CONCERTO: A randomized, placebo-controlled trial of oral laquinimod in relapsing-remitting multiple sclerosis.

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).

Polytrauma from a North American Black Bear Attack.

Bear attacks, although rare, can inflict life-threatening injuries. We present the case of a 50-y-old woman from rural Pennsylvania who was attacked by a North American black bear, Ursus americanus. She sustained multiple complex injuries including near-complete scalp avulsion, bilateral ear avulsions, and fractures of the face, ribs, and pelvis. These injuries are similar to those sustained in other bear maulings reported in the literature and required both acute intervention and a multidisciplinary approach to recovery.

International consensus on quality standards for brain health-focused care in multiple sclerosis.

BACKGROUND: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. OBJECTIVES: We sought to develop internationally applicable quality standards for timely, brain health-focused MS care. METHODS: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define 'core', 'achievable' and 'aspirational' time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. RESULTS: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. CONCLUSION: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.

Relationship between brain volume loss and cognitive outcomes among patients with multiple sclerosis: a systematic literature review.

Patients with multiple sclerosis (MS) experience varying rates of brain volume (BV) loss ranging from 0.5 to 1.5 % per year. In addition, 66 % of patients with MS experience cognitive impairment, resulting in impact on daily activities. A systematic literature review (2003-2013) was conducted to identify all studies reporting a relationship between whole BV measures and selected patient outcomes measuring cognition, including the Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test (PASAT) and MS Functional Composite (MSFC) scores. We identified 18 studies reporting associations between whole BV and cognitive outcomes. Six studies (33 %) examined the association between BV and SDMT; all six studies reported that BV loss (BVL) was significantly associated with a decline in SDMT scores (all p < 0.05). Among 14 studies (78 %) that examined the association between BV and PASAT scores, 12 (86 %) found a significant relationship between BVL and lower PASAT scores (all p < 0.05). Of the seven studies (39 %) that looked at BV and MSFC, six studies (86 %) found BVL significantly associated with lower MSFC scores (all p < 0.05). Our study demonstrated that BVL is associated with declines in cognition in MS patients across several cognition measures. The results of this study suggest that BV is a critical component of disease activity and progression in MS and has implications for treatment decisions to minimize BVL and preserve cognitive functioning.

Glatiramer acetate ameliorates experimental autoimmune neuritis.

Glatiramer acetate (GA) is one of the first-line disease-modifying medications that have been approved for the treatment of multiple sclerosis via immune modulatory mechanisms. However, it remains unclear whether the immunomodulation effect of GA is central nervous system (CNS) antigen specific. Here, we explored the mechanism of action of GA by subcutaneously injecting GA in experimental autoimmune neuritis (EAN) rats, an animal model for Guillain-Barré syndrome (GBS). Clinical, electrophysiological and histological findings showed that neurological deficits, demyelination and axonal injury of sciatic nerves were all significantly attenuated in Lewis rats when GA was administered before immunization with peripheral nervous system antigen P0. Our results further demonstrated that GA treatment inhibited either P0 or myelin basic protein (MBP) (CNS antigen)-stimulated auto-immune T-cell proliferation in vitro. GA administrated at 10 days after induction of EAN when neurological sign became apparent also ameliorated the severity of disease, inhibited T-cell response to P0 and MBP and induced shift of proinflammatory and immune modulatory cytokines. Collectively, our findings suggested that GA attenuated neurological deficits in EAN rats and that the immune modulatory mechanisms of GA were not CNS antigen specific.

Fluctuations in appraisal over time in the context of stable versus non-stable health.

PURPOSE: This study seeks to estimate clinically significant change in quality of life (QOL) appraisal by comparing changes in appraisal over 6 months of follow-up in people with multiple sclerosis who experienced no change in symptoms versus those with worsening symptoms. This estimation is important for enabling valid interpretation of longitudinal change, both in terms of ensuring the comparison of scores and for response shift estimation. METHODS: This is a secondary analysis of longitudinal data (N = 859) of participants in the North American Research Committee on Multiple Sclerosis registry. Patient groupings were characterized on the basis of self-reported symptom change over 1 year of follow-up and compared in terms of their responses to the QOL Appraisal Profile. Bonferroni adjustments reduced the type I error rate, and interpretation was restricted to those comparisons with small or larger effect sizes using Cohen's criteria. RESULTS: The Symptoms Unchanged group evidenced more change in Frame of Reference goal delineation themes and Combinatory Algorithm, whereas the Symptoms Worse group evidenced more change in Sampling of Experience and Standards of Comparison items. The group differences were, however, not large or statistically significant in most cases, likely due to being under-powered to detect interaction effects. CONCLUSIONS: Many aspects of appraisal are relatively constant in the context of unchanging and changing symptom experience, but symptom changes led patients to make substantial shifts in what experiences they sample when thinking about their health-related QOL. These underlying cognitive processes may help people to maintain homeostasis in their perceived QOL.

A randomized, double-blind, placebo-controlled trial of duloxetine for the treatment of pain in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) often report neuropathic pain (NP-MS). The purpose of this study was to assess the efficacy and tolerability of duloxetine as treatment for NP-MS. METHODS: In this study, 239 adults with NP-MS (duloxetine = 118, placebo = 121) were randomized to duloxetine 60 mg (30 mg for 1 week, then 60 mg for 5 weeks) or placebo once daily for a 6-week acute therapy phase, followed by a 12-week open-label extension phase (duloxetine 30 to 120 mg/day). Eligible patients had MS for ≥ 1 year and a score ≥ 4 on daily average pain intensity (API) ratings for ≥ 4 of 7 days immediately before randomization. Patients rated API daily on an 11-point numeric scale (0 [no pain] to 10 [worst possible pain]) in an electronic diary. The primary efficacy measure, change in weekly API ratings, was analyzed longitudinally with a mixed-model repeated-measures analysis. Completion, reasons for discontinuation, and treatment-emergent adverse event incidence were compared by Fisher's exact test. RESULTS: Duloxetine-treated patients had statistically greater mean improvement in API vs. placebo at Week 6 (-1.83 vs. -1.07, P = 0.001). Treatment completion did not significantly differ between groups. Discontinuation due to adverse events was statistically greater for duloxetine vs. placebo (13.6% vs. 4.1%, P = 0.012). Decreased appetite was reported significantly more often by duloxetine-treated patients (5.9% vs. 0%, P = 0.007). CONCLUSIONS: This study found analgesic efficacy of duloxetine for NP-MS. Duloxetine is not approved for treatment of this condition. The duloxetine safety profile of this study was consistent with the known profile in other patient populations.

Noncontingent reinforcement in the treatment of pediatric feeding disorder: A concise review.

This concise review summarizes the literature on noncontingent reinforcement in the treatment of pediatric feeding disorder from 2018 to 2022. We reviewed 15 published behavior-analytic feeding studies to identify how often the term noncontingent reinforcement is used, what form of noncontingent reinforcement is delivered, and what the effects of noncontingent reinforcement are on behavior when it is included in treatment. Implications and directions for future research are discussed.

A Continuum of Methods for Assessing Preference for Conversation Topics.

Among individuals with a diagnosis of autism spectrum disorders (ASD), conversation topic preference could influence social skills in many ways. For example, an individual with advanced vocal-verbal skills, but just learning to join a conversation, might be less inclined to participate if the topic chosen is not preferred. However, commonly used preference assessment procedures have not been applied to evaluating conversation-topic preferences. Therefore, the purpose of the current experiment was to conduct three different types of assessments that varied in efficiency, the degree of certainty they allow, and clients with whom they are likely to be applicable and acceptable. In particular, we conducted a self-report preference assessment, a multiple-stimulus-without-replacement (MSWO) preference assessment, and a response restriction conversation assessment (RRCA). Each assessment identified a preferred topic of conversation, but the RRCA was the only assessment that was able to differentiate which topics would maintain a conversation. Implications for assessment and intervention procedures related to complex social skills are discussed and directions for future research are proposed.

Teaching an Infant to Request Help.

Teaching an infant manual signs is beneficial as it promotes early communication, improves socialization, and can functionally replace behaviors such as crying and whining. Improving early communication also may reduce the probability of an infant engaging in dangerous behavior, like unsafe climbing. The purpose of this study was to extend Thompson et al. (Journal of Applied Behavior Analysis 40:15-23, 2007) by teaching an 8-month-old infant, who was noted to display developmental delays, to sign for "help" when preferred items were inaccessible. Similar to Thompson et al., delayed prompting and differential reinforcement was efficacious in teaching the infant to sign for "help," and the skill generalized to situations that were previously associated with unsafe climbing. However, undesirable generalization of signs for "help" when the infant could independently access the items was observed. Additional teaching was necessary to ensure signing for "help" occurred under appropriate antecedent control. Supplementary Information: The online version contains supplementary material available at 10.1007/s40616-023-00198-9.

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial.

INTRODUCTION: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. METHODS: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. RESULTS: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. CONCLUSION: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. CLINICAL TRIALS REGISTRATION: Substudy of ENSEMBLE (NCT03085810). REGISTRATION: March 21, 2017.

Cognitive reserve and patient-reported outcomes in multiple sclerosis.

BACKGROUND: Adaptation and compensation in the face of changing pathology may be better understood by considering the concept of cognitive reserve, which may protect against disability in multiple sclerosis (MS). OBJECTIVES: The present work investigates the relationship between cognitive reserve and demographic characteristics, health behaviors, and patient-reported outcomes (PROs). METHODS: Cross-sectional data (n=1142) were drawn from the North American Research Committee on MS (NARCOMS) Registry, from whom additional survey data were collected. Cognitive reserve was measured using the Stern and Sole-Padulles measures, the O*NET occupational classification system, and the Godin Leisure-Time Exercise Questionnaire. PROs were assessed using generic (SF -12v2, Perceived Deficits Questionnaire, Ryff Psychological Well-Being, Diener Satisfaction with Life Scale) and disease-specific (Patient-Determined Disease Steps, Performance Scales) measures. Psychometric analysis created unidimensional cognitive reserve subscales. Regression models examined relationships between cognitive reserve, demographic characteristics, and PROs. RESULTS: The cognitive reserve measures assessed distinct but related constructs. Individuals with high cognitive reserve were more likely to report lower levels of perceived disability and perceived cognitive deficits, and higher levels of physical health, mental health, and well-being. Both active and passive reserve are associated with better outcomes, independent of demographic factors, and these associations apply to both generic and disease-specific outcomes. CONCLUSIONS: This expanded measurement of cognitive reserve captures both the passive and active aspects of the construct, and there is a consistent and substantial relationship with PROs. Individuals with high passive and/or active reserve are healthier and experience higher levels of well-being.

"Seeing" in NARCOMS: a look at vision-related quality of life in the NARCOMS registry.

BACKGROUND: Research on vision-related quality of life (QOL) in multiple sclerosis (MS) is still limited. Tools such as the Visual Functioning Questionnaire-25 (VFQ-25) and the Vision Performance Scale (VPS) facilitate assessments of the severity of visual impairment and its impact on daily life. OBJECTIVE: The objective of this paper is to examine vision-related QOL, comorbid eye conditions, use of visual aids and utilization of eye-care providers in the North American Research Committee on Multiple Sclerosis (NARCOMS) population, and to explore these issues in those with a history of optic neuritis (ON) and diplopia. METHODS: In 2008, NARCOMS registrants reported on their use of visual aids, the VFQ-25, VPS, history of ON, diplopia, refractive error conditions (REC) and comorbid eye diseases (CED). We conducted regression analyses and correlations between select variables. RESULTS: The response rate for the survey was 60.4%. Of the 9107 responders, 66.7% reported visual disability measured by VPS. Of respondents, 43.1% had a history of ON and 38.6% reported prior diplopia. Frequencies of myopia (51.8%), hyperopia (26.6%), and uveitis (3.4%) exceeded those expected for the general population. Mean (SD) VFQ-25 composite score was 82.0 (14.2). A history of ON or diplopia accounted for 9.7% of the variance in the VFQ-25; 90.6% of respondents used glasses or contact lenses. Rates of utilizations of eye-care providers were lower than expected. CONCLUSION: Prior ON, diplopia, REC and CED adversely impact vision-related QOL in MS. Increased utilization of eye-care providers and use of visual aids could improve vision-related QOL in people with MS.

The Multiple Sclerosis Intimacy and Sexuality Questionnaire -- re-validation and development of a 15-item version with a large US sample.

BACKGROUND: Sexual dysfunction is common in multiple sclerosis (MS) but reliable and valid measurement in this population is needed. OBJECTIVE: The objective of this research is to re-validate the Multiple Sclerosis Intimacy and Sexuality Questionnaire-19 in a large US sample. METHODS: A total of 6300 MS patients from the NARCOMS registry completed the MSISQ-19. Unforced principal component analysis utilizing oblique rotation with Kaiser Normalization validated its construct validity. RESULTS: The scree plot supported a three-component solution, with 63% of total variance explained. The components mirrored the original validation study measuring primary, secondary, and tertiary sexual dysfunction. PCA suggested the scale could be shortened to 15 items, which were found to apply equally well to males and females (with one primary item specific for each sex). The components were moderately intercorrelated (Pearson rs ranged from 0.5 to 0.67). The secondary subscale correlated most highly with self-reported disability (r (6081) = 0.44, p < 0.001), whereas the tertiary subscale correlated most highly with psychological distress (r (5992) = -.37, p < 0.001). Cronbach's alpha for the total scale (0.92) and the subscales (primary, 0.87; secondary, 0.82; tertiary, 0.91) demonstrated good reliability. CONCLUSION: The revised 15-item MSISQ is a reliable and valid measure of sexual dysfunction in men and women with MS.

Cognitive reserve and symptom experience in multiple sclerosis: a buffer to disability progression over time?

OBJECTIVE: To investigate the possible buffering effect of cognitive reserve on symptom experience for multiple sclerosis (MS) disease course. DESIGN: Secondary analysis of longitudinal data from the North American Research Committee on MS Registry. SETTING: Registry study and web-based supplemental survey. PARTICIPANTS: People with MS (N=859). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Two health outcome measures, the Symptom Inventory and the Performance Scales, were collected biannually over 1 and 6 years, respectively. Active and passive cognitive reserve was measured using the Stern Leisure Activities and the Sole-Padulles Childhood Enrichment tools, respectively. Linear regression, chi-square, multilevel random-effects modeling, and classification and regression tree modeling were used to compare cross-sectional means, disease course by cognitive reserve, longitudinal trajectories, and active cognitive reserve item endorsement by disability groups, respectively. RESULTS: Patients with high-active reserve had a lesser symptom burden than those with low-active reserve independent of passive reserve (P<.01). Cognitive reserve was associated with course of disease, such that high-active patients were overrepresented among relapsing-remitting patients, and underrepresented among patients with progressive disease (χ(2)=14.7, P<.03). Longitudinal modeling revealed a significant interaction of active reserve and time in mobility, fatigue, and overall disability in the whole sample (P<.05 in all comparisons). Among patients whose disability trajectories changed over time, active cognitive reserve was associated with less deterioration (P<.001). Passive cognitive reserve evidenced no effect in the longitudinal analyses. Active cognitive reserve scores across disability groups had a similar range but comprised different items, indicating that patients maintain active cognitive reserve with different activities as the disease progresses. CONCLUSIONS: Our findings suggest that active cognitive reserve is a buffer for functional limitation across disability groupings. Cognitive reserve may provide an alternative lens for thinking about the disease course of MS, providing a longer "runway" until disability accrual through cortical remodeling. Loss of cognitive reserve may explain the onset of progressive disease in MS.

An Assessment of Response to Conversation Cues of Uninterest Conducted via Telehealth.

Individuals diagnosed with autism spectrum disorder (ASD) exhibit deficits in social interaction and communication. Kronfli, Vollmer, et al. developed an in-person assessment to evaluate participant response to social cues indicating uninterest in a conversation. In the current study, we sought to extend these procedures to the assessment of conversation skills via telehealth given the ongoing pandemic and so that participants in remote areas could receive services. Participants were exposed to a hierarchy of social cues of uninterest ranging in salience from one-word responses to a clear verbal statement of uninterest until they demonstrated sensitivity to a social cue. One participant who did not demonstrate sensitivity to any cues received instruction using Behavioral Skills Training. Initial results support the utility of using a remote assessment model to screen for sensitivity to specific social cues in conversations and to provide services to participants via telehealth.

An evaluation of methods for studying the effects of conditioned reinforcement on human choice.

Shahan et al. (2006) found that the relative rate of pigeons' pecking on two observing responses (i.e., responses that only produced an S+ or stimulus correlated with primary reinforcement) was well described by the relative rate of S+ delivery. Researchers have not evaluated the effects of S+ delivery rate in a concurrent observing response procedure with human subjects, so the necessary procedural modifications for studying the effects of conditioned reinforcement on human choice remain unclear. The purpose of the current study was to conduct an additive component analysis of modifications to the procedures of Shahan et al. (2006). We evaluated the additive effects of introducing response cost, a changeover response, and ordinal discriminative stimuli on correspondence with the results of Shahan et al. and the quality of fits of the generalized matching equation. When our procedures were most similar to those of Shahan et al., we observed low rates of observing and indifference between the two observing responses. For the group of subjects with whom all three additive components were included, we obtained the highest level of sensitivity to relative rate of S+ delivery, but the slope and R2 of our fits of the generalized matching equation were still much lower than those obtained by Shahan et al. Potential reasons for these discrepancies, methods of resolving them, and implications for future research are discussed.

Reflections and Critical Directions for Toilet Training in Applied Behavior Analysis.

Achieving toileting independence is a critical skill that yields several benefits of pressing social, developmental, and health-related importance. The seminal behavioral approach to toilet training established the conceptualization of continence and framework for toileting research thereafter. Contemporary researchers continue to evaluate toilet training procedures that produce efficacious outcomes for young children that closely align with current applied behavior analysis (ABA) ethics and standards of practice. Despite the overall success of behavior-analytic toileting approaches, there are critical directions still worthy of consideration and investigation. In this paper, we acknowledge the seminal roots and many of the contemporary contributions. We also critically reflect on current practices while proposing necessary areas to advance behavior-analytic toilet training research.

Recommendations Regarding Use of the Term "Ignore" in Applied Behavior Analysis.

Ignore is a common term used in behavioral assessment, behavior intervention plans, textbooks, and research articles. In the present article, we recommend against the typical usage of the term in most applications of behavior analysis. First, we briefly outline some history of the use of the term in behavior analysis. Then, we describe six main concerns about ignore and the implications for its continued use. Finally, we address each of these concerns with proposed solutions, such as alternatives to the use of ignore.

Evaluation of schedule thinning following treatment for aggression maintained by access to higher level restrictive and repetitive behavior.

One of the diagnostic characteristics of individuals with autism spectrum disorders includes engaging in restricted and repetitive behavior. Research has shown that individuals will often display problem behavior when access to restricted and repetitive behavior is blocked. The purpose of the current study was to evaluate the use of functional communication training and schedule thinning to treat aggression displayed by three children diagnosed with autism spectrum disorders when higher level restrictive and repetitive behavior was blocked. Further, we assessed whether all steps in a schedule-thinning sequence were necessary as well as extended the practicality of these procedures by removing the continuous signal during the delay to reinforcement. The results indicated that functional communication with schedule thinning reduced aggression related to blocking access to engaging in higher level restrictive and repetitive behavior for all participants.