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Objective Emotional distress is common in both survivors and their informal caregivers following admission to a neuroscience intensive care unit (Neuro-ICU) and can negatively affect their individual recovery and quality of life. Neuro-ICU survivor-caregiver dyads can influence each other's emotional distress over time, but whether such influence emerges during dyadic treatment remains unknown. The present study involved secondary data analysis of Neuro-ICU dyads enrolled in a randomized clinical trial of a dyadic resiliency intervention, Recovering Together (RT), versus a health education attention placebo control to test dyadic similarities in emotional distress before and after treatment. Method Data were collected from 58 dyads following Neuro-ICU admission. Emotional distress (depression, anxiety, and posttraumatic stress) was assessed at baseline, 6 weeks (postintervention), and 12 weeks later. Nonindependence within survivor-caregiver dyads was examined (i.e., correlations between cross-sectional symptoms and changes in symptoms over time); mutual influence of emotional functioning over time (i.e., "partner effects") was examined using cross-lagged path analyses. Results There were strong, positive cross-sectional correlations between survivor and caregiver distress at postintervention and follow-up and between changes in survivor and caregiver distress from baseline to postintervention and postintervention to follow-up. There were no partner effects. Conclusions Neuro-ICU survivors and their informal caregivers show similar changes in emotional distress after treatment. These findings highlight the potential benefits of intervening on both survivor and caregiver distress following Neuro-ICU admission. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective The expanding power and accessibility of personal technology provide an opportunity to reduce burdens and costs of traditional clinical site‐centric therapeutic trials in Parkinson’s disease and generate novel insights. The value of this approach has never been more evident than during the current COVID‐19 pandemic. We sought to (1) establish and implement the infrastructure for longitudinal, virtual follow‐up of clinical trial participants, (2) compare changes in smartphone‐based assessments, online patient‐reported outcomes, and remote expert assessments, and (3) explore novel digital markers of Parkinson’s disease disability and progression. Methods Participants from two recently completed phase III clinical trials of inosine and isradipine enrolled in Assessing Tele‐Health Outcomes in Multiyear Extensions of Parkinson’s Disease trials (AT‐HOME PD), a two‐year virtual cohort study. After providing electronic informed consent, individuals complete annual video visits with a movement disorder specialist, smartphone‐based assessments of motor function and socialization, and patient‐reported outcomes online. Results From the two clinical trials, 226 individuals from 42 states in the United States and Canada enrolled. Of these, 181 (80%) have successfully downloaded the study’s smartphone application and 161 (71%) have completed patient‐reported outcomes on the online platform. Interpretation It is feasible to conduct a large‐scale, international virtual observational study following the completion of participation in brick‐and‐mortar clinical trials in Parkinson’s disease. This study, which brings research to participants, will compare established clinical endpoints with novel digital biomarkers and thereby inform the longitudinal follow‐up of clinical trial participants and design of future clinical trials.

We sought to determine if a novel online health tool, called Down Syndrome Clinic to You (DSC2U), could improve adherence to national Down syndrome (DS) guidelines. We also sought to determine if primary care providers (PCPs) and caregivers are satisfied with this personalized online health tool. In a national, randomized controlled trial of 230 caregivers who had children or dependents with DS without access to a DS specialist, 117 were randomized to receive DSC2U and 113 to receive usual care. The primary outcome was adherence to five health evaluations indicated by national guidelines for DS. DSC2U is completed electronically, in all mobile settings, by caregivers at home. The outputs—personalized checklists—are used during annual wellness visits with the patient’s PCP. A total of 213 participants completed a 7-month follow-up evaluation. In the intention-to-treat analysis, the intervention group had a 1.6-fold increase in the number of indicated evaluations that were recommended by the primary care provider or completed compared with controls. Both caregivers and PCPs reported high levels of satisfaction with DSC2U. DSC2U improved adherence to the national DS health-care guidelines with a novel modality that was highly valued by both caregivers and PCPs.

Objective To collect preliminary data on the effects of mexiletine on cortical and axonal hyperexcitability in sporadic amyotrophic lateral sclerosis (ALS) in a phase 2 double-blind randomized controlled trial. Methods Twenty ALS subjects were randomized to placebo and mexiletine 300 mg or 600 mg daily for 4 weeks and assessed by transcranial magnetic stimulation and axonal excitability studies. The primary endpoint was change in resting motor threshold (RMT). Results RMT was unchanged with 4 weeks of mexiletine (combined active therapies) as compared to placebo, which showed a significant increase (p=0.039). Reductions of motor evoked potential (MEP) amplitude (p=0.013) and accommodation half-time (p=0.002), secondary outcome measures of cortical and axonal excitability, respectively, were also evident at 4 weeks on mexiletine. Conclusions The relative stabilization of RMT in the treated subjects was unexpected and could be attributed to unaccounted sources of error or chance. However, a possible alternative cause is neuromodulation preventing an increase. The change in MEP amplitude and accommodation half-time supports the reduction of cortical and axonal hyperexcitability with mexiletine. This article is protected by copyright. All rights reserved.

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

Higher serum urate concentration is associated with decreased risk of Parkinson’s disease (PD) as well as slower disease progression, but its relationship with severity of PD remains unclear. This study investigated whether changes in serum urate concentration over 5 years were associated with disease progression assessed by MDS-UPDRS Part III score, Hoehn and Yahr stage, or DaTscan imaging. Average serum urate concentration was stable over time and change in serum urate concentration did not correlate with worsening of measures of PD progression. These results suggest that serum urate concentration is not a monitoring biomarker of PD progression in early stages.

Background Spinal manipulation may reduce migraine frequency, but effects of multimodal chiropractic care on migraine frequency have not been evaluated. Methods We conducted a pilot randomized controlled trial comparing multimodal chiropractic care + enhanced usual care (MCC+) versus enhanced usual care alone (EUC) among adult women with episodic migraine. EUC was comprised of usual medical care and migraine education literature. MCC+ participants received 10 sessions of chiropractic care over 14 weeks. Primary aims evaluated feasibility of recruitment, retention, protocol adherence, and safety. Change in migraine days was a secondary aim. Results Of 422 patients screened, 61 were randomized over 20 months. Fifty-seven (93%) completed daily migraine logs during the intervention, 51 (84%) completed final follow-up, and 45 (74%) completed all assessments. Twenty-four of 29 MCC+ participants (83%) attended > 75% of the chiropractic sessions. Ninety-eight non-serious adverse events were reported by 26 participants (43%) with 39 events among 11 EUC participants and 59 events among 15 MCC+ participants. MCC+ participants experienced greater reductions in migraine days (−2.9 days for MCC+ vs. −1.0 days for EUC, difference = −1.9; 95% confidence interval: −3.5, −0.4). Conclusions Pre-specified feasibility criteria were not met, but deficits were remediable. Preliminary data support a definitive trial of MCC+ for migraine. Trial Registration This study is registered at Clinicaltrials.gov (NCT03177616).

ObjectiveTo identify markers of resistance to developing Parkinson disease (PD) among LRRK2 mutation carriers (LRRK2+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation.MethodsPlasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2−/PD+, and 65 LRRK2−/UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between LRRK2 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with p value corrections for multiple comparisons.ResultsPlasma caffeine concentration was lower in patients with PD vs UC (p < 0.001), more so among LRRK2+ carriers (by 76%) than among LRRK2− participants (by 31%), with significant interaction between LRRK2 and PD status (p = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in LRRK2+/PD+ compared to LRRK2+/UC with significant interaction effect with the LRRK2+ mutation (p < 0.001).ConclusionsMetabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic LRRK2 mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among LRRK2 mutation carriers.

Two purines, caffeine and urate, have been associated with a reduced risk of idiopathic Parkinson's disease (PD) in multiple cohorts and populations. The Harvard Biomarkers Study (HBS) is a longitudinal study designed to accelerate the discovery and validation of molecular diagnostic and progression markers of early-stage PD. To investigate whether these 'reduced risk' factors are associated with PD within this cohort, we conducted a cross-sectional, case-control study in 566 subjects consisting of idiopathic PD patients and healthy controls. Caffeine intake as assessed by a validated questionnaire was significantly lower in idiopathic PD patients compared to healthy controls in males (mean difference -125 mg/day, p < 0.001) but not in females (mean difference -30 mg/day, p = 0.29). A strong inverse association was also observed with plasma urate levels both in males (mean difference -0.46 mg/dL, p = 0.017) and females (mean difference -0.45 mg/dL, p = 0.001). Both analyses stratified for sex and adjusted for age, body mass index, and either urate level or caffeine consumption, respectively. These results highlight the robustness of caffeine intake and urate as factors inversely associated with idiopathic PD.

An entity of regression in Down syndrome (DS) exists that affects adolescents and young adults and differs from autism spectrum disorder and Alzheimer disease. Since 2017, an international consortium of DS clinics assembled a database of patients with unexplained regression and age- and sex-matched controls. Standardized data on clinical symptoms and tiered medical evaluations were collected. Elements of the proposed definition of unexplained regression in DS were analyzed by paired comparisons between regression cases and matched controls. We identified 35 patients with DS and unexplained regression, with a mean age at regression of 17.5 years. Diagnostic features differed substantially between regression cases and matched controls (p

Background Insomnia and low iron stores are common in children with autism spectrum disorders, and low iron stores have been associated with sleep disturbance. Methods We performed a randomized placebo-controlled trial of oral ferrous sulfate to treat insomnia in children with autism spectrum disorders and low normal ferritin levels. Twenty participants who met inclusion criteria and whose insomnia did not respond to sleep education were randomized to 3 mg/kg/day of ferrous sulfate (n = 9) or placebo (n = 11) for three months. Results Iron supplementation was well tolerated, and no serious adverse events were reported. Iron supplementation improved iron status (+18.4 ng/mL active versus −1.6 ng/mL placebo, P = 0.044) but did not significantly improve the primary outcome measures of sleep onset latency (−11.0 minutes versus placebo, 95% confidence interval −28.4 to 6.4 minutes, P = 0.22) and wake time after sleep onset (−7.7 minutes versus placebo, 95% confidence interval −22.1 to 6.6 min, P = 0.29) as measured by actigraphy. Iron supplementation was associated with improvement in the overall severity score from the Sleep Clinical Global Impression Scale (−1.5 points versus placebo, P = 0.047). Changes in measures of daytime behavior did not differ between groups. Conclusion This trial demonstrated no improvement in primary outcome measures of insomnia in subjects treated with ferrous sulfate compared with placebo. Interpretation was limited by low enrollment.

To examine effects of a virtual mind–body group for adolescents with neurofibromatoses (NF1 and NF2; Resilient Youth with Neurofibromatosis; RY-NF) on multiple resiliency factors against a health education attention control (Health Education for Youth with Neurofibromatosis; HE-NF) using data from a randomized controlled trial. Specifically, our research question was whether adolescents randomized to the RY-NF (versus the HE-NF) would have greater improvements in resiliency factors at post-intervention and whether these gains would be maintained at 6-month follow-up. Adolescents with NF (n = 51; M age 12–17) were randomly assigned to RY-NF (n = 27) or HE-NF (n = 24). Resiliency factors (mindfulness, coping, gratitude, optimism, and social support) were collected at baseline, post-intervention (88%), and 6-month follow-up (82%). Participation in the RY-NF was associated with greater pre-to-post improvements in gratitude (Mdifference = 4.38; 95% CI—0.52–8.23; p = .027) and mindfulness (Mdifference= 9.41; 95% CI 4.40–14.42.; p

IMPORTANCE: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. OBJECTIVE: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. DESIGN, PARTICIPANTS, AND SETTING: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (

Background Stress and negative emotions contribute to atrial fibrillation (AF). Mind-body practices decrease stress and negative emotions and may reduce AF episodes and improve quality of life for patients with AF. Objective We examined the effects of a multimodal mind-body program, the SMART Program, on AF-related quality of life in patients with paroxysmal AF (PAF). Methods In this randomized, waitlist-controlled pilot trial, 18 subjects with PAF participated in an 8-week SMART Program delivered online immediately or 3 months later. Validated measures were completed at baseline and at 3 and 6 months (waitlist group only). Results Comparing pre- vs post-program scores among all 18 participants, subjects reported improvement in AF-related quality of life (Cohen's d=0.75, P = .005) and depression (d = 0.50, P = .05) but not anxiety (d = 0.35, P = .16). Subjects also reported improvements in AF symptom severity (P = .026), distress (P = .014), positive affect (P = .003), and ability to cope with stress (P = .001). Compared to waitlist control subjects, those in the immediate group reported improvement in positive affect (d = 1.20, P = .021) and coping with stress (d = 1.36, P = .011) after participating in the program. Conclusion The SMART Program, delivered virtually, may enhance positive emotions and coping with stress as well as decrease negative emotions and AF symptoms. These results warrant a larger trial to better understand the potential benefits of such programs for patients with PAF.

ObjectiveTo investigate whether women and men with Parkinson disease (PD) differ in their biochemical and clinical responses to long-term treatment with inosine.MethodsThe Safety of Urate Elevation in Parkinson’s Disease (SURE-PD) trial enrolled 75 people with early PD and baseline serum urate below 6 mg/dL and randomized them to 3 double-blinded treatment arms: oral placebo or inosine titrated to produce mild (6.1–7.0 mg/dL) or moderate (7.1–8.0 mg/dL) serum urate elevation for up to 2 years. Parkinsonism, serum urate, and plasma antioxidant capacity were measured at baseline and repeatedly on treatment; CSF urate was assessed once, at 3 months. Here in secondary analyses results are stratified by sex.ResultsInosine produced an absolute increase in average serum urate from baseline that was 50% greater in women (3.0 mg/dL) than in men (2.0 mg/dL), consistent with expected lower baseline levels in women. Similarly, only among women was CSF urate significantly greater on mild or moderate inosine (+87% [p < 0.001] and +98% [p < 0.001], respectively) than on placebo (in contrast to men: +10% [p = 0.6] and +14% [p = 0.4], respectively). Women in the higher inosine dosing group showed a 7.0 Unified Parkinson’s Disease Rating Scale (UPDRS) points/year lower rate of decline vs placebo (p = 0.01). In women, slower rates of UPDRS change were associated with greater increases in serum urate (r = −0.52; p = 0.001), and with greater increases in plasma antioxidant capacity (r = −0.44; p = 0.006). No significant associations were observed in men.ConclusionsInosine produced greater increases in serum and CSF urate in women compared to men in the SURE-PD trial, consistent with the study's design and with preliminary evidence for slower clinical decline in early PD among women treated with urate-elevating doses of inosine.Clinicaltrials.gov identifierNCT00833690.Classification of evidenceThis study provides Class II evidence that inosine produced greater urate elevation in women than men and may slow PD progression in women.

Objectives: We recently found that metformin attenuated weight gain due to mixed dopamine and serotonin receptor antagonists, commonly termed atypical antipsychotics, in children and adolescents with autism spectrum disorder (ASD). Previous studies have found that genetic variation predicts response to metformin in diabetes. In this study, we aimed to assess whether response to metformin for weight gain in this population is associated with variants in five genes previously implicated in metformin response in diabetes. Methods: Youth with ASD who experienced significant weight gain while taking mixed receptor antagonist medications were randomly assigned to metformin or placebo for 16 weeks, followed by open-label metformin treatment for 16 weeks. In the 53 participants with available DNA samples, we used a linear, mixed model analysis to assess response in the first 16 weeks of metformin treatment, whether in the randomized or open-label period, based upon genotypes at polymorphisms in five genes previously associated with metformin response in diabetes: ATM, SLC2A2, MATE1, MATE2, and OCT1. Results: In the primary analysis, both ATM and OCT1 showed significant effects of genotype on change in body mass index z-scores, the primary outcome measure, during the first 16 weeks of treatment with metformin. No other polymorphism showed a significant difference. Conclusion: As has been shown for metformin treatment in diabetes, genetic variation may predict response to metformin for weight gain in youth with ASD treated with mixed receptor antagonists. Further work is needed to replicate these findings and evaluate whether they can be used prospectively to improve outcomes.

Objectives Tai Chi (TC) may benefit older adults with a variety of diseases and disabilities. We tested the hypothesis that TC improves physical function in older adults living in low-income housing facilities. Design Cluster randomized controlled trial. Setting Subsidized housing facilities in Boston, Massachusetts, and neighboring communities. Participants Volunteers were recruited from 15 facilities. The 180 randomized participants were 60 years of age or older, able to understand English and participate in TC, expected to remain in the facility for 1 year, and able to walk independently. Intervention TC classes were conducted in the housing facilities twice/week for 1 year and compared with monthly health promotion educational classes and social calls. Measurements The primary outcome was physical function measured by the Short Physical Performance Battery (SPPB). Secondary outcomes included other aspects of physical and cognitive function, and falls. Results An interim analysis revealed less improvement over 12 months in SPPB scores among TC participants (+.20 units; 95% confidence interval [CI] = -.20 to +.60; P = .69) vs control participants (+.51 units; 95% CI = +.15 to +.87; P = .007), a difference of -.31 units (95% CI = -.66 to .04; P = .082). This met the criterion for futility, and the Data Safety Monitoring Board recommended trial termination. No differences were found in 6- or 12-month changes favoring TC in any secondary outcomes or adverse events. Conclusion In older adults with multiple chronic conditions living in subsidized housing facilities, 6 and 12 months of twice/week TC classes were not associated with improvements in functional health. J Am Geriatr Soc 67:1812-1819, 2019.

Background: Nutritional status is an important prognostic factor in Amyotrophic Lateral Sclerosis (ALS). We wished to study the safety, tolerability and efficacy of nutritional counseling with or without an mHealth application to maintain or increase body weight in ALS, compared to standard care. Methods: In this randomized open-label, standard-of-care-controlled, single-center clinical trial, we randomly assigned adults with ALS to one of three nutritional interventions: counseling by their physician or nurse (“standard care”), counseling by a registered dietitian (RD) (“in-person”), or counseling supported by a mHealth app (“mHealth”). Both intervention arms received tailored nutrition recommendations and recorded dietary intake and weight biweekly (mHealth) or monthly (in-person). The primary outcome of weight and secondary and tertiary outcomes of calorie intake, ALSFRS-R, and quality of life (QOL) were recorded at each clinic visit and analyzed in an ITT mixed model analysis. Results: A total of 88 participants were enrolled of whom 78 were included in this analysis. The three arms were well-balanced except for excess males in the mHealth arm and greater weight lost at baseline in the in-person arm. Participants in the mHealth arm increased their calorie intake at month 3 to an average of 94% (95% CI: 85, 103) of recommended calories, compared to 81% (95% CI: 72, 91, p= 0.06 vs. mHealth) in the standard care arm. After 6 months, calorie intake and change in weight was not different among the three arms. QOL scores in the mHealth arm were stable over three months (0.3 points, 95% CI: -1.7, 2.2) compared to worsening in standard care (-2.1 points, 95% CI: -4.0, -0.2, p = 0.09 vs. mHealth), but all scores declined by six months. ALSFRS-R total scores declined by an average of -2.6 points (95% CI: -5.1, -0.1) over six months in the mHealth arm (p=0.13 vs. standard care) compared to -5.8 points (95% CI: -8.2, -3.4, p=0.74 vs. standard care) in the in-person and -5.2 points (95% CI: -7.6, -2.9) in the standard care arm. Conclusions: Nutritional counseling is safe but did not increase weight compared to standard care in ALS patients. Trial Registration: Clinicaltrials.gov identifier NCT02418546. Registered April 16, 2015. Keywords: Amyotrophic Lateral Sclerosis, ALS, Neurodegenerative disease, mobile health technology, mHealth, nutrition, nutritional counseling, randomized controlled trial

OBJECTIVE LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. METHODS Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. RESULTS Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p

Introduction: Universally established comprehensive clinical bulbar scales objectively assessing disease progression in amyotrophic lateral sclerosis (ALS) are currently lacking. The goal of this working group project is to design a best practice set of provisional bulbar ALS guidelines, available for immediate implementation within all ALS clinics. Methods: ALS specialists across multiple related disciplines participated in a series of clinical bulbar symposia, intending to identify and summarize the currently accepted best practices for the assessment and management of bulbar dysfunction in ALS Results: Summary group recommendations for individual speech, Augmentative and Alternative Communication (AAC), and swallowing sections were achieved, focusing on the optimal proposed level of care within each domain. Discussion: We have identified specific clinical recommendations for each of the 3 domains of bulbar functioning, available for incorporation within all ALS clinics. Future directions will be to establish a formal set of bulbar guidelines through a methodological and evidence-based approach. Muscle Nerve 59:531–531, 2019. Fil: Pattee, Gary L.. No especifíca; Fil: Plowman, Emily K.. University of Florida; Estados Unidos Fil: Garand, Kendrea L.. University of Alabama at Birmingahm; Estados Unidos Fil: Costello, John. No especifíca; Fil: Brooks, Benjamin Rix. No especifíca; Fil: Berry, James D.. No especifíca; Fil: Smith, Richard A.. No especifíca; Fil: Atassi, Nazem. No especifíca; Fil: Chapin, Jennifer L.. University of Florida; Estados Unidos Fil: Yunusova, Yana. University of Toronto; Canadá Fil: McIlduff, Courtney E.. No especifíca; Fil: Young, Eufrosina. No especifíca; Fil: Macklin, Eric A.. No especifíca; Fil: Locatelli, Eduardo R.. No especifíca; Fil: Silani, Vincenzo. Università degli Studi di Milano; Italia Fil: Heitzman, Daragh. No especifíca; Fil: Wymer, James. University of Florida; Estados Unidos Fil: Goutman, Stephen A.. No especifíca; Fil: Gelinas, Deborah F.. No especifíca; Fil: Perry, Bridget. No especifíca; Fil: Nalipinski, Paige. No especifíca; Fil: Stipancic, Kaila. Children's Hospital Boston; Estados Unidos Fil: O'Brien, Meghan. Children's Hospital Boston; Estados Unidos Fil: Sullivan, Stacey L.. No especifíca; Fil: Pioro, Erik P.. No especifíca; Fil: Gargiulo Monachelli, Gisella Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET; Argentina Fil: Green, Jordan R.. No especifíca

ObjectiveTo evaluate the safety and efficacy of l-serine in humans with hereditary sensory autonomic neuropathy type I (HSAN1).MethodsIn this randomized, placebo-controlled, parallel-group trial with open-label extension, patients aged 18–70 years with symptomatic HSAN1 were randomized to l-serine (400 mg/kg/day) or placebo for 1 year. All participants received l-serine during the second year. The primary outcome measure was the Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNS). Secondary outcomes included plasma sphingolipid levels, epidermal nerve fiber density, electrophysiologic measurements, patient-reported measures, and adverse events.ResultsBetween August 2013 and April 2014, we enrolled and randomized 18 participants, 16 of whom completed the study. After 1 year, the l-serine group experienced improvement in CMTNS relative to the placebo group (−1.5 units, 95% CI −2.8 to −0.1, p = 0.03), with evidence of continued improvement in the second year of treatment (−0.77, 95% CI −1.67 to 0.13, p = 0.09). Concomitantly, deoxysphinganine levels dropped in l-serine-treated but not placebo-treated participants (59% decrease vs 11% increase; p < 0.001). There were no serious adverse effects related to l-serine.ConclusionHigh-dose oral l-serine supplementation appears safe in patients with HSAN1 and is potentially effective at slowing disease progression.Clinicaltrials.gov identifierNCT01733407.Classification of evidenceThis study provides Class I evidence that high-dose oral l-serine supplementation significantly slows disease progression in patients with HSAN1.

Introduction/aims We tested safety, tolerability, and target engagement of tocilizumab in amyotrophic lateral sclerosis (ALS) patients. Methods Twenty-two participants, whose peripheral blood mononuclear cell (PBMC) gene expression profile reflected high messenger ribonucleic acid (mRNA) expression of inflammatory markers, were randomized 2:1 to 3 tocilizumab or placebo treatments (weeks 0, 4, and 8; 8 mg/kg intravenous). Participants were followed every 4 weeks in a double-blind fashion for 16 weeks and assessed for safety, tolerability, plasma inflammatory markers, and clinical measures. Cerebrospinal fluid (CSF) was collected at baseline and after the third treatment. Participants were genotyped for Asp358 Ala polymorphism of the IL6R gene. Results Baseline characteristics, safety, and tolerability were similar between treatment groups. One serious adverse event was reported in the placebo group; no deaths occurred. Mean plasma C-reactive protein (CRP) level decreased by 88% in the tocilizumab group and increased by 4% in the placebo group (-3.0-fold relative change, P Discussion Tocilizumab treatment was safe and well tolerated. PBMC gene expression profile was inadequate as a predictive or pharmacodynamic biomarker. Treatment reduced CRP levels in plasma and CSF, with CSF effects potentially dependent on IL6R Asp358 Ala genotype. IL-6 trans-signaling may mediate a distinct central nervous system response in individuals inheriting the IL6R C allele. These results warrant further study in ALS patients where IL6R genotype and CRP levels may be useful enrichment biomarkers. Classification of evidence This study provides Class I evidence that tocilizumab therapy is safe and well tolerated in ALS patients with high mRNA expression of inflammatory markers. Clinical trial registration Registered at ClinicalTrials.gov (NCT02469896). This article is protected by copyright. All rights reserved.

Objective Disease modification in Parkinson disease (PD) has remained an elusive goal, in spite of large investments over several decades. Following a large meeting of experts, this review article discusses the state of the science, possible reasons for past PD trials’ failures to demonstrate disease-modifying benefit, and potential solutions. Methods The National Institute of Neurological Disorders and Stroke (NINDS) convened a meeting including leaders in the field and representatives of key stakeholder groups to discuss drug therapy with the goal of disease modification in PD. Results Important lessons can be learned from previous attempts, as well as from other fields. The selection process for therapeutic targets and agents differs among various organizations committed to therapeutic development. The areas identified as critical to target in future research include the development of relevant biomarkers, refinements of the targeted patient populations, considerations of novel trial designs, and improving collaborations between all stakeholders. Conclusions We identify potential barriers to progress in disease modification for Parkinson's and propose a set of research priorities that may improve the likelihood of success.

© 2021 International Parkinson and Movement Disorder Society, Background: Expectations of benefit have an important therapeutic impact. How well study participants understand the concept of slowing disease progression and how their expectations of benefit are shaped in related clinical trials is not well known. Objective: We aimed to assess expectancy and treatment arm preference of participants in a disease-modification trial in Parkinson disease (PD). Methods: Participant expectations and treatment preference were assessed before treatment randomization in the SURE-PD3 trial (NCT02642393). Results: We included 297 PD patients (0.71 ± 0.67 years after diagnosis). Pre-randomization, 90% of participants expressed a preference for inosine (active treatment) allocation (n = 266/297), and 53% (n = 158) expected to be "somewhat" or "a lot better" in their symptoms over 2 years of treatment with inosine. Conclusions: Participants of a disease-modification trial in PD had likely unrealistic expectations of benefit (ie, improvement in symptoms over years), which may affect clinical trial interpretation and calls for improved education in future disease-modification trials in PD. © 2021 International Parkinson and Movement Disorder Society.

Background/Objectives This study was designed to test the impact of Tai Chi (TC) on healthcare utilization and cost in older adults living in low-income senior housing. We hypothesized that TC would improve overall health enough to reduce the use of emergency department (ED) and inpatient services. Design Cluster randomized controlled trial with randomization at the housing site level. Setting Greater Boston, Massachusetts. Participants The study includes 6 sites with 75 individuals in the TC treatment condition and 6 sites with 67 individuals in the health education control condition. Intervention Members of the treatment group received up to a year-long intervention with twice weekly, in-person TC exercise sessions along with video-directed exercises that could be done independently at home. The comparison group received monthly, in-person healthy aging education classes (HE). Study recruitment took place between August, 2015 and October, 2017. Key outcomes included acute care utilization (inpatient stays, observation stays and emergency department visits). In addition, the cost of utilization was estimated using the age, sex and race adjusted allowed amount from Medicare claims for a geographically similar population aged ≥ 65. Results The results suggested a possible reduction in the rate of ED visits in the TC group vs. controls (rate ratio = 0.476, p-value = 0.06), but no findings achieved statistical significance. Adjusted estimates of imputed costs of ED and hospital care were similar between TC and HE, averaging approximately $3,000 in each group. Conclusion ED utilization tended to be lower over 6 to 12 months of TC exercises compared to HE in older adults living in low-income housing, although estimated costs of care were similar.

Background Every year, approximately 42 million people sustain a mild traumatic brain injury (mTBI, also known as concussion), with particularly high rates among college-aged individuals. A substantial proportion of these people (44%-64%) develop persistent symptoms that are challenging to treat, costly, and associated with significant disability. Anxiety has emerged as a risk factor for progression from acute to persistent mTBI symptoms. Objective This study aims to develop, adapt, and establish the feasibility of the Toolkit for Optimal Recovery after Concussions (TOR-C), an innovative mind-body program aimed at preventing persistent symptoms among young adults with mTBI and comorbid anxiety. Here, we describe the proposed study design, methodology, measurement, and treatment manuals. Methods In phase 1, we will conduct individual, live video qualitative interviews (up to n=20) with college-aged individuals with mTBI and comorbid anxiety to inform adaptation of the intervention and study procedures. In phase 2, an open pilot of the live video TOR-C (n=5) with exit interviews will be conducted to explore the initial feasibility, acceptability, and credibility of the program and to refine the study procedures. Phase 3 will involve conducting a feasibility randomized controlled trial (N=50) of the TOR-C versus a health education control (Health Enhancement for Concussions; HE-C), both delivered via live video, to establish feasibility of recruitment procedures (screening, eligibility, and enrollment) and data collection; feasibility, credibility, and acceptability of the live video TOR-C and HE-C (adherence, retention, fidelity, and satisfaction) following prespecified benchmarks; and a signal of improvement in outcomes. Results Phase 1 of the study has been approved by the Massachusetts General Hospital Institutional Review Board. Study completion is anticipated by early 2025. Conclusions We will develop and test the first mind-body intervention focused on prevention of persistent symptoms following mTBI in young adults with comorbid anxiety problems. This will allow us to establish feasibility markers in postconcussive symptoms, anxiety, disability, and fear avoidance to inform a future efficacy trial of the TOR-C versus HE-C. International Registered Report Identifier (IRRID) PRR1-10.2196/25746

Introduction Neurofibromatosis type 2 (NF2) is a rare, progressive and incurable genetic disorder associated with progressive hearing loss and eventual deafness. As a group, patients with NF report high levels of stress and depressive symptoms. However, no studies have explored improvement in these symptoms after psychosocial interventions. We have previously shown that a mind-body program tailored to adults with NF2 who are deaf (the Relaxation Response and Resiliency Program for Deaf NF2, d3RP-NF2) improves quality of life and resiliency over and above a Health Enhancement program when both are delivered via live-video and assisted by Communication Access Realtime Translation (CART). Here we tested the effects of the programs on depression and perceived stress. Methods Forty-five patients with NF2 and significant hearing loss were randomized to the d3RP-NF2 or Health-Enhancement program and completed measures of depression (PHQ-9) and perceived stress (PSS-10) at baseline, post-intervention, and six-month follow-up. Results Patients randomized to the d3RP-NF2 program, but not to the control condition, experienced significant decreases on both measures from baseline to post-test, which were maintained at follow-up (within group tests). However, improvements following the d3RP-NF2 program was not significantly higher than those observed in the control group (between group tests). Conclusion Results provide the first evidence of improvement in symptoms of depression and perceived stress among deaf patients living with NF2 who participate in a virtual mind-body program.

Background: Oxidative stress and protein aggregation are key mechanisms in amyotrophic lateral sclerosis (ALS) disease. Reduced glutathione (GSH) is the most important intracellular antioxidant that protects neurons from reactive oxygen species. We hypothesized that levels of GSH measured by MR spectroscopic imaging (MRSI) in the motor cortex and corticospinal tract are linked to clinical trajectory of ALS patients.Objectives: Investigate the value of GSH imaging to probe clinical decline of ALS patients in combination with other neurochemical and structural parameters.Methods: Twenty-four ALS patients were imaged at 3 T with an advanced MR protocol. Mapping GSH levels in the brain is challenging, and for this purpose, we used an optimized spectral-edited 3D MRSI sequence with real-time motion and field correction to image glutathione and other brain metabolites. In addition, our imaging protocol included (i) an adiabatic T1ρ sequence to image macromolecular fraction of brain parenchyma, (ii) diffusion tensor imaging (DTI) for white matter tractography, and (iii) high-resolution anatomical imaging.Results: We found GSH in motor cortex (r = −0.431, p = 0.04) and corticospinal tract (r = −0.497, p = 0.016) inversely correlated with time between diagnosis and imaging. N-Acetyl-aspartate (NAA) in motor cortex inversely correlated (r = −0.416, p = 0.049), while mean water diffusivity (r = 0.437, p = 0.033) and T1ρ (r = 0.482, p = 0.019) positively correlated with disease progression measured by imputed change in revised ALS Functional Rating Scale. There is more decrease in the motor cortex than in the white matter for GSH compared to NAA, glutamate, and glutamine.Conclusions: Our study suggests that a panel of biochemical and structural imaging biomarkers defines a brain endophenotype, which can be used to time biological events and clinical progression in ALS patients. Such a quantitative brain endophenotype may stratify ALS patients into more homogeneous groups for therapeutic interventions compared to clinical criteria.

IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor nervous system. Clinical studies have demonstrated cortical and spinal motor neuron hyperexcitability using transcranial magnetic stimulation and threshold tracking nerve conduction studies, respectively, although metrics of excitability have not been used as pharmacodynamic biomarkers in multi-site clinical trials. OBJECTIVE: To ascertain whether ezogabine decreases cortical and spinal motor neuron excitability in ALS. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled phase 2 randomized clinical trial sought consent from eligible participants from November 3, 2015, to November 9, 2017, and was conducted at 12 US sites within the Northeast ALS Consortium. Participants were randomized in equal numbers to a higher or lower dose of ezogabine or to an identical matched placebo, and they completed in-person visits at screening, baseline, week 6, and week 8 for clinical assessment and neurophysiological measurements. INTERVENTIONS: Participants were randomized to receive 600 mg/d or 900 mg/d of ezogabine or a matched placebo for 10 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was change in short-interval intracortical inhibition (SICI; SICI(−1) was used in analysis to reflect stronger inhibition from an increase in amplitude) from pretreatment mean at screening and baseline to the full-dose treatment mean at weeks 6 and 8. The secondary outcomes included levels of cortical motor neuron excitability (including resting motor threshold) measured by transcranial magnetic stimulation and spinal motor neuron excitability (including strength-duration time constant) measured by threshold tracking nerve conduction studies. RESULTS: A total of 65 participants were randomized to placebo (23), 600 mg/d of ezogabine (23), and 900 mg/d of ezogabine (19 participants); 45 were men (69.2%) and the mean (SD) age was 58.3 (8.8) years. The SICI(−1) increased by 53% (mean ratio, 1.53; 95% CI, 1.12-2.09; P = .009) in the 900-mg/d ezogabine group vs placebo group. The SICI(−1) did not change in the 600-mg/d ezogabine group vs placebo group (mean ratio, 1.15; 95% CI, 0.87-1.52; P = .31). The resting motor threshold increased in the 600-mg/d ezogabine group vs placebo group (mean ratio, 4.61; 95% CI, 0.21-9.01; P = .04) but not in the 900-mg/d ezogabine group vs placebo group (mean ratio, 1.95; 95% CI, −2.64 to 6.54; P = .40). Ezogabine caused a dose-dependent decrease in excitability by several other metrics, including strength-duration time constant in the 900-mg/d ezogabine group vs placebo group (mean ratio, 0.73; 95% CI, 0.60 to 0.87; P

Neuro-ICU hospitalization for an acute neurological illness is often traumatic and associated with heightened emotional distress and reduced quality of life (QoL) for both survivors and their informal caregivers (i.e., family and friends providing unpaid care). In a pilot study, we previously showed that a dyadic (survivor and caregiver together) resiliency intervention (Recovering Together [RT]) was feasible and associated with sustained improvement in emotional distress when compared with an attention placebo educational control. Here we report on changes in secondary outcomes assessing QoL. Survivors (n = 58) and informal caregivers (n = 58) completed assessments at bedside and were randomly assigned to participate together as a dyad in the RT or control intervention (both 6 weeks, two in-person sessions at bedside and four sessions via live video post discharge). We measured QoL domain scores (physical health, psychological, social relations, and environmental), general QoL, and QoL satisfaction using the World Health Organization Quality of Life Abbreviated Instrument at baseline, post treatment, and 3 months’ follow-up. We conducted mixed model analyses of variance with linear contrasts to estimate (1) within-group changes in QoL from baseline to post treatment and from post treatment to 3 months’ follow-up and (2) between-group differences in changes in QoL from baseline to post treatment and from post treatment to 3 months’ follow-up. We found significant within-group improvements from baseline to post treatment among RT survivors for physical health QoL (mean difference 1.73; 95% confidence interval [CI] 0.39–3.06; p = 0.012), environmental QoL (mean difference 1.29; 95% CI 0.21–2.36; p = 0.020), general QoL (mean difference 0.55; 95% CI 0.13–0.973; p = 0.011), and QoL satisfaction (mean difference 0.87; 95% CI 0.36–1.37; p = 0.001), and those improvements sustained through the 3-month follow-up. We found no significant between-group improvements for survivors or caregivers from baseline to post treatment or from post treatment to 3 months’ follow-up for any QoL variables (i.e., domains, general QoL, and QoL satisfaction together). In this pilot study, we found improved QoL among survivors, but not in caregivers, who received RT and improvements sustained over time. These RT-related improvements were not significantly greater than those observed in the control. Results support a fully powered randomized controlled trial to allow for a definitive evaluation of RT-related effects among dyads of survivors of acute brain injury and their caregivers.

Key Points Question Is participation in a dyadic resiliency intervention associated with a measurable reduction in symptoms of depression, anxiety, and posttraumatic stress (PTS) compared with participation in an educational control? Findings In this pilot, single-blind, randomized clinical trial of 58 dyads of survivors of the neuroscience intensive care unit and their informal caregivers, survivors and caregivers who received the active intervention experienced a significant reduction in symptoms of depression, anxiety, and PTS. Meaning In this pilot randomized clinical trial, the dyadic resiliency intervention was feasible, and the findings suggest that it may prevent chronic emotional distress in survivors of acute brain injury and their caregivers., This pilot randomized clinical trial evaluates the feasibility and preliminary effect of the novel dyadic resiliency intervention Recovering Together in reducing symptoms of depression, anxiety, and posttraumatic stress among patients hospitalized in the neuroscience intensive care unit and their informal caregivers., Importance To our knowledge, there are no evidence-based interventions to prevent chronic emotional distress (ie, depression, anxiety, and posttraumatic stress [PTS]) in critical care survivors and their informal caregivers. Objective To determine the feasibility and preliminary effect of the novel dyadic resiliency intervention Recovering Together (RT) on reducing symptoms of depression, anxiety, and PTS among hospitalized patients and their informal caregivers. Design, Setting, and Participants This single-blind, pilot randomized clinical trial of RT vs an educational control was conducted among 58 dyads in which either the survivor or caregiver endorsed clinically significant symptoms of depression, anxiety, or PTS. The study was conducted in the neuroscience intensive care unit at Massachusetts General Hospital. Data were collected from September 2019 to March 2020. Interventions Both RT and control programs had 6 sessions (2 at bedside and 4 via live video after discharge), and both survivor and caregiver participated together. Main Outcomes and Measures The primary outcomes were feasibility of recruitment and intervention delivery, credibility, and satisfaction. The secondary outcomes included depression and anxiety (measured by the Hospital Depression and Anxiety Scale), PTS (measured by the PTSD Checklist–Civilian Version), and intervention targets (ie, mindfulness, measured by the Cognitive and Affective Mindfulness Scale–Revised; coping, measured by the Measure of Current Status–Part A; and dyadic interpersonal interactions, measured by the Dyadic Relationship Scale). Main outcomes and targets were assessed at baseline, 6 weeks, and 12 weeks. Results The 58 dyads were randomized to RT (29 dyads [50.0%]; survivors: mean [SD] age, 49.3 [16.7] years; 9 [31.0%] women; caregivers: mean [SD] age, 52.4 [14.3] years; 22 [75.9%] women) or control (29 dyads [50.0%]; survivors: mean [SD] age, 50.3 [16.4] years; 12 [41.3%] women; caregivers, mean [SD] age, 52.1 [14.9], 17 [58.6%] women). Feasibility (recruitment [76%], randomization [100%], and data collection [83%-100%]), adherence (86%), fidelity (100%; κ = 0.98), satisfaction (RT: 57 of 58 [98%] with scores >6; control: 58 of 58 [100%] with scores >6), credibility (RT: 47 of 58 [81%] with scores >6; control: 46 of 58 [80%] with scores >6), and expectancy (RT: 49 of 58 [85%] with scores >13.5; 51 of 58 [87%] with scores >13.5) exceeded benchmarks set a priori. Participation in RT was associated with statistically and clinically significant improvement between baseline and postintervention in symptoms of depression (among survivors: −4.0 vs −0.6; difference, −3.4; 95% CI, −5.6 to −1.3; P = .002; among caregivers: −3.8 vs 0.6; difference, −4.5; 95% CI, −6.7 to −2.3; P

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate–taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR Clinicaltrials.gov number, NCT03127514.)

Background Chronic pain is associated with poor physical and emotional functioning. Nonpharmacological interventions can help, but improvements are small and not sustained. Previous clinical trials do not follow recommendations to comprehensively target objectively measured and performance-based physical function in addition to self-reported physical function. Objective This study aimed to establish feasibility benchmarks and explore improvements in physical (self-reported, performance based, and objectively measured) and emotional function, pain outcomes, and coping through a pilot randomized controlled trial of a mind-body physical activity program (GetActive) with and without a digital monitoring device (GetActive-Fitbit), which were iteratively refined through mixed methods. Methods Patients with chronic pain were randomized to the GetActive (n=41) or GetActive-Fitbit (n=41) programs, which combine relaxation, cognitive behavioral, and physical restoration skills and were delivered in person. They completed in-person assessments before and after the intervention. Performance-based function was assessed with the 6-min walk test, and step count was measured with an ActiGraph. Results Feasibility benchmarks (eg, recruitment, acceptability, credibility, therapist adherence, adherence to practice at home, ActiGraph wear, and client satisfaction) were good to excellent and similar in both programs. Within each program, we observed improvement in the 6-min walk test (mean increase=+41 m, SD 41.15; P Conclusions These preliminary findings support a fully powered efficacy trial of the two programs against an education control group. We present a model for successfully using the Initiative on the Methods, Measurement, and Pain Assessment in Clinical Trials criteria for a comprehensive assessment of physical function and following evidence-based models to maximize feasibility before formal efficacy testing. Trial Registration ClinicalTrial.gov NCT03412916; https://clinicaltrials.gov/ct2/show/NCT03412916

BACKGROUND Chronic pain is associated with poor physical and emotional functioning. Nonpharmacological interventions can help, but improvements are small and not sustained. Previous clinical trials do not follow recommendations to comprehensively target objectively measured and performance-based physical function in addition to self-reported physical function. OBJECTIVE This study aimed to establish feasibility benchmarks and explore improvements in physical (self-reported, performance based, and objectively measured) and emotional function, pain outcomes, and coping through a pilot randomized controlled trial of a mind-body physical activity program (GetActive) with and without a digital monitoring device (GetActive-Fitbit), which were iteratively refined through mixed methods. METHODS Patients with chronic pain were randomized to the GetActive (n=41) or GetActive-Fitbit (n=41) programs, which combine relaxation, cognitive behavioral, and physical restoration skills and were delivered in person. They completed in-person assessments before and after the intervention. Performance-based function was assessed with the 6-min walk test, and step count was measured with an ActiGraph. RESULTS Feasibility benchmarks (eg, recruitment, acceptability, credibility, therapist adherence, adherence to practice at home, ActiGraph wear, and client satisfaction) were good to excellent and similar in both programs. Within each program, we observed improvement in the 6-min walk test (mean increase=+41 m, SD 41.15; PGetActive group and mean increase=+50 m, SD 58.63; PGetActive-Fitbit group) and self-reported physical function (P=.001; effect size of 0.62 SD units for the GetActive group and P=.02; effect size of 0.38 SD units for the GetActive-Fitbit group). The mean step count increased only among sedentary patients (mean increase=+874 steps for the GetActive group and +867 steps for the GetActive-Fitbit group). Emotional function, pain intensity, pain coping, and mindfulness also improved in both groups. Participants rated themselves as much improved at the end of the program, and those in the GetActive-Fitbit group noted that Fitbit greatly helped with increasing their activity. CONCLUSIONS These preliminary findings support a fully powered efficacy trial of the two programs against an education control group. We present a model for successfully using the Initiative on the Methods, Measurement, and Pain Assessment in Clinical Trials criteria for a comprehensive assessment of physical function and following evidence-based models to maximize feasibility before formal efficacy testing. CLINICALTRIAL ClinicalTrial.gov NCT03412916; https://clinicaltrials.gov/ct2/show/NCT03412916

Introduction: Approximately 15% of the US population experiences migraine, with women afflicted three times as often as men. While medications are often used as first-line treatments, up to 50% of people with migraine pursue complementary and integrative medicine. One promising non-pharmacological approach for migraine is chiropractic care, due to the co-occurrence of migraine disease and musculoskeletal tension and pain. To date, no large-scale trials have evaluated the impact of a comprehensive model of chiropractic care on migraine. Methods: The Integrative Migraine Pain Alleviation through Chiropractic Therapy (IMPACT) study is a two-arm pilot pragmatic randomized clinical trial evaluating a multimodal chiropractic care intervention plus enhanced usual care (UC) vs. enhanced UC alone for adult women with episodic migraine. A total of 60 women aged 20–55 who meet criteria for episodic migraine will be randomly assigned to an evidence-informed, musculoskeletal focused multimodal chiropractic care (10 sessions over 14 weeks) plus enhanced UC vs. enhanced UC alone. Enhanced UC includes conventional care, migraine education materials, and biweekly check-in phone calls. Study specific aims include: 1) Determine safety and feasibility of the study design; 2) Provide preliminary data on the effectiveness of chiropractic care on migraine frequency, severity, duration and medication use; and 3) Provide preliminary estimates of the effects of chiropractic care on disability, health-related quality of life, and psychosocial well-being. Discussion: Findings will be used to inform the design of a full-scale trial evaluating chiropractic care for women with episodic migraines. Keywords: Episodic migraine, Chiropractic care, Complementary and integrative health, Pragmatic trial

BACKGROUND AND OBJECTIVES: Children with autism spectrum disorder (ASD) have a higher prevalence of epilepsy compared with general populations. In this pilot study, we prospectively identified baseline risk factors for the development of seizures in individuals with ASD and also identified characteristics sensitive to seizure onset up to 6 years after enrollment in the Autism Speaks Autism Treatment Network. METHODS: Children with ASD and no history of seizures at baseline who either experienced onset of seizures after enrollment in the Autism Treatment Network or remained seizure free were included in the analysis. RESULTS: Among 472 qualifying children, 22 (4.7%) experienced onset of seizures after enrollment. Individuals who developed seizures after enrollment exhibited lower scores at baseline on all domains of the Vineland Adaptive Behavior Scales, greater hyperactivity on the Aberrant Behavior Checklist (25.4 ± 11.8 vs 19.2 ± 11.1; P = .018), and lower physical quality of life scores on the Pediatric Quality of Life Inventory (60.1 ± 24.2 vs 76.0 ± 18.2; P < .001). Comparing change in scores from entry to call-back, adjusting for age, sex, length of follow-up, and baseline Vineland II composite score, individuals who developed seizures experienced declines in daily living skills (−8.38; 95% confidence interval −14.50 to −2.50; P = .005). Adjusting for baseline age, sex, and length of follow-up, baseline Vineland II composite score was predictive of seizure development (risk ratio = 0.95 per unit Vineland II composite score, 95% confidence interval 0.92 to 0.99; P = .007). CONCLUSIONS: Individuals with ASD at risk for seizures exhibited changes in adaptive functioning and behavior.

Background: Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). Methods: Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. Findings: Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP. Between UOx gKO, cKO, or Tg mice and their respective wild type littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. Interpretation: Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. Funding: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative. Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The study protocol of PD patients was approved by the institutional review boards of the Administrative Coordination Center at Massachusetts General Hospital (MGH), the Clinical Coordination Center at University of Rochester and all clinical sites, and participants provided written informed consent.

Objective To test the safety, tolerability, and urate‐elevating capability of the urate precursor inosine taken orally or by feeding tube in people with amyotrophic lateral sclerosis (ALS). Methods This was a pilot, open‐label trial in 25 participants with ALS. Treatment duration was 12 weeks. The dose of inosine was titrated at pre‐specified time points to elevate serum urate levels to 7–8 mg/dL. Primary outcomes were safety (as assessed by the occurrence of adverse events [AEs]) and tolerability (defined as the ability to complete the 12‐week study on study drug). Secondary outcomes included biomarkers of oxidative stress and damage. As an exploratory analysis, observed outcomes were compared with a virtual control arm built using prediction algorithms to estimate ALSFRS‐R scores. Results Twenty‐four out of 25 participants (96%) completed 12 weeks of study drug treatment. One participant was unable to comply with study visits and was lost to follow‐up. Serum urate rose to target levels in 6 weeks. No serious AEs attributed to study drug and no AEs of special concern, such as urolithiasis and gout, occurred. Selected biomarkers of oxidative stress and damage had significant changes during the study period. Observed changes in ALSFRS‐R did not differ from baseline predictions. Interpretation Inosine appeared safe, well tolerated, and effective in raising serum urate levels in people with ALS. These findings, together with epidemiological observations and preclinical data supporting a neuroprotective role of urate in ALS models, provide the rationale for larger clinical trials testing inosine as a potential disease‐modifying therapy for ALS.

AIMS A recent double-blind placebo-controlled crossover 70-day trial demonstrated that a fixed combination of dextromethorphan and quinidine (DM/Q) improves speech and swallowing function in most patients with amyotrophic lateral sclerosis. In this study, a subset of participants, many of whom did not substantially improve while on DM/Q, were re-evaluated using computer-based speech analyses and expert clinician ratings of the overall severity of speech impairment. METHODS Speech samples were recorded from the subset of 10 patients at four visits made at approximately 30-day intervals. The recordings were analysed by automated computer-based analysis of speech pausing patterns. Severity of speech impairment was rated by three experienced speech-language pathologists using direct magnitude estimation. Scores on patient-reported and clinician-administered scales of bulbar motor involvement were obtained at each visit. RESULTS The effects of DM/Q were detected on several of the objective speech measures, including total pause duration (s) (Cohen's d = 0.73, 95% confidence interval (CI) -1.70, 0.24), pause time (%) (d = 0.77, 95% CI -1.75, 0.21), and mean speech event duration (s) (d = 0.52, 95% CI -0.44, 1.47), but not on clinician ratings of speech or the speech components of the self-report or clinician-administered scales. CONCLUSIONS These findings suggest that even patients with modest improvement while on DM/Q may experience quantifiable improvements in speech when assessed using sensitive and objective measures. This study provides additional evidence of the positive impact of DM/Q on one or more of the neural systems that control bulbar motor function and production of speech.

Objectives: Studies in humans and rodents suggest that metformin, a medicine typically used to treat type 2 diabetes, may have beneficial effects on memory. We sought to determine whether metformin improved spatial or verbal memory in children with autism spectrum disorder (ASD) and overweight associated with atypical antipsychotic use. Methods: We studied the effects of metformin (Riomet®) concentrate on spatial and verbal memory in 51 youth with ASD, ages 6 through 17 years, who were taking atypical antipsychotic medications, had gained significant weight, and were enrolled in a trial of metformin for weight management. Phase 1 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group comparison of metformin (500–850 mg given twice a day) versus placebo. During Phase 2, all participants took open-label metformin from week 17 through week 32. We assessed spatial and verbal memory using the Neuropsychological Assessment 2nd Edition (NEPSY–II) and a modified children's verbal learning task. Results: No measures differed between participants randomized to metformin versus placebo, at either 16 or 32 weeks, after adjustment for multiple comparisons. Sixteen-week change in memory for spatial location on the NEPSY–II was nominally better among participants randomized to placebo. However, patterns of treatment response across all measures revealed no systematic differences in performance, suggesting that metformin had no effect on spatial or verbal memory in these children. Conclusions: Although further study is needed to support these null effects, the overall impression is that metformin does not affect memory in overweight youth with ASD who were taking atypical antipsychotic medications.

Background Boys with autism spectrum disorder (ASD) have lower bone mineral density (BMD) than typically developing controls. Differences in diet and exercise may contribute to low BMD. Objective Our aim was to examine macro- and micronutrient intakes and self-reported physical activity in boys with ASD compared to TDC and the relationship of these variables with BMD. Design/methods We conducted a cross-sectional study of 49 boys (25 ASD, 24 typically developing controls) assessed for 3-day food records and physical activity records, and BMD of the whole body less head, hip, and spine using dual-energy x-ray absorptiometry. Fasting levels of 25(OH) vitamin D and calcium were obtained. Participants Participants were adolescent boys, aged 8 to 17 years, recruited from a clinic population (ASD) or community advertisements (ASD and typically developing controls) matched for age. Results ASD participants were approximately 9 months younger than typically developing control participants on average. Body mass index and serum vitamin D and calcium levels were similar. Boys with ASD consumed 16% fewer calories, with a larger percentage obtained from carbohydrates, and 37% less animal protein and 20% less fat than typically developing controls. A lower proportion of ASD participants were categorized as "very physically active" (27% vs 79%; P z scores were 0.7 to 1.2 standard deviations lower in ASD than typically developing controls at all locations. Higher animal protein, calcium, and phosphorus intakes were associated positively with bone density measures in boys with ASD. Conclusions Compared to typically developing controls, boys with ASD had lower protein, calcium, and phosphorus intakes, activity levels, and BMD z scores at the lumbar spine, femoral neck, total hip, and whole body less head. Protein, calcium, and phosphorus intakes were associated positively with BMD.

The neurofibromatoses (NF) are incurable genetic disorders that can cause nerve sheath tumors, chronic pain, and disfiguration. Patients with NF report lower quality of life and greater distress, and may benefit from programs that promote resiliency. To test effects of an 8-week mind–body program (Relaxation Response Resiliency Program for NF [3RP-NF]) on resiliency, using data derived from a larger randomized controlled trial of the 3RP-NF versus attention placebo control (Vranceanu et al. in Neurology 87:806–814, 2016). Participants (N = 63; 46 female; 52 White) were randomized to 3RP-NF (n = 32, M age = 42.86) or control (n = 31, M age = 39.90), completed intervention sessions via group videoconferencing, and provided self-report measures of resiliency (i.e., perceived coping abilities, perceived social support, gratitude, optimism, spiritual well-being, mindfulness) at baseline, post-intervention, and 6-month follow-up. All participants attended at least 6/8 sessions and 83% (N = 52) provided 6-month follow-up data. The 3RP-NF (vs. control) produced greater improvements from pre- to post-intervention in perceived coping abilities (M difference = 6.68; p = .008), perceived social support (M difference = 9.16; p = .032), and mindfulness (M difference = 2.23; p = .035), which were maintained at 6-month follow up. We did not observe group differences in spiritual well-being, optimism, or gratitude. The 3RP-NF produced sustained increases in multiple dimensions of resiliency (perceived coping abilities, perceived social support, and mindfulness). Promoting resiliency may be particularly important for a population that is underserved and living with a chronic, incurable illness.

Supporting the health of growing numbers of frail older adults living in subsidized housing requires interventions that can combat frailty, improve residents’ functional abilities, and reduce their health care costs. Tai Chi is an increasingly popular multimodal mind–body exercise that incorporates physical, cognitive, social, and meditative components in the same activity and offers a promising intervention for ameliorating many of the conditions that lead to poor health and excessive health care utilization. The Mind Body-Wellness in Supportive Housing (Mi-WiSH) study is an ongoing two-arm cluster randomized, attention-controlled trial designed to examine the impact of Tai Chi on functional indicators of health and health care utilization. We are enrolling participants from 16 urban subsidized housing facilities (n=320 participants), conducting the Tai Chi intervention or education classes and social calls (attention control) in consenting subjects within the facilities for one year, and assessing these subjects at baseline, 6 months, and 1 year. Physical function (quantified by the Short Physical Performance Battery), and health care utilization (emergency visits, hospitalizations, skilled nursing and nursing home admissions), assessed at 12 months are co-primary outcomes. Our discussion highlights our strategy to balance pragmatic and explanatory features into the study design, describes efforts to enhance site recruitment and participant adherence, and summarizes our broader goal of post study dissemination if effectiveness and cost-effectiveness are demonstrated, by preparing training and protocol manuals for use in housing facilities across the U.S.

INTRODUCTION: Immune activation is implicated in ALS progression. Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa randomized controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS. METHODS: Randomization was 2:1 (fingolimod:placebo). Treatment duration was four weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole blood gene expression. RESULTS: Thirty participants were randomized; 28 received drug (fingolimod 18; placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo; NS). FEV1 and FEV1/SVC changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (p

Obstructive sleep apnea (OSA) occurs at a high prevalence in patients with Down syndrome (DS). A polysomnogram, which is often cumbersome and challenging, remains the gold standard method of diagnosing OSA. OSA in patients with DS is often attributed to skeletal and soft-tissue structural alterations that are characteristic of the DS phenotype; as such, we hypothesized that assessing anthropometric facial measurements may be predictive of OSA in patients with DS. We used the 3dMDface sterophotography system to capture and create 3D facial images, and we subsequently identified facial landmarks using a single, experienced investigator and utilizing proprietary software to calculate inter-landmark distances and angles. We compared our findings with similar data for neurotypically developing participants. We further compared the findings in participants with DS with and without OSA. Participants with DS had maxillomandibular hypoplasia with smaller ear, nose, and eye measurements compared to neurotypically developing peers. We found no statistically significant differences in 3D photogrammetric measurements between participants with DS with or without OSA.

Study objectives The study aimed to compare urinary biomarkers in patients with Down syndrome (DS) with and without obstructive sleep apnea (OSA) to those of age- and sex-matched neurotypically developing healthy controls (HC). We further investigated whether we could predict OSA in patients with DS using these biomarkers. Methods Urine samples were collected from 58 patients with DS the night before or the morning after their scheduled overnight polysomnogram or both, of whom 47 could be age- and sex-matched to a sample of 43 HC. Concentrations of 12 neurotransmitters were determined by enzyme-linked immunosorbent assay. Log-transformed creatinine-corrected assay levels were normalized. Normalized z -scores were compared between patients with DS vs. HC, between patients with DS with vs. without OSA, and to derive composite models to predict OSA. Results Most night-sampled urinary biomarkers were elevated among patients with DS relative to matched HC. No urinary biomarker levels differed between patients with DS with vs. without OSA. A combination of four urinary biomarkers predicted AHI > 1 with a positive predictive value of 90% and a negative predictive value of 68%. Conclusions Having DS, even in the absence of concurrent OSA, is associated with a different urinary biomarker profile when compared to that of HC. Therefore, while urinary biomarkers may be predictive of OSA in the general pediatric population, a different approach is needed in interpreting urinary biomarker assays in patients with DS. Certain biomarkers also seem promising to be predictive of OSA in patients with DS. No clinical trial was indicated in the undertaking of this work.

Introduction: Improved outcome measures are essential to efficiently screen the growing number of potential amyotrophic lateral sclerosis (ALS) therapies. Methods: This longitudinal study of 100 (70 male) participants with ALS compared Accurate Test of Limb Isometric Strength (ATLIS), using a fixed, wireless load cell, with ALS Functional Rating Scale-Revised (ALSFRS-R) and vital capacity (VC). Results: Participants enrolled at 5 U.S. sites. Data were analyzed from 66 participants with complete ATLIS, ALSFRS-R, and VC data over at least 3 visits. Change in ATLIS was less variable both within- and among-person than change in ALSFRS-R or VC. Additionally, participants who had normal ALSFRS-R arm and leg function averaged 12 to 32% below expected strength values measured by ATLIS. Conclusions: ATLIS was more sensitive to change than ALSFRS-R or VC and could decrease sample size requirements by approximately one-third. The ability of ATLIS to detect prefunctional change has potential value in early trials. Muscle Nerve 56: 710–715, 2017

Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection. Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos Fil: Schwarzschild, Michael A.. Massachusetts General Hospital; Estados Unidos Fil: Tanner, Caroline M.. University of California; Estados Unidos Fil: Fernandez, Hubert H.. Cleveland Clinic; Estados Unidos Fil: Simon, David K.. Harvard Medical School; Estados Unidos Fil: Leverenz, James B.. Cleveland Clinic; Estados Unidos Fil: Merola, Aristide. University of Cincinnati; Estados Unidos Fil: Chen Plotkin, Alice. University of Pennsylvania; Estados Unidos Fil: Brundin, Patrik. Van Andel Research Institute. Center for Neurodegenerative Science; Estados Unidos Fil: Kauffman, Marcelo Andres. Universidad Austral; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina Fil: Erro, Roberto. Universita di Verona; Italia. University College London; Reino Unido Fil: Kieburtz, Karl. University of Rochester Medical Center; Estados Unidos Fil: Woo, Daniel. University of Cincinnati; Estados Unidos Fil: Macklin, Eric A.. Massachusetts General Hospital; Estados Unidos Fil: Standaert, David G.. University of Alabama at Birmingahm; Estados Unidos Fil: Lang, Anthony E.. University of Toronto; Canadá

Obstructive sleep apnea (OSA) occurs frequently in people with Down syndrome (DS) with reported prevalences ranging between 55% and 97%, compared to 1–4% in the neurotypical pediatric population. Sleep studies are often uncomfortable, costly, and poorly tolerated by individuals with DS. The objective of this study was to construct a tool to identify individuals with DS unlikely to have moderate or severe sleep OSA and in whom sleep studies might offer little benefit. An observational, prospective cohort study was performed in an outpatient clinic and overnight sleep study center with 130 DS patients, ages 3–24 years. Exclusion criteria included previous adenoid and/or tonsil removal, a sleep study within the past 6 months, or being treated for apnea with continuous positive airway pressure. This study involved a physical examination/medical history, lateral cephalogram, 3D photograph, validated sleep questionnaires, an overnight polysomnogram, and urine samples. The main outcome measure was the apnea-hypopnea index. Using a Logic Learning Machine, the best model had a cross-validated negative predictive value of 73% for mild obstructive sleep apnea and 90% for moderate or severe obstructive sleep apnea; positive predictive values were 55% and 25%, respectively. The model included variables from survey questions, medication history, anthropometric measurements, vital signs, patient’s age, and physical examination findings. With simple procedures that can be collected at minimal cost, the proposed model could predict which patients with DS were unlikely to have moderate to severe obstructive sleep apnea and thus may not need a diagnostic sleep study.