Background Stroke results in balance disorders and these directly affect autonomy and quality of life. The purpose of this systematic review and meta-analysis was to determine the efficacy of physical therapy (PT) on balance and postural control after stroke. Methods We included all randomized controlled trials assessing the efficacy of PT on balance and postural control in adult patients after stroke without language restriction. Medline, Embase/Scopus, Cochrane Central Register of Controlled Trials, PEDro, Pascal, and Francis databases were searched until January 2019. Primary outcomes were balance (Berg Balance scale and Postural Assessment Scale for Stroke) and postural control with postural deviation or stability measurement in sitting or standing static evaluation. A pair of independent reviewers selected studies, extracted data, and assessed risk of bias. Meta-analyses with subgroups (categories of PT, time post-stroke, and lesion location) and meta-regression (duration of PT) were conducted. Results A total of 145 studies (n = 5912) were selected from the 13,123 records identified. For balance, evidence was found in favor of the efficacy of functional task-training alone (standardized mean difference 0.39, 95% confidence interval [0.09; 0.68], heterogeneity I 2 = 63%) or associated with musculoskeletal intervention and/or cardiopulmonary intervention (0.37, [0.19; 0.55], I 2 = 48%), electrostimulation (0.91, [0.49; 1.34], I 2 = 52%) immediately after intervention, compared to sham treatment or usual care (ST/UC). For postural deviation eyes open, assistive devices were more effective than no treatment (-0.21, [-0.37; -0.05], I 2 = 0%) immediately after intervention; for postural stability eyes open, functional task-training and sensory interventions were more effective than ST/UC (0.97, [0.35; 1.59], I 2 = 65% and 0.80, [0.46; 1.13], I 2 = 37% respectively) immediately after intervention. Conclusions Functional task-training associated with musculoskeletal intervention and/or cardiopulmonary intervention and sensory interventions seem to be immediately effective in improving balance and postural stability, respectively. The heterogeneity of PT and the weak methodological quality of studies limited the interpretation and the confidence in findings.

Background The last international consensus on the management of type 2 diabetes (T2D) recommends SGLT-2 inhibitors or GLP-1 agonists for patients with clinical cardiovascular (CV) disease; metformin remains the first-line glucose lowering medication. Last studies suggested beneficial effects of SGLT-2 inhibitors or GLP-1 agonists compared to DPP-4 inhibitors, in secondary CV prevention. Recently, a potential benefit of SGLT-2 inhibitors in primary CV prevention also has been suggested. However, no comparison of all the new and the old hypoglycemic drugs is available on CV outcomes. We aimed to compare the effects of old and new hypoglycemic drugs in T2D, on major adverse cardiovascular events (MACE) and mortality. Methods and findings We conducted a systematic review and network meta-analysis of clinical trials. Randomized trials, blinded or not, assessing contemporary hypoglycemic drugs on mortality or MACE in patients with T2D, were searched for in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov. References screening and data extraction were done by multiple observers. Each drug was analyzed according to its therapeutic class. A random Bayesian network meta-analysis model was used. The primary outcomes were overall mortality, cardiovascular mortality, and MACE. Severe adverse events and severe hypoglycemia were also recorded. 175,966 patients in 34 trials from 1970 to 2018 were included. No trials evaluating glinides or alpha glucosidase inhibitors were found. 17 trials included a majority of patients with previous cardiovascular history, 16 trials a majority of patients without. Compared to control, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.84 [95% CrI: 0.74; 0.95]), SGLT-2 inhibitors and GLP-1 agonists with a decreased risk of MACE (OR = 0.89 [95% CrI: 0.81; 0.98] and OR = 0.88 [95% CrI: 0.81; 0.95], respectively). Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a decreased risk of overall mortality (OR = 0.82 [95% CrI: 0.69; 0.98]), GLP-1 agonists with a decreased risk of MACE (OR = 0.88 [95% CrI: 0.79; 0.99]). Insulin was also associated with an increased risk of MACE compared to GLP-1 agonists (OR = 1.19 [95% CrI: 1.01; 1.42]). Insulin and sulfonylureas were associated with an increased risk of severe hypoglycemia. In the trials including a majority of patients without previous CV history, the comparisons of SGLT-2 inhibitors, metformin and control did not showed significant differences on primary outcomes. We limited our analysis at the therapeutic class level. Conclusions SGLT-2 inhibitors and GLP-1 agonists have the most beneficial effects, especially in T2D patients with previous CV diseases. Direct comparisons of SGLT-2 inhibitors, GLP-1 agonists and metformin are needed, notably in primary CV prevention. Trial registration PROSPERO CRD42016043823 . ...

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Distal hereditary motor neuropathy represents a group of motor inherited neuropathies leading to distal weakness. We report a family of two brothers and a sister affected by distal hereditary motor neuropathy in whom a homozygous variant c.3G > T (p.1Met? ) was identified in the COQ7 gene. This gene encodes a protein required for Coenzyme Q10 biosynthesis, a component of the respiratory chain in mitochondria. Mutations of COQ7 were previously associated with severe multi-organ disorders characterized by early childhood onset and developmental delay. Using patient blood sample and fibroblasts derived from a skin biopsy, we investigated the pathogenicity of the variant of unknown significance c.3G > T (p.1Met? ) in the COQ7 gene and the effect of Coenzyme Q10 supplementation in vitro. We showed that this variation leads to a severe decrease in COQ7 protein levels in the patient’s fibroblasts, resulting in a decrease in Coenzyme Q10 production, and in the accumulation of 6-demethoxycoenzyme Q10, the COQ7 substrate. Interestingly, such accumulation was also found in the patient’s plasma. Normal Coenzyme Q10 and 6-demethoxycoenzyme Q10 levels were restored in vitro by using the Coenzyme Q10 precursor 2,4-dihydroxybenzoic acid, thus bypassing COQ7 requirement. Coenzyme Q10 biosynthesis deficiency is known to impair mitochondrial respiratory chain. Seahorse experiments showed that the patient’s cells mainly rely on glycolysis to maintain sufficient ATP production. Consistently, the replacement of glucose by galactose in the culture medium of these cells reduced their proliferation rate. Interestingly, normal proliferation was restored by Coenzyme Q10 supplementation in the culture medium, suggesting a therapeutic avenue for these patients. Altogether, we have identified the first example of recessive distal hereditary motor neuropathy caused by a homozygous variation in the COQ7 gene, which should thus be included in the gene panels used to diagnose peripheral inherited neuropathies. Furthermore, 6-demethoxycoenzyme Q10 accumulation in the blood can be used to confirm the pathogenic nature of the mutation. Finally, supplementation with Coenzyme Q10 or derivatives should be considered to prevent the progression of COQ7-related peripheral inherited neuropathy in diagnosed patients.

MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like (SMA-like) with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge. Here we report the characterization of an in vitro model to evaluate the pathogenicity of variants of unknown significance based on MORC2 overexpression in a neuroblastoma cell line SH-EP or in cortical neurons. Likewise, we show that MORC2 mutants affect survival and trigger apoptosis over time in SH-EP cell line. Furthermore, overexpression in primary cortical neurons increases apoptotic cell death and decreases neurite outgrowth. Altogether, these approaches establish the pathogenicity of two new variants p.G444R and p.H446Q in three patients from two families. These new mutations in MORC2 gene are associated with autosomal dominant CMT and with adult late onset SMA-like phenotype, further increasing the spectrum of clinical manifestations associated with MORC2 mutations.

The aim of this study was to propose a ranking of the currently available antidiabetic drugs, regarding vascular clinical outcomes, in patients with type 2 diabetes, through a network meta-analysis approach. Randomized clinical trials, regardless of the blinding design, testing contemporary antidiabetic drugs, and considering clinically relevant outcomes in patients with type 2 diabetes mellitus will be included. The primary outcomes of this analysis will be overall mortality, cardiovascular mortality, and major cardiovascular events. Diabetic microangiopathy will be a secondary outcome. Adverse events, hypoglycemia, weight evolution, bariatric surgery, and discontinuation of the treatment will also be recorded. Each drug will be analyzed according to its therapeutic class: biguanide, alpha-glucosidase inhibitors, sulfonylureas, glitazones, glinides, insulin, DPP-4 inhibitors, GLP-1 analogs, and gliflozins. The treatment effect of each drug class will be compared using pairwise meta-analysis and a Bayesian random model network meta-analysis. Sensitivity analyses will be conducted according to the quality of the studies and the glycemic control. The report will follow the PRISMA checklist for network meta-analysis. Results of the search strategy and of the study selection will be presented in a PRISMA compliant flowchart. The treatment effects will be summarized with odds ratio (OR) estimates and their 95% credible intervals. A ranking of the drugs will be proposed. Our network meta-analysis should allow a clinically relevant ranking of the contemporary antidiabetic drugs.

MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z),