Intravenous immunoglobulin is safe and effective in controlling pre-existing paraneoplastic neuromuscular diseases in cancer patients treated with immune checkpoint inhibitors: two case reports and literature review.

Immune checkpoint inhibitors cause rare but potentially fatal neuromuscular complications, leading to a concern to use these agents in cancer patients with pre-existing autoimmune or inflammatory neuromuscular diseases. We report two such patients with paraneoplastic dermatomyositis and "seronegative" paraneoplastic demyelinating neuropathy, respectively, who have been successfully treated with immune checkpoint inhibitor monotherapy as well as maintenance intravenous immunoglobulin. While controlling the paraneoplastic or autoimmune neuromuscular diseases, the use of intravenous immunoglobulin did not compromise the anti-cancer effect of immune checkpoint inhibitor.

Precision targeting of autoantigen-specific B cells in muscle-specific tyrosine kinase myasthenia gravis with chimeric autoantibody receptor T cells.

Muscle-specific tyrosine kinase myasthenia gravis (MuSK MG) is an autoimmune disease that causes life-threatening muscle weakness due to anti-MuSK autoantibodies that disrupt neuromuscular junction signaling. To avoid chronic immunosuppression from current therapies, we engineered T cells to express a MuSK chimeric autoantibody receptor with CD137-CD3ζ signaling domains (MuSK-CAART) for precision targeting of B cells expressing anti-MuSK autoantibodies. MuSK-CAART demonstrated similar efficacy as anti-CD19 chimeric antigen receptor T cells for depletion of anti-MuSK B cells and retained cytolytic activity in the presence of soluble anti-MuSK antibodies. In an experimental autoimmune MG mouse model, MuSK-CAART reduced anti-MuSK IgG without decreasing B cells or total IgG levels, reflecting MuSK-specific B cell depletion. Specific off-target interactions of MuSK-CAART were not identified in vivo, in primary human cell screens or by high-throughput human membrane proteome array. These data contributed to an investigational new drug application and phase 1 clinical study design for MuSK-CAART for the treatment of MuSK autoantibody-positive MG.

Predictors of employment for adults with intellectual and developmental disabilities participating in a postsecondary transition program in the United States.

BACKGROUND: Previous research has shown that post-secondary collegiate vocational educational programs often have positive effects on employment outcomes for young adults with intellectual and developmental disabilities. AIMS: Using secondary data of a program in the United States collected over several years, we examined which intervention components of a postsecondary education transition program predicted subsequent employment for young adults with intellectual and developmental disabilities. MATERIALS & METHODS: The sample consisted of 56 individuals that participated in a transition-services collegiate program; Crossing Points, University of Alabama. RESULTS: Results were able to robustly indicate that acquiring job-specific skills was a much better predictor than global measures of intellectual or adaptive behaviour. Additionally, survival curve analyses as an innovative approach to this population showed that there was a positive relation between the number of job-specific training sessions and eventual community employment. DISCUSSION: Results are discussed in relation to a historical parallel movement to expand inclusion of students with intellectual and developmental disabilities in the least restrictive educational setting for primary and secondary public education years. CONCLUSION: In conclusion, the results of the current study suggest positive findings with job-skills training both specific and general.

Enrichment of serum IgG4 in MuSK myasthenia gravis patients.

Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disease belonging to a growing group of IgG4 autoimmune diseases (IgG4-AIDs), in which the majority of pathogenic autoantibodies are of the IgG4 subclass. The more prevalent form of MG with acetylcholine receptor (AChR) antibodies is caused by IgG1-3 autoantibodies. A dominant role for IgG4 in autoimmune disease is intriguing due to its anti-inflammatory characteristics. It is unclear why MuSK autoantibodies are predominantly IgG4. We hypothesized that MuSK MG patients have a general predisposition to generate IgG4 responses, therefore resulting in high levels of circulating IgG4. To investigate this, we quantified serum Ig isotypes and IgG subclasses using nephelometric and turbidimetric assays in MuSK MG and AChR MG patients not under influence of immunosuppressive treatment. Absolute serum IgG1 was increased in both MuSK and AChR MG patients compared to healthy donors. In addition, only MuSK MG patients on average had significantly increased and enriched serum IgG4. Although more MuSK MG patients had elevated serum IgG4, for most the IgG4 serum levels fell within the normal range. Correlation analyses suggest MuSK-specific antibodies do not solely explain the variation in IgG4 levels. In conclusion, although serum IgG4 levels are slightly increased, the levels do not support ubiquitous IgG4 responses in MuSK MG patients as the underlying cause of dominant IgG4 MuSK antibodies.

Introduction to the Special Section: Translating Advanced Quantitative Techniques for Single-Case Experimental Design Data.

The articles in this special section offer strategies to single-case experimental design (SCED) researchers to interpret their outcomes, communicate their results, and compare the results using common, quantitative results. Advancing quantitative methods applied to SCED data will facilitate communication with scientists and other professionals that do not typically interpret graphed data of the dependent variable. Horner and Ferron aptly note that innovative statistical procedures are improving the precision and credibility of SCED research as disseminate our findings to an increasingly diverse audience. This special section promotes the translation of these quantitative methods to encourage their adoption in research using single case experimental designs.

Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study.

OBJECTIVE: To determine whether rituximab is safe and potentially beneficial, warranting further investigation in an efficacy trial for acetylcholine receptor antibody-positive generalized MG (AChR-Ab+ gMG). METHODS: The B-Cell Targeted Treatment in MG (BeatMG) study was a randomized, double-blind, placebo-controlled, multicenter phase-2 trial that utilized a futility design. Individuals 21-90 years of age, with AChR-Ab+ gMG (MG Foundation of America Class II-IV) and receiving prednisone ≥15 mg/day were eligible. The primary outcome was a measure of steroid-sparing effect, defined as the proportion achieving ≥75% reduction in mean daily prednisone dose in the 4-weeks prior to week 52 and with clinical improvement or no significant worsening as compared to the 4-week period prior to randomization. The co-primary outcome was safety. Secondary outcomes included MG-specific clinical assessments. Fifty-two individuals were randomized (1:1) to either a two-cycle rituximab/placebo regimen, with follow-up through 52-weeks. RESULTS: Of the 52 participants included, mean (±SD) age at enrollment was 55.1 (±17.1) years; 23 (44.2%) were female, and 31 (59.6%) were MGFA Class II. The mean (±SD) baseline prednisone dose was 22.1 (±9.7) mg/day. The primary steroid-sparing outcome was achieved in 60% of those on rituximab vs. 56% on placebo. The study reached its futility endpoint (p=0.03) suggesting that the pre-defined clinically meaningful improvement of 30% due to rituximab over placebo was unlikely to be achieved in a subsequent, larger trial. No safety issues identified. CONCLUSIONS: While rituximab was safe and well-tolerated, these results suggest that there is a low probability of observing the defined clinically meaningful steroid-sparing effect over a 12-month period in a phase-3 trial of mild-moderately symptomatic AChR-Ab+ gMG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for mild-to-moderate AChR-Ab+ gMG, compared with placebo, rituximab is safe but unlikely to reduce steroid use by an absolute difference of at least 30% at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02110706.

Optimal number of baseline sessions before changing phases within single-case experimental designs.

Recommendations vary considerably for the minimum or optimal number of baseline sessions to conduct within single-case experimental design clinical analyses or research studies. We examined the optimal number of baseline sessions that produced minimal bias. First, we examined the relation between the number of baseline sessions and the degree of bias in calculating estimates of treatment effect size. As the number of baseline sessions increased, the bias in effect size estimates decreased, r = -0.36, p < 0.001. s, we examined what would be the minimum number of baseline sessions associated with varying levels of bias. Bias of approximately ten percent was associated with four to five baseline sessions. Bias of about five percent was associated with six to seven baseline sessions. Third, we examined the relation between standard deviation and varying levels of bias. As the number of baseline sessions increases, the standard deviation for the phase decreased, r = -0.89, p < 0.001. Fourth, we examined what value of standard deviation in the baseline phase was associated with equal to or more than five versus ten percent bias. When considering five or ten percent bias, the optimal level of standard deviation was 0.59 or less.

Examining the correlation between symptoms of obsessive compulsive disorder and autism spectrum disorder in a community-based sample of adults.

We examined the association between obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) symptoms among a community-based sample of adults (n = 217) that completed an OCD and ASD screening instrument. Approximately 39% of the sample that met the ASD screener cutoff criteria also met the screener cutoff criteria for OCD. The correlation between overall OCD symptoms (i.e., obsessions and compulsions) and ASD symptoms was small but statistically significant for the entire sample of participants. Similarly, obsession and compulsion subscales showed almost identical results for correlation with ASD symptoms (i.e., small but statistically significant) for the entire sample. These results suggest that levels of compulsions and obsessions are equally correlated with ASD symptoms, and neither elevated compulsions nor obsessions differentially predicted the severity of ASD symptoms in a community-based sample of adults. However, when the analysis was restricted to only the participants that met screening criteria cutoff score for ASD, statistically significant results occurred with only elevated compulsions accurately predicting severity of ASD symptoms. These results suggest that compulsive behavior appears to be a good candidate for targeting intervention resources for individuals with characteristics of ASD given the mounting data suggesting that compulsions are more common than obsessions.

Examining the Relation between Self-reported ASD Symptoms and Sensory Sensitivities from a Community-based Sample of Adults.

Atypical responses to sensory stimuli, termed sensory sensitivities, are a commonly reported symptom for individuals diagnosed with Autism Spectrum Disorder (ASD). In this community-based study of 604 adults, the correlation between sensory sensitivities and ASD symptoms was r = 0.23, p < .001, representing a smaller relation than estimates previously reported in the peer-reviewed research. Additionally, when examining only participants who met or exceeded the ASD screening cutoff score, the relation between sensory sensitivities and ASD symptoms was only slightly larger at r = 0.25, p < .001. Forty-four percentage who met the screening cutoff score for ASD also reported the lowest degree of sensory sensitivities. Finally, just over one-third who met the screening cutoff score for ASD had the highest sensory sensitivities. Sensory sensitivities did not appear to be a consistent feature across adults meeting the ASD screening cutoff score, but a proportion meeting the ASD screening cutoff score also exhibited the most extreme sensory sensitivities.

International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update.

OBJECTIVE: To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature. METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting "yes") was used to approve minor changes in grammar and syntax to improve clarity. RESULTS: The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment. CONCLUSION: This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.

Epidemiological evidence for a hereditary contribution to myasthenia gravis: a retrospective cohort study of patients from North America.

OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.

Treatment Burst Data Points and Single Case Design Studies: A Bayesian N-of-1 Analysis for Estimating Treatment Effect Size.

Single-case experimental designs (SCED) evaluate treatment effects for each participant, but it is difficult to aggregate and quantify treatment effects across SCED participants receiving the same type of treatment. We applied Bayesian analytic procedures to SCED data aggregated across participants that have previously only been applied to large-N and group design studies of treatment effect sizes. For the current study, we defined transient elevated treatment data points as (1) above the range of the last five baseline sessions during the first three sessions of treatment (i.e., extinction burst); (2) within or above the range of baseline after the first three treatment sessions (i.e., recurrence burst); or (3) thinning phase data points above the last three prethinning treatment data points (i.e., thinning burst). Results indicated that the treatment effect sizes remained large regardless of controlling for transient elevated treatment data points. Finally, we examined the effects of reinforcer schedule thinning on estimates of treatment effect size. Results indicated a moderate negative impact of schedule thinning on treatment effect size with a 16% decrease in effect size. Recommendations for research and practice are provided, and the utility of using Bayesian analysis in single-case experimental designs is discussed.

Muscle-Specific Kinase Myasthenia Gravis.

Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)-negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG. MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction. The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass. MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles. MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life. Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors. Therefore, current treatment involves immunosuppression, primarily by corticosteroids. In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions. Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.

Renewal of fear and avoidance in humans to escalating threat: Implications for translational research on anxiety disorders.

Exposure-based treatment for threat avoidance in anxiety disorders often results in fear renewal. However, little is known about renewal of avoidance. This multimodal laboratory-based treatment study used an ABA renewal design and an approach-avoidance (AP-AV) task to examine renewal of fear/threat and avoidance in twenty adults. In Context A, 9 visual cues paired with increases in probabilistic money loss (escalating threats) produced increases in ratings of feeling threatened and loss expectancies and skin-conductance responses (SCR). During the AP-AV task, a monetary reinforcer was available concurrently with threats. Approach produced the reinforcer or probabilistic loss, while avoidance prevented loss and forfeited reinforcement. Escalating threat produced increasing avoidance and ratings. In Context B with Pavlovian extinction, threats signaled no money loss and SCR declined. During the AP-AV task, avoidance and ratings also declined. In a return to Context A with Pavlovian threat extinction in effect during the AP-AV task, renewal was observed. Escalating threat was associated with increasing ratings and avoidance in most participants. SCR did not show renewal. These are the first translational findings to highlight renewal of avoidance in humans. Further research should identify individual difference variables and altered neural mechanisms that may confer increased risk of avoidance renewal.

Validation of the triple timed up-and-go test in Lambert-Eaton myasthenia.

INTRODUCTION: There are no validated, practical, and quantitative measures of disease severity in Lambert-Eaton myasthenia (LEM). METHODS: Data from the Effectiveness of 3,4-Diaminopyridine in Lambert-Eaton Myasthenic Syndrome (DAPPER) trial were analyzed to assess triple timed up-and-go (3TUG) reproducibility and relationships between 3TUG times and other measures of LEM severity. RESULTS: The coverage probability technique showed ≥0.90 probability for an acceptable 3TUG difference of ≤0.2, indicating that it is reproducible in LEM patients. The correlation between 3TUG times and lower extremity function scores was significant in subjects who continued and in those who were withdrawn from 3,4-diaminopyridine free base. Worsening patient-reported Weakness Self-Assessment Scale and Investigator Assessment of Treatment Effect scores corresponded with prolongation of 3TUG times. DISCUSSION: The 3TUG is reproducible, demonstrates construct validity for assessment of lower extremity function in LEM patients, and correlates with changes in patient and physician assessments. These findings, along with prior reliability studies, indicate 3TUG is a valid measure of disease severity in LEM.

Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement.

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

Assessing wandering risk among individuals with Alzheimer's disease and dementia: a pilot study.

BACKGROUND: We examined a screening instrument to assess risk for wandering among individuals with Alzheimer's disease and dementia according to caregiver informants. METHODS: Pilot data were collected on the Risk of Wandering (RoW) screening instrument by 48 responses from an online survey using the Alzheimer's Association Trial Match system. RESULTS: Results indicated acceptable evidence of the internal consistency of scores for the data obtained, α = 0.81. Receiver operating characteristic curve results indicated acceptable evidence of the screening instrument scores' ability to discriminate between individuals who eloped and those who did not wander off, AUC = 0.72, P = 0.003. CONCLUSIONS: A cut-off score for future use is suggested along with directions for future research. The development of a screening instrument would appear to be preferable to restricting the movement of these individuals or unnecessarily invading their privacy through monitoring devices while simultaneously balancing the desire to prevent distress, serious injury, or death.

Telehealth and in-person training outcomes for novice discrete trial training therapists.

The efficacy and efficiency of telehealth and in-person training were compared while teaching seven undergraduate students to implement components of discrete trial training. A multiple-baseline design across skills with elements of multiple probe and delayed multiple baseline combined with an alternating-treatments design was used to evaluate the effects of behavioral skills training (BST) on (a) implementing a multiple stimulus without replacement preference assessment, (b) setting up an instructional context, (c) delivering antecedent prompts, and (d) delivering consequences for accurate and inaccurate responding. Two skills were trained via telehealth and two skills were trained in-person using BST procedures with a mock student. All participants provided high acceptability ratings for both training procedures. Results also showed that telehealth training was as efficacious and efficient as in-person training for all skills across all participants. Five of six participants showed high levels of maintenance of the newly acquired skills; these five also exhibited the skills during a novel instructional task.