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BackgroundTobacco smoking is the leading cause of preventable death in the United States, and the annual economic burden attributable to smoking exceeds US $300 billion. Obstacles to smoking cessation include limited access and adherence to effective cessation interventions. Technology can help overcome these obstacles; many smartphone apps have been developed to aid smoking cessation, but few that conform to the US clinical practice guideline (USCPG) have been rigorously tested and reported in the literature. Clickotine is a novel smartphone app for smoking cessation, designed to deliver the essential features of the USCPG and engineered to engage smokers by personalizing intervention components. ObjectiveOur objective was to assess the engagement, efficacy, and safety of Clickotine in an initial, single-arm study. Outcomes measured were indicators of engagement with the smartphone app (number of app opens, number of interactions with the Clickotine program, and weeks active with Clickotine), cessation outcomes of 7- and 30-day self-reported abstinence from smoking, and negative health events. MethodsWe recruited US residents between 18 and 65 years of age who owned an iPhone and smoked 5 or more cigarettes daily for the study via online advertising. Respondents were prescreened for eligibility by telephone and, if appropriate, directed to a Web portal to provide informed consent, confirm eligibility, and download the Clickotine app. Participants completed study assessments via the online portal at baseline and after 8 weeks. Data were collected in Amazon S3 with no manual data entry, and access to all data was maximally restrictive, logged, and auditable. ResultsA total of 416 participants downloaded the app and constituted the intention-to-treat (ITT) sample. On average, participants opened the Clickotine app 100.6 times during the 8-week study (median 69), logged 214.4 interactions with the Clickotine program (median 178), and remained engaged with Clickotine for 5.3 weeks (median 5). Among the ITT sample, 45.2% (188/416) reported 7-day abstinence and 26.2% (109/416) reported 30-day abstinence from smoking after 8 weeks. Completer analysis focused on 365 (87.7%) of the 416 enrolled participants who completed the 8-week questionnaire revealed that 51.5% (188/365) of completers reported 7-day abstinence and 29.9% (109/365) reported 30-day abstinence. Few adverse events, mostly consistent with nicotine withdrawal symptoms, were reported and overall no safety signal was detected. ConclusionsIn this initial single-arm trial, Clickotine users appeared to demonstrate encouraging indicators of engagement in terms of the number of app opens, number of program interactions, and continued engagement over time. Clickotine users reported encouraging quit rates while reporting few adverse events. Future research is warranted to assess Clickotine’s efficacy in a randomized controlled trial. Trial RegistrationClinicaltrials.gov NCT02656745; https://clinicaltrials.gov/ct2/show/NCT02656745 (Archived by WebCite at http://www.webcitation.org/6peTT4x60)

Spasticity is common in multiple sclerosis (MS), often leading to functional limitations and disability. We developed a conceptual model of spasticity in MS integrating expert opinion, recent literature, and experiences of clinicians and people with MS spasticity. A conceptual model was developed based on a targeted literature review of articles published between 2014 and 2019, followed by input from clinicians, then input from participants with MS spasticity. Multidisciplinary experts on spasticity provided guidance at each step. Key concepts of the integrated spasticity conceptual model included: moderators; triggers; modifiers; treatment; objective manifestations; subjective experience; physical, functional, social, and emotional/psychological impacts; and long-term consequences. Participants with MS spasticity most frequently endorsed spasms, tightness, and pain as descriptors of spasticity. Some participants with MS spasticity had difficulty distinguishing spasticity from other MS symptoms (e.g. muscle weakness). Some triggers, emotional/psychological impacts, and long-term consequences of spasticity reported by participants with MS spasticity were not previously identified in the published literature. This conceptual model of spasticity, integrating published literature with the experience of clinicians, people with MS spasticity, and experts, demonstrates the complex, multidimensional nature of MS spasticity. This model may be used to improve clinician–patient dialogue, research, and patient care. Many people with multiple sclerosis (MS) have spasticity, generally in the lower limbs, but this symptom is complex and multidimensional and therefore difficult to characterize. MS spasticity may be influenced by moderators, triggers, modifiers, and treatment, all of which can affect objective measures and the subjective experience of spasticity. MS spasticity can have physical, functional, social, and emotional/psychological impacts as well as long-term consequences that can affect rehabilitation and ultimately reduce health-related quality of life for people with MS. Given that people with MS may view spasticity differently than their rehabilitation providers, providers should ask patients about their spasticity, including their moderators, triggers, modifiers, experience, impacts, long-term consequences, and effects on quality of life. This conceptual model provides a framework to improve clinician-patient dialogue, research, and rehabilitation for MS spasticity. [ABSTRACT FROM AUTHOR]

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod's efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months (n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo (p < 0.0001). The other secondary endpoint, time to first relapse, and annualized relapse rate (an exploratory endpoint) were numerically lower (both, p = 0.0001). No unexpected safety findings were reported with laquinimod 0.6 mg. Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992). [ABSTRACT FROM AUTHOR]

Background: As cannabis products become increasingly accessible across the United States, it is important to understand the contemporary use of cannabis for managing multiple sclerosis (MS) symptoms. Methods: We invited participants with MS from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry (aged 18 years or older) to complete a supplemental survey on cannabis use between March and April 2020. Participants reported cannabis use, treated symptoms, patterns, preferences, methods of use, and the factors limiting use. Findings are reported using descriptive statistics. Results: Of the 6934 participants invited, 3249 responded. Of the respondents, 31% reported having ever used cannabis to treat MS symptoms, with 20% currently using cannabis. The remaining 69% had never used cannabis for MS symptoms, for reasons including not enough data about efficacy (40%) and safety (27%), and concerns about legality (25%) and cost (18%). The most common symptoms current users were attempting to treat were spasticity (80%), pain (69%), and sleep problems (61%). Ever users (vs never users) were more likely to be younger, be non-White, have lower education, reside in the Northeast and West, be unemployed, be younger at symptom onset, be currently smoking, and have higher levels of disability and MS-related symptoms (all P < .001). Conclusions: Despite concerns about insufficient safety and efficacy data, legality, and cost, almost one-third of NARCOMS Registry respondents report having tried nonprescription cannabis products in an attempt to alleviate their symptoms. Given the lack of efficacy and safety data on such products, future research in this area is warranted. [ABSTRACT FROM AUTHOR]

Background: Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea. Objectives: Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD). Methods: Phase 2, double‐blind, 4‐week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo). Outcomes (safety/tolerability [primary]; Epworth Sleepiness Scale [ESS]; Maintenance of Wakefulness Test [MWT]) were assessed weekly. P values are nominal. Results: Common adverse events (n = 66): nausea (10.7%), dizziness (7.1%), dry mouth (7.1%), headache (7.1%), anxiety (5.4%), constipation (5.4%), dyspepsia (5.4%). ESS decreased both placebo (−4.78) and solriamfetol (−4.82 to −5.72; P > 0.05). MWT improved dose‐dependently with solriamfetol, increasing by 5.05 minutes with 300 mg relative to placebo (P = 0.0098). Conclusions: Safety/tolerability was consistent with solriamfetol's known profile. There were no significant improvements on ESS; MWT results suggest possible benefit with solriamfetol in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Background: Baseline brain volume (BV) is predictive at a group level but is difficult to interpret at the single patient level. Objective: To validate BV cutoffs able to identify clinically relevant atrophy in relapsing-remitting multiple sclerosis (RRMS) patients. Methods: The expected normalized brain volume (NBV) for each patient was calculated using RRMS patients from two phase III clinical trials, applying a linear formula developed on the baseline variable of an independent data set. The difference between these expected NBV values and those actually observed was calculated and used to categorize the patients in the low-NBV, medium-NBV, and high-NBV groups. Results: The 2-year probability of 3-month confirmed disability worsening was significantly associated with the NBV categorization (p = 0.006), after adjusting for treatment effect. Taking the high-NBV group as a reference, the hazard ratios for the medium-NBV and low-NBV groups were 1.22 (95% confidence interval (CI): 0.85-1.76, p = 0.27) and 1.69 (95% CI: 1.11-2.57, p = 0.01), respectively. Conclusion: This study validates the use of BV cutoffs to identify clinically relevant atrophy in RRMS study by showing that the three groups classified according to the baseline NBV adjusted for the other prognostic variables have a significant prognostic impact on the risk of disability progression. [ABSTRACT FROM AUTHOR]

Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25-Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621-625. [ABSTRACT FROM AUTHOR]

Background and Purpose: Two definitions of T1 hypointense (T1H) lesions can be derived from pre-contrast images: those that may or may not have a corresponding gadolinium-enhancing correlate on post-contrast images (T1H total), and those that are simultaneously non-gadolinium-enhancing on post-contrast scans (T1H non-enhancing). To determine the differences in lesion evolution between these two T1H definitions, we examined the effect of glatiramer acetate 40 mg/mL three times weekly subcutaneous injection (GA40) on the number of new or enlarging T1H total and T1H non-enhancing lesions in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: The Phase III GALA study randomized 1404 RRMS subjects 2:1 to receive GA40 or placebo for 12 months. MRI scans were obtained at baseline and at months 6 and 12. Cumulative numbers of T1H total and of T1H non-enhancing lesions were analyzed using an adjusted negative binomial regression model. A total of 1,357 patients had MRI data collected at either the month 6 or month 12 visit. Results: Among the 1,357 patients with MRI scans performed at either the month 6 or month 12 visit, 883 treated with GA40 developed an adjusted cumulative mean of 1.72 T1H total lesions versus 2.62 in 440 placebo controls (risk ratio, .66; 95% CI, .54-.80; P < .0001). On T1H non-enhanced scans, GA40-treated patients developed an adjusted cumulative mean of 1.35 T1H non-enhancing lesions versus 1.91 in placebo controls (risk ratio, .71; CI, .58-.87; P = .0009). Conclusions: GA40 significantly reduced the number of new or enlarging T1H total lesions and T1H non-enhancing lesions compared with placebo. Although the treatment effect magnitude was comparable with both definitions, the use of T1H non-enhancing lesions may be more relevant for more uniform standardization in future clinical trials. [ABSTRACT FROM AUTHOR]

To evaluate the prevalence of cannabis use for MS symptom management and factors associated with its use among current users in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry. An online, supplemental survey regarding use of tetrahydrocannabinol (THC)-containing cannabis for MS symptoms. A voluntary, self-report registry for PwMS. Active, US NARCOMS participants (N=6934), of whom 3249 (47%;) responded to the survey. Not applicable. The prevalence of, and reasons for, using or not using cannabis, as well as behaviors and attitudes of current users. Findings were summarized using descriptive statistics. The proportion of respondents who reported using cannabis for MS symptoms was 31%. Among the 69% of respondents who did not use cannabis for MS symptoms, the most common reasons were insufficient efficacy (40%) or safety (27%) data. Overall, 636 respondents (20%) reported current use (within last 30 days). Smoking (33%) and eating (20%) were the two most common primary modes of administration. A portion of current users started cannabis before using a prescribed MS symptom management drug (23%) or rehabilitation therapy (45%). The most common target symptoms were spasticity (80%), pain (69%), and sleep problems (61%). Of the 511 current users treating spasticity, 321 (63%) were using additional symptom management therapies (59% using drugs; 11% using physical/occupational therapy) and 190 (37%) were using only cannabis. Although concerns about efficacy, safety, and other factors prevent some PwMS from trying cannabis, 31% have tried and 20% are currently using non-FDA-approved cannabis products for MS symptom relief. Of those currently using cannabis to treat spasticity, over a third were using only cannabis. Funding: Greenwich Biosciences, Inc. Joanne Wagner, Kathryn Nichol, and Joshua Steinerman have a financial relationship with Greenwich Biosciences. Amber Salter has nothing to disclose. Robert Fox has a financial relationship with AB Science, Actelion, Biogen, Celgene, EMD Serono, Genentech, Immunic, Novartis, Sanofi, and TG Therapeutics. Gary Cutter has a financial relationship with Antisense Therapeutics, Astra-Zeneca, Avexis Pharmaceuticals, Biodelivery Sciences International, Biogen, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, Click Therapeutics, CSL Behring, Galmed Pharmaceuticals, Genentech, Genzyme, GreenValley Pharma Ltd, GW Pharmaceuticals, Klein-Buendel Incorporated, Mapi Pharmaceuticals LTD, Medday, Medimmune/Viela Bio, Merck, Merck/Pfizer, Merck/Serono, Immunic, Neurim, Neurogenesis LTD, Novartis, Novartis, OncoImmune, Ophazyme, Opko Biologics, Osmotica Pharmaceuticals, Perception Neurosciences, Reata Pharmaceuticals, Reckover Pharmaceuticals, Recursion/Cerexis Pharmaceuticals, Regeneron, Roche, SAB BIotherapeutics, Sanofi-Aventis, Teva pharmaceuticals, TG Therapeutics, VielaBio Inc, and Vivus. Karry Smith has a financial relationship with Abbott/St Jude, Boston Scientific, Greenwich Biosciences, and Medtronic. [ABSTRACT FROM AUTHOR]

The natural history of life span cognitive performance and its late-life determinants have been studied from an array of perspectives. Significant insights come from psychological disciplines, including cognitive, developmental, and neuropsychology, as well as from medical specialties, such as geriatrics, neurology, psychiatry, neuroradiology, and neuropathology, that contribute to the growing interdisciplinary scientific field: cognitive neuroscience of aging. This survey of longitudinal studies of aging suggests that disease-oriented investigations commonly do not adequately consider normative cognitive changes, whereas developmental studies do not sufficiently measure and model nonnormative cognitive aging. This article argues for an integrative perspective that considers both of these influences on cognitive trajectories and presents a series of methodological concerns that have not been addressed comprehensively. Interdisciplinary methods from longitudinal observational studies should be leveraged to enable translational interventions to promote brain longevity. [ABSTRACT FROM AUTHOR]

To develop a conceptual model of spasticity in MS that integrates the experience of persons with MS (pwMS) and clinicians, in accordance with Food and Drug Administration guidance on patient-focused drug development. Targeted literature review of published articles (2014–2019) and input from three spasticity clinical experts (MC, FB, EFF) followed by one-time interviews with a separate group of three clinicians experienced in spasticity treatment/research and semi-structured interviews with pwMS. Patient interview data were collected until concept saturation (no new information provided on successive interviews). Iterative feedback from the three clinical experts and GW spasticity research team guided further refinements. Phone interviews. Three clinical experts; 3 clinicians experienced in spasticity treatment/research; 20 patients with MS ≥12 months and spasticity ≥6 months. Not applicable. Key concepts of MS spasticity included objective manifestations; subjective patient experiences; triggers; moderators; physical, functional, emotional, and social impacts; and long-term consequences. Of 282 abstracts reviewed, 23 full-text articles were used to develop the draft model. The interviewed pwMS were on average 47.3 years old and had self-reported spasticity for an average 12.3 years. Spasms, pain, and stiffness were spasticity descriptors most frequently endorsed by both pwMS and the literature. Some pwMS had difficulty distinguishing spasticity from other MS symptoms (e.g., muscle weakness, tremor, numbness). Some triggers (e.g., skin lesions, constipation, stress), emotional impacts (e.g., embarrassment, frustration), and long-term consequences of spasticity (e.g., loss of employment or driving ability) were reported by pwMS but not in the recent literature. MS Spasticity is complex, multidimensional, and heterogeneous. Clinicians and pwMS may use different descriptors. This integrated conceptual model may enhance future research and management of spasticity in pwMS. Francois Bethoux has a financial relationship with Adamas Pharmaceuticals, Biogen, Genentech, Greenwich Biosciences, Helius Medical, MedRhythms, Osmotica Pharmaceuticals, Qr8, and Springer Publishing. Michelle Cameron has a financial relationship with Adamas Pharmaceuticals, Greenwich Biosciences, and Helius Medical. William R. Lenderking has a financial relationship with Evidera. Erica Zaiser and Katelyn N. Cutts have a financial relationship with Evidera. Joshua R. Steinerman, Joanne Wagner, and Edelle Field-Fote have a financial relationship with Greeenwich Biosciences. [ABSTRACT FROM AUTHOR]