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Speech perception testing, defined as providing standardized speech stimuli and requiring a listener to provide a behavioral and scored response, has been an integral part of the audiologic test battery since the beginning of the audiology profession. Over the past several decades, limitations in the diagnostic and prognostic validity of standard speech perception testing as routinely administered in the clinic have been noted, and the promotion of speech-in-noise testing has been highlighted. This review will summarize emerging and innovative approaches to speech-in-noise testing with a focus on five applications: (1) pediatric considerations promoting the measurement of sensory and cognitive components separately; (2) appropriately serving underrepresented populations with special attention to racial, ethnic, and linguistic minorities, as well as considering biological sex and/or gender differences as variables of interest; (3) binaural fitness for duty assessments of functional hearing for occupational settings that demand the ability to detect, recognize, and localize sounds; (4) utilization of speech-in-noise tests in pharmacotherapeutic clinical trials with considerations to the drug mechanistic action, the patient populations, and the study design; and (5) online and mobile applications of hearing assessment that increase accessibility and the direct-to-consumer market.

Purpose: The aim of this study was to provide insight for the feasibility and outcomes of hybrid (combination of in-person office and Internet-based appointments) audiology services. Method: This pilot included two phases. First, we surveyed audiologists regarding what elements of a best-practice, in-person delivery of a hearing intervention could be delivered via Internet-based appointments. Next, we piloted the feasibility and assessed outcomes of the procedures identified. Ten first-time hearing aid users aged 70 years and older were fit with Phonak Audeo M90-312T hearing aids. Two Internet-based follow-up appointments were completed using the myPhonak app. We administered the Hearing Handicap Inventory for the Elderly–Screening Version (HHIE-S), the Client Oriented Scale of Improvement (COSI), the Quick Speech-in-Noise Test (QuickSIN), and real-ear aided responses (REARs) to determine whether participants experienced improvements on hearing-related outcomes. The Telehealth Acceptance Questionnaire (TAQ) and the Visit-Specific Satisfaction Questionnaire (VSQ-9) were administered to gauge comfort with telehealth and satisfaction with Internet-based appointments. Results: Survey results revealed that after an initial in-person appointment, nearly all follow-up hearing intervention components could be delivered remotely. We performed Wilcoxon signed-ranks tests to determine if the baseline and outcome results differed for outcomes. Baseline scores improved after 6 weeks ( p s = .02 and. 005 for QuickSIN and HHIE-S) for speech-in-noise performance and self-perceived hearing difficulties. REARs from 500 to 4000 Hz measured after 6 weeks did not differ from baseline ( p s = .612 and .398 for the right and left ears), suggesting no significant deviation from prescriptive targets because of remote fitting adjustments. All participants reported improvement in COSI goals after the intervention. TAQ results suggested that comfort with telehealth improved after attending Internet-based appointments ( p = .005). VSQ-9 results revealed no differences in reported patient satisfaction between in-person and Internet-based appointments. Conclusions: We were able to develop a feasible hybrid audiology service delivery model for older adults. Our results enhance the evidence base for the implementation of telehealth audiology services.

To better understand the hearing health learning needs of Hispanic/Latino adults by assessing hearing healthcare (HHC) knowledge, attitudes, and behaviors to inform the development of a culturally and linguistically appropriate self-management program. Through a series of focus groups with members of the target audience, this study explored knowledge about hearing loss and interventions, cultural facilitators and barriers to HHC utilization, and preferences for hearing health education and information delivery. Opinions were also received on patient education materials designed to increase self-efficacy for managing hearing loss in daily life.This work was guided by a practical framework of culturally competent interventions for addressing disparities in health and healthcare, centered on structural, clinical, and organizational barriers to care. A hybrid individualistic social psychology and social constructionist approach was used to build programmatic theory related to the primary research objective. Focus group goals were to generate a combination of personal opinions and collective experiences from participants with an a priori plan to analyze data using combined content analysis/grounded theory methods. Purposive sampling was used to select 31 participants who were Spanish-speaking, identified as Hispanic/Latino, and who had normal hearing or self-reported hearing difficulties. Thirteen focus groups were conducted using Microsoft Teams, and each group was audio and video recorded for later off-line transcription, translation, and analysis. A constant comparison approach was used to systematically organize focus group data into a structured format for interpretation. Transcripts were coded independently by two investigators, and emergent themes were derived and interpreted from the coded data.Major and minor themes tied to the framework for culturally competent interventions included those related to sociocultural barriers to care. Structural barriers, including inconsistent access to quality care, lack of culturally and linguistically appropriate patient education materials, appointment wait times and intake processes, and referrals to specialty care, were most frequently experienced by participants. Clinical barriers most frequently cited were a lack of culturally and linguistically congruent healthcare providers and lack of language access during healthcare visits. Other major themes included hearing loss lived experiences, family and familism, and hearing-related patient education needs and preferences.Focus group results were integrated into a Spanish-language hearing loss self-management program that is currently being evaluated in a randomized controlled trial. The themes uncovered provided insight regarding the knowledge, attitudes, and beliefs about hearing loss and HHC, including hearing-related learning needs, of Hispanic/Latino adults in this sample.

Background: The use of advanced magnetic resonance imaging (MRI) techniques in MS research has led to new insights in lesion evolution and disease outcomes. It has not yet been determined if, or how, pre-lesional abnormalities in normal-appearing white matter (NAWM) relate to the long-term evolution of new lesions. Objective: To investigate the relationship between abnormalities in MRI measures of axonal and myelin volume fractions (AVF and MVF) in NAWM preceding development of black-hole (BH) and non-BH lesions in people with MS. Methods: We obtained magnetization transfer and diffusion MRI at 6-month intervals in patients with MS to estimate MVF and AVF during lesion evolution. Lesions were classified as either BH or non-BH on the final imaging visit using T1 maps. Results: Longitudinal data from 97 new T2 lesions from 9 participants were analyzed; 25 lesions in 8 participants were classified as BH 6–12 months after initial appearance. Pre-lesion MVF, AVF, and MVF/AVF were significantly lower, and T1 was significantly higher, in the lesions that later became BHs ( p 0.05). Conclusion: The present work demonstrated that pre-lesion abnormalities are associated with worse long-term lesion-level outcome.

Background: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections. Objective: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNβ1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570). Methods: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model. Results: Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen’s d: RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNβ1a ( p Conclusion: Ocrelizumab effectively reduced thalamic volume loss compared with IFNβ1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.

Purpose: This investigation adapted a well-studied language treatment method, Enhanced Conversational Recast, paired with auditory bombardment to a teletherapy format. Method: The study used a single case series approach ( n = 7) to determine the feasibility of teletherapy with children ages 5 and 6 years of age. Treatment targeted grammatical errors in the context of dialogic reading and craft activities. Clinicians administered 24 doses in the form of focused conversational recasting, followed by 12 doses consisting of simple sentences containing the grammatical forms targeted for remediation. Children were treated for up to 26 sessions, with four children treated on consecutive weekdays and three treated twice a week. Treatment progress was operationalized as generalization of target grammatical forms to untreated linguistic contexts, as well as spontaneous use of the treated form. To control for nontreatment effects, generalization of an untreated form was also tracked throughout the treatment period. Results: Six of the seven children showed clinically meaningful gains in the use of the grammatical forms targeted for treatment within the treatment period. This was true for children enrolled in both treatment schedules. Learning for treated forms was retained after treatment was discontinued. In comparison, no change was seen for untreated forms for six of the seven children. Conclusions: The results suggest that this treatment method is feasible in a telepractice format, even with young children. The range of individual results is generally comparable to previous face-to-face versions of this treatment.

Background: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. Objective: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. Methods: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). Results: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66–0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65–0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. Conclusion: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. Trial registration number: NCT01665144

Background: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). Objective: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). Methods: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo ( n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. Results: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. Conclusion: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Diffusely abnormal white matter, characterised by biochemical changes of myelin in the absence of frank demyelination, has been associated with clinical progression in secondary progressive multiple sclerosis. However, little is known about changes of diffusely abnormal white matter over time and their relation to focal white matter lesions. The objectives of this work were: (i) to characterize the longitudinal evolution of focal white matter lesions, diffusely abnormal white matter and diffusely abnormal white matter that transforms into focal white matter lesions; and (ii) to determine whether gadolinium enhancement, known to be associated with the development of new focal white matter lesions, is also related to diffusely abnormal white matter voxels that transform into focal white matter lesions. Our data included 4220 MRI scans of 689 secondary progressive multiple sclerosis participants, followed for 156 weeks, and 2677 scans of 686 relapsing-remitting multiple sclerosis participants, followed for 96 weeks. Focal white matter lesions and diffusely abnormal white matter were segmented using a previously validated, automatic thresholding technique based on normalized T2 intensity values. Using longitudinally registered images, diffusely abnormal white matter voxels at each visit that transformed into focal white matter lesions on the last MRI scan as well as their overlap with gadolinium-enhancing lesion masks were identified. Our results showed that the average yearly rate of conversion of diffusely abnormal white matter to focal white matter lesions was 1.27 cm3 for secondary progressive multiple sclerosis and 0.80 cm3 for relapsing-remitting multiple sclerosis. Focal white matter lesions in secondary progressive multiple sclerosis participants significantly increased (t = 3.9; P = 0.0001) while diffusely abnormal white matter significantly decreased (t = −4.3 P We conclude that diffusely abnormal white matter transforms into focal white matter lesions over time in both relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis. Diffusely abnormal white matter appears to represent a form of pre-lesional pathology that contributes to T2 lesion volume increase over time, independent of new focal inflammation and gadolinium enhancement.

Objectives: To examine Influenza and COVID-19 vaccine concerns and uptake among adult patients in a Southern safety-net health system. Methods: Trained research assistants conducted a structured telephone interview from April to October 2021. Of 118 participants, mean age was 57.7 years, 63.6% were female, 55.1% were Black, 42.4% white, and 54.2% reported rural residence. Results: Among participants, 44.9% had received the influenza vaccine during the 2020 to 2021 season, and 66.1% had received the COVID-19 vaccine. Participants who received the influenza vaccine were more likely to report getting a COVID-19 vaccine compared to those who reported not getting a flu vaccine (81.1% vs 53.8%, P = .002). Black adults were significantly less likely than white adults (29.2% vs 46.0%, P = .048) and bordering on significance, males less likely than females (27.9% vs 41.3%, P = .054) to have reported receiving both vaccines. Of note, 25.4% of participants did not get either vaccine. The most common reasons for not getting the influenza vaccine were not being concerned about getting the flu (13.8%) and belief the vaccine gave them the flu (12.3%). The primary reasons for not getting a COVID-19 vaccine were concern about vaccine safety (22.5%), concern about side effects (20.0%), and belief they were not going to get sick (20.0%). Conclusions: These findings could help direct regional vaccine messaging and clinical communication to improve vaccine uptake among underserved populations.

Background Introduction of telehealth for gynaecological oncology consultations aims to improve access to specialised care for rural and remote Queensland women with gynaecological malignancies. Aims This survey examines patient satisfaction with gynaecological oncology consultations via telehealth after introduction of the service in Far North Queensland in 2017. Materials and methods Patients who accessed the gynaecological oncology telehealth service at Cairns Hospital from January 2019 to June 2020 were invited to participate in the study. Demographic details and results of a satisfaction survey were investigated. The questionnaire included 16 statements measured on a five-point Likert scale and three open-ended questions, which were coded into related responses and predominant themes developed. Results Fifty-three patients completed the study. The mean satisfaction score across all questions was 90.5% (standard deviation 8.7%). The lowest overall patient score was 77.5% and the highest was 100%. Themes emerging from the open questions were emotions experienced by women, communication, relationship building and acceptability of the service. Conclusions Patients were highly satisfied with the telehealth service. Our findings encourage further development and research into telehealth care models for surgical disciplines such as gynaecological oncology.

Proteins evolve through the modular rearrangement of elements known as domains. Extant, multidomain proteins are hypothesized to be the result of domain accretion, but there has been limited experimental validation of this idea. Here, we introduce a technique for genetic minimization by iterative size-exclusion and recombination (MISER) for comprehensively making all possible deletions of a protein. Using MISER, we generate a deletion landscape for the CRISPR protein Cas9. We find that the catalytically-dead Streptococcus pyogenes Cas9 can tolerate large single deletions in the REC2, REC3, HNH, and RuvC domains, while still functioning in vitro and in vivo, and that these deletions can be stacked together to engineer minimal, DNA-binding effector proteins. In total, our results demonstrate that extant proteins retain significant modularity from the accretion process and, as genetic size is a major limitation for viral delivery systems, establish a general technique to improve genome editing and gene therapy-based therapeutics., Proteins evolve through the modular rearrangement of domains. Here the authors introduce MISER, a minimization by iterative size-exclusion and recombination method to make all possible deletions of a protein, uncovering functions for Cas9 domains involved in DNA binding.

Due to the prevalence of distress following a cancer diagnosis, routine symptom and distress screening is recommended as best practice. RTs perceive psychosocial support and screening to be part of their role, however feel they lack the education and skills to perform this confidently. The study aimed to evaluate the impact of providing communication skills training (RT Prepare CST) on the perceived barriers, knowledge, attitude, role, and confidence of radiation therapists (RTs) in using routine symptom and distress screening.A single-arm, pre-post intervention design was implemented. All RTs at one regional and one rural centre participated in RT Prepare CST. RTs completed a questionnaire: pre-intervention (T1); immediately post-intervention (T2); and, three months post-intervention (T3). Cochran's Q and McNemar's tests for non-parametric data were conducted to compare outcomes over time.Of 39 RTs approached, 37 (95%) consented to participate with 36 (92%) completing questionnaires at all three time points. Significant and sustained improvements post-intervention were noted from T1-T3 including: confidence in describing the PROMPT-Care tool to patients (p=0.002), discussing psychosocial issues (p=0.014); recognising signs of anxiety/depression (p0.001); dealing with signs of anxiety (p=0.002), depression (p=0.015) and distress (p=0.008) as well as agreeing 'the tool is useful in identifying psychosocial problems' (p=0.029).RT Prepare CST was effective in increasing confidence, knowledge and attitudes of RTs in the psychosocial care of patients with a change in RT behaviour noted by a significant increase in the number of patients screened following the intervention. Providing routine CST and emotional cues training to RTs enhances their ability to care for patients holistically, equipping them with skills to be included within a psychosocial model of care. Engaged leadership and role models are essential to sustain the learnings from education programs and provide an environment to discuss and define roles within radiation therapy departments.

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit–risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0–2), then DMF (Years 3–10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04–10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF ( n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120–0.169)), while for PBO/DMF ( n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0–2 years, 0.330 (95% CI, 0.266–0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118–0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF’s positive benefit/risk profile for long-term RRMS treatment.

In most cases, multiple sclerosis (MS) begins with a relapsing-remitting course followed by insidious disability worsening that is independent from clinically apparent relapses and is termed secondary progressive MS (SMPS). Major differences exist between relapsing-remitting MS (RRMS) and SPMS, especially regarding therapeutic response to treatment. This review provides an overview of the pathology, differentiation, and challenges in the diagnosis and treatment of SPMS. We emphasize the criticality of conversion from a relapsing-remitting to a secondary progressive disease course not only because such conversion is evidence of disability progression, but also because, until recently, treatments that effectively reduced disability progression in relapsing MS were not proven to be effective in SPMS. Clear clinical, imaging, immunologic, or pathologic criteria marking the transition from RRMS to SPMS have not yet been established. Early identification of SPMS will require tools that, together with the use of appropriate treatments, may result in better long-term outcomes for the population of patients with SPMS.

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.

Introduction This study aimed to evaluate radiation therapists’ (RTs) perceptions regarding the perceived barriers, knowledge, attitudes, confidence and role in administering an electronic screening tool to routinely screen for cancer patients’ symptoms and distress. Methods RTs at two radiation therapy departments completed a cross‐sectional paper/pen survey to assess their demographic and workplace characteristics, perceptions of barriers, knowledge, attitudes, confidence and opinion of their role in symptom and distress screening. Responses were evaluated using simple frequencies and free‐text responses using thematic analysis. Results Of 39 RTs approached, 37 (95%) participated. The majority had not previously attended any emotional cues (77%) or psychosocial training (86%); 68% reported confidence discussing psychosocial concerns and recognising signs of anxiety and depression in patients, and 65% felt discussing patients’ psychosocial concerns was part of their role. Administering the tool to patients was agreed to be the role of RTs by 38% of participants. Lack of education about psychosocial issues was the highest‐ranked barrier to delivering the patient screening tool, with 74% of RTs responding ‘it has made it difficult’. Conclusion Whilst RTs are willing to play a role in patients’ psychosocial support, they do not feel able to fulfil this role adequately because they lacked knowledge and confidence to administer symptom and distress screening. This research has highlighted the need for RT education on psychosocial concerns and recognising and responding to emotional cues. Understanding the impact education may have on the knowledge, attitude, confidence and role of RTs performing routine symptom and distress screening is required., Routine distress screening for cancer patients is recommended as best practice cancer care. Radiation therapists performing this task were surveyed. Results indicate that although they see this as an important part of patient care, current barriers including the process, lack of confidence, knowledge and education make it difficult to perform this role.

This article represents an implementation-focused evaluation of a multicultural peer-consultation team situated within a psychiatry department in a large academic medical center in the Southern United States. The evaluation comprised anonymous self-report questionnaires ( n = 14) as well as individual ( n = 3) or group interviews ( n = 10) conducted by outside independent evaluators. Participants were current and former team members (i.e., graduate trainees, mental health care providers, clinical and research staff members) who voluntarily participated in this multimethod implementation evaluation. Results indicated that attendance on the team had several important impacts on members, and most notably an increased ability to provide multiculturally competent care, that is treatment that carefully and routinely considers the influence of culture and context on patients and therefore their clinical presentation. Further, no negative impacts from participating on the team were noted. A primary strength of the team's sustainability is that participation on the team was deemed to be relevant and useful by current and former team members. A major barrier to participation on the team is competing demands, such as high clinical loads. We conclude that this model for multicultural peer-consultation holds promise as an effective and implementable educational method for mental health care professionals. We discuss strengths, limitations, and future directions for research.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is now recognized as distinct from multiple sclerosis (MS). Objective: To evaluate the importance of considering myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin-G (IgG) serology when applying MS diagnostic criteria in children. Methods: Within a prospective cohort of children meeting MS criteria (median follow-up = 6 years, interquartile range (IQR) = 4–9), we measured MOG-IgG in serial archived serum obtained from presentation, and compared imaging and clinical features between seropositive and seronegative participants. Results: Of 65 children meeting MS criteria (median age = 14.0 years, IQR = 10.9–15.1), 12 (18%) had MOG-IgG at disease onset. Seropositive participants were younger, had brain magnetic resonance imaging (MRI) features atypical for MS, rarely had cerebrospinal fluid (CSF) oligoclonal bands (2/8, 25%), and accumulated fewer T2 lesions over time. On serial samples, 5/12 (42%) were persistently seropositive, 5/12 (42%) became seronegative, and 2/12 (17%) had fluctuating results. All 12 children experienced a disease course different from typical MS. Conclusion: While children with MOG-IgG can have clinical, CSF, and MRI features conforming to MS criteria, the presence of MOG-IgG is associated with atypical features and predicts a non-MS disease course. Given MOG-IgG seropositivity can wane over time, testing at first attack is of considerable importance for the diagnosis of MOGAD.

Background: The Oxford Big Data Institute, multiple sclerosis (MS) physicians and Novartis aim to address unresolved questions in MS with a novel comprehensive clinical trial data set. Objective: The objective of this study is to describe the Novartis–Oxford MS (NO.MS) data set and to explore the relationships between age, disease activity and disease worsening across MS phenotypes. Methods: We report key characteristics of NO.MS. We modelled MS lesion formation, relapse frequency, brain volume change and disability worsening cross-sectionally, as a function of patients’ baseline age, using phase III study data (≈8000 patients). Results: NO.MS contains data of ≈35,000 patients (>200,000 brain images from ≈10,000 patients), with >10 years follow-up. (1) Focal disease activity is highest in paediatric patients and decreases with age, (2) brain volume loss is similar across age and phenotypes and (3) the youngest patients have the lowest likelihood (Conclusion: NO.MS will illuminate questions related to MS characterisation, progression and prognosis. Age modulates relapse frequency and, thus, the phenotypic presentation of MS. Disease worsening across all phenotypes is mediated by age and appears to some extent be independent from new focal inflammatory activity.

Objective: To understand how longitudinal serum neurofilament light chain (sNfL) patterns can inform its use as a prognostic biomarker in multiple sclerosis (MS) and evaluate whether sNfL reflects MS disease activity and disease-modifying therapy usage. Methods: This was a post hoc analysis of longitudinal data and samples from the ADVANCE trial (NCT00906399) of patients with relapsing–remitting MS (RRMS). sNfL was measured every 3 months for 2 years, then every 6 months for 4 years. Regression models explored how sNfL data predicted 4-year values of brain volume, expanded disability status scale score, and T2 lesions. sNfL levels were assessed in those receiving placebo, peginterferon beta-1a, and those with disease activity. Results: Baseline sNfL was a predictor of 4-year brain atrophy and development of new T2 lesions. Clinical ( p = 0.02) and magnetic resonance imaging (MRI) ( p Conclusion: These data support sNfL as a prognostic and disease-monitoring biomarker for RRMS.

Methamphetamine-associated cardiomyopathy is the leading cause of death linked with illicit drug use. Here we show that Sigmar1 is a therapeutic target for methamphetamine-associated cardiomyopathy and defined the molecular mechanisms using autopsy samples of human hearts, and a mouse model of “binge and crash” methamphetamine administration. Sigmar1 expression is significantly decreased in the hearts of human methamphetamine users and those of “binge and crash” methamphetamine-treated mice. The hearts of methamphetamine users also show signs of cardiomyopathy, including cellular injury, fibrosis, and enlargement of the heart. In addition, mice expose to “binge and crash” methamphetamine develop cardiac hypertrophy, fibrotic remodeling, and mitochondrial dysfunction leading to contractile dysfunction. Methamphetamine treatment inhibits Sigmar1, resulting in inactivation of the cAMP response element-binding protein (CREB), decreased expression of mitochondrial fission 1 protein (FIS1), and ultimately alteration of mitochondrial dynamics and function. Therefore, Sigmar1 is a viable therapeutic agent for protection against methamphetamine-associated cardiomyopathy., Chowdhury Abdulla and Richa Aishwarya et al. report that methamphetamine exposure in mice leads to cardiomyopathy via the signaling receptor Sigmar1. They find that methamphetamine inhibits Sigmar1, which alters mitochondrial function, and show that their findings are consistent with observations in hearts from human methamphetamine users.

BACKGROUND: Evidence of the effectiveness of treatment for obesity delivered in primary care settings in underserved populations is lacking. METHODS: We conducted a cluster-randomized trial to test the effectiveness of a high-intensity, lifestyle-based program for obesity treatment delivered in primary care clinics in which a high percentage of the patients were from low-income populations. We randomly assigned 18 clinics to provide patients with either an intensive lifestyle intervention, which focused on reduced caloric intake and increased physical activity, or usual care. Patients in the intensive-lifestyle group participated in a high-intensity program delivered by health coaches embedded in the clinics. The program consisted of weekly sessions for the first 6 months, followed by monthly sessions for the remaining 18 months. Patients in the usual-care group received standard care from their primary care team. The primary outcome was the percent change from baseline in body weight at 24 months. RESULTS: All 18 clinics (9 assigned to the intensive program and 9 assigned to usual care) completed 24 months of participation; a median of 40.5 patients were enrolled at each clinic. A total of 803 adults with obesity were enrolled: 452 were assigned to the intensive-lifestyle group, and 351 were assigned to the usual-care group; 67.2% of the patients were Black, and 65.5% had an annual household income of less than $40,000. Of the enrolled patients, 83.4% completed the 24-month trial. The percent weight loss at 24 months was significantly greater in the intensive-lifestyle group (change in body weight, −4.99%; 95% confidence interval [CI], −6.02 to −3.96) than in the usual-care group (−0.48%; 95% CI, −1.57 to 0.61), with a mean between-group difference of −4.51 percentage points (95% CI, −5.93 to −3.10) (P

The nucleotide exchange factor Son of Sevenless (SOS) catalyzes the activation of RAS by converting it from its inactive GDP-bound state to its active GTP-bound state. Recently, we have reported the discovery of small-molecule allosteric activators of SOS1 that can increase the amount of RAS-GTP in cells. The compounds can inhibit ERK phosphorylation at higher concentrations by engaging a feedback mechanism. To further study this process, we sought different chemical matter from an NMR-based fragment screen using selective methyl labeling. To aid this process, several Ile methyl groups located in different binding sites of the protein were assigned and used to categorize the NMR hits into different classes. Hit to lead optimization using an iterative structure-based design paradigm resulted in compounds with improvements in binding affinity. These improved molecules of a different chemical class increase SOS1cat-mediated nucleotide exchange on RAS and display cellular action consistent with our prior results.

There is an unmet need in multiple sclerosis (MS) therapy for treatments to stop progressive disability. The development of treatments may be accelerated if novel biomarkers are developed to overcome the limitations of traditional imaging outcomes revealed in early phase trials. In January 2019, the International Progressive MS Alliance convened a standing expert panel to consider potential tissue fluid biomarkers in MS in general and in progressive MS specifically. The panel focused their attention on neurofilament light chain (NfL) in serum or plasma, examining data from both relapsing and progressive MS. Here, we report the initial conclusions of the panel and its recommendations for further research. Serum NfL (sNfL) is a plausible marker of neurodegeneration that can be measured accurately, sensitively, and reproducibly, but standard procedures for sample processing and analysis should be established. Findings from relapsing and progressive cohorts concur and indicate that sNfL concentrations correlate with imaging and disability measures, predict the future course of the disease, and can predict response to treatment. Importantly, disease activity from active inflammation (i.e., new T2 and gadolinium-enhancing lesions) is a large contributor to sNfL, so teasing apart disease activity from the disease progression that drives insidious disability progression in progressive MS will be challenging. More data are required on the effects of age and comorbidities, as well as the relative contributions of inflammatory activity and other disease processes. The International Progressive MS Alliance is well positioned to advance these initiatives by connecting and supporting relevant stakeholders in progressive MS.

Objective Accelerated brain volume loss has been noted following immunoablative autologous hematopoietic stem cell transplantation (IAHSCT) for multiple sclerosis. As with other MS treatments, this is often interpreted as ‘pseudoatrophy’, related to reduced inflammation. Treatment‐related neurotoxicity may be contributory. We sought objective evidence of post‐IAHSCT toxicity by quantifying levels of Neurofilament Light Chain (sNfL) and Glial Fibrillary Acidic Protein (sGFAP) before and after treatment as markers of neuroaxonal and glial cell damage. Methods Sera were collected from 22 MS patients pre‐ and post‐IAHSCT at 3, 6, 9, and 12 months along with 28 noninflammatory controls. sNfL and sGFAP quantification was performed using the SiMoA single‐molecule assay. Results Pre‐IAHSCT levels of sNfL and sGFAP were elevated in MS patients compared with controls (geometric mean sNfL 21.8 vs. 6.4 pg/mL, sGFAP 107.4 vs. 50.7 pg/mL, P = 0.0001 for both). Three months after IAHSCT, levels of sNfL and sGFAP increased from baseline by 32.1% and 74.8%, respectively (P = 0.0029 and 0.0004). sNfL increases correlated with total busulfan dose (P = 0.034), EDSS score worsening at 6 months (P = 0.041), and MRI grey matter volume loss at 6 months (P = 0.0023). Subsequent NfL levels reduced to less than baseline (12‐month geometric mean 11.3 pg/mL P = 0.0001) but were still higher than controls (P = 0.0001). sGFAP levels reduced more slowly but at 12 months were approaching baseline levels (130.7 pg/mL). Interpretation There is direct evidence of transient CNS toxicity immediately after IAHSCT which may be chemotherapy mediated and contributes to transient increases in MRI atrophy.

We examined knowledge of Alzheimer’s disease and related dementias (ADRD), resources, and research opportunities among older African American (AA) and Caucasian caregivers. A mixed methods design integrated qualitative (focus group) and quantitative (survey) data from Northwest Louisiana. Eight focus groups (59 adults, 92% female, 78% AA, 25% rural) revealed limited knowledge. Quantitative findings from 117 ADRD caregivers (83% female, 72% AA, 30% limited heath literacy, 27% low income) indicated participants obtained information from providers (54%), friends and relatives (32%), and the internet (37%). Barriers to care were cost (24%) and lack of family agreement (17%). Few families used adult daycare (8%) or support groups (28%). Concerns about research participation were violation of privacy (30%) and fear of patient distress (27%). Distrust of doctors was minimal (3%). Findings did not vary by race. There is a need for clear, literacy-appropriate information about ADRD, caregiver resources, and clinical trials.

Background and ObjectivesLittle is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis (MS). We performed metagenomic analyses using stool samples from individuals with pediatric-onset MS and unaffected controls.MethodsPersons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty patients with MS (McDonald criteria) with symptom onset ResultsIndividuals with MS were aged 13.6 years (mean) at symptom onset and 8 were DMD-naive. Mean ages at stool sample were 16.1 and 15.4 years for MS and control participants, respectively; 80% were girls. Alpha diversity of enzymes and proteins did not differ by disease or DMD status (p > 0.20), but metabolic pathways, gene annotations, and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio 10, p = 0.044) and Methanobrevibacter abundance (log2 fold change [LFC] 1.7, p = 0.0014), but lower homolactic fermentation abundance (LFC −0.48, p = 0.039). Differences by DMD status included lower phosphate butyryl transferase for DMD-naive vs exposed patients with MS (LFC −1.0, p = 0.033).DiscussionThe gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS vs controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.

ObjectiveThis study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).BackgroundPrevious post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.Design/MethodsIn this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup.ResultsHigh versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both pConclusionThis study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients.

Purpose: The aim of this study was to determine the prevalence of any and chronic tinnitus among female and male individuals from varied Hispanic/Latino backgrounds and to estimate associations between risk factors for chronic tinnitus. Method: Our analysis used cross-sectional baseline data collected from 2008 to 2011 from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). Prevalence estimates and multivariable logistic regression were conducted using survey methodology. Participants included 15,768 adults (8,229 women and 7,539 men) aged 18–76 years. The primary outcome of interest was chronic tinnitus, defined as self-reported tinnitus lasting ≥ 5 min at a time and at least once per week. We hypothesized that after adjusting for covariates, the risk factors of depressed and anxious symptoms, smoking history, hypertension, and noise exposure history would be associated with higher odds of chronic tinnitus. Results: Unstratified prevalence for any tinnitus was 32.9%, and for chronic tinnitus, it was 12.1%. Sex-stratified results demonstrated that 2,995 female individuals (36.4%) and 2,187 male individuals (29.0%) reported any tinnitus, and of these, 1,043 female individuals (12.7%) and 870 male individuals (11.5%) reported chronic tinnitus. In the fully adjusted model, depressed and anxious symptoms as well as recreational noise exposure were associated with higher odds of chronic tinnitus in female individuals (odds ratios [ ORs ] = 1.06, confidence interval [CI; 1.04, 1.07]; 1.02, CI [1.01, 1.04]; and 1.40, CI [1.20, 1.62]) and in male individuals ( OR s = 1.06, CI [1.03, 1.08]; 1.05, CI [1.02, 1.08]; and 1.30, CI [1.05, 1.65]). Current smoking was a risk factor for chronic tinnitus in male individuals ( OR = 1.53, CI [1.16, 2.02]). Conclusions: Prevalence of any and chronic tinnitus in the HCHS/SOL baseline cohort is higher than that reported in previous studies, particularly among female individuals. Understanding risk factors associated with tinnitus is important for the development of culturally and linguistically appropriate public health programs that consider sex differences and promote lifestyle modifications known to lower the odds of experiencing tinnitus.

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Funding: Biogen.

Examine COVID-19 knowledge, concerns, behaviors, stress, and sources of information among patients in a safety-net health system in Louisiana. Research assistants surveyed participants via structured telephone interviews from April to October 2020. The data presented in this study were obtained in the pre-vaccine availability period. Of 623 adult participants, 73.5% were female, 54.7% Black, and 44.8% lived in rural small towns; mean age was 48.69. Half (50.5%) had spoken to a healthcare provider about the virus, 25.8% had been tested for COVID-19; 11.4% tested positive. Small town residents were less likely to be tested than those in cities (21.1% vs 29.3%, p = 0.05). Knowledge of COVID-19 symptoms and ways to prevent the disease increased from (87.9% in the spring to 98.9% in the fall, p

The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC.

This study aimed to evaluate the laboratory-related outcomes of participants who were offered genomic testing based on cancer family history risk assessment tools.Patients from clinics that serve populations with access barriers, who are screened at risk for a hereditary cancer syndrome based on adapted family history collection tools (the Breast Cancer Genetics Referral Screening Tool and PREMMOf all the participants, 87% successfully returned a saliva kit. Overall, 5% had a pathogenic/likely pathogenic cancer risk variant and 1% had a secondary finding. Almost all (14/15, 93%) participants completed recommended consultations with nongenetics providers after an average of 17 months. The recommended actions (eg, breast magnetic resonance imaging) were completed by 17 of 25 participants. Participant personal history of cancer and PREMMThis accessible model of hereditary cancer risk assessment and genetic testing yielded results that were often acted upon by patients and physicians.

Background: Therapeutic options for children with multiple sclerosis are scarce. Teriflunomide is approved in more than 80 countries for the treatment of adults with relapsing multiple sclerosis. The TERIKIDS study examined the safety and efficacy of teriflunomide in children with relapsing multiple sclerosis. Methods: The TERIKIDS trial was a multicentre, phase 3, double-blind, parallel-group, randomised, placebo-controlled study conducted at 57 clinical centres in 22 countries in Asia, Europe, the Middle East, North Africa, and North America. The trial enrolled patients aged 10–17 years, diagnosed with relapsing multiple sclerosis and with at least one relapse in the year preceding screening or at least two relapses in the 2 years preceding screening. Patients were randomly assigned (2:1) to oral teriflunomide (dosage equivalent to 14 mg in adults) or matching placebo, using an interactive web and voice response system, for up to 96 weeks. Personnel in all sites and all patients were masked to study treatment in the double-blind period. Early entry into a subsequent 96-week open-label extension phase was possible before the end of the double-blind period for patients with confirmed clinical relapse or high MRI activity (at least five new or enlarged T2 lesions at week 24, followed by at least nine new or enlarged T2 lesions at week 36, or at least five new or enlarged T2 lesions at weeks 36 and 48, or at weeks 48 and 72). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period. Key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Efficacy endpoints were analysed in the intention-to-treat population, and safety was assessed in all patients randomly assigned to treatment and exposed to the double-blind study medication. This study is registered with ClinicalTrials.gov (trial number NCT02201108) and is closed to recruitment, but an additional optional open-label extension is ongoing. Findings: Between July 24, 2014, and the date of last patient visit on Oct 25, 2019, 185 patients were screened for eligibility, 166 (90%) were enrolled, and 109 were randomly assigned teriflunomide and 57 were randomly assigned placebo. 102 (94%) of 109 and 53 (93%) of 57 completed the double-blind period. Switch to the ongoing open-label extension because of high MRI activity was more frequent than anticipated in the placebo group (14 [13%] of 109 patients in the teriflunomide group vs 15 [26%] of 57 in the placebo group), decreasing the power of the study. After 96 weeks, there was no difference in time to first confirmed clinical relapse with teriflunomide compared with placebo (hazard ratio 0·66, 95% CI 0·39–1·11; p=0·29). Teriflunomide reduced the number of new or enlarged T2 lesions versus placebo by 55% (relative risk 0·45, 95% CI 0·29–0·71; p=0·00061), and the number of gadolinium-enhancing lesions by 75% (relative risk 0·25, 0·13–0·51; p

Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low ( 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated.EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1.As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%).After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs.ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.

Pegvaliase is approved to reduce phenylalanine (Phe) levels for people with phenylketonuria (PKU). PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862) data were analyzed to evaluate the relationship between Phe and inattention in adult participants with PKU. In the modified-intent-to-treat population (N = 156), baseline mean (SE) plasma Phe was 1263 (29) μmol/L and the Attention Deficit Hyperactivity Disorder Rating Scale-IV Inattentive (IA) symptoms score was 9.8 (0.5). Mean (SE) IA scores fell 9.0 (1.1) in Quartile 1 (Phe reduction between 1166 and 2229 μmol/L) versus 4.3 (0.7) in Quartile 4 (Phe reduction of 139 μmol/L to increase of 934 μmol/L), p = 0.004. Least squares mean (SE) change from baseline IA score was -7.9 (0.7) for participants with final Phe ≤ 360 μmol/L and -4.5 (0.7) for final Phe > 360 μmol/L, p < 0.001. In the inattention subgroup, IA scores fell 13.3 (1.5) in Quartile 1 (Phe reduction between 1288 and 2229 μmol/L) versus 6.2 (1.3) in Quartile 4 (Phe reduction of 247 to increase of 934 μmol/L), p = 0.009. Inattention symptoms improved among those whose Phe levels decreased, particularly those with high baseline IA scores. IA improvements were larger among participants with the greatest plasma Phe reductions, supporting this value as a therapeutic goal.

Headache disorders in children and adolescents are common. Among the different headache disorders, migraine and tension headache are highly prevalent and often debilitating. Pharmacological treatments for pediatric patients are often not approved or effective. Practice guidelines for prevention of pediatric headache and migraine are now incorporating information and recommendations regarding non-pharmacologic therapeutic options. Understanding the mechanism of action, safety, and efficacy of the non-pharmacologic as well as mindful-based therapeutic alternatives currently available for the management and treatment of headache and migraine may allow additional treatment alternatives for children with these conditions.Studies have been published looking at non-pharmacologic treatments, and mindful-based approaches, namely relaxation, mindfulness meditation, yoga, and hypnosis as options for the treatment of headache and migraine, although there are few that examine these in children and adolescents. Several recent studies that have relevance to the care of children with headache and migraine are reviewed. Non-pharmacologic and mindful-based approaches for the prevention and treatment of headache and migraine in children show safety and efficacy data that is promising. Consider incorporating these multi-modal approaches into the therapeutic management strategies for the child or adolescent with headache and migraine. Additional prospective studies and/or randomized-controlled trials are necessary to further assess the efficacy and cost-effectiveness of these methods.

Key Points Question What features distinguish spinal cord involvement in children with myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), multiple sclerosis (MS), and seronegative monophasic myelitis? Findings In this cohort study of 107 children with acquired demyelinating syndromes, features distinguishing children with MOGAD from those with MS and seronegative myelitis included longitudinally extensive spinal cord lesions, complete cross-sectional involvement, H-sign, and leptomeningeal enhancement. Myelitis in MOGAD often demonstrates substantial clinical and radiological resolution; longitudinally extensive lesions were rare in children with MS and less frequent than previously reported. Meaning These findings suggest that MOGAD-associated myelitis is characterized by prominent gray matter and leptomeningeal involvement, features that may serve as useful diagnostic clues., This cohort study examines the clinical and magnetic resonance imaging (MRI) features and outcomes associated with spinal cord involvement in pediatric myelin oligodendrocyte glycoprotein antibody–associated disease, multiple sclerosis, and seronegative monophasic myelitis., Importance The recognition of magnetic resonance imaging (MRI) features associated with distinct causes of myelitis in children is essential to guide investigations and support diagnostic categorization. Objective To determine the clinical and MRI features and outcomes associated with spinal cord involvement in pediatric myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD), multiple sclerosis (MS), and seronegative monophasic myelitis. Design, Setting, and Participants In this cohort study, participants were recruited between 2004 and 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study, which enrolled youth younger than 18 years presenting within 90 days of an acquired demyelinating syndrome. Of the 430 participants recruited, those with lesions on available spine MRI and anti-MOG testing performed on archived samples obtained close to clinical presentation were selected. Participants with poor-quality images and final diagnoses of nondemyelinating disease, anti–aquaporin 4 antibody positivity, and relapsing seronegative myelitis were excluded. Data analysis was performed from December 2019 to November 2020. Main Outcomes and Measures Spinal cord involvement was evaluated on 324 MRI sequences, with reviewers blinded to clinical, serological, and brain MRI findings. Associated clinical features and disability scores at 5 years of follow-up were retrieved. Results were compared between groups. Results A total of 107 participants (median [IQR] age at onset, 11.14 [5.59-13.39] years; 55 girls [51%]) were included in the analyses; 40 children had MOGAD, 21 had MS, and 46 had seronegative myelitis. Longitudinally extensive lesions were very common among children with MOGAD (30 of 40 children [75%]), less common among those with seronegative myelitis (20 of 46 children [43%]), and rare in children with MS (1 of 21 children [5%]). Axial gray matter T2-hyperintensity (ie, the H-sign) was observed in 22 of 35 children (63%) with MOGAD, in 14 of 42 children (33%) with seronegative myelitis, and in none of those with MS. The presence of leptomeningeal enhancement was highly suggestive for MOGAD (22 of 32 children [69%] with MOGAD vs 10 of 38 children [26%] with seronegative myelitis and 1 of 15 children [7%] with MS). Children with MOGAD were more likely to have complete lesion resolution on serial images (14 of 21 children [67%]) compared with those with MS (0 of 13 children). Conclusions and Relevance These findings suggest that several features may help identify children at presentation who are more likely to have myelitis associated with MOGAD. Prominent involvement of gray matter and leptomeningeal enhancement are common in pediatric MOGAD, although the pathological underpinning of these observations requires further study.

Although deep networks have been shown to perform very well on a variety of medical imaging tasks, inference in the presence of pathology presents several challenges to common models. These challenges impede the integration of deep learning models into real clinical workflows, where the customary process of cascading deterministic outputs from a sequence of image-based inference steps (e.g. registration, segmentation) generally leads to an accumulation of errors that impacts the accuracy of downstream inference tasks. In this paper, we propose that by embedding uncertainty estimates across cascaded inference tasks, performance on the downstream inference tasks should be improved. We demonstrate the effectiveness of the proposed approach in three different clinical contexts: (i) We demonstrate that by propagating T2 weighted lesion segmentation results and their associated uncertainties, subsequent T2 lesion detection performance is improved when evaluated on a proprietary large-scale, multi-site, clinical trial dataset acquired from patients with Multiple Sclerosis. (ii) We show an improvement in brain tumour segmentation performance when the uncertainty map associated with a synthesised missing MR volume is provided as an additional input to a follow-up brain tumour segmentation network, when evaluated on the publicly available BraTS-2018 dataset. (iii) We show that by propagating uncertainties from a voxel-level hippocampus segmentation task, the subsequent regression of the Alzheimer's disease clinical score is improved.

OBJECTIVE Studies investigating hearing interventions under-utilise and under-report treatment fidelity planning, implementation, and assessment. This represents a critical gap in the field that has the potential to impede advancements in the successful dissemination and implementation of interventions. Thus, our objective was to describe treatment fidelity planning and implementation for hearing intervention in the multi-site Ageing and Cognitive Health Evaluation in Elders (ACHIEVE) randomised controlled trial. DESIGN Our treatment fidelity plan was based on a framework defined by the National Institutes of Health Behaviour Change Consortium (NIH BCC), and included strategies to enhance study design, provider training, and treatment delivery, receipt, and enactment. STUDY SAMPLE To assess the fidelity of the ACHIEVE hearing intervention, we distributed a checklist containing criteria from each NIH BCC core treatment fidelity category to nine raters. RESULTS The ACHIEVE hearing intervention fidelity plan satisfied 96% of NIH BCC criteria. Our assessment suggested a need for including clear, objective definitions of provider characteristics and non-treatment aspects of intervention delivery in future fidelity plans. CONCLUSIONS The ACHIEVE hearing intervention fidelity plan can serve as a framework for the application of NIH BCC fidelity strategies for future studies and enhance the ability of researchers to reliably implement evidence-based interventions.

Objectives: The purpose of this study was to determine the following: (1) the level of physical activity (PA) achieved during commercial active virtual reality (VR) games, and (2) which active VR g...

Objectives: We sought to determine what factors, including acculturation (language and social contact preferences), were associated with self-perceived hearing handicap among adults from Hispanic/Latino background. We utilized the Aday-Andersen behavioral model of health services utilization to frame our hypotheses that predisposing characteristics (age, sex, education, city of residence, Hispanic/Latino background, and acculturation), enabling resources (annual income and current health insurance coverage), and need (measured hearing loss and self-reported hearing loss) would be related to clinically-significant self-perceived hearing handicap as measured by the Hearing Handicap Inventory - Screening (HHI-S) version. Design: We analyzed baseline data collected from 2008 to 2011 as part of the multisite Hispanic Community Health Study/Study of Latinos. Data were from 6585 adults with hearing loss (defined by a worse-ear 500, 1000, 2000, and 4000 Hz pure-tone average [PTA] of ≥25 dB HL and/or a 4000, 6000, and 8000 Hz high-frequency PTA of ≥25 dB HL) aged 18 to 74 years from various Hispanic/Latino backgrounds. We conducted a series of multivariable logistic regression models examining the roles of independent variables of interest representing predisposing, enabling, and need indicators on the occurrence of clinically-significant self-perceived hearing handicap (e.g., HHI-S score > 8). Results: Among included participants, 953 (14.5%) had an HHI-S score >8. The final model revealed significant associations between predisposing characteristics, enabling resources, need, and HHI-S outcome. Predisposing characteristics and need factors were associated with higher odds of reporting self-perceived hearing handicap (HHI-S score >8) including acculturation as measured by the Short Acculturation Scale for Hispanics (odds ratio [OR] = 1.28, 95% confidence interval [CI]: 1.09-1.50), female sex (OR = 1.72, 95% CI: 1.27-2.33), and poorer worse ear 500, 1000, 2000, and 4000 Hz PTA (OR = 1.02, 95% CI: 1.01-1.03); suggesting that a 5-decibel increase in a person's PTA was consistent with 10% higher odds of a HHI-S score of >8. Greater enabling resources were associated with lower odds of reporting clinically-significant self-perceived hearing handicap: compared with individuals with income $75,000/year was 0.28 (95% CI: 0.13-0.59]; p-trend < 0.0001). Conclusions: Our findings suggest there are associations between predisposing, enabling and need variables consistent with the Aday-Andersen model and self-perceived hearing handicap among adults from Hispanic/Latino background. The influence of language and culture on perceived hearing loss and associated handicap is complex, and deserves more attention in future studies. Our findings warrant further investigation into understanding the role of language and language access in hearing health care utilization and outcomes, as the current body of literature is small and shows mixed outcomes.

ObjectiveWe compared the prevalence of physical and mental conditions and rate of health care utilization in mothers of children with multiple sclerosis (MS) (MS-mothers) with that of mothers of children without MS (non-MS-mothers).MethodsUsing population-based administrative data from Ontario, Canada, we identified MS-mothers and non-MS-mothers, matched on maternal age at childbirth, region, and the child's age and sex at the time of MS diagnosis. We compared the prevalence of any physical condition or any mood or anxiety disorder between the cohorts, in the child's MS diagnosis year, and 5 years before and after diagnosis. We compared rates of physician visits before diagnosis, during the diagnosis year, and after the child's diagnosis using multivariable regression models with generalized estimating equations adjusting for maternal age, socioeconomic status, region of residence, and index year.ResultsWe identified 156 MS-mothers and 624 non-MS-mothers. MS-mothers had a higher prevalence of any physical condition and of any mood or anxiety disorder than non-MS-mothers, before, during, and after their child's diagnosis. On multivariable analysis, MS-mothers did not have higher rates of primary care visits (rate ratio [RR] 1.04; 95% confidence interval [CI] 0.90–1.20), but exhibited increased odds of having any psychiatry visits (odds ratio 1.60; 95% CI 1.10–2.31); the rate of visits did not differ when they did occur (RR 0.66; 95% CI 0.33–1.30).ConclusionMothers of children with MS use more mental health services before and after their child's MS diagnosis than mothers of children without MS. Pediatric health care providers should consider the mental well-being of mothers and their children with MS.

Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF’s distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Ozanimod, a sphingosine 1-phosphate receptor modulator, selectively binds to receptor subtypes 1 and 5 with high affinity. The RADIANCE phase 2 study showed that ozanimod had better efficacy than placebo on MRI measures, with a favourable safety profile, in participants with relapsing multiple sclerosis. The SUNBEAM study aimed to assess the safety and efficacy of ozanimod versus intramuscular interferon beta-1a in participants with relapsing multiple sclerosis.SUNBEAM was a randomised, double-blind, double-dummy, active-controlled phase 3 trial done at 152 academic medical centres and clinical practices in 20 countries. We enrolled participants aged 18-55 years with relapsing multiple sclerosis, baseline expanded disability status scale (EDSS) score of 0·0-5·0, and either at least one relapse within the 12 months before screening or at least one relapse within 24 months plus at least one gadolinium-enhancing lesion within 12 months before screening. Participants were randomly assigned 1:1:1 by a blocked algorithm stratified by country and baseline EDSS score to at least 12 months treatment of either once-daily oral ozanimod 1·0 mg or 0·5 mg or weekly intramuscular interferon beta-1a 30 μg. Participants, investigators, and study staff were masked to treatment assignment. The primary endpoint was annualised relapse rate (ARR) during the treatment period and was assessed in the intention-to-treat population. Safety was assessed in all participants according to the highest dose of ozanimod received. This trial is registered at ClinicalTrials.gov, number NCT02294058 and EudraCT, number 2014-002320-27.Between Dec 18, 2014, and Nov 12, 2015, 1346 participants were enrolled and randomly assigned to ozanimod 1·0 mg (n=447), ozanimod 0·5 mg (n=451), or interferon beta-1a (n=448). 91 (6·8%) participants discontinued the study drug (29 in the ozanimod 1·0 mg group; 26 in the ozanimod 0·5 mg group; and 36 in the interferon beta-1a group). Adjusted ARRs were 0·35 (0·28-0·44) for interferon beta-1a, 0·18 (95% CI 0·14-0·24) for ozanimod 1·0 mg (rate ratio [RR] of 0·52 [0·41-0·66] vs interferon beta-1a; p0·0001), and 0·24 (0·19-0·31) for ozanimod 0·5 mg (RR 0·69 [0·55-0·86] vs interferon beta-1a; p=0·0013). Few ozanimod-treated participants discontinued treatment because of adverse events (13 [2·9%] who received ozanimod 1·0 mg; seven [1·5%] who received ozanimod 0·5 mg; and 16 [3·6%] who received interferon beta-1a). No first-dose, clinically significant bradycardia or second-degree or third-degree atrioventricular block was reported. The incidence of serious adverse events was low and similar across treatment groups (13 [2·9%] participants who received ozanimod 1·0 mg; 16 [3·5%] who received ozanimod 0·5 mg; and 11 [2·5%] who received interferon beta-1a). No serious opportunistic infections occurred in ozanimod-treated participants.In participants with relapsing multiple sclerosis treated for at least 12 months, ozanimod was well tolerated and demonstrated a significantly lower relapse rate than interferon beta-1a. These findings provide support for ozanimod as an oral therapy for individuals with relapsing multiple sclerosis.Celgene International II.

Purpose The majority of colorectal cancer (CRC) research using the fecal immunochemical test (FIT) has studied short-term screening results in predominantly urban areas. The purpose of this study was to evaluate the effectiveness of 2 outreach strategies embedded in a health literacy intervention on repeat CRC screening in rural community clinics. Methods A 2-arm randomized controlled trial was conducted in 4 rural clinics in Louisiana. During a regularly scheduled clinic visit, participants ages 50-75 received a FIT kit and brief educational intervention. Participants were randomized to receive an automated call or a personal call by a prevention counselor after 4 weeks and 8 weeks if FIT kits were not returned. In year 2, materials were mailed, and follow-up calls were conducted as in year 1. The primary outcome was repeat FIT-the return of the FIT kit in both years. Participants Of 568 eligible participants, 55% were female, 67% were African American, and 39% had low health literacy. Findings Repeat FIT rates were 36.5% for those receiving the automated call and 33.6% for those receiving a personal call (P = .30). No annual FITs were returned in 30% of participants, while only 1 FIT was returned by 35% of participants (31% only year 1 and 4% only year 2). Conclusion Sustaining CRC screening with FIT is challenging in rural clinics. A lower cost automated call was just as effective as the personal call in promoting repeat annual screening. However, more intensive strategies are needed to improve long-term FIT screening among rural participants.

Inborn errors of metabolism have traditionally been viewed as the quintessential single gene disorders; defects in one gene leads to loss of activity of one enzyme causing a metabolic imbalance and clinical disease. However, reality has never been quite that simple, and the classic "one gene-one enzyme" paradigm has been upended in many ways. Multiple gene defects can lead to the same biochemical phenotype, often with different clinical symptoms. Additionally, different mutations in the same gene can cause variable phenotypes, often most dramatic when a disease can be identified by pre-symptomatic screening. Moreover, response to therapy is not homogeneous across diseases and specific mutations. Perhaps the biggest deviation from traditional monogenic inheritance is in the setting of synergistic heterozygosity, a multigenic inheritance pattern in which mutations in multiple genes in a metabolic pathway lead to sufficient disruption of flux through the pathway, mimicking a monogenic disorder caused by homozygous defects in one gene in that pathway. In addition, widespread adoption of whole exome and whole genome sequencing in medical genetics has led to the realization that individual patients with apparently hybrid phenotypes can have mutations in more than one gene, leading to a mixed genetic disorder. Each of these situations point to a need for as much precision as possible in diagnosing metabolic disease, and it is likely to become increasingly critical to drive therapy. This article examines examples in traditional monogenic disorders that illustrates these points and define inborn errors of metabolism as complex genetic traits on the leading edge of precision medicine.