HRV (p > 0.05, r = -0.129). We recommend non-electrical methods of measuring muscle activity for future studies. The NPRS and QoC can be administered virtually. Time-domain HRV measures could increase the validity of the protocol. The variables should be explored further virtually to enhance the protocol before eventual ICU studies.

Collective Weakness Is Associated With Time to Mortality in Americans.

ABSTRACT: McGrath, R, McGrath, BM, Jurivich, D, Knutson, P, Mastrud, M, Singh, B, and Tomkinson, GR. Collective weakness is associated with time to mortality in Americans. J Strength Cond Res 38(7): e398-e404, 2024-Using new weakness cutpoints individually may help estimate time to mortality, but their collective use could improve value. We sought to determine the associations of (a) each absolute and body size normalized cut point and (b) collective weakness on time to mortality in Americans. The analytic sample included 14,178 subjects aged ≥50 years from the 2006-2018 waves of the Health and Retirement Study. Date of death was confirmed from the National Death Index. Handgrip dynamometry measured handgrip strength (HGS). Men were categorized as weak if their HGS was <35.5 kg (absolute), <0.45 kg·kg -1 (body mass normalized), or <1.05 kg·kg -1 ·m -2 (body mass index [BMI] normalized). Women were classified as weak if their HGS was <20.0 kg, <0.337 kg·kg -1 , or <0.79 kg·kg -1 ·m -2 . Collective weakness categorized persons as below 1, 2, or all 3 cutpoints. Cox proportional hazard regression models were used for analyses. Subject values below each absolute and normalized cutpoint for the 3 weakness parameters had a higher hazard ratio for early all-cause mortality: 1.45 (95% confidence interval [CI]: 1.36-1.55) for absolute weakness, 1.39 (CI: 1.30-1.49) for BMI normalized weakness, and 1.33 (CI: 1.24-1.43) for body mass normalized weakness. Those below 1, 2, or all 3 weakness cut points had a 1.37 (CI: 1.26-1.50), 1.47 (CI: 1.35-1.61), and 1.69 (CI: 1.55-1.84) higher hazard for mortality, respectively. Weakness determined by a composite measure of absolute and body size adjusted strength capacity provides robust prediction of time to mortality, thus potentially informing sports medicine and health practitioner discussions about the importance of muscle strength during aging.

The effects of inspiratory muscle training on biomarkers of muscle damage in recovered COVID-19 patients after weaning from mechanical ventilation.

Background: COVID-19 patients experience respiratory muscle damage, leading to reduced respiratory function and functional capacity often requiring mechanical ventilation which further increases susceptibility to muscle weakness. Inspiratory muscle training (IMT) may help mitigate this damage and improve respiratory function and functional capacity. Methods: We studied the effects of IMT on muscle damage biomarkers, respiratory function, and functional capacity in COVID-19 recovered young adults, successfully weaned from mechanical ventilation. Participants were randomly allocated to either an IMT (n = 11) or control (CON; n = 11) intervention for 4 weeks. The IMT group performed 30 dynamic inspiratory efforts twice daily, at 50% of their maximal inspiratory mouth pressure (PMmax) while the CON group performed 60 inspiratory efforts at 10% of pMmax daily. Serum was collected at baseline, week two, and week four to measure creatine kinase muscle-type (CKM), fast skeletal troponin-I (sTnI) and slow sTnI. Results: Time × group interaction effects were observed for CKM and slow sTnI, but not for fast sTnI. Both were lower at two and 4 weeks for the IMT compared to the CON group, respectively. Time × group interaction effects were observed for forced expiratory volume in 1s, forced vital capacity, PMmax and right- and left-hand grip strength. These were higher for the IMT compared to the CON group. Conclusion: Four weeks of IMT decreased muscle damage biomarkers and increased respiratory function and grip strength in recovered COVID-19 patients after weaning from mechanical ventilation.

[THE MUSCULAR COMPONENT OF FIBROMYALGIA PATHOPHYSIOLOGY].

INTRODUCTION: Fibromyalgia syndrome (FMS) is a chronic pain syndrome, prevalent in women more than men. The main symptoms are widespread musculoskeletal pain, fatigue, and weakness. To date, the pathophysiological mechanisms are unclear, and there are several pathogenic theories elucidating this condition. In this review, we summarized articles published in the past few years, regarding the effect of musculoskeletal dysfunction on FMS. We focused on the musculoskeletal system and central nervous system (CNS) disarrays.

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill.

Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca(2+) dysregulation is present through altered Ca(2+) homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

Increased short interval intracortical inhibition in participants with previous hamstring strain injury.

PURPOSE: Cortical mechanisms may contribute to weakness in participants with previous hamstring strain injury. This study aims to examine intra-cortical inhibition (SICI) and corticospinal excitability in previously injured participants. METHODS: In this cross-sectional study, TMS was used to examine SICI, silent period, silent period: MEP ratios and area under the stimulus response curve in the biceps femoris and medial hamstrings. Comparisons were made between participants with (n = 10) and without (n = 10) previous hamstring strain injury. Motor threshold and isometric knee flexor strength were also compared between participants and the relationship between strength and SICI in control and previously injured participants was examined. RESULTS: Isometric knee flexor strength was lower in previously injured limbs compared with control limbs (mean difference = - 41 Nm (- 26%) [95% CI = - 80 to - 2 Nm], p = 0.04, Cohen's d = - 1.27) and contralateral uninjured limbs (mean difference = - 23 Nm (- 17%), [95% CI = - 40 to - 6 Nm], p = 0.01, Cohen's d = - 0.57). Previously injured limbs exhibited smaller responses to paired pulse stimulation (i.e. greater levels of SICI) in the biceps femoris compared with control limbs (mean difference = - 19%, [95% CI = - 34 to - 5%], p = 0.007, Cohen's d = - 1.33). Isometric knee flexor strength was associated with the level of SICI recorded in the biceps femoris in previously injured participants (coefficient = 23 Nm [95% CI = 7-40 Nm], adjusted R2 = 0.31, p = 0.01). There were no differences in markers of corticospinal excitability between previously injured and control limbs (all p > 0.24, all Cohen's d < 0.40). CONCLUSION: Athletes with previous injury in the biceps femoris exhibit increased SICI in this muscle compared with control participants. Increased SICI is related to lower levels of hamstring strength, and rehabilitation programs targeting the removal of intra-cortical inhibition should be considered.

Prognostic factors for recurrent idiopathic clubfoot deformity: a systematic literature review and meta-analysis.

Background and purpose - After initial clubfoot correction through Ponseti treatment, recurrence rates range from 26% to 48%. Even though various factors have been associated with increased recurrence risk, systematic assessments of the prognostic capacity of recurrence risk factors and their clinical relevance are lacking. Therefore we assessed clinically relevant prognostic factors for recurrent idiopathic clubfoot deformity after initial correction through Ponseti treatment. Methods - PubMed, Embase, Cinahl, and Web of Science were systematically searched for studies investigating the association between clinically relevant factors and recurrence rates. Prognostic factors were qualitatively assessed and included in the meta-analysis if ≥ 2 studies investigated the same factor and methods were comparable. Results - 34 articles were included in the qualitative synthesis, of which 22 were also included in the meta-analysis. Meta-analysis revealed that poor evertor muscle activity (OR = 255, 95% CI 30-2,190), brace non-compliance (OR = 10, CI 5-21), no additional stretching (OR = 31, CI 10-101), more casts (OR = 3.5, CI 1.6-7.8), lower education level of parents (OR = 1.8, CI 1.2-2.6), non-marital status of parents (OR = 1.8, CI 1.1-3.0), and higher Dimeglio scores (OR = 1.9, CI 1.2-3.3) were associated with higher recurrence rates. Interpretation - Brace non-compliance and poor evertor muscle activity have been identified as main recurrence risk factors and are therefore important to be closely monitored during clinical follow-up of clubfoot patients. Adding additional stretching during the bracing protocol might be promising in the quest to prevent relapse, but scientific evidence for clear clinical treatment recommendations is still limited.

Multimodal Assessment of the Motor System in Patients With Chronic Ischemic Stroke.

BACKGROUND AND PURPOSE: Despite continuing efforts in the multimodal assessment of the motor system after stroke, conclusive findings on the complementarity of functional and structural metrics of the ipsilesional corticospinal tract integrity and the role of the contralesional hemisphere are still lacking. This research aimed to find the best combination of motor system metrics, allowing the classification of patients into 3 predefined groups of upper limb motor recovery. METHODS: We enrolled 35 chronic ischemic stroke patients (mean 47 [26-66] years old, 29 [6-58] months poststroke) with a single supratentorial lesion and unilateral upper extremity weakness. Patients were divided into 3 groups, depending on upper limb motor recovery: good, moderate, and bad. Nonparametric statistical tests and regression analysis were used to investigate the relationships among microstructural (fractional anisotropy (FA) ratio of the corticospinal tracts at the internal capsule (IC) level (classic method) and along the length of the tracts (Fréchet distance), and of the corpus callosum) and functional (motor evoked potentials [MEPs] for 2 hand muscles) motor system metrics. Stratification rules were also tested using a decision tree classifier. RESULTS: IC FA ratio in the IC and MEP absence were both equally discriminative of the bad motor outcome (96% accuracy). For the 3 recovery groups' classification, the best parameter combination was IC FA ratio and the Fréchet distance between the contralesional and ipsilesional corticospinal tract FA profiles (91% accuracy). No other metrics had any additional value for patients' classification. MEP presence differed for 2 investigated muscles. CONCLUSIONS: This study demonstrates that better separation between 3 motor recovery groups may be achieved when considering the similarity between corticospinal tract FA profiles along its length in addition to region of interest-based assessment and lesion load calculation. Additionally, IC FA ratio and MEP absence are equally important markers for poor recovery, while for MEP probing it may be important to investigate more than one hand muscle.

Mouse model of severe recessive RYR1-related myopathy.

Ryanodine receptor type I (RYR1)-related myopathies (RYR1 RM) are a clinically and histopathologically heterogeneous group of conditions that represent the most common subtype of childhood onset non-dystrophic muscle disorders. There are no treatments for this severe group of diseases. A major barrier to therapy development is the lack of an animal model that mirrors the clinical severity of pediatric cases of the disease. To address this, we used CRISPR/Cas9 gene editing to generate a novel recessive mouse model of RYR1 RM. This mouse (Ryr1TM/Indel) possesses a patient-relevant point mutation (T4706M) engineered into 1 allele and a 16 base pair frameshift deletion engineered into the second allele. Ryr1TM/Indel mice exhibit an overt phenotype beginning at 14 days of age that consists of reduced body/muscle mass and myofibre hypotrophy. Ryr1TM/Indel mice become progressively inactive from that point onward and die at a median age of 42 days. Histopathological assessment shows myofibre hypotrophy, increased central nuclei and decreased triad number but no clear evidence of metabolic cores. Biochemical analysis reveals a marked decrease in RYR1 protein levels (20% of normal) as compared to only a 50% decrease in transcript. Functional studies at end stage show significantly reduced electrically evoked Ca2+ release and force production. In summary, Ryr1TM/Indel mice exhibit a post-natal lethal recessive form of RYR1 RM that pheno-copies the severe congenital clinical presentation seen in a subgroup of RYR1 RM children. Thus, Ryr1TM/Indel mice represent a powerful model for both establishing the pathomechanisms of recessive RYR1 RM and pre-clinical testing of therapies for efficacy.