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Critical Care (London, England) Nov 2023Severe weakness associated with critical illness (CIW) is common. This narrative review summarizes the latest scientific insights and proposes a guide for clinicians to... (Review)
Review
BACKGROUND
Severe weakness associated with critical illness (CIW) is common. This narrative review summarizes the latest scientific insights and proposes a guide for clinicians to optimize the diagnosis and management of the CIW during the various stages of the disease from the ICU to the community stage.
MAIN BODY
CIW arises as diffuse, symmetrical weakness after ICU admission, which is an important differentiating factor from other diseases causing non-symmetrical muscle weakness or paralysis. In patients with adequate cognitive function, CIW can be easily diagnosed at the bedside using manual muscle testing, which should be routinely conducted until ICU discharge. In patients with delirium or coma or those with prolonged, severe weakness, specific neurophysiological investigations and, in selected cases, muscle biopsy are recommended. With these exams, CIW can be differentiated into critical illness polyneuropathy or myopathy, which often coexist. On the general ward, CIW is seen in patients with prolonged previous ICU treatment, or in those developing a new sepsis. Respiratory muscle weakness can cause neuromuscular respiratory failure, which needs prompt recognition and rapid treatment to avoid life-threatening situations. Active rehabilitation should be reassessed and tailored to the new patient's condition to reduce the risk of disease progression. CIW is associated with long-term physical, cognitive and mental impairments, which emphasizes the need for a multidisciplinary model of care. Follow-up clinics for patients surviving critical illness may serve this purpose by providing direct clinical support to patients, managing referrals to other specialists and general practitioners, and serving as a platform for research to describe the natural history of post-intensive care syndrome and to identify new therapeutic interventions. This surveillance should include an assessment of the activities of daily living, mood, and functional mobility. Finally, nutritional status should be longitudinally assessed in all ICU survivors and incorporated into a patient-centered nutritional approach guided by a dietician.
CONCLUSIONS
Early ICU mobilization combined with the best evidence-based ICU practices can effectively reduce short-term weakness. Multi-professional collaborations are needed to guarantee a multi-dimensional evaluation and unitary community care programs for survivors of critical illnesses.
Topics: Humans; Critical Illness; Intensive Care Units; Activities of Daily Living; Muscular Diseases; Muscle Weakness; Frailty; Polyneuropathies
PubMed: 37957759
DOI: 10.1186/s13054-023-04676-3 -
Journal of Neurology Oct 2023Becker muscular dystrophy (BMD) is one of the most frequent among neuromuscular diseases, affecting approximately 1 in 18,000 male births. It is linked to a genetic... (Review)
Review
Becker muscular dystrophy (BMD) is one of the most frequent among neuromuscular diseases, affecting approximately 1 in 18,000 male births. It is linked to a genetic mutation on the X chromosome. In contrast to Duchenne muscular dystrophy, for which improved care and management have changed the prognosis and life expectancy of patients, few guidelines have been published for management of BMD. Many clinicians are inexperienced in managing the complications of this disease. In France, a committee of experts from a wide range of disciplines met in 2019 to establish recommendations, with the goal of improving care of patients with BMD. Here, we present the tools to provide diagnosis of BMD as quickly as possible and for differential diagnoses. Then, we describe the multidisciplinary approach essential for optimum management of BMD. We give recommendations for the initial assessment and follow-up of the neurological, respiratory, cardiac, and orthopedic consequences of males who present with BMD. Finally, we describe the optimal therapeutic management of these complications. We also provide guidance on cardiac management for female carriers.
Topics: Humans; Male; Female; Muscular Dystrophy, Duchenne; Heterozygote; Prognosis; Diagnosis, Differential; Mutation
PubMed: 37422773
DOI: 10.1007/s00415-023-11837-5 -
Journal of Advanced Research Jan 2024Investigating the genetic markers and genomic signatures related to chicken meat production by combing multi-omics methods could provide new insights into modern chicken...
INTRODUCTION
Investigating the genetic markers and genomic signatures related to chicken meat production by combing multi-omics methods could provide new insights into modern chicken breeding technology systems.
OBJECT
Chicken is one of the most efficient and environmentally friendly livestock, especially the fast-growing white-feathered chicken (broiler), which is well known for high meat yield, but the underlying genetic basis is poorly understood.
METHOD
We generated whole-genome resequencing of three purebred broilers (n = 748) and six local breeds/lines (n = 114), and sequencing data of twelve chicken breeds (n = 199) were obtained from the NCBI database. Additionally, transcriptome sequencing of six tissues from two chicken breeds (n = 129) at two developmental stages was performed. A genome-wide association study combined with cis-eQTL mapping and the Mendelian randomization was applied.
RESULT
We identified > 17 million high-quality SNPs, of which 21.74% were newly identified, based on 21 chicken breeds/lines. A total of 163 protein-coding genes underwent positive selection in purebred broilers, and 83 genes were differentially expressed between purebred broilers and local chickens. Notably, muscle development was proven to be the major difference between purebred broilers and local chickens, or ancestors, based on genomic and transcriptomic evidence from multiple tissues and stages. The MYH1 gene family showed the top selection signatures and muscle-specific expression in purebred broilers. Furthermore, we found that the causal gene SOX6 influenced breast muscle yield and also related to myopathy occurrences. A refined haplotype was provided, which had a significant effect on SOX6 expression and phenotypic changes.
CONCLUSION
Our study provides a comprehensive atlas comprising the typical genomic variants and transcriptional characteristics for muscle development and suggests a new regulatory target (SOX6-MYH1s axis) for breast muscle yield and myopathy, which could aid in the development of genome-scale selective breeding aimed at high meat yield in broiler chickens.
Topics: Animals; Chickens; Genome-Wide Association Study; Genomics; Gene Expression Profiling; Meat; Muscular Diseases
PubMed: 36871617
DOI: 10.1016/j.jare.2023.02.016 -
Frontiers in Immunology 2023Idiopathic inflammatory myopathies (IIMs) are common autoimmune diseases that affect skeletal muscle quality and function. The lack of an early diagnosis and treatment... (Review)
Review
Idiopathic inflammatory myopathies (IIMs) are common autoimmune diseases that affect skeletal muscle quality and function. The lack of an early diagnosis and treatment can lead to irreversible muscle damage. Non-coding RNAs (ncRNAs) play an important role in inflammatory transfer, muscle regeneration, differentiation, and regulation of specific antibody levels and pain in IIMs. ncRNAs can be detected in blood and hair; therefore, ncRNAs detection has great potential for diagnosing, preventing, and treating IIMs in conjunction with other methods. However, the specific roles and mechanisms underlying the regulation of IIMs and their subtypes remain unclear. Here, we review the mechanisms by which micro RNAs and long non-coding RNA-messenger RNA networks regulate IIMs to provide a basis for ncRNAs use as diagnostic tools and therapeutic targets for IIMs.
Topics: Humans; Myositis; RNA, Untranslated; Autoimmune Diseases; MicroRNAs; Muscle, Skeletal
PubMed: 37744337
DOI: 10.3389/fimmu.2023.1227945 -
Circulation Research Jul 2023Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with...
BACKGROUND
Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD. Herein, we examined the role of AHR activation in the myopathy of PAD and CKD.
METHODS
AHR-related gene expression was evaluated in skeletal muscle obtained from mice and human PAD patients with and without CKD. AHR (skeletal muscle-specific AHR knockout) mice with and without CKD were subjected to femoral artery ligation, and a battery of assessments were performed to evaluate vascular, muscle, and mitochondrial health. Single-nuclei RNA sequencing was performed to explore intercellular communication. Expression of the constitutively active AHR was used to isolate the role of AHR in mice without CKD.
RESULTS
PAD patients and mice with CKD displayed significantly higher mRNA expression of classical AHR-dependent genes (, , and ) when compared with either muscle from the PAD condition with normal renal function (<0.05 for all 3 genes) or nonischemic controls. AHR significantly improved limb perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and strength, as well as enhanced mitochondrial function in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function.
CONCLUSIONS
These findings establish AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in CKD. Further, the totality of the results provides support for testing of clinical interventions that diminish AHR signaling in these conditions.
Topics: Animals; Humans; Mice; Ischemia; Mice, Knockout; Muscle, Skeletal; Muscular Diseases; Peripheral Arterial Disease; Receptors, Aryl Hydrocarbon; Renal Insufficiency, Chronic
PubMed: 37325935
DOI: 10.1161/CIRCRESAHA.123.322875 -
Neurology Jul 2023Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND OBJECTIVES
Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM.
METHODS
After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms.
RESULTS
Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity.
DISCUSSION
Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated.
TRIAL REGISTRATION INFORMATION
Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017.
CLINICALTRIALS
gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9.
CLASSIFICATION OF EVIDENCE
This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.
Topics: Humans; Female; Middle Aged; Male; Quality of Life; Merozoite Surface Protein 1; Mitochondrial Myopathies; Fatigue; Double-Blind Method; Treatment Outcome
PubMed: 37268435
DOI: 10.1212/WNL.0000000000207402 -
Current Opinion in Neurology Oct 2023Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our... (Review)
Review
PURPOSE OF REVIEW
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our purpose was to summarize the main objectives of the scientific community on this topic and the moving trajectories of research from the past to the present.
RECENT FINDINGS
To date, research is mainly oriented toward deciphering the molecular and pathogenetic basis of the disease by investigating DUX4-mediated muscle alterations. Accordingly, FSHD drug development has been escalating in the last years in an attempt to silence DUX4 or to block its downstream effectors. Breakthroughs in the field include the awareness that new biomarkers and outcome measures are required for tracking disease progression and patient stratification. The need to develop personalized therapeutic strategies is also crucial according to the phenotypic variability observed in FSHD subjects.
SUMMARY
We analysed 121 literature reports published between 2021 and 2023 to assess the most recent advances in FSHD clinical and molecular research.
Topics: Humans; Muscular Dystrophy, Facioscapulohumeral; Biomarkers; Drug Development; Homeodomain Proteins; Muscle, Skeletal
PubMed: 37338810
DOI: 10.1097/WCO.0000000000001176 -
International Journal of Molecular... Jul 2023Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on... (Review)
Review
Over the last decade, our understanding of spliceosome structure and function has significantly improved, refining the study of the impact of dysregulated splicing on human disease. As a result, targeted splicing therapeutics have been developed, treating various diseases including spinal muscular atrophy and Duchenne muscular dystrophy. These advancements are very promising and emphasize the critical role of proper splicing in maintaining human health. Herein, we provide an overview of the current information on the composition and assembly of early splicing complexes-commitment complex and pre-spliceosome-and their association with human disease.
Topics: Humans; RNA Splicing; Spliceosomes; Muscular Dystrophy, Duchenne; Muscular Atrophy, Spinal; RNA Precursors
PubMed: 37511171
DOI: 10.3390/ijms241411412 -
Current Opinion in Rheumatology Nov 2023Imaging techniques such as MRI, ultrasound and PET/computed tomography (CT) have roles in the detection, diagnosis and management of myositis or idiopathic inflammatory... (Review)
Review
PURPOSE OF REVIEW
Imaging techniques such as MRI, ultrasound and PET/computed tomography (CT) have roles in the detection, diagnosis and management of myositis or idiopathic inflammatory myopathy (IIM). Imaging research has also provided valuable knowledge in the understanding of the pathology of IIM. This review explores the latest advancements of these imaging modalities in IIM.
RECENT FINDINGS
Recent advancements in imaging of IIM have seen a shift away from manual and qualitative analysis of the images. Quantitative MRI provides more objective, and potentially more sensitive characterization of fat infiltration and inflammation in muscles. In addition to B-mode ultrasound changes, shearwave elastography offers a new dimension to investigating IIM. PET/CT has the added advantage of including IIM-associated findings such as malignancies.
SUMMARY
It is evident that MRI, ultrasound and PET/CT have important roles in myositis. Continued technological advancement and a quest for more sophisticated applications help drive innovation; this has especially been so of machine learning/deep learning using artificial intelligence and the developing promise of texture analysis.
Topics: Humans; Positron Emission Tomography Computed Tomography; Artificial Intelligence; Myositis; Inflammation; Muscle, Skeletal
PubMed: 37656661
DOI: 10.1097/BOR.0000000000000975 -
Ugeskrift For Laeger Oct 2023
Topics: Humans; Heart Failure; Muscular Diseases; Respiration Disorders; Soft Tissue Injuries
PubMed: 37921112
DOI: No ID Found