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Background: In randomized clinical trials, when treatments do not work equally effectively across stratifications of participants, observed event rates may differ from those hypothesized leading to deviations in estimated power. Objectives: To investigate the effect of distributions of baseline Expanded Disability Status Scale (EDSS) proportions in relapsing-remitting multiple sclerosis (RRMS) on the trial outcome, confirmed disability progression rate (CDPR), and power. Methods: We reported CDPRs in the CombiRx trial by baseline EDSS and by groups (1st (0, 1), 2nd (1.5, 2), 3rd (2.5, 3), and 4th (⩾3.5)) and investigated the effect of different combinations of baseline EDSS proportions on the trial outcome and power. Results: There were 244 (25.4%) participants in the 1st group, 368 (38.4%) in the 2nd group, 223 (23.3%) in the 3rd group, and 124 (12.9%) in the 4th group with CDPRs of 40.1%, 13.9%, 11.2%, and 16.9%, respectively. Both CDPR and power increased when the proportion of the 1st group increased in hypothetical trials with equal sample sizes in each arm, and a 10% increase in the 1st group led to a 5% increase in power. Conclusion: Various baseline EDSS proportions yielded different CDPRs and power, suggesting caution in interpretation of treatment effects across trials that enrolled participants with different proportions of baseline EDSS. [ABSTRACT FROM AUTHOR]

Background: The results of two randomized phase 3 trials that investigated the use of laquinimod in patients with relapsing-remitting multiple sclerosis were analyzed using a propensity score model.Methods: The propensity score in each study was defined as the probability of an individual patient being assigned to either the laquinimod or placebo study arm. The analysis included two main stages: (1) calculation of a propensity score for each patient, given a broad set of baseline covariates that included second-degree interactions, and (2) incorporation of the propensity score as another covariate into the predefined primary analysis model to test the treatment effect of laquinimod (0.6 mg/d) vs placebo on the annualized relapse rate (ARR).Results: The BRAVO study showed baseline imbalances for T2 volume and the proportion of patients with gadolinium (Gd)-enhancing lesions, both parameters known to correlate with risk of relapse. Adjustment using the propensity score as a categorical variable showed that the estimated difference in ARR between laquinimod and placebo was 0.078, in favor of laquinimod. In ALLEGRO, the baseline Gd-enhancing lesion mean score was higher for placebo vs laquinimod. When the primary analysis model was adjusted for the propensity score as a categorical variable, the covariate adjusted difference in mean ARR between laquinimod and placebo was 0.084, in favor of laquinimod.Conclusions: Propensity scores addressing differences in baseline characteristics may be helpful to better understand whether observed treatment effect differences in randomized controlled trials are accurate results or result from inherent differences between patients with multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Many post hoc analyses of clinical trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are in small Phase 2 trials. Subject heterogeneity may lead to statistically significant post hoc results that cannot be replicated in larger follow-up studies. Objective: We investigated the extent of this problem using simulation studies mimicking current trial methods with post hoc analyses based on ApoE4 carrier status. Methods: We used a meta-database of 24 studies, including 3,574 subjects with mild AD and 1,171 subjects with MCI/prodromal AD, to simulate clinical trial scenarios. Post hoc analyses examined if rates of progression on the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog) differed between ApoE4 carriers and non-carriers. Results: Across studies, ApoE4 carriers were younger and had lower baseline scores, greater rates of progression, and greater variability on the ADAS-cog. Up to 18% of post hoc analyses for 18-month trials in AD showed greater rates of progression for ApoE4 non-carriers that were statistically significant but unlikely to be confirmed in follow-up studies. The frequency of erroneous conclusions dropped below 3% with trials of 100 subjects per arm. In MCI, rates of statistically significant differences with greater progression in ApoE4 non-carriers remained below 3% unless sample sizes were below 25 subjects per arm. Conclusions: Statistically significant differences for ApoE4 in post hoc analyses often reflect heterogeneity among small samples rather than true differential effect among ApoE4 subtypes. Such analyses must be viewed cautiously. ApoE genotype should be incorporated into the design stage to minimize erroneous conclusions. [ABSTRACT FROM AUTHOR]

Changes in hardware or image-processing settings are a common issue for large multicenter studies. To pool MRI data acquired under these changed conditions, it is necessary to demonstrate that the changes do not affect MRI-based measurements. In these circumstances, classical inference testing is inappropriate because it is designed to detect differences, not prove similarity. We used a method known as statistical equivalence testing to address this limitation. Equivalence testing was carried out on 3 datasets: (1) cortical thickness and automated hippocampal volume estimates obtained from healthy individuals imaged using different multichannel head coils; (2) manual hippocampal volumetry obtained using two readers; and (3) corpus callosum area estimates obtained using an automated method with manual cleanup carried out by two readers. Equivalence testing was carried out using the "two one-sided tests" (TOST) approach. Power analyses of the TOST were used to estimate sample sizes required for well-powered equivalence testing analyses. Mean and standard deviation estimates from the automated hippocampal volume dataset were used to carry out an example power analysis. Cortical thickness values were found to be equivalent over 61% of the cortex when different head coils were used (q < .05, false discovery rate correction). Automated hippocampal volume estimates obtained using the same two coils were statistically equivalent (TOST P = 4.28 × 10(-15) ). Manual hippocampal volume estimates obtained using two readers were not statistically equivalent (TOST P = .97). The use of different readers to carry out limited correction of automated corpus callosum segmentations yielded equivalent area estimates (TOST P = 1.28 × 10(-14) ). Power analysis of simulated and automated hippocampal volume data demonstrated that the equivalence margin affects the number of subjects required for well-powered equivalence tests. We have presented a statistical method for determining if morphometric measures obtained under variable conditions can be pooled. The equivalence testing technique is applicable for analyses in which experimental conditions vary over the course of the study. [ABSTRACT FROM AUTHOR]

Relapse rates and thus the impact of therapies have been decreasing. Why they decline and the impact on our ability to understand which treatments are better require more than simple math. The objective of this review is to discuss the impact of regression to the mean, changes in outcome effects and how we compare outcomes over time and among studies. This paper provides discourse on the topics of regression to the mean, some examples of the pitfalls of changes and some difficulties in the interpretation of the common percentage change in outcomes. The results show that we can often be deceived by what we think we see and they also demonstrate how such confusion evolves in the literature. This article aims to caution against the over-interpretation of changes from baseline, which are helped along by regression towards the mean and other factors. Furthermore, how we interpret changes from baseline requires care and not wishful thinking, coupled with careful digestion of seemingly reasonable explications of results. [ABSTRACT FROM AUTHOR]

An introduction to an article on the temporal trends in the diagnosis of primary progressive multiple sclerosis is presented.

Inebilizumab, an anti-CD19 B-cell-depleting antibody, demonstrated safety and efficacy in neuromyelitis optica spectrum disorder in the randomised controlled period of the N-MOmentum trial. Here, end-of-study data, including the randomised controlled period and open-label extension period, are reported. In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov , NCT02200770 , and is now complete. Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4], 197 [91%] of 216 were female, 19 [9%] were male, 115 [53%] were White, 45 [21%] were Asian, 19 [9%] were American Indian or Alaskan Native, and 19 [9%] were Black or African American). As of data cutoff for this end of study analysis (Dec 18, 2020; median exposure 1178 days [IQR 856–1538], total exposure of 730 person-years) 225 participants formed the any inebilizumab population, and 208 (92%) participants were AQP4-IgG seropositive. Overall, 63 adjudicated neuromyelitis optica spectrum disorder attacks occurred in 47 (21%) of 225 treated participants (60 attacks occurred in 44 [21%] of 208 in the AQP4-IgG seropositive subgroup); 40 (63%) of 63 attacks occurred in 34 (15%) of 225 treated participants during the first year of treatment. Of individuals who had an adjudicated attack while receiving inebilizumab, 36 (77%) of 47 were subsequently attack-free at the end of 4 years. Annualised attack rates decreased year-on-year, with end-of-study adjusted annualised attack rates being similar in the any inebilizumab-AQP4-IgG seropositive subgroup (0·097 [95% CI 0·070–0·14]) and any inebilizumab populations (0·092 [0·067–0·13]). Overall, 208 (92%) of 225 participants who received any inebilizumab had at least one treatment-emergent adverse event, the most frequent of which were urinary tract infection (59 [26%]), nasopharyngitis (47 [21%]), and arthralgia (39 [17%]). Infection rates did not increase over 4 years. Three (1%) of 225 participants in the any inebilizumab population died during the open-label period (one each due to a CNS event of unknown cause and pneumonia, respiratory insufficiency resulting from an neuromyelitis optica spectrum disorder attack and viral pneumonia related to COVID-19), all of which were deemed to be unrelated to treatment. Data from the end-of-study analysis of the N-MOmentum trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with neuromyelitis optica spectrum disorder, which supports the role of inebilizumab as a CD19+ B-cell-depleting therapy in neuromyelitis optica spectrum disorder. MedImmune and Viela Bio/Horizon Therapeutics, now part of Amgen. [ABSTRACT FROM AUTHOR]

Objective: Most states prohibit sales of alcohol to customers who are apparently intoxicated, and many require training in responsible beverage service (RBS), with the aim of reducing driving while intoxicated (DWI) and other harms. Sales to apparently intoxicated patrons were assessed in onsite alcohol sales establishments and compared across three states. Method: A sample of 180 licensed onsite alcohol establishments was selected in California (n = 60), New Mexico (n = 60), and Washington State (n = 60). States had different RBS training histories, content, and procedures. Research confederates, trained to feign cues of intoxication, visited each establishment twice. The pseudo-intoxicated patron (PP) ordered an alcoholic beverage while displaying intoxication cues. Sale of alcohol was the primary outcome. Results: At 179 establishments assessed, PPs were served alcohol during 56.5% of 356 visits (35.6% of establishments served and 22.6% did not serve at both visits). Alcohol sales were less frequent in New Mexico (47.9% of visits; odds ratio [OR] = 0.374, p = .008) and Washington State (49.6%; OR = 0.387, p = .012) than in California (72.0%). Servers less consistently refused service at both visits (6.8%) in California than New Mexico (33.9%) or Washington (27.1%), χ²(4, n = 177) = 16.72, p = .002. Alcohol sales were higher when intoxication cues were less obvious (p < .001). Conclusions: Overservice of alcohol to apparently intoxicated customers was frequent and likely elevated risk of DWI and other harms. The lower sales in New Mexico and Washington than California may show that a policy approach prohibiting sales to intoxicated customers combined with well-established RBS training can reduce overservice. Further efforts are needed to reduce overservice. [ABSTRACT FROM AUTHOR]

Dental caries results from the dissolution of mineralized dental tissues by the metabolic by-products of oral bacteria colonizing the surface of teeth. The principal modality for dealing with this infectious process is through restorative treatment which removes the pathologic tissue and replaces it with a variety of inert materials. The purpose of this study was to evaluate the effect of traditional restorative treatment on select oral bacterial populations. Fifty-two females demonstrating high levels of inert streptococci (≥2.5 × 10[SUP4] colony forming units (cfu) per ml saliva) with no more than four missing posterior teeth were recruited for this study. Salivary levels of mutans streptococci, lactobacilli, total streptococci, and total cultivable bacteria were evaluated before, during, and after restorative treatment. Initial DMFS scores were established by two standardized examiners using bitewing radiographs and clinical examination, which was conducted under optimal conditions. All restorative treatment was completed by faculty members of the University of Alabama School of Dentistry using treatment plans developed by the DMFS examiners. The participants received a mean of 16.4 restored surfaces, which resulted in significant reductions of all the bacterial populations tested. All microbial populations monitored were predicted to return to their baseline levels within 151 days after restorative treatment in 50% of the participants. This study shows that conventional restorative treatment results in a significant reduction of bacterial populations including those associated with the dental caries process, i.e., mutans streptococci and lactobacilli. Although restorative treatment is essential for replacing form and function to the dentition, it does not appear to have a prolonged effect on any of the salivary bacterial populations monitored, including those thought responsible for dental caries. [ABSTRACT FROM AUTHOR]

Cotinine was measured in the serum of nearly all 5, 115 18-30 year old, Black and White, men and women participating in the Coronary Artery Risk Development in (Young) Adults Study, 30 percent of whom reported current cigarette smoking. Ninety-five percent of the reported smokers had serum cotinine levels indicative of smoking (> 13 ng/ml). The median cotinine level was higher in Black than White Smokers (221 ng/ml versus 170 ng/ml; 95 percent CI for difference: 34,65) in spite of the fact that estimated daily nicotine exposure and serum thiocyanate were higher in Whites. The difference persisted after controlling for number of cigarettes, nicotine, content, frequency of inhalation, weekly sidestream smoke exposure, age gender, and education. A reporting bias and nicotine intake were ruled out as explanations for the racial difference suggesting that the metabolism of nicotine or the excretion of cotinine may differ by race. Racial differences in cotinine levels may provide clues to the reasons for the observed lower cessation rates and higher rates of some smoking-related caners in Blacks. [ABSTRACT FROM AUTHOR]

Background: Outcome measures need to be valid and have good test–retest reliability and responsiveness. We compared the responsiveness of the RAND-12 and the Health Utilities Index—mark III (HUI3) in persons with multiple sclerosis (MS). Methods: In Spring 2018 and 2019, North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants completed the HUI3, the RAND-12, and reported disability (Patient Determined Disease Steps (PDDS)) and employment status (full-time, part-time, and no). We used changes in PDDS and employment status as anchors. We assessed responsiveness using effect size, standardized response mean, and the responsiveness index. We used relative efficiency (RE) to compare the responsiveness of the health-related quality of life (HRQOL) scores, adjusting for sociodemographic factors. Results: We included 4769 participants in the analysis. They had a mean (standard deviation (SD)) age of 60.9 (10.1) years, and 3826 participants (80.2%) were women. RE was highest for the HUI3 for changes in in disability status (HUI3: 1.0, Physical Component Score-12 (PCS-12): 0.80, and Mental Component Score-12 (MCS-12): 0.41) and for changes in employment status (HUI3: 1.0, PCS-12: 0.70, and MCS-12: 0.17). Conclusion: The HUI3 was more responsive to changes in disability and employment status than the PCS-12 or MCS-12. Given the HUI3's other strong psychometric properties, it may be the preferred generic measure of HRQOL in MS. [ABSTRACT FROM AUTHOR]

Background: Clinical practice, expert opinion, and evidence-based guidelines recommend daily stretching as first-line treatment for multiple sclerosis (MS) spasticity, but this has not been evaluated by fully powered clinical trials. Objective: To determine whether MS Spasticity: Take Control (STC), a guideline-based program of spasticity education and stretching exercises has different effects on the impact of spasticity than a control program of different spasticity education and range of motion (ROM) exercises. Methods: Ambulatory people with self-reported MS spasticity were randomly assigned to STC or ROM, delivered in same duration, facilitator-led, group classes, face-to-face (F2F) initially and later virtually, due to coronavirus disease 2019 (COVID-19). Multiple Sclerosis Spasticity Scale (MSSS) scores were compared between groups at 1 (primary outcome) and 6 months after interventions. Results: A total of 231 people enrolled. There was no significant difference in MSSS scores between STC and ROM at 1 month (mean difference = 0.28, 95% (confidence interval (CI)) = [−9.45 to 10.01], p = 0.955). There were significant group mean improvements in MSSS scores and most other outcomes at 1 and 6 months. Conclusion: Education with stretching exercises, the first-line recommended treatment for MS spasticity, and education with ROM exercises may both improve MS spasticity to a similar degree. This study debunks the belief that stretching is essential to managing MS spasticity. [ABSTRACT FROM AUTHOR]

The use of natalizumab has likely been limited by its association with progressive multifocal leukoencephalopathy (PML), an infection caused by the human polyomavirus John Cunningham (JC). Three factors were recently identified that contribute to the overall risk of natalizumab-associated PML: (1) Positive serostatus for anti-JCV antibodies, (2) prior use of immunosuppressants, and (3) duration of natalizumab therapy. This risk stratification algorithm has not led to a reduction in the incidence of PML in natalizumab-treated patients with multiple sclerosis between April 2010 and February 2014. This observation may appear perplexing, as treatment duration and JCV serostatus are modifiable risk factors. Potential reasons for the lack of success of companion diagnostics that determine the overall risk of natalizumab-associated PML are discussed. [ABSTRACT FROM AUTHOR]

Background: Cross-sectional studies suggest self-reported cancer history is associated with decreased risk of Alzheimer's disease (AD). However, little is known about how self-reported cancer affects longitudinal AD progression, the primary outcome in clinical trials and observational studies.Objective: To determine self-reported cancer history's effect on longitudinal AD progression in an observational study.Methods: We utilized data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to evaluate progression to AD by self-reported all-cancer, breast, prostate, colorectal, or non-melanoma skin cancer history. Linear mixed effects models were used to examine baseline differences and rates of progression on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) by self-reported cancer history. Age at AD onset was examined using consensus clinical diagnoses with Cox proportional hazards regression.Results: Among 1,271 participants, models revealed no significant differences in progression over time but did reveal significantly lower baseline ADAS-Cog score, indicating better cognition at a given age in those with self-reported cancer history. Cox models indicated those with self-reported cancer history had significantly later age of AD onset (HR: 0.67, 95% CI: 0.53-0.85) after adjustment for covariates.Conclusion: Participants with self-reported cancer history entered ADNI with better cognition and later age of AD onset, but progressed similarly to participants without such history, indicating differences in AD between those with and without self-reported cancer history emerge early in the disease course. Such differences in longitudinal progression by self-reported cancer history could affect AD trials and observational studies, given the current focus on early disease course. Further investigation is warranted with detailed longitudinal assessment of cancer and AD. [ABSTRACT FROM AUTHOR]

We have previously shown that cannabidiol (CBD; Epidiolex®) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12 weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the other antiepileptic drugs (AEDs) had an effect on seizure frequency or severity at 12, 24, or 48 weeks after therapy initiation. One hundred and thirty-two adults and children with TRE receiving CBD were studied prospectively. Participants were separated into two groups — either taking (CBD + clobazam) or not taking concomitant clobazam (CBD − clobazam). In the secondary analyses, participants were divided into groups depending on whether they were taking at least 1/4 of the other AEDs shown to interact with CBD (iAED). Seizure counts and Chalfont Seizure Severity Scale (CSSS) were obtained at baseline, 12, 24, and 48 weeks. Groups were compared at each respective time point in the study using generalized estimating equations (GEE) analyses. All groups demonstrated statistically significant reductions in seizure frequency and severity from baseline (all P < 0.05). When participants on CBD + clobazam were compared with CBD − clobazam, there were no significant differences in seizure frequency and severity reduction between the groups at 12 weeks (both P > 0.05). When comparing groups with iAEDs vs. group without iAEDs, independent of coadministration of clobazam, no differences in treatment response were observed (all P > 0.05). Longitudinal analyses up to 48 weeks after therapy initiation did not reveal any differences in treatment response between groups. These analyses suggest that concomitant to CBD, AEDs may not have an effect on reducing seizure frequency and severity in patients with TRE. • No study addresses if drug interactions with cannabidiol influence seizure control. • Analyzed if certain AEDs changed seizure frequency or severity in open-label CBD study • At 12 weeks, no change to frequency or severity with CBD + clobazam. • No difference in seizure frequency/severity at 48 weeks with other interacting drugs. • CBD drug interactions did not appear to affect seizure control in our study. [ABSTRACT FROM AUTHOR]

Background: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. Objective: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. Methods: We held an international workshop with experts in clinical trial design. Results: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. Conclusion: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions. [ABSTRACT FROM AUTHOR]

Multiple sclerosis typically has onset in young adults and new disease activity diminishes with age. Most clinical trials of disease-modifying therapies for multiple sclerosis have not enrolled individuals older than 55 years. Observational studies suggest that risk of return of disease activity after discontinuation of a disease-modifying therapies is greatest in younger patients with recent relapses or MRI activity. We aimed to determine whether risk of disease recurrence in older patients with no recent disease activity who discontinue disease-modifying therapy is increased compared to those who remain on disease-modifying therapy. DISCOMS was a multicentre, randomised, controlled, rater-blinded, phase 4, non-inferiority trial. Individuals with multiple sclerosis of any subtype, 55 years or older, with no relapse within the past 5 years or new MRI lesion in the past 3 years while continuously taking an approved disease-modifying therapy were enrolled at 19 multiple sclerosis centres in the USA. Participants were randomly assigned (1:1 by site) with an interactive response technology system to either continue or discontinue disease-modifying therapy. Relapse assessors and MRI readers were masked to patient assignment; patients and treating investigators were not masked. The primary outcome was percentage of individuals with a new disease event, defined as a multiple sclerosis relapse or a new or expanding T2 brain MRI lesion, over 2 years. We assessed whether discontinuation of disease-modifying therapy was non-inferior to continuation using a non-inferiority, intention-to-treat analysis of all randomly assigned patients, with a predefined non-inferiority margin of 8%. This trial is registered at ClinicalTrials.gov , NCT03073603 , and is completed. 259 participants were enrolled between May 22, 2017, and Feb 3, 2020; 128 (49%) were assigned to the continue group and 131 (51%) to the discontinue group. Five participants were lost to follow-up (continue n=1, discontinue n=4). Six (4·7%) of 128 participants in the continue group and 16 (12·2%) of 131 in the discontinue group had a relapse or a new or expanding brain MRI lesion within 2 years. The difference in event rates was 7·5 percentage points (95% CI 0·6–15·0). Similar numbers of participants had adverse events (109 [85%] of 128 vs 104 [79%] of 131) and serious adverse events (20 [16%] vs 18 [14%]), but more adverse events (422 vs 347) and serious adverse events (40 vs 30) occurred in the discontinue group. The most common adverse events were upper respiratory infections (20 events in 19 [15%] participants in the continue group and 37 events in 30 [23%] participants in the discontinue group). Three participants in the continue group and four in the discontinue group had treatment-related adverse events, of which one in each group was a serious adverse event (multiple sclerosis relapse requiring admission to hospital). One participant in the continue group and two in the discontinue group died; no deaths were deemed to be related to treatment. We were unable to reject the null hypothesis and could not conclude whether disease-modifying therapy discontinuation is non-inferior to continuation in patients older than 55 years with multiple sclerosis and no recent relapse or new MRI activity. Discontinuation of disease-modifying therapy might be a reasonable option in patients older than 55 years who have stable multiple sclerosis, but might be associated with a small increased risk of new MRI activity. Patient-Centered Outcomes Research Institute and the National Multiple Sclerosis Society. [ABSTRACT FROM AUTHOR]

Objective To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol ( CBD; Epidiolex) and the commonly used antiepileptic drugs ( AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs. Methods In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate. Results Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01). Significance Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD. [ABSTRACT FROM AUTHOR]

Background: We undertook a phase-III, randomized controlled trial (RCT) that examined the effectiveness of a behavioral intervention based on social cognitive theory (SCT) and delivered through the Internet using e-learning approaches for immediate and sustained increases in physical activity among persons with multiple sclerosis (MS). Method: The study followed a parallel group RCT design. Persons with MS (N = 318) were randomized into either behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions. The conditions were administered over a 6-month period by persons who were uninvolved in screening, recruitment, random assignment, and outcome assessment. There was a 6-month follow-up period without access of conditions. We collected outcome data every 6 months over the 12-month period. The primary outcome was device-measured minutes/day of moderate-to-vigorous physical activity (MVPA). The data analysis involved a modified intent-to-treat approach (i.e. those who received the allocated conditions) using a linear mixed model. Results: There was a significant group by time interaction on the primary outcome of device-measured minutes/day of MVPA (p < 0.005). MVPA was increased immediately after the 6-month period in the behavioral intervention compared with control, and this difference was sustained over the 6-month follow-up. Conclusion: This study provides evidence for the effectiveness of a widely scalable approach for increasing MVPA in persons with MS. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. With advances in HIV treatment, people with HIV (PWH) are living longer but experience aging-related comorbidities, including cognitive deficits, at higher rates than the general population. Previous studies have shown alterations in lysosomal proteins in blood from PWH with severe dementia. However, these markers have not been evaluated in PWH with milder neurocognitive impairment. We sought to determine whether levels of the lysosomal cysteine protease cathepsin B (CatB) and its endogenous inhibitor cystatin B (CysB) were altered in PWH with neurocognitive impairment and whether antiretroviral therapy (ART) further influenced these levels. Peripheral blood mononuclear cells were obtained from the tenofovir arm of a multicenter clinical trial in which ART-naive, HIV+ participants received treatment for 48 weeks (ACTG A5303, NCT01400412). PWH were divided by neurocognitive status (eg, with or without neurocognitive impairment) before ART initiation. Intracellular levels of CatB and CysB were measured in T cells and monocytes by means of flow cytometry. Levels of CysB were significantly decreased in both CD4+ T cells and CD8+ T cells after 48 weeks of ART in HIV+ participants without neurocognitive impairment but not in participants with neurocognitive impairment. Levels of CysB were increased in CD14+ monocytes from the participants with neurocognitive impairment after ART. Levels of CysB and CatB positively correlated regardless of HIV, neurocognitive status, or exposure to ART. These findings suggest that CysB has the potential to provide mechanistic insight into HIV-associated neurocognitive disorders or provide a molecular target for systemic monitoring or treatment of neurocognitive impairment in the context of ART and should be investigated further. [ABSTRACT FROM AUTHOR]

Background: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. Methods: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. Results: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. Conclusions: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401.) N Engl J Med 2006;355:354-64. [ABSTRACT FROM AUTHOR]

Background and objectives: Thalamic atrophy (TA) represents a biomarker of neurodegeneration and associated dysfunction/decline in physical and cognitive functioning among persons with multiple sclerosis (MS). Aerobic fitness, as an end point of exercise training, represents a promising target for restoring function in MS, but it is unknown if such effects differ by TA. This cross-sectional study examined whether aerobic fitness was differentially associated with cognitive processing speed and walking endurance in persons with MS who present with and without TA. Methods: 44 fully ambulatory persons with MS completed a graded exercise test for measuring aerobic fitness (VO2peak) and underwent 3T MRI for measuring TA, the Symbol Digit Modalities Test (SDMT), and the 6-min walk (6MW). We performed Spearman correlations (rs) among VO2peak, SDMT, and 6MW scores overall, and in persons with and without TA. We applied Fisher's z-test for comparing correlations based on TA status. Results: When controlling for age, EDSS score, and global MRI measures of atrophy, VO2peak was strongly associated with SDMT scores (prs = 0.74, p < 0.01) and 6MW performance (prs = 0.77, p < 0.01) in persons with TA, whereas VO2peak was not associated with SDMT scores (prs = − 0.01, p = 0.99) or 6MW performance (prs = 0.25, p = 0.38) in those without TA. The correlations between VO2peak and SDMT (z = 2.86, p < 0.01) and VO2peak and 6MW (z = 2.33, p = 0.02) were significantly stronger in the TA group. Discussion: This study provides initial evidence of strong, selective associations among aerobic fitness, cognitive processing speed, and walking endurance in persons with TA as a biomarker for MS-related neurodegeneration. Such data support TA as a moderator of the association among aerobic fitness, cognitive processing speed, and walking endurance in persons with MS. Future research should carefully consider the role of TA when designing trials of aerobic exercise, cognition, and mobility in MS. [ABSTRACT FROM AUTHOR]

The presence of patient heterogeneity in dose finding studies is inherent (i.e. groups with different maximum tolerated doses). When this type of heterogeneity is not accounted for in the trial design, subjects may be exposed to toxic or suboptimal doses. Options to handle patient heterogeneity include conducting separate trials or splitting the trial into arms. However, cost and/or lack of resources may limit the feasibility of these options. If information is shared between the groups, then both of these options do not benefit from using the shared information. Extending current dose finding designs to handle patient heterogeneity maximizes the utility of existing methods within a single trial. We propose a modification to the time-to-event continual reassessment method to accommodate two groups using a two-parameter model and maximum likelihood estimation. The operating characteristics of the design are investigated through simulations under different scenarios including the scenario where one conducts two separate trials, one for each group, using the one-sample time-to-event continual reassessment method. [ABSTRACT FROM AUTHOR]

Background: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS. Objective: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample. Methods: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS. Results: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT; r = −0.01; r = −0.04), California Verbal Learning Test-II (CVLT-II; r = 0.05; r = 0.05), or Brief Visuospatial Memory Test–Revised (BVMT-R; r = −0.14; r = −0.14) z -scores controlling for age, sex, and education. MVPA and SDMT (r = 0.05), CVLT-II (r = −0.07), and BVMT-R (r = 0.01) z -scores were not significantly correlated. Conclusion: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS. [ABSTRACT FROM AUTHOR]

Background: Accurate longitudinal modelling of cognitive decline is a major goal of Alzheimer's disease and related dementia (ADRD) research. However, the impact of subject-specific effects is not well characterized and may have implications for data generation and prediction.Objective: This study seeks to address the impact of subject-specific effects, which are a less well-characterized aspect of ADRD cognitive decline, as measured by the Alzheimer's Disease Assessment Scale's Cognitive Subscale (ADAS-Cog).Methods: Prediction errors and biases for the ADAS-Cog subscale were evaluated when using only population-level effects, robust imputation of subject-specific effects using model covariances, and directly known individual-level effects fit during modelling as a natural control. Evaluated models included pre-specified parameterizations for clinical trial simulation, analogous mixed-effects regression models parameterized directly, and random forest ensemble models. Assessment used a meta-database of Alzheimer's disease studies with validation in simulated synthetic cohorts.Results: All models observed increases in variance under imputation leading to increased prediction error. Bias decreased with imputation except under the pre-specified parameterization, which increased in the meta-database, but was attenuated under simulation. Known fitted subject effects gave the best prediction results.Conclusion: Subject-specific effects were found to have a profound impact on predicting ADAS-Cog. Reductions in bias suggest imputing random effects assists in calculating results on average, as when simulating clinical trials. However, reduction in error emphasizes population-level effects when attempting to predict outcomes for individuals. Forecasting future observations greatly benefits from using known subject-specific effects. [ABSTRACT FROM AUTHOR]

Background: Rett syndrome is a unique neurodevelopmental disorder, affecting approximately one in 10,000 live female births, most experiencing reduced growth. We characterized pubertal trajectories in females with Rett syndrome. We hypothesized that pubertal trajectory deviates from the general female population with early pubertal onset and delayed menarche.Methods: Participants were individuals enrolled in the Rett Syndrome Natural History Study with clinical diagnosis of Rett syndrome or mutations in MECP2. Intervals to thelarche, adrenarche, and menarche were assessed by survival analysis; body mass index, mutation type, clinical severity, and pubertal milestone relationships were assessed by log-likelihood test; pathway synchrony (relationship between thelarche, adrenarche, and menarche) was assessed by chi-squared analysis.Results: Compared with the general female population, more than 25% initiated puberty early, yet entered menarche later (median age 13.0 years). A total of 19% experienced delayed menarche. Median length of puberty, from thelarche to menarche, was 3.9 years. Higher body mass index correlated with earlier thelarche and adrenarche but not menarche; milder mutations correlated with earlier menarche; and milder clinical presentation correlated with earlier thelarche and menarche. Fifty-two percent entered puberty in synchrony, but different from the general population, 15% led with thelarche and 32% with adrenarche.Conclusions: Pubertal trajectories in Rett syndrome differ from general population, entering puberty early and reaching menarche later. Body mass index affects pubertal timing, but the relationship between specific mutations, clinical presentation, and underlying neuroendocrine pathology is less clear. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: The objective of this study is to determine if change in acetylcholine receptor antibody (AChR-ab) levels reflects change in clinical severity in patients with myasthenia gravis (MG). Methods: We reviewed results from a prospective trial in MG and from all 85 patients in an MG Clinic who had AChR-ab determinations performed at least twice by the same commercial laboratory. Results: Change in AChR-ab levels correlated only weakly with change in clinical severity. AChR-ab levels fell in 92% of patients who improved and in 63% who did not. A fall in AChR-ab level had a positive predictive value for clinical improvement of 83% and a negative predictive value of only 59%. Conclusions: AChR-ab levels fell in almost all patients who improved, but also in most patients who did not. Thus, we do not recommend commercially available AChR-ab levels as a biomarker of improvement in MG. However, antibody levels might be useful as a marker for inadequate immunotherapy. Muscle Nerve 49:483-486, 2014 [ABSTRACT FROM AUTHOR]

Background: We reported that a social cognitive theory-based (SCT), Internet-delivered behavioral intervention increased device-measured minutes/day of moderate-to-vigorous physical activity (MVPA) over a 6-month period among persons with multiple sclerosis (MS). This paper examined the pattern and predictors of heterogeneity in change for MVPA. Based on previous research, we hypothesized that mild MS disability, fewer MS symptoms, lower baseline MVPA, and positive SCT characteristics (e.g., high exercise self-efficacy) would be associated with greater change in MVPA.Persons with MS (N = 318) were randomized into behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions that were administered via Internet websites and supported with behavioral coaching. Demographic, clinical, symptom, behavioral, and SCT data were from before the 6-month period of delivering the conditions, and MVPA data were from before and after the 6-month period. We examined heterogeneity based on waterfall plots, box plots, and the Levene statistic. We identified predictors of MVPA change using bivariate correlation and multiple, linear regression analyses per condition.The Levene statistic indicated statistically significant heterogeneity of variances for MVPA change between conditions (p = .003), and the waterfall plots and box plots indicated greater heterogeneity in MVPA change for the behavioral intervention. MVPA change score was correlated with baseline MVPA (r =  − .33 and r =  − .34, p = .0004 and p = .0001) in both conditions and walking impairment (r =  − .188, p = .047) and race (r = .233, p = .014) in the behavioral intervention condition. The regression analysis indicated that baseline MVPA (Standardized B =  − .449, p = .000002), self-reported walking impairment (Standardized B =  − .310, p = .0008), and race (Standardized B = .215, p = .012) explained 25.6% of variance in MVPA change for the behavioral intervention condition.We provide evidence for walking impairment, baseline MVPA, and race as predictors of the heterogeneity in the pattern of MVPA change with a behavioral intervention.Method: We reported that a social cognitive theory-based (SCT), Internet-delivered behavioral intervention increased device-measured minutes/day of moderate-to-vigorous physical activity (MVPA) over a 6-month period among persons with multiple sclerosis (MS). This paper examined the pattern and predictors of heterogeneity in change for MVPA. Based on previous research, we hypothesized that mild MS disability, fewer MS symptoms, lower baseline MVPA, and positive SCT characteristics (e.g., high exercise self-efficacy) would be associated with greater change in MVPA.Persons with MS (N = 318) were randomized into behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions that were administered via Internet websites and supported with behavioral coaching. Demographic, clinical, symptom, behavioral, and SCT data were from before the 6-month period of delivering the conditions, and MVPA data were from before and after the 6-month period. We examined heterogeneity based on waterfall plots, box plots, and the Levene statistic. We identified predictors of MVPA change using bivariate correlation and multiple, linear regression analyses per condition.The Levene statistic indicated statistically significant heterogeneity of variances for MVPA change between conditions (p = .003), and the waterfall plots and box plots indicated greater heterogeneity in MVPA change for the behavioral intervention. MVPA change score was correlated with baseline MVPA (r =  − .33 and r =  − .34, p = .0004 and p = .0001) in both conditions and walking impairment (r =  − .188, p = .047) and race (r = .233, p = .014) in the behavioral intervention condition. The regression analysis indicated that baseline MVPA (Standardized B =  − .449, p = .000002), self-reported walking impairment (Standardized B =  − .310, p = .0008), and race (Standardized B = .215, p = .012) explained 25.6% of variance in MVPA change for the behavioral intervention condition.We provide evidence for walking impairment, baseline MVPA, and race as predictors of the heterogeneity in the pattern of MVPA change with a behavioral intervention.Results: We reported that a social cognitive theory-based (SCT), Internet-delivered behavioral intervention increased device-measured minutes/day of moderate-to-vigorous physical activity (MVPA) over a 6-month period among persons with multiple sclerosis (MS). This paper examined the pattern and predictors of heterogeneity in change for MVPA. Based on previous research, we hypothesized that mild MS disability, fewer MS symptoms, lower baseline MVPA, and positive SCT characteristics (e.g., high exercise self-efficacy) would be associated with greater change in MVPA.Persons with MS (N = 318) were randomized into behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions that were administered via Internet websites and supported with behavioral coaching. Demographic, clinical, symptom, behavioral, and SCT data were from before the 6-month period of delivering the conditions, and MVPA data were from before and after the 6-month period. We examined heterogeneity based on waterfall plots, box plots, and the Levene statistic. We identified predictors of MVPA change using bivariate correlation and multiple, linear regression analyses per condition.The Levene statistic indicated statistically significant heterogeneity of variances for MVPA change between conditions (p = .003), and the waterfall plots and box plots indicated greater heterogeneity in MVPA change for the behavioral intervention. MVPA change score was correlated with baseline MVPA (r =  − .33 and r =  − .34, p = .0004 and p = .0001) in both conditions and walking impairment (r =  − .188, p = .047) and race (r = .233, p = .014) in the behavioral intervention condition. The regression analysis indicated that baseline MVPA (Standardized B =  − .449, p = .000002), self-reported walking impairment (Standardized B =  − .310, p = .0008), and race (Standardized B = .215, p = .012) explained 25.6% of variance in MVPA change for the behavioral intervention condition.We provide evidence for walking impairment, baseline MVPA, and race as predictors of the heterogeneity in the pattern of MVPA change with a behavioral intervention.Conclusion: We reported that a social cognitive theory-based (SCT), Internet-delivered behavioral intervention increased device-measured minutes/day of moderate-to-vigorous physical activity (MVPA) over a 6-month period among persons with multiple sclerosis (MS). This paper examined the pattern and predictors of heterogeneity in change for MVPA. Based on previous research, we hypothesized that mild MS disability, fewer MS symptoms, lower baseline MVPA, and positive SCT characteristics (e.g., high exercise self-efficacy) would be associated with greater change in MVPA.Persons with MS (N = 318) were randomized into behavioral intervention (n = 159) or attention/social contact control (n = 159) conditions that were administered via Internet websites and supported with behavioral coaching. Demographic, clinical, symptom, behavioral, and SCT data were from before the 6-month period of delivering the conditions, and MVPA data were from before and after the 6-month period. We examined heterogeneity based on waterfall plots, box plots, and the Levene statistic. We identified predictors of MVPA change using bivariate correlation and multiple, linear regression analyses per condition.The Levene statistic indicated statistically significant heterogeneity of variances for MVPA change between conditions (p = .003), and the waterfall plots and box plots indicated greater heterogeneity in MVPA change for the behavioral intervention. MVPA change score was correlated with baseline MVPA (r =  − .33 and r =  − .34, p = .0004 and p = .0001) in both conditions and walking impairment (r =  − .188, p = .047) and race (r = .233, p = .014) in the behavioral intervention condition. The regression analysis indicated that baseline MVPA (Standardized B =  − .449, p = .000002), self-reported walking impairment (Standardized B =  − .310, p = .0008), and race (Standardized B = .215, p = .012) explained 25.6% of variance in MVPA change for the behavioral intervention condition.We provide evidence for walking impairment, baseline MVPA, and race as predictors of the heterogeneity in the pattern of MVPA change with a behavioral intervention. [ABSTRACT FROM AUTHOR]

Objective: Primary progressive multiple sclerosis (PPMS) does not respond well to immunomodulatory or immunosuppressive treatment. Chronic activation of microglia has been implicated in the pathophysiology of PPMS. The antimalarial drug hydroxychloroquine (HCQ) reduces the activity of human microglia and has neuroprotective effects in vitro. Methods: We conducted a single‐arm, phase II futility trial of 200 mg oral HCQ twice daily for 18 months. In an effort to investigate disability worsening in the absence of overt focal inflammation, we excluded participants with contrast enhancing lesions on a screening magnetic resonance imaging (MRI). The primary end point was ≥20% worsening on the timed 25‐foot walk measured between 6 and 18 months of follow‐up. Results: Based on original trial data, 40% of the cohort were expected to worsen. We used a Simon 2‐stage design to compare a null hypothesis of 40% of the cohort worsening against the one‐sided alternative of 20%. Using a 5% type 1 error rate and 80% power, HCQ treatment would be deemed successful if fewer than 10 of 35 participants experienced clinically significant worsening. The study met its primary end point, as only 8 of 35 participants worsened between 6 and 18 months. HCQ was overall well‐tolerated, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were unlikely related to HCQ use. Interpretation: HCQ treatment was associated with reduced disability worsening in people with PPMS. HCQ is a promising treatment candidate in PPMS and should be investigated further in randomized controlled clinical trials. ANN NEUROL 2021;90:940–948 [ABSTRACT FROM AUTHOR]

Background: In the N-MOmentum trial, the risk of an adjudicated neuromyelitis optica spectrum disorder (NMOSD) attack was significantly reduced with inebilizumab compared with placebo. Objective: To demonstrate the robustness of this finding, using pre-specified sensitivity and subgroup analyses. Methods: N-MOmentum is a prospective, randomized, placebo-controlled, double-masked trial of inebilizumab, an anti-CD19 monoclonal B-cell-depleting antibody, in patients with NMOSD. Pre-planned and post hoc analyses were performed to evaluate the primary endpoint across a range of attack definitions and demographic groups, as well as key secondary endpoints. Results: In the N-MOmentum trial (ClinicalTrials.gov: NCT02200770), 174 participants received inebilizumab and 56 received placebo. Attack risk for inebilizumab versus placebo was consistently and significantly reduced, regardless of attack definition, type of attack, baseline disability, ethnicity, treatment history, or disease course (all with hazard ratios < 0.4 favoring inebilizumab, p < 0.05). Analyses of secondary endpoints showed similar trends. Conclusion: N-MOmentum demonstrated that inebilizumab provides a robust reduction in the risk of NMOSD attacks regardless of attack evaluation method, attack type, patient demographics, or previous therapy. The N-MOmentum study is registered at ClinicalTrials.gov: NCT2200770. [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction: Complement activation at the neuromuscular junction is a primary cause of acetylcholine receptor loss and failure of neuromuscular transmission in myasthenia gravis (MG). Eculizumab, a humanized monoclonal antibody, blocks the formation of terminal complement complex by specifically preventing the enzymatic cleavage of complement 5 (C5). Methods: This study was a randomized, double-blind, placebo-controlled, crossover trial involving 14 patients with severe, refractory generalized MG (gMG). Results: Six of 7 patients treated with eculizumab for 16 weeks (86%) achieved the primary endpoint of a 3-point reduction in the quantitative myasthenia gravis (QMG) score. Examining both treatment periods, the overall change in mean QMG total score was significantly different between eculizumab and placebo ( P = 0.0144). After assessing data obtained from all visits, the overall change in mean QMG total score from baseline was found to be significantly different between eculizumab and placebo ( P < 0.0001). Eculizumab was well tolerated. Conclusion: The data suggest that eculizumab may have a role in treating severe, refractory MG. Muscle Nerve, 2013 [ABSTRACT FROM AUTHOR]

Objective A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30μg intramuscularly weekly and glatiramer acetate (GA) 20mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis. Methods A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics. Results Combination IFN + GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results. Interpretation Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences. ANN NEUROL 2013;73:327-340 [ABSTRACT FROM AUTHOR]

Fas ligand (FasL) gene therapy for cancer has shown promise in rodents; however, its efficacy in higher mammals remains unknown. Here, we used intratumoral FasL gene therapy delivered in an adenovirus vector (Ad-FasL) as neoadjuvant to standard of care in 56 dogs with osteosarcoma. Tumors from treated dogs had greater inflammation, necrosis, apoptosis, and fibrosis at day 10 (amputation) compared to pretreatment biopsies or to tumors from dogs that did not receive Ad-FasL. Survival improvement was apparent in dogs with inflammation or lymphocyte-infiltration scores >1 (in a 3-point scale), as well as in dogs that had apoptosis scores in the top 50th percentile (determined by cleaved caspase-3). Survival was no different than that expected from standard of care alone in dogs with inflammation scores ≤1 or apoptosis scores in the bottom 50th percentile. Reduced Fas expression by tumor cells was associated with prognostically advantageous inflammation, and this was seen only in dogs that received Ad-FasL. Together, the data suggest that Ad-FasL gene therapy improves survival in a subset of large animals with naturally occurring tumors, and that at least in some tumor types like osteosarcoma, it is most effective when tumor cells fail to express Fas. [ABSTRACT FROM AUTHOR]

BACKGROUND: Inhaled nitric oxide (iNO) is an effective therapy for pulmonary hypertension and hypoxic respiratory failure in term infants. Fourteen randomized controlled trials (n = 3430 infants) have been conducted on preterm infants at risk for chronic lung disease (CLD). The study results seem contradictory. DESIGN/METHODS: Individual-patient data meta-analysis included randomized controlled trials of preterm infants (<37 weeks' gestation). Outcomes were adjusted for trial differences and correlation between siblings. RESULTS: Data from 3298 infants in 12 trials (96%) were analyzed. There was no statistically significant effect of iNO on death or CLD (59% vs 61%: relative risk [RR]: 0.96 [95% confidence interval (CD: 0.92-1.01]; P= .11) or severe neurologic events on imaging (25%vs23%: RR: 1.12 [95% CI: 0.98--1.28]; P = .09). There were no statistically significant differences in iNO effect according to any of the patient-level characteristics tested. In trials that used a starting iNO dose of >5 vs ≤5 ppm there was evidence of improved outcome (interaction P = .02); however, these differences were not observed at other levels of exposure to iNO. This result was driven primarily by 1 trial, which also differed according to overall dose, duration, timing, and indication for treatment; a significant reduction in death or CLD (RR: 0.85 [95% CI: 0.74--0.98]) was found. CONCLUSIONS: Routine use of iNO for treatment of respiratory failure in preterm infants cannot be recommended. The use of a higher starting dose might be associated with improved outcome, but because there were differences in the designs of these trials, it requires further examination. [ABSTRACT FROM AUTHOR]

Background: The risk of elbow or shoulder injury for young baseball pitchers is unknown.Purpose/Hypothesis: The purpose of this study was to quantify the cumulative incidence of throwing injuries in young baseball pitchers who were followed for 10 years. Three hypotheses were tested: Increased amount of pitching, throwing curveballs at a young age, and concomitantly playing catcher increase a young pitcher’s risk of injury.Study Design: Cohort study; Level of evidence, 3.Methods: In sum, 481 youth pitchers (aged 9 to 14 years) were enrolled in a 10-year follow-up study. Participants were interviewed annually. Injury was defined as elbow surgery, shoulder surgery, or retirement due to throwing injury. Fisher exact test compared the risk of injury between participants who pitched at least 4 years during the study and those who pitched less. Fisher exact tests were used to investigate risks of injury for pitching more than 100 innings in at least 1 calendar year, starting curveballs before age 13 years, and playing catcher for at least 3 years.Results: The cumulative incidence of injury was 5.0%. Participants who pitched more than 100 innings in a year were 3.5 times more likely to be injured (95% confidence interval = 1.16 to 10.44). Pitchers who concomitantly played catcher seemed to be injured more frequently, but this trend was not significant with the study sample size.Conclusion: Pitching more than 100 innings in a year significantly increases risk of injury. Playing catcher appears to increase a pitcher’s risk of injury, although this trend is not significant. The study was unable to demonstrate that curveballs before age 13 years increase risk of injury.Clinical Relevance: The risk of a youth pitcher sustaining a serious throwing injury within 10 years is 5%. Limiting the number of innings pitched per year may reduce the risk of injury. Young baseball pitchers are encouraged to play other positions as well but might avoid playing catcher. [ABSTRACT FROM AUTHOR]

Abstract: Adaptation to a sustained stimulus is an important phenomenon in psychophysical experiments. When studying the response to an experimental task, the investigator has to account for the change in perceived stimulus intensity with repeated stimulus application and, if the stimulus is sustained, for the change in intensity during the presentation. An example of a sustained stimulus is the cold pressor task (CPT). The task has been used both as an experimental pain task and to study cardiovascular physiology. In functional imaging research, the CPT has been used to evaluate cognitive processing of a noxious stimulus. Investigators typically model the stimulus in a block design as a categorical (on–off) stimulus and do not account for a temporal change in stimulus perception. If the perceived stimulus changes over time, the results may be misleading. Therefore, we characterized the time course of cold pain in human volunteers and developed a model of the temporal characteristics of perceived cold pain. Fifteen healthy participants underwent cold pain testing by immersing their right foot into a container filled with ice water (2°C) for 30s alternating with a 30s immersion into a container filled with tepid water 32°C (control). Participants rated the pain intensity using an electronic slide algometer. Using a mixed general linear model (effectively a polynomial regression model), we determined that pain ratings follow a crescendo–decrescendo pattern that can be described well using a quadratic model. We conclude that the time course of quantitative perception differs fundamentally from the time course of stimulus presentation. This may be important when looking for the physiological correlates of perception as opposed to the presence of a stimulus per se. [Copyright &y& Elsevier]

We assessed the performance of items from the Quantitative Myasthenia Gravis (QMG), MMT (Manual Muscle Test), and MG-ADL (Myasthenia Gravis - Activities of Daily Living) scales, using data from two recently completed treatment trials of generalized MG. Items were selected that were relevant to manifestations of MG, meaningful to both the physician and the patient, and responsive to clinical change. After the 10 items were chosen, they were weighted based on input from MG experts from around the world, considering factors such as quality of life, disease severity, risk, prognosis, validity, and reliability. The MG Composite is easy to administer, takes less than 5 minutes to complete, and requires no equipment. Weighting of the response options of the 10 items should result in ordinal scores that better represent MG status and are more responsive to meaningful clinical change. To better determine its suitability for clinical use and for treatment trials, the MG Composite will be tested prospectively at several academic medical centers and will be used as a secondary measure of efficacy in pending clinical trials of MG. Muscle Nerve 38: 1553-1562, 2008 [ABSTRACT FROM AUTHOR]

Abstract: We present our experience planning and launching a multinational, NIH/NINDS funded study of thymectomy in myasthenia gravis. We highlight the additional steps required for international sites and analyze and contrast the time investment required to bring U.S. and non-U.S. sites into full regulatory compliance. Results show the mean time for non-U.S. centers to achieve regulatory approval was significantly longer (mean 13.4±0.96 months) than for U.S. sites (9.67±0.74 months; p =0.0175, t-test). The delay for non-U.S. sites was mainly attributable to Federalwide Assurance certification and State Department clearance. [Copyright &y& Elsevier]

We describe the process whereby a recently developed myasthenia gravis (MG)-specific quality-of-life (QOL) instrument was reduced from 60 items to 15 items while maintaining potential usefulness in the clinic and in prospective treatment trials. In data from a recently completed prospective trial of mycophenolate mofetil (MMF) in MG, the MG-QOL15 correlated as highly as the 60-item MG-QOL for physical and social domains of the 36-item health survey of the Medical Outcomes Study Short Form (SF-36). Correlation coefficients for the MG-QOL15 were similar to the 60-item MG-QOL for the Quantitative Myasthenia Gravis (QMG), MG-specific Manual Muscle Testing (MG-MMT), and the MG-specific Activities of Daily Living (MG-ADL) scores at week 0 and for change in scores from week 0 to week 12 in the MMF trial. Using the physician global impression at week 12 of the trial as the 'gold standard,' the MG-QOL15 demonstrated high sensitivity. Because the MG-QOL15 instrument can be quickly and easily administered and interpreted, it is a potential QOL measure for treatment trials and the clinical evaluation of patients with MG. Muscle Nerve, 2008 [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) remains a significant clinical problem through its diverse etiologies, the challenges of robust measurements of injury and recovery, and its progression to chronic kidney disease (CKD). Bridging the gap in our knowledge of this disorder requires bringing together not only the technical resources for research but also the investigators currently endeavoring to expand our knowledge and those who might bring novel ideas and expertise to this important challenge. The University of Alabama at Birmingham-University of California-San Diego O'Brien Center for Acute Kidney Injury Research brings together technical expertise and programmatic and educational efforts to advance our knowledge in these diverse issues and the required infrastructure to develop areas of novel exploration. Since its inception in 2008, this O'Brien Center has grown its impact by providing state-of-the-art resources in clinical and preclinical modeling of AKI, a bioanalytical core that facilitates measurement of critical biomarkers, including serum creatinine via LC-MS/MS among others, and a biostatistical resource that assists from design to analysis. Through these core resources and with additional educational efforts, our center has grown its investigator base to include >200 members from 51 institutions. Importantly, this center has translated its pilot and catalyst funding program with a $37 return per dollar invested. Over 500 publications have resulted from the support provided with a relative citation ratio of 2.18 ± 0.12 (iCite). Through its efforts, this disease-centric O'Brien Center is providing the infrastructure and focus to help the development of the next generation of researchers in the basic and clinical science of AKI. This center creates the promise of the application at the bedside of the advances in AKI made by current and future investigators. [ABSTRACT FROM AUTHOR]

Objective: Blood tests to monitor disease activity, attack severity, or treatment impact in neuromyelitis optica spectrum disorder (NMOSD) have not been developed. This study investigated the relationship between serum glial fibrillary acidic protein (sGFAP) concentration and NMOSD activity and assessed the impact of inebilizumab treatment.Methods: N-MOmentum was a prospective, multicenter, double-blind, placebo-controlled, randomized clinical trial in adults with NMOSD. sGFAP levels were measured by single-molecule arrays (SIMOA) in 1,260 serial and attack-related samples from 215 N-MOmentum participants (92% aquaporin 4-immunoglobulin G-seropositive) and in control samples (from healthy donors and patients with relapsing-remitting multiple sclerosis).Results: At baseline, 62 participants (29%) exhibited high sGFAP concentrations (≥170 pg/ml; ≥2 standard deviations above healthy donor mean concentration) and were more likely to experience an adjudicated attack than participants with lower baseline concentrations (hazard ratio [95% confidence interval], 3.09 [1.6-6.1], p = 0.001). Median (interquartile range [IQR]) concentrations increased within 1 week of an attack (baseline: 168.4, IQR = 128.9-449.7 pg/ml; attack: 2,160.1, IQR = 302.7-9,455.0 pg/ml, p = 0.0015) and correlated with attack severity (median fold change from baseline [FC], minor attacks: 1.06, IQR = 0.9-7.4; major attacks: 34.32, IQR = 8.7-107.5, p = 0.023). This attack-related increase in sGFAP occurred primarily in placebo-treated participants (FC: 20.2, IQR = 4.4-98.3, p = 0.001) and was not observed in inebilizumab-treated participants (FC: 1.1, IQR = 0.8-24.6, p > 0.05). Five participants (28%) with elevated baseline sGFAP reported neurological symptoms leading to nonadjudicated attack assessments.Interpretation: Serum GFAP may serve as a biomarker of NMOSD activity, attack risk, and treatment effects. ANN NEUROL 2021;89:895-910. [ABSTRACT FROM AUTHOR]

Objective: An online training in responsible marijuana vendor (RMV) practices was evaluated for effects on compliance with ID checking regulations. Method: A random sample of state-licensed recreational marijuana stores (n = 175) in Colorado and Washington State was selected in 2016-2017 and was enrolled in a randomized pretest-posttest controlled design. After baseline assessment, 75 stores were randomly assigned to a usual and customary training control group, stratified by state and region. The remaining stores (n = 100) were invited to use the RMV training. Stores were posttested at 3 and 9 months postrandomization. The primary outcome was refusal of sale measured with pseudo-underage patrons who attempted to enter stores and purchase cannabis without a state-approved ID. Results: There was no difference by treatment group in refusal of pseudo-underage patron buyers (baseline: 92.5% intervention vs. 94.7% control; 3-month post-test 94.8% vs. 97.5%; 9-month posttest 97.5% vs. 97.1%, p = .286 [one tailed, adjusted for covariates]). The use of training increased refusals at store entry (trained: 65.9% baseline 82.5%, 3 months 79.9%, 9 months; not trained: 82.6%, 83.1%, 84.5%, p = .020 [two tailed, adjusted for covariates]). This difference was especially evident in Washington State (trained: 40.3%, 65.1%, 60.4%; not trained: 57.9%, 68.5%, 72.3%) but not in Colorado (trained: 95.2%, 101.0%, 101.4; not trained: 95.7%, 98.6%, 99.2%, p = .033 [two tailed, adjusted for covariates]). Conclusions: When used by store personnel, online RMV training increased refusal of buyers who appeared young and did not provide a state-approved ID. However, it did not improve refusal rates overall. Stores that had lower refusals at baseline and used the training may have benefited from it. [ABSTRACT FROM AUTHOR]

In a randomized clinical trial, six applications of an I[SUB2]-NaF or a placebo solution were administered to the mothers' dentition at the time of tooth emergence of her infant, to evaluate its effect on transmission of mutans streptococci (MS) to the infant. MS and other bacterial levels were periodically monitored in 48 mother-infant pairs until the child's third birthday. There were significant reductions in maternal salivary MS (P=0.04), lactobacilli (P=0.04), total streptococci (P=0.002), and total cultivable organisms (P=0.004) immediately following treatment. In children, 3-yr incidence of MS colonization and the time of acquisition of MS or the caries experience did not differ significantly between the two groups. We conclude that short-term application of I[SUB2]-NaF to the maternal dentition of predentate infants significantly lowers MS, lactobacilli, total streptococci, and total cultivable bacteria in mothers' saliva, but does not influence the incidence and the time of acquisition of MS or the caries experience in children. [ABSTRACT FROM AUTHOR]

Background: Researchers studying health-related quality of life (HRQOL) in multiple sclerosis (MS) can choose from many instruments, but findings from studies which use different instruments cannot be easily combined. We aimed to develop a crosswalk that associates scores from the RAND-12 to scores on the Health Utilities Index—Mark III (HUI3) in persons with MS. Methods: In 2018, participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry completed the RAND-12 and the HUI3 to assess HRQOL. We used item-response theory (IRT) and equipercentile linking approaches to develop a crosswalk between instruments. We compared predicted scores for the HUI3 from each crosswalk to observed scores using Pearson correlations, intraclass correlation coefficients (ICCs), and Bland–Altman plots. Results: Of 11,389 invited participants, 7129 (62.6%) responded. Predicted and observed values of the HUI3 from the IRT-linking method were moderately correlated (Pearson r = 0.76) with good concordance (ICC = 0.72). However, the Bland–Altman plots suggested biased prediction. Predicted and observed values from the equipercentile linking method were also moderately correlated (Pearson r = 0.78, ICC = 0.78). The Bland–Altman plots suggested no bias. Conclusion: We developed a crosswalk between the RAND-12 and the HUI3 in the MS population which will facilitate data harmonization efforts. [ABSTRACT FROM AUTHOR]

Background: To determine if early epilepsy surgery mitigates detrimental effects of refractory epilepsy on development, we investigated surgical and neurodevelopmental outcomes in children with tuberous sclerosis complex who underwent surgery before age two years.Methods: Prospective multicenter observational study of 160 children with tuberous sclerosis complex. Surgical outcome was determined for the seizure type targeted by surgery. We obtained Vineland Adaptive Behavior Scales, Second Edition (Vineland-II); Mullen Scales of Early Learning; and Preschool Language Scales, Fifth Edition, at age three, six, nine, 12, 18, 24, and 36 months. Surgical cases were compared with children without seizures, with controlled seizures, and with medically refractory seizures.Results: Nineteen children underwent surgery (median age 17 months, range 3.7 to 21.3), and mean follow-up was 22.8 months (range 12 to 48). Surgical outcomes were favorable in 12 (63%, Engel I-II) and poor in seven (37%, Engel III-IV). Nine (47%) had new or ongoing seizures distinct from those surgically targeted. All children with seizures demonstrated longitudinal decline or attenuated gains in neurodevelopment, the surgical group scoring the lowest. Favorable surgical outcome was associated with increased Mullen Scales of Early Learning receptive and expressive language subscores compared with the medically refractory seizure group. A nonsignificant but consistent pattern of improvement with surgery was seen in all tested domains.Conclusions: These pilot data show neurodevelopmental gains in some domains following epilepsy surgery. A properly powered, prospective multicenter observational study of early epilepsy surgery is needed, using both surgical and developmental outcome metrics. [ABSTRACT FROM AUTHOR]

Objective: To describe the presence of practice effects in persons with Alzheimer disease (AD) or mild cognitive impairment (MCI) and to evaluate how practice effects affect cognitive progression and the outcome of clinical trials. Methods: Using data from a meta-database consisting of 18 studies including participants from the Alzheimer disease Cooperative Study (ADCS) and the Alzheimer Disease Neuroimaging Initiative (ADNI) with ADAS-Cog11 as the primary outcome, we defined practice effects based on the improvement in the first two ADAS-Cog11 scores and then estimated the presence of practice effects and compared the cognitive progression between participants with and without practice effects. The robustness of practice effects was investigated using CDR SB, an outcome independent the definition itself. Furthermore, we evaluated how practice effects can affect sample size estimation. Results: The overall percent of practice effects for AD participants was 39.0% and 53.3% for MCI participants. For AD studies, the mean change from baseline to 2 years was 12.8 points for the non-practice effects group vs 7.4 for the practice effects group; whereas for MCI studies, it was 4.1 for non-practice effects group vs 0.2 for the practice effects group. AD participants without practice effects progressed 0.9 points faster than those with practice effects over a period of 2 years in CDR-SB; whereas for MCI participants, the difference is 0.7 points. The sample sizes can be different by over 35% when estimated based on participants with/without practice effects. Conclusion: Practice effects were prevalent and robust in persons with AD or MCI and affected the cognitive progression and sample size estimation. Planning of future AD or MCI clinical trials should account for practice effects to avoid underpower or considers target trials or stratification analysis based on practice effects. [ABSTRACT FROM AUTHOR]