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This phase 2, double-blind, placebo-controlled, hypothesis-generating study evaluated the effects of oral reldesemtiv, a fast skeletal muscle troponin activator, in patients with spinal muscular atrophy (SMA). Patients ≥ 12 years of age with type II, III, or IV SMA were randomized into 2 sequential, ascending reldesemtiv dosing cohorts (cohort 1: 150 mg bid or placebo [2:1]; cohort 2: 450 mg bid or placebo [2:1]). The primary objective was to determine potential pharmacodynamic effects of reldesemtiv on 8 outcome measures in SMA, including 6-minute walk distance (6MWD) and maximum expiratory pressure (MEP). Changes from baseline to weeks 4 and 8 were determined. Pharmacokinetics and safety were also evaluated. Patients were randomized to reldesemtiv 150 mg, 450 mg, or placebo (24, 20, and 26, respectively). The change from baseline in 6MWD was greater for reldesemtiv 450 mg than for placebo at weeks 4 and 8 (least squares [LS] mean difference, 35.6 m [p = 0.0037] and 24.9 m [p = 0.058], respectively). Changes from baseline in MEP at week 8 on reldesemtiv 150 and 450 mg were significantly greater than those on placebo (LS mean differences, 11.7 [p = 0.038] and 13.2 cm H2O [p = 0.03], respectively). For 6MWD and MEP, significant changes from placebo were seen in the highest reldesemtiv peak plasma concentration quartile (Cmax > 3.29 μg/mL; LS mean differences, 43.3 m [p = 0.010] and 28.8 cm H2O [p = 0.0002], respectively). Both dose levels of reldesemtiv were well tolerated. Results suggest reldesemtiv may offer clinical benefit and support evaluation in larger SMA patient populations. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to comprehensively review the literature addressing the physiological effects of hypothermia and its association with the appropriate core body temperature for extubation following coronary artery bypass surgery. Methods: The electronic databases MEDLINE, CINAHL and Web of Science via OVID were used to identify studies for the literature review. Search words used included 'core temperature', 'arrhythmia', 'cardiac', 'cardiac surgery', 'hypothermia', 'extubation', 'temperature', 'rewarming', and 'shivering'. Results: The literature search yielded 55 articles that met our inclusion criteria. No studies specifically identified the benefit of extubation at 36.5 ° C. Although temperatures varied, arrhythmias resulting from hypothermia were not reported until core body temperature dropped below 33 ° C. Conclusion: This comprehensive literature review suggests extubation at lower temperatures (between 34 ° C and 36 ° C) may be viable if shivering and other factors known to contribute to myocardial stress can be controlled. These findings offer the possibility of earlier extubation which may promote beneficial health outcomes. [ABSTRACT FROM AUTHOR]

• Retinal injury in youth with MS can be estimated by optical coherence tomography. • Initial optic neuritis episodes have a prominent impact on retinal sctructures. • Subsequent episodes are associated with less injury, probably due to plateauing effect. • Also non-optic neuritis MS relapses are associated with small amounts of retinal injury. • Youth with MS show presence of chronic retinal neurodegenerative injury. Objectives To determine to what extent acute demyelinating episodes versus chronic degenerative phenomena drive retinal neuroaxonal damage in pediatric acquired demyelinating syndromes (ADS). Methods We acquired optical coherence tomography (OCT) data (follow-up range: 2 weeks – 5 years, at variable intervals from presentation) in pediatric participants who had multiple sclerosis (MS), monophasic ADS, or were healthy. Multivariable mixed effects models were used to assess the association of the number of demyelinating episodes (either optic neuritis [ON], or non-ON relapses) with changes in retinal nerve fiber layer (RNFL) or ganglion cell layer-inner plexiform layer (GCIPL) thickness. Results 64 OCT sans from 23 MS, and 33 scans from 12 monophasic ADS participants were compared with 68 scans from 62 healthy participants. The first ON episode had the biggest impact on RNFL or GCIPL thickness in monophasic ADS (RNFL: -7.9 µm, CI=5.5, p = 0.0056; GCIPL: -8.4 µm, CI=4.4, p = 0.0002) and MS (RNFL: -16 µm, CI = 3.7, p < 10−6; GCIPL: -15 µm, CI = 2.6, p < 10−6). Non-ON relapses were also associated with small but significant retinal thickness reductions in MS (RNFL: -2.6 µm/relapse, CI = 1.4, p = 0.0003; GCIPL: -2.8 µm/relapse, CI = 0.89, p < 10−6). MS participants showed progressive GCIPL thinning independent of acute demyelinating episodes (-2.7 µm/year, CI = 1.9, p = 0.0058). Conclusions We showed a prominent impact of early ON episodes on OCT measures of neuroaxonal structure in patients with ADS. We also demonstrated negative effects of non-ON relapses, and the presence of chronic retinal neurodegenerative changes, in youth with MS. [ABSTRACT FROM AUTHOR]

In this mixed-methods study, utilization data for disease-modifying therapies were reviewed to determine the adherence rate among our pediatric multiple sclerosis cohort. Adolescents were interviewed to explore their experiences with multiple sclerosis and the impact of peer relationships on adherence to treatment. Seventeen adolescents (6 male, 11 female) started interferon β or glatiramer acetate before age 18. The mean age at first drug start date was 15.8 years. Eight of the adolescents (47%) discontinued treatment after a median duration of 20 months. Many of the adolescents struggled to integrate the injections into their daily lives, with peers either facilitating or impeding this transition. In conclusion, adolescents in this cohort had difficulty adhering to disease-modifying therapies, and peers played an important role in mediating their adjustment to multiple sclerosis. Specific strategies are required to improve adolescents'' adherence to treatment, including less intrusive options and enhancing peer support. [Copyright &y& Elsevier]

• We present the fourth documented potential case suggestive of "true" neuromyelitis optica spectrum disorder (NMOSD) meeting the current criteria associated with dengue infection. • Most reported cases of acute dengue infection presenting with a core clinical phenotype listed in the 2015 NMOSD diagnostic criteria were not tested for AQP4-IgG antibody. • Cases with acute DENV-infection with a neurological manifestation presented with a spinal cord phenotype, the majority with a LETM. • AQP4-IgG status might be helpful in a suggestive neurological presentation associated with dengue infection and subsequent decisions regarding long term immunotherapy. : Neuromyelitis Optica Spectrum Disorder can be associated with parainfectious and post-infectious triggers. Dengue virus infection is one of the most common arbovirus infections in the world, and may present with neurological manifestations. : We present a case of DENV-associated with LETM and positive aquaporin-4 IgG, and a systematic review of published cases. : Medline (Ovid) and PubMed were search through June 2021, for case reports, series and observational studies that described patients with DENV-associated LETM and/or NMOSD. : An adolescent girl who had recently immigrated from a Dengue-endemic region presented with a LETM with high positive AQP4-IgG titer and seropositive DENV IgM/IgG antibodies. She responded well to steroids and subsequently started maintenance rituximab for her NMOSD diagnosis. Literature review: 22 publications describing 27 patients met inclusion criteria. In addition to this case, three published cases met current criteria for NMOSD with serological evidence of acute DENV infection. : It is unknown whether there is a pathophysiological association between DENV infection and NMOSD. Regardless, if an immune-mediated event is suspected, particularly NMOSD, appropriate immunotherapy should be considered early. Decision regarding long term immunotherapy may depend on index of suspicion of true NMOSD, and this is where AQP4-IgG status and follow-up is helpful. [ABSTRACT FROM AUTHOR]

This study examined health-related quality of life and parental stress among pediatric neuromuscular patients with or without home mechanical ventilation. Parents completed the Parenting Stress Index or Stress Index for Parents of Adolescents, depending on their child''s age. The Pediatric Quality of Life Inventory measured quality of life in children with neuromuscular disease. One hundred and nine families participated; 19 (17%) families had a child with neuromuscular disease requiring home mechanical ventilation. Overall, children on home mechanical ventilation had significantly lower mean total Pediatric Quality of Life Inventory scores than nonventilated children (47.9 versus 61.5, respectively; P = 0.013). No significant difference in mean total stress scores was found between parents of pediatric neuromuscular patients with or without home mechanical ventilation. Despite their child''s lower health-related quality of life, parents of pediatric neuromuscular patients requiring home mechanical ventilation did not report significantly higher parental stress than parents of nonventilated children or parents in the normative sample. We postulated that for parents living with the constant demands of caring for their child with neuromuscular disease requiring home mechanical ventilation, these caretaking demands, over time, had become part of “normal” life and were not identified as creating additional stress. [Copyright &y& Elsevier]

Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov , NCT02851797 , and is complete. Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1–11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17–1·37) for boys receiving givinostat and 1·48 (1·32–1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745–0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. Italfarmaco. [ABSTRACT FROM AUTHOR]

• Domagrozumab at 5, 20, and 40 mg/kg was generally safe and well tolerated. • Primary endpoint of mean change from baseline in 4SC time at week 49 was not met. • Efficacy measures did not support a significant treatment effect with domagrozumab. • Nonsignificant increase in muscle volume was observed with domagrozumab vs placebo. We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (–7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619 [ABSTRACT FROM AUTHOR]

Abstract: Purpose: 1) To describe adolescents’ responses to a client satisfaction and family-centered care survey; 2) to examine the relationship between satisfaction with health care and health-related quality of life (HRQL) among these adolescents; and 3) to determine if adolescents and their parents differ in their satisfaction with services. Methods: We recruited 104 adolescents who attended the Alberta Children’s Hospital pediatric neurology clinic. Each family completed the Client Satisfaction Questionnaire (CSQ), the Family Centered Care Survey (FCCS), the Measure of Processes of Care (MPOC) survey, the Give Youth a Voice (GYV) survey, and the Pediatric Quality of Life Inventory (PedsQL). Results: Of 116 eligible families, 104 (90%) completed the study. The majority (83%) of adolescents were satisfied with services provided. Adolescents who were very satisfied on the CSQ and the FCCS had higher PedsQL psychosocial scores (p = .009 and .013, respectively). Multivariate analysis revealed that adolescents’ psychosocial HRQL was the most significant predictor of their satisfaction with care (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01 to 1.06). There was a difference between parents’ and adolescents’ responses to the FCCS (p = .02), with adolescents being less satisfied overall. Conclusions: Given that adolescents and parents differ in their satisfaction with health care, it is helpful to have direct input from adolescents on health services surveys. The positive relationship between adolescents’ psychosocial HRQL and satisfaction with care highlights the potential impact of emotional health on subjective rating of services. Further studies should determine if improvement in adolescents’ mental health is associated with greater satisfaction with health care and/or increased adherence with medical treatments. [Copyright &y& Elsevier]

Introduction: Increased use of ENDS in the U.S. is related to acute adverse events from liquid nicotine exposure. This paper provides national estimates of U.S. hospital emergency department visits for exposures from liquid nicotine exposure in individuals aged ≥5 years.Methods: In 2018-2019, data from the 2013-2017 National Electronic Injury Surveillance System All Injury Program were used to identify cases of liquid nicotine-related exposures in individuals aged ≥5 years. National estimates of exposures related to liquid nicotine exposure in ENDS for those aged ≥5 years by demographic characteristics, symptoms, diagnoses, and treatment dispositions were calculated.Results: From 2013 to 2017, an estimated 2,718 cases related to liquid nicotine among those aged ≥5 years were treated in U.S. hospital emergency departments. Most exposures occurred among those who were aged ≥25 years (51.7%), white (74.1%), and male (51.9%). Most case patients were treated and released from the hospitals, and 7.5% were admitted. Poisoning was the most common diagnosis of these exposures (82.7%). The most common symptoms were cardiovascular (29.7%).Conclusions: This study provides national estimates of emergency department visits for injury and poisoning cases related to nicotine exposure from ENDS among individuals aged ≥5 years. Although long-term health outcome studies of liquid nicotine exposure are not available, these estimates provide some insight into the acute health effects. Findings from this study may inform education programs aimed at preventing exposures related to ENDS products. [ABSTRACT FROM AUTHOR]

Abstract: Background: Duchenne muscular dystrophy is an X-linked recessive muscular dystrophy. Clinical management primarily involves rehabilitation strategies aimed at preserving functional mobility as long as possible. Side-alternating vibration therapy is a rehabilitation intervention that has shown promise in a number of different neuromuscular disorders, and has the potential to preserve strength, functional mobility, and bone mass. There has been little research regarding the tolerance to side-alternating vibration therapy in muscle diseases such as Duchenne muscular dystrophy. Methods: Four patients were recruited for a pilot study assessing the safety and tolerance of side-alternating vibration therapy in individuals with Duchenne muscular dystrophy. All patients participated in a 4-week training period involving side-alternating vibration therapy sessions three times per week. Serum creatine kinase was measured, and adverse effects reviewed at each session with functional mobility assessed before and after the training period. Results: All patients tolerated the training protocol well, and there were no major changes in functional mobility. One patient had a transient increase in creatine kinase during the study; however, levels of this enzyme were stable overall when comparing the pretraining and posttraining values. Some patients reported subjective improvement during the training period. Conclusions: Side-alternating vibration therapy is well tolerated in children with Duchenne muscular dystrophy and may have potential to improve or maintain functional mobility and strength in these patients. [Copyright &y& Elsevier]

Summary: Background: HLA-DRB1*15 genotype, previous infection with Epstein-Barr virus, and vitamin D insufficiency are susceptibility factors for multiple sclerosis, but whether they act synergistically to increase risk is unknown. We aimed to assess the contributions of these risk factors and the effect of established precursors of multiple sclerosis, such as brain lesions on MRI and oligoclonal bands in CSF at the time of incident demyelination, on development of multiple sclerosis in children. Methods: In our prospective national cohort study, we assessed children who presented with incident CNS demyelination to any of the 16 paediatric health-care facilities or seven regional health-care facilities in Canada. We did univariate and multivariable analyses to assess contributions of HLA-DRB1*15, Epstein-Barr virus, vitamin D status, MRI evidence of brain lesions, and CSF oligoclonal bands as determinants of multiple sclerosis. We used classification and regression tree analyses to generate a risk stratification algorithm for clinical use. Findings: Between Sept 1, 2004, and June 30, 2010, we screened 332 children of whom 302 (91%) were eligible and followed-up for a median of 3·14 years (IQR 1·61–4·51). 63 (21%) children were diagnosed with multiple sclerosis after a median of 127 days (99–222). Although the risk of multiple sclerosis was increased with presence of one or more HLA-DRB1*15 alleles (hazard ratio [HR] 2·32, 95% CI 1·25–4·30), reduced serum 25-hydroxyvitamin D concentration (HR per 10 nmol/L decrease 1·11, 1·00–1·25), and previous Epstein-Barr-virus infection (HR 2·04, 0·99–4·20), no interactions between these variables were detected on multivariate analysis. Multiple sclerosis was strongly associated with baseline MRI evidence of one or more brain lesion (HR 37·9, 5·26–273·85) or CSF oligoclonal bands (6·33, 3·35–11·96), suggesting established disease. One patient diagnosed with multiple sclerosis had a normal MRI scan, and therefore sensitivity of an abnormal MRI scan for multiple sclerosis diagnosis was 98·4%. Interpretation: Risk of multiple sclerosis in children can be stratified by presence of HLA-DRB1*15 alleles, remote Epstein-Barr virus infection, and low serum 25-hydroxyvitamin D concentrations. Similar to previous studies in adults, brain lesions detected on MRI and CSF oligoclonal bands in children are probable precursors to the clinical onset of multiple sclerosis. Children with a normal MRI are very likely to have a monophasic illness. Funding: Canadian Multiple Sclerosis Scientific Research Foundation. [Copyright &y& Elsevier]

Summary: Background: The full spectrum of clinical manifestations and outcome, and the potential importance of regional or demographic features or viral triggers in paediatric multiple sclerosis (MS), has yet to be fully characterised. Our aim was to determine some of these characteristics in children with MS. Methods: 137 children with MS and 96 control participants matched by age and geographical region were recruited in a multinational study. They underwent structured clinical-demographic interviews, review of academic performance, physical examination, disability assessment (MS patients only), and standardised assays for IgG antibodies directed against Epstein-Barr virus, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. Findings: MS was relapsing-remitting at diagnosis in 136 (99%) children. The first MS attack resembled acute disseminated encephalomyelitis (ADEM) in 22 (16%) of the children, most under 10 years old (mean age 7·4 [SD 4·2] years). Children with ADEM-like presentations were significantly younger than were children with polyfocal (11·2 [4·5] years; p<0·0001) or monofocal (12·0 [3·8] years; p=0·0005) presentations. Permanent physical disability (EDSS≥4·0) developed within 5 years in 15 (13%) of the 120 children for whom EDSS score was available. 23 (17%) had impaired academic performance, which was associated with increasing disease duration (p=0·02). Over 108 (86%) of the children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared with only 61 (64%) of matched controls (p=0·025, adjusted for multiple comparisons). Children with MS did not differ from controls in seroprevalence of the other childhood viruses studied, nor with respect to month of birth, sibling number, sibling rank, or exposure to young siblings. Interpretation: Paediatric MS is a relapsing-remitting disease, with presenting features that vary by age at onset. MS in children might be associated with exposure to EBV, suggesting a possible role for EBV in MS pathobiology. [Copyright &y& Elsevier]