Youth Oriented Activity Trackers: Comprehensive Laboratory- and Field-Based Validation

Background: Commercial activity trackers are growing in popularity among adults and some are beginning to be marketed to children. There is, however, a paucity of independent research examining the validity of these devices to detect physical activity of different intensity levels. Objectives: The purpose of this study was to determine the validity of the output from 3 commercial youth-oriented activity trackers in 3 phases: (1) orbital shaker, (2) structured indoor activities, and (3) 4 days of free-living activity. Methods: Four units of each activity tracker (Movband [MB], Sqord [SQ], and Zamzee [ZZ]) were tested in an orbital shaker for 5-minutes at three frequencies (1.3, 1.9, and 2.5 Hz). Participants for Phase 2 (N=14) and Phase 3 (N=16) were 6-12 year old children (50% male). For Phase 2, participants completed 9 structured activities while wearing each tracker, the ActiGraph GT3X+ (AG) research accelerometer, and a portable indirect calorimetry system to assess energy expenditure (EE). For Phase 3, participants wore all 4 devices for 4 consecutive days. Correlation coefficients, linear models, and non-parametric statistics evaluated the criterion and construct validity of the activity tracker output. Results: Output from all devices was significantly associated with oscillation frequency (r=.92-.99). During Phase 2, MB and ZZ only differentiated sedentary from light intensity (PPr=.76, .86, and .59 for the MB, SQ, and ZZ, respectively). Conclusions: Across study phases, the SQ demonstrated stronger validity than the MB and ZZ. The validity of youth-oriented activity trackers may directly impact their effectiveness as behavior modification tools, demonstrating a need for more research on such devices

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD

Assessing COVID-19 testing strategies in K-12 schools in underserved populations: Study protocol for a cluster-randomized trial

BACKGROUND: Since March 2020, COVID-19 has disproportionately impacted communities of color within the United States. As schools have shifted from virtual to in-person learning, continual guidance is necessary to understand appropriate interventions to prevent SARS-CoV-2 transmission. Weekly testing of students and staff for SARS-CoV-2 within K-12 school setting could provide an additional barrier to school-based transmission, especially within schools unable to implement additional mitigation strategies and/or are in areas of high transmission. This study seeks to understand the role that weekly SARS-CoV-2 testing could play in K-12 schools. In addition, through qualitative interviews and listening sessions, this research hopes to understand community concerns and barriers regarding COVID-19 testing, COVID-19 vaccine, and return to school during the COVID-19 pandemic. METHODS/DESIGN: Sixteen middle and high schools from five school districts have been randomized into one of the following categories: (1) Weekly screening + symptomatic testing or (2) Symptomatic testing only. The primary outcome for this study will be the average of the secondary attack rate of school-based transmission per case. School-based transmission will also be assessed through qualitative contact interviews with positive contacts identified by the school contact tracers. Lastly, new total numbers of weekly cases and contacts within a school-based quarantine will provide guidance on transmission rates. Qualitative focus groups and interviews have been conducted to provide additional understanding to the acceptance of the intervention and barriers faced by the community regarding SARS-CoV-2 testing and vaccination. DISCUSSION: This study will provide greater understanding of the benefit that weekly screening testing can provide in reducing SARS-CoV-2 transmission within K-12 schools. Close collaboration with community partners and school districts will be necessary for the success of this and similar studies. TRIAL REGISTRATION: NCT04875520 . Registered May 6, 2021

Sampling bias and incorrect rooting make phylogenetic network tracing of SARS-COV-2 infections unreliable.

There is obvious interest in gaining insights into the epidemiology and evolution of the virus that has recently emerged in humans as the cause of the coronavirus disease 2019 (COVID-19) pandemic. The recent paper by Forster et al. (1), analyzed 160 SARS-CoV-2 full genomes available (https://www.gisaid.org/) in early March 2020. The central claim is the identification of three main SARS-CoV-2 types, named A, B, and C, circulating in different proportions among Europeans and Americans (types A and C) and East Asian (type B). According to a median-joining network analysis, variant A is proposed to be the ancestral type because it links to the sequence of a coronavirus from bats, used as an outgroup to trace the ancestral origin of the human strains. The authors further suggest that the “ancestral Wuhan B-type virus is immunologically or environmentally adapted to a large section of the East Asian population, and may need to mutate to overcome resistance outside East Asia”. There are several serious flaws with their findings and interpretation. First, and most obviously, the sequence identity between SARS-CoV-2 and the bat virus is only 96.2%, implying that these viral genomes (which are nearly 30,000 nucleotides long) differ by more than 1,000 mutations. Such a distant outgroup is unlikely to provide a reliable root for the network. Yet, strangely, the branch to the bat virus, in Figure 1 of the paper, is only 16 or 17 mutations in length. Indeed, the network seems to be mis-rooted because (see Supplementary Figure 4) a virus from Wuhan from week 0 (24th December 2019) is portrayed as a descendant of a clade of viruses collected in weeks 1-9 (presumably from many places outside China), which makes no evolutionary (2), nor epidemiological sense (3).N

Efficacy of BETTER transitional care intervention for diverse patients with traumatic brain injury and their families: Study protocol of a randomized controlled trial

Objective The purpose of this study is to examine the efficacy of BETTER (Brain Injury, Education, Training, and Therapy to Enhance Recovery) vs. usual transitional care management among diverse adults with traumatic brain injury (TBI) discharged home from acute hospital care and families. Methods This will be a single-site, two-arm, randomized controlled trial (N = 436 people, 218 patient/family dyads, 109 dyads per arm) of BETTER, a culturally- and linguistically-tailored, patient- and family-centered, TBI transitional care intervention for adult patients with TBI and families. Skilled clinical interventionists will follow a manualized protocol to address patient/family needs. The interventionists will co-establish goals with participants; coordinate post-hospital care, services, and resources; and provide patient/family education and training on self- and family-management and coping skills for 16 weeks following hospital discharge. English- and Spanish-speaking adult patients with mild-to-severe TBI who are discharged directly home from the hospital without inpatient rehabilitation or transfer to other settings (community discharge) and associated family caregivers are eligible and will be randomized to treatment or usual transitional care management. We will use intention-to-treat analysis to determine if patients receiving BETTER have a higher quality of life (primary outcome, SF-36) at 16-weeks post-hospital discharge than those receiving usual transitional care management. We will conduct a descriptive, qualitative study with 45 dyads randomized to BETTER, using semi-structured interviews, to capture perspectives on barriers and facilitators to participation. Data will be analyzed using conventional content analysis. Finally, we will conduct a cost/budget impact analysis, evaluating differences in intervention costs and healthcare costs by arm. Discussion Findings will guide our team in designing a future, multi-site trial to disseminate and implement BETTER into clinical practice to enhance the standard of care for adults with TBI and families. The new knowledge generated will drive advancements in health equity among diverse adults with TBI and families. Trial registration NCT05929833

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research