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Kerri A Schoedel,1 Sarah A Morrow,2 Edward M Sellers3,4 1Altreos Research Partners, Inc., Toronto, 2Western University, London, 3DL Global Partners, Inc., Toronto, 4University of Toronto, Toronto, Ontario, Canada Abstract: Pseudobulbar affect (PBA) is a common manifestation of brain pathology associated with many neurological diseases, including amyotrophic lateral sclerosis, Alzheimer’s disease, stroke, multiple sclerosis, Parkinson’s disease, and traumatic brain injury. PBA is defined by involuntary and uncontrollable expressed emotion that is exaggerated and inappropriate, and also incongruent with the underlying emotional state. Dextromethorphan/quinidine (DM/Q) is a combination product indicated for the treatment of PBA. The quinidine component of DM/Q inhibits the cytochrome P450 2D6-mediated metabolic conversion of dextromethorphan to its active metabolite dextrorphan, thereby increasing dextromethorphan systemic bioavailability and driving the pharmacology toward that of the parent drug and away from adverse effects of the dextrorphan metabolite. Three published efficacy and safety studies support the use of DM/Q in the treatment of PBA; significant effects were seen on the primary end point, the Center for Neurologic Study-Lability Scale, as well as secondary efficacy end points and quality of life. While concentration–effect relationships appear relatively weak for efficacy parameters, concentrations of DM/Q may have an impact on safety. Some special safety concerns exist with DM/Q, primarily because of the drug interaction and QT prolongation potential of the quinidine component. However, because concentrations of dextrorphan (which is responsible for many of the parent drug’s side effects) and quinidine are lower than those observed in clinical practice with these drugs administered alone, some of the perceived safety issues may not be as relevant with this low dose combination product. However, since patients with PBA have a variety of other medical problems and are on numerous other medications, they may not tolerate DM/Q adverse effects, or may be at risk for drug interactions. Some caution is warranted when initiating DM/Q treatment, particularly in patients with underlying risk factors for torsade de pointes and in those receiving medications that may interact with DM/Q. Keywords: clinical pharmacology, Nuedexta, drug interactions, CYP2D6, QTc interval, CNS-LS

Blayne Welk,1 Sarah A Morrow,2 Wendy Madarasz,3 Patrick Potter,4 Keith Sequeira41Department of Surgery, Division of Urology, 2Department of Clinical Neurosciences, Western University, London, ON, Canada; 3St Joseph's Health Care, London Ontario, Canada; 4Department of Physical Medicine and Rehabilitation, Western University, London, ON, CanadaBackground: There is no single patient-reported instrument that was developed specifically to assess symptoms and bladder-related consequences for neurogenic bladder dysfunction. The purpose of this study was to identify and consolidate items for a novel measurement tool for this population.Methods: Item generation was based on a literature review of existing instruments, open-ended semistructured interviews with patients, and expert opinion. Judgment-based item reduction was performed by a multidisciplinary expert group. The proposed questionnaire was sent to external experts for review.Results: Eight neurogenic quality of life measures and 29 urinary symptom-specific instruments were identified. From these, 266 relevant items were extracted and used in the creation of the new neurogenic symptom score. Qualitative interviews with 16 adult patients with neurogenic bladder dysfunction as a result of spinal cord injury, multiple sclerosis, or spina bifida were completed. Dominant themes included urinary incontinence, urinary tract infections, urgency, and bladder spasms. Using the literature review and interview data, 25 proposed items were reviewed by 12 external experts, and the questions evaluated based on importance on a scale of 1 (not important) to 5 (very important). Retained question domains had high mean importance ratings of 3.1 to 4.3 and good agreement with answer hierarchy.Conclusion: The proposed neurogenic bladder symptom score is a novel patient-reported outcome measure. Further work is underway to perform a data-based item reduction and to assess the validity and reliability of this instrument.Keywords: urinary bladder, neurogenic, questionnaires, quality of life, outcome assessment, health status indicators, lower urinary tract symptoms

Rationale: Lungs of adult mice exposed to hyperoxia as newborns are simplified and exhibit reduced function much like that observed in people who had bronchopulmonary dysplasia (BPD) as infants. Because survivors of BPD also show increased risk for symptomatic respiratory infections, we investigated how neonatal hyperoxia affected the response of adult mice infected with influenza A virus infection.Objectives: To determine whether neonatal hyperoxia increased the severity of influenza A virus infection in adult mice.Methods: Adult female mice exposed to room air or hyperoxia between Postnatal Days 1 and 4 were infected with a sublethal dose of influenza A virus.Measurements and Main Results: The number of macrophages, neutrophils, and lymphocytes observed in airways of infected mice that had been exposed to hyperoxia as neonates was significantly greater than in infected siblings that had been exposed to room air. Enhanced inflammation correlated with increased levels of monocyte chemotactic protein-1 (CCL2) in lavage fluid, whereas infection-associated changes in IFN-gamma, IL-1beta, IL-6, tumor necrosis factor-alpha, KC, granulocyte-macrophage colony-stimulating factor, and macrophage inflammatory protein-1alpha, and production of virus-specific antibodies, were largely unaffected. Increased mortality of mice exposed to neonatal hyperoxia occurred by Day 14 of infection, and was associated with persistent inflammation and fibrosis.Conclusions: These data suggest that the disruptive effect of hyperoxia on neonatal lung development also reprograms key innate immunoregulatory pathways in the lung, which may contribute to exacerbated pathology and poorer resistance to respiratory viral infections typically seen in people who had BPD. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Despite this, genetic drivers of BPD are poorly understood. The objective of this study is to better understand the impact of single nucleotide polymorphisms (SNPs) previously associated with BPD by examining associations with other phenotypes. We drew pediatric subjects from the biorepository at the Center for Applied Genomics to identify associations between these SNPs and 2,146 imputed phenotypes. Methylation data, external cohorts, and in silico validation methods were used to corroborate significant associations. We identified 60 SNPs that were previously associated with BPD. We found a significant association between rs3771150 and rs3771171 and mean eosinophil percentage in a European cohort of 6,999 patients and replicated this in external cohorts. Both SNPs were also associated with asthma, COPD and FEV1/FVC ratio. These SNPs displayed associations with methylation probes and were functionally linked to ST2 (IL1RL1) levels in blood and lung tissue. Our findings support a genetic justification for the epidemiological link between BPD and asthma. Given the well-established link between ST2 and type 2 inflammation in asthma, these findings provide a rationale for future studies exploring the role of type 2 inflammation in the pathogenesis of BPD., (© 2024. The Author(s).)

Cognitive symptoms affect disease management and activities of daily living for people living with multiple sclerosis (MS). This summary of research article summarises previously published discussions ('What is the true impact of cognitive impairment for people living with multiple sclerosis? A commentary of symposium discussions at the 2020 European Charcot Foundation') from the 2020 European Charcot Foundation meeting between a patient expert living with MS, a neuropsychologist and a neurologist about the impact of cognitive impairment on people living with MS. These discussions highlighted that cognitive impairment may be under-prioritised in MS care and has a substantial impact on the daily lives of people living with MS. To address this, the panel recommended improved awareness about impaired cognition in MS, improved communication between people living with MS and healthcare professionals, and routine cognition screening. This will help improve management of cognitive symptoms to maximise the quality of life of people living with MS., (© 2024. The Author(s).)

Introduction: Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy., Methods: Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features., Results: People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls., Conclusion: Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy., (© 2024. The Author(s).)

Background: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient., Objective: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting., Methods: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed., Results: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized β = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized β = -0.14, p = 0.028) in a linear regression model., Conclusions: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert Zivadinov has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Protembis, Filterlex and Novartis for speaking and consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Protembis, CorEvitas and V-WAVE Medical. Niels Bergsland and Dejan Jakimovski have nothing to disclose. Myassar Zarif, Samuel Hunter, Stephen Newman, Tom Fuchs and Mary Ann Picone have not declared any conflict of interest. Bianca Weinstock-Guttman received honoraria as a speaker and/or as a consultant for Biogen Idec, Sanofi &Genzyme, Genentech, Novartis, BMS, Bayer, Horizon and Janssen. Dr Weinstock-Guttman received research funds from Biogen Idec, Genentech and Novartis. Lorena Lorefice received honoraria for consultancy and speaking from Biogen, Novartis, Sanofi, Genzyme, Merck and Bristol Myers Squibb. Menno Schoonheim: Serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck. Sarah A. Morrow, in the last 3 years, has served as an advisory board member or received consulting fees from Biogen Idec; BMS/Celgene; EMDSerono; Novartis; Roche; Sanofi. She has participated in a speaker’s bureau for Biogen Idec; BMS/Celgene; EMDSerono; Novartis; Roche; Sanofi. She has received research support from Biogen Idec; EMDSerono, Novartis, Roche; Sanofi Genzyme. She has participated as a site investigator in clinical trials sponsored by Bristol Myers Squibb/Celgene; EMDSerono; Novartis; Roche; Sanofi. Gabriel Pardo received grants (to the institution) from Biogen, EMD Serono, Roche/Genentech, Sanofi Genzyme, Novartis, Abbvie, and BMS; consultant and/or speaker bureau for Biogen, EMD Serono, Roche/Genentech, Sanofi Genzyme, Novartis, Janssen, BMS, TG Therapeutics, PRIME Education, and MSAA. Mark Gudesblatt received honoraria from Biogen and Genentech. Jacqueline Nicholas received research grants from Biogen, Novartis, PCORI, Genentech, University of Buffalo, EMD Serono; Consulting for EMD Serono, Genentech, Greenwich Biosciences, Novartis, TG Therapeutics and Sanofi; Speaking honoraria for BMS, EMD Serono, Horizon, TG Therapeutics. Andrew Smith received honorariums from EMD Serono and Sanofi Genzyme for speaking bureau and combination for Genzyme for an advisory board. Mahmoud A. AbdelRazek received consultant fees from Bristol Myers Squibb. Wachy Vongchucherd, Jon Riolo and Diego Silva are employees of Bristol Myers Squibb. Michael G. Dwyer has received personal compensation from Bristol Myers Squibb and Filterlex for consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, Octave, Mapi Pharma, Protembis, CorEvitas and V-WAVE Medical. Ralph HB. Benedict has received consultation or speaking fees from Bristol Myer Squibb, Biogen, Merck, EMD Serono, Roche, Immune Therapeutics, Novartis, and Sanofi-Genzyme., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Multiple sclerosis (MS) is a chronic, neurodegenerative, inflammatory condition usually associated with physical disability. Clinical care has been skewed toward the physical manifestations of the disease, yet a range of silent symptoms occurs including the cognitive aspects of MS. In a 2018 meeting of MS in the 21st Century (MS21), an international steering committee comprising both specialists and patient experts recognised that the 'invisible symptoms' of MS pose a significant challenge to patient engagement. These findings prompted the European Charcot Foundation (ECF) MS21 symposium (2020), where a panel consisting of two leading MS clinicians and an MS patient expert (who were all members of the MS21 steering group) gathered to discuss the impact of cognitive impairment on the everyday lives of people with MS.The perspectives and experiences of the panellists are summarised in this paper. The key points raised were that (1) the cognitive manifestations of MS are under-recognised and have consequently been undermanaged from a clinical perspective and (2) cognitive impairment due to MS has a significant impact upon daily living and patient quality of life. During discussions about how these challenges can be addressed, the panel advocated for an improvement in education about cognitive symptoms for people living with MS and healthcare professionals (HCPs) to raise awareness about this aspect of MS. Furthermore, the panel emphasised the importance of open and proactive communication between HCPs and their patients with MS about cognitive symptoms to reduce the stigma attached to these symptoms. In the opinion of the panel, future clinical trials which include cognitive outcomes as key endpoints are needed. Reflecting this point, cognitive impairment in MS care also needs to be treated as an important disease symptom, as is done with physical symptoms of the disease. Implementing early and routine cognition screening and promoting measures for protecting cognition to people living with MS, such as cognitive rehabilitation and a 'brain-healthy' lifestyle, are actions which can drive forward the recognition of cognitive impairment as a care priority.If prioritised as highly as physical disability in both the MS care and clinical drug development setting, and proactively discussed in conversations between HCPs and patients with MS, the 'invisibility' of cognitive impairment in MS can be lifted and a better quality of life can be promoted for people living with MS., (© 2023. The Author(s).)

Many medical organizations have begun to confront the longstanding problem of inequalities in health care delivery and the undeniable effect of disparities on health outcomes. The Consortium of Multiple Sclerosis Centers (CMSC) recognizes that disparities affect the lives of many people with multiple sclerosis (MS) and acknowledges the need to address this as an organization. The CMSC recently (1) appointed a task force, (2) conducted a survey of its membership, (3) commissioned this review article and call to action, and (4) formulated a mission statement on diversity, equity, and inclusion (DEI), which was adopted by the CMSC's Board of Governors in March 2023. This paper summarizes recent literature on health care disparities in MS, particularly those relating to race/ethnicity, sexual orientation, and gender identity. It presents findings from CMSC's survey of members' awareness of DEI issues, the need for education and resources for MS care providers, and existing institutional policies on DEI in the members' practice settings. It also presents the task force's recommendations for next steps, which includes the goal of greater diversity in the MS workforce of the future. The CMSC will continue to revisit DEI policies and practices over time with the goal of motivating greater awareness, momentum, and positive changes within the MS community., Competing Interests: CONFLICTS OF INTEREST: The authors have no conflicts of interest to disclose. FINANCIAL DISCLOSURE: Medical writer Katherine Wandersee received compensation from the CMSC for assisting members of the task force in completing the manuscript., (© 2023 Consortium of Multiple Sclerosis Centers.)

Bacterial pneumonia in neonates can cause significant morbidity and mortality when compared to other childhood age groups. To understand the immune mechanisms that underlie these age-related differences, we employed a mouse model of Escherichia coli pneumonia to determine the dynamic cellular and molecular differences in immune responsiveness between neonates (PND 3-5) and juveniles (PND 12-18), at 24, 48, and 72 hr. Cytokine gene expression from whole lung extracts was also quantified at these time points, using quantitative RT-PCR. E. coli challenge resulted in rapid and significant increases in neutrophils, monocytes, and γδT cells, along with significant decreases in dendritic cells and alveolar macrophages in the lungs of both neonates and juveniles. E. coli -challenged juvenile lung had significant increases in interstitial macrophages and recruited monocytes that were not observed in neonatal lungs. Expression of IFNγ-responsive genes was positively correlated with the levels and dynamics of MHCII-expressing innate cells in neonatal and juvenile lungs. Several facets of immune responsiveness in the wild-type neonates were recapitulated in juvenile MHCII -/- juveniles. Employing a pre-clinical model of E. coli pneumonia, we identified significant differences in the early cellular and molecular dynamics in the lungs that likely contribute to the elevated susceptibility of neonates to bacterial pneumonia and could represent targets for intervention to improve respiratory outcomes and survivability of neonates., Competing Interests: SM, JV, RN, NM, JP, BS, RC, MS, AS No competing interests declared, (© 2023, McGrath-Morrow et al.)

Bacterial pulmonary infections are a major cause of morbidity and mortality in neonates, with less severity in older children. Previous studies demonstrated that the DNA of CD4 + T cells in the mouse lung, whose primary responsibility is to coordinate the immune response to foreign pathogens, is differentially methylated in neonates compared with juveniles. Nevertheless, the effect of this differential DNA methylation on CD4 + T cell gene expression and response to infection remains unclear. Here we treated E. coli-infected neonatal (4-day-old) and juvenile (13-day-old) mice with decitabine (DAC), a DNA methyltransferase inhibitor with broad-spectrum DNA demethylating activity, and performed simultaneous genome-wide DNA methylation and transcriptional profiling on lung CD4 + T cells. We show that juvenile and neonatal mice experienced differential demethylation in response to DAC treatment, with larger methylation differences observed in neonates. By cross-filtering differentially expressed genes between juveniles and neonates with those sites that were demethylated in neonates, we find that interferon-responsive genes such as Ifit1 are the most down-regulated methylation-sensitive genes in neonatal mice. DAC treatment shifted neonatal lung CD4 + T cells toward a gene expression program similar to that of juveniles. Following lung infection with E. coli, lung CD4 + T cells in neonatal mice exhibit epigenetic repression of important host defense pathways, which are activated by inhibition of DNA methyltransferase activity to resemble a more mature profile., (© 2023. The Author(s).)

Objective: The literature that has examined healthcare access and needs of the multiple sclerosis (MS) population is limited. Currently, no research has engaged healthcare providers delivering services to this population to examine their perspectives on the provision of MS care in Canada. We aimed to summarize what good MS care should look like according to Canadian healthcare providers working with people with MS, and to identify the supports and resources required, within their care setting, to enable this standard of care., Methods: A qualitative descriptive approach was taken to analyze data from participants who responded to additional open-ended survey questions, within a larger "MS Models of Care Survey" targeting Canadian healthcare providers working with persons with MS., Results: Currently, a gap exists between what healthcare providers working with persons with MS believe MS care should encompass and what they are able to offer. Participants emphasized that their MS clinics are currently understaffed and patient-to-provider ratios are high, leaving very little time to address the array of healthcare concerns their patients present with. The healthcare providers overwhelmingly described that moving toward multidisciplinary team-based MS care that includes appropriate numbers of MS-trained neurologists, nurses, physiotherapists, occupational therapists, and mental health providers working within one location would be their prioritized approach to comprehensively managing MS care. This model of care enables all professionals to effectively coordinate care and use their time efficiently by only focusing on their area of expertise, all while meeting the needs of their patient in one setting, reducing wait-times and improving overall care., Conclusion: To meet the care needs of Canadians with MS, the healthcare system must consider standardizing and funding multidisciplinary team-based MS clinics, comparable to Stroke units, which continue to show favorable health outcomes after years of implementation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Petrin, Marrie, Devonshire, Jichici, Hrebicek, Metz, Morrow, Oh, Smyth and Donkers.)

Background: Up to 90% of people with multiple sclerosis (PwMS) subjectively report fatigue as one of their worst symptoms. Fatigability is an objectively measured component of fatigue. Cognitive fatigability (CF) is a breakdown in task performance following sustained cognitive effort. There is a paucity of interventions targeting CF in MS. The prior success of behavioural interventions at improving subjective fatigue suggests that their adaptation may yield similar results for CF. Given the relationship between CF, sleep quality, and mood, a behavioural intervention targeting these factors, such as cognitive behavioural therapy (CBT), is warranted. Given the multidimensional nature of fatigue, a multifaceted approach targeting lifestyle factors and coping (e.g., fatigue management education supplemented by CBT for insomnia and exercise) might prove efficacious., Aim: We describe a protocol for a pilot feasibility study to design and implement a multi-dimensional behavioural intervention to improve CF in PwMS., Methods: Stage 1 : development of a multi-dimensional group-based videoconference-delivered behavioural intervention based on a previously successful fatigue management program for PwMS. A facilitator manual will be drafted. Course material will focus on four themes: body (sleep and physical activity), mood (impact of depression and anxiety), mind (cognitive contributions), and context (pacing and communication). Stage 2 : a needs assessment survey will be completed by 100 PwMS for input on what factors are important contributors to their CF. Modifications will be made to the course material and manual. Stage 3 : the facilitator-delivered intervention will include 20 PwMS. After baseline assessment, participants will attend weekly 70-min videoconference group sessions for 8 weeks, including homework assignments. Follow-up assessment will re-evaluate outcomes. Stage 4 : analysis and dissemination of results. The primary outcome is improvement in CF. Additional feasibility outcomes will determine if a randomized control trial (RCT) is pursued. Stage 5 : refine the intervention based on outcomes and feedback from participants. Determining which aspects participants felt were most effective will help inform RCT design., Conclusion: The long-term goal is to ensure that PwMS have access to effective interventions in real-world settings to improve quality of life and enhance their ability to participate in cognitively demanding activities that they enjoy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Walker, Berard, Islam, Pilutti, Morrow and Finlayson.)

Objective: Little work has evaluated integrated models of care in multiple sclerosis (MS) and the composition of MS care teams across Canada is largely unknown. We aimed to gather information regarding existing models of MS care across Canada, and to assess the perceptions of health care providers (HCPs) regarding the models of care required to fully meet the needs of the person with MS., Methods: We conducted an anonymous online survey targeting Canadian HCPs working in MS Clinics, and neurologists delivering MS care whether or not they were based in an MS Clinic. We queried the types of HCPs delivering care within formal MS Clinics, wait times for HCPs, the perceived importance of different types of HCPs for good quality care, assessments conducted, and whether clinic databases were used. We summarized survey responses using descriptive statistics., Results: Of the 716 HCPs to whom the survey was distributed, 100 (13.9%) people responded. Of the 100 respondents, 85 (85%) indicated that their clinical practice included people with MS and responded to specific questions about clinical care. The most common types of providers within MS Clinics with integrated models of care were neurologists and MS nurses. Of 23 responding MS Clinics, 10 (43.5%) indicated that there were not enough neurologists, and 16 (69.6%) indicated that there were not enough non-neurologist HCPs to provide adequate care. More than 50% of clinics reported wait times exceeding 3 months for physiatrists, physiotherapists, psychiatrists, psychologists, neuropsychologists and urologists; in some clinics wait times for these providers exceeded 1 year. Multiple disciplines were identified as important or very important for delivering good quality MS care. Over 90% of respondents thought it was important for neurologists, nurse practitioners, MS nurses and psychiatrists to be co-located within MS Clinics., Conclusion: Canadian HCPs viewed the ideal MS service as being multidisciplinary in nature and ideally integrated. Efforts are needed to improve timely access to specialized MS care in Canada, and to evaluate how outcomes are influenced by access to care., Competing Interests: RM receives research funding from: CIHR, Research Manitoba, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, Crohn's and Colitis Canada, National Multiple Sclerosis Society, CMSC. She is a co-investigator on a study funded in part by Biogen Idec and Roche Canada. She is supported by the Waugh Family Chair in Multiple Sclerosis. SD receives research funding from the: Canadian Institute of Health Research, Multiple Sclerosis Society of Canada, Saskatchewan Health Research Foundation, Saskatchewan Centre for Patient Oriented Research, Saskatchewan Ministry of Health, Branch Out Neurological Foundation, Praxis Spinal Cord Institute, and Canadian Partnership for Stroke Recovery. LM receives research funding from the MS Society of Canada, Brain Canada, Roche, Biogen Idec and the Government of Alberta. SM has in the past 3 years served on advisory boards for Biogen Idec, Bristol Myers Squibb/Celgene, EMD Serono, Novartis, Roche, Sanofi Genzyme, Teva Neurosciences; Received Investigator Initiated Grant Funds from MS Society of Canada, National MS Society and CIHR, as well as Biogen Idec, Novartis, Roche, Sanofi Genzyme; Acted as site PI for multi-center trials funded by AbbVie, Bristol Myers Squibb/Celgene, Novartis, Genzyme, Roche, Sanofi Genzyme. JO has received research funding from the MS Society of Canada, National MS Society, NIH, Brain Canada, Biogen-Idec, Roche, and EMD-Serono. She has received personal compensation for consulting or speaking from Biogen-Idec, BMS, EMD-Serono, Novartis, Roche, Sanofi-Genzyme, Roche, and Alexion. She is supported by the Waugh Family Chair in MS Research at the University of Toronto. PS has received unrestricted research support from Biogen-Idec; and has received consulting fees and honoraria for speaking activities from Biogen-Idec and Roche. She receives research funding from the MS Society of Canada, Brain Canada, Roche, Biogen Idec and the Government of Alberta. VD has received honoraria for speaking/advisory boards from Biogen, Serono, Roche, Sanofi-Genzyme, Novartis and Teva Neuroscience. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marrie, Donkers, Jichici, Hrebicek, Metz, Morrow, Oh, Pétrin, Smyth and Devonshire.)

Background: Patients with MS have an altered gut microbiota compared to healthy individuals, as well as elevated small intestinal permeability, which may be contributing to the development and progression of the disease., Objective: We sought to investigate if fecal microbiota transplantation was safe and tolerable in MS patients and if it could improve abnormal intestinal permeability., Methods: Nine patients with MS were recruited and provided monthly FMTs for up to six months. The primary outcome investigated was change in peripheral blood cytokine concentrations. The secondary outcomes were gut microbiota composition, intestinal permeability, and safety (assessed with EDSS and MRI)., Results: The study was terminated early and was subsequently underpowered to assess whether peripheral blood cytokines were altered following FMTs. FMTs were safe in this group of patients. Two of five patients had elevated small intestinal permeability at baseline that improved to normal values following FMTs. Significant, donor-specific, beneficial alterations to the MS patient gut microbiota were observed following FMT., Conclusion: FMT was safe and tolerable in this cohort of RRMS patients, may improve elevated small intestinal permeability, and has the potential to enrich for an MS-protective microbiota. Further studies with longer follow-up and larger sample sizes are required to determine if FMT is a suitable therapy for MS., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Ataxia telangiectasia (A-T) is a rare autosomal recessive disease caused by mutations in the ataxia telangiectasia mutated ( ATM ) gene. In the absence of a family history, the diagnosis of A-T is usually not made until the child is older and symptomatic. Classic A-T is characterized by a constellation of clinical symptoms including progressive ataxia, oculocutaneous telangiectasias and sinopulmonary disease and is usually associated with absence of ATM protein. Other laboratory features associated with A-T include elevated serum levels of alpha-fetoprotein (AFP) and increased chromosomal breakage with in vitro exposure to ionizing radiation. Sinopulmonary symptoms can occur to varying degrees across the lifespan. Some children will also have hypogammaglobulinemia and impaired antibody responses requiring supplemental gamma globulin. People with hypomorphic ATM mutations are often considered to have mild A-T with onset of ataxia and neurological progression occurring later in life with less impairment of the immune system. The risk of malignancy, however, is significantly increased in people with either classic or mild A-T. While hematological malignancies are most common in the first two decades of life, solid organ malignancies become increasingly common during young adulthood. Deterioration of neurologic function with age is associated with dysphagia with aspiration, growth faltering, loss of ambulation and decline in pulmonary function, morbidities that contribute to shortened life expectancy and decreased quality of life. Premature death is often due to malignancies or chronic respiratory insufficiency. A-T is currently managed with supportive care and symptomatic treatment. Current clinical trials, however, represent progress and hope towards disease-modifying therapies for A-T., Competing Interests: Professor Maureen A Lefton-Greif reports grants from National Institutes of Health (1R21TR003534), grants from Pediatric Clinical Research Center, grants from A-T Children’s Project, during the conduct of the study. Dr Howard M Lederman report grants from A-T Children’s Project, during the conduct of the study; contract to participate in a drug trial for A-T, and personal fees for serving on the medical advisory board from EryDel, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2021 McGrath-Morrow et al.)

Background: Ataxia telangiectasia (A-T) is a DNA repair disorder that affects multiple body systems. Neurological problems and immunodeficiency are two important features of this disease. At this time, two main severity groups are defined in A-T: classic (the more severe form) and mild. Poor growth is a common problem in classic A-T. An objective of this study was to develop growth references for classic A-T. Another objective was to compare growth patterns in classic A-T and mild A-T with each other and with the general population, using the CDC growth references. A final objective was to examine the effects of chronic infection on height., Results: We found that classic A-T patients were smaller overall, and suffered from height and weight faltering that continued throughout childhood and adolescence. When compared to the CDC growth references, the median heights and weights for both male and female patients eventually fell to or below the 3rd centile on the CDC charts. Height faltering was more pronounced in females. Birthweight was lower in the classic A-T group compared to mild A-T and the general population, whereas birth length was not. Finally, we investigated height and BMI faltering in relation to number of infections and found no association., Conclusions: Classic A-T appears to affect growth in utero. Although children appear to grow well in very early life, faltering begins early, and is unrelenting.

Background: Expanded Disability Status Scale (EDSS) scores of 4.0 or greater are determined primarily by maximum walking distance (MWD). Estimation of MWD by persons with multiple sclerosis (MS) is often used due to the impracticality of formally walking a person with MS in a clinic setting. Previous studies have demonstrated discrepancies between estimated and actual MWDs. Whether Timed 25-Foot Walk test (T25FW) values can be used to predict MWD is currently unknown. This study aimed to determine whether T25FW time is predictive of MWD in persons with MS., Methods: This study is a post hoc analysis of a previously described prospective cohort study. Persons with MS with an EDSS score of 3.5 to 5.5 were included. The participant's T25FW values and MWD were measured., Results: Of the 38 adult participants (mean age, 50.8 years; 27 women [71%]), 24 (63%) had relapsing-remitting MS. The median EDSS score was 4.5 (range, 3.5-5.5). The T25FW times were divided into seven categories (<5.0, 5.0-5.9, 6.0-6.9, 7.0-7.9, 8.0-8.9, 9.0-9.9, and ≥10.0 seconds). The MWDs were divided into corresponding EDSS score categories: ≥500, 300-499, 200-299, 100-199, and ≤99 m. Ordinal logistic regression, when controlled for age, found the T25FW categories to be predictive of EDSS score (χ 2 = 17.630, df = 7, P = .014)., Conclusions: The T25FW value may be used as a surrogate estimate of MWD. Further studies are needed to confirm the reliability of the T25FW in predicting MWD., Competing Interests: Financial Disclosures: Dr Berger is a consultant for Roche, EMD Serono, Sanofi Genzyme, Biogen, and Novartis and an advisory board member for Roche and Novartis. Dr Morrow has, in the past 3 years, served on advisory boards for Biogen, EMD Serono, Sanofi Genzyme Canada, Novartis, and Roche; has received investigator-initiated grant funds from Biogen, Novartis, and Roche; and has acted as site principal investigator for multicenter trials funded by Novartis, Genzyme, Roche, Adamas, and AbbVie. The other authors declare no conflicts of interest., (© 2020 Consortium of Multiple Sclerosis Centers.)

Importance: Cognitive impairment is a debilitating symptom of multiple sclerosis (MS) that affects up to 70% of patients. An improved understanding of the underlying pathology of MS-related cognitive impairment would provide considerable benefit to patients and clinicians., Objective: To determine whether there is an association between myelin damage in tissue that appears completely normal on standard clinical imaging, but can be detected by myelin water imaging (MWI), with cognitive performance in MS., Design, Setting, and Participants: In this cross-sectional study, participants with MS and controls underwent cognitive testing and magnetic resonance imaging (MRI) from August 23, 2017, to February 20, 2019. Participants were recruited through the University of British Columbia Hospital MS clinic and via online recruitment advertisements on local health authority websites. Cognitive testing was performed in the MS clinic, and MRI was performed at the adjacent academic research neuroimaging center. Seventy-three participants with clinically definite MS fulfilling the 2017 revised McDonald criteria for diagnosis and 22 age-, sex-, and education-matched healthy volunteers without neurological disease were included in the study. Data analysis was performed from March to November 2019., Exposures: MWI was performed at 3 T with a 48-echo, 3-dimensional, gradient and spin-echo (GRASE) sequence. Cognitive testing was performed with assessments drawn from cognitive batteries validated for use in MS., Main Outcomes and Measures: The association between myelin water measures, a measurement of the T2 relaxation signal from water in the myelin bilayers providing a specific marker for myelin, and cognitive test scores was assessed using Pearson correlation. Three white matter regions of interest-the cingulum, superior longitudinal fasciculus (SLF), and corpus callosum-were selected a priori according to their known involvement in MS-related cognitive impairment., Results: For the 95 total participants, the mean (SD) age was 49.33 (11.44) years. The mean (SD) age was 50.2 (10.7) years for the 73 participants with MS and 46.4 (13.5) for the 22 controls. Forty-eight participants with MS (66%) and 14 controls (64%) were women. The mean (SD) years of education were 14.7 (2.2) for patients and 15.8 (2.5) years for controls. In MS, significant associations were observed between myelin water measures and scores on the Symbol Digit Modalities Test (SLF, r = -0.490; 95% CI, -0.697 to -0.284; P < .001; corpus callosum, r = -0.471; 95% CI, -0.680 to -0.262; P < .001; and cingulum, r = -0.419; 95% CI, -0.634 to -0.205; P < .001), Selective Reminding Test (SLF, r = -0.444; 95% CI, -0.660 to -0.217; P < .001; corpus callosum, r = -0.411; 95% CI, -0.630 to -0.181; P = .001; and cingulum, r = -0.361; 95% CI, -0.602 to -0.130; P = .003), and Controlled Oral Word Association Test (SLF, r = -0.317; 95% CI, -0.549 to -0.078; P = .01; and cingulum, r = -0.335; 95% CI, -0.658 to -0.113; P = .006). No significant associations were found in controls., Conclusions and Relevance: This study used MWI to demonstrate that otherwise normal-appearing brain tissue is diffusely damaged in MS, and the findings suggest that myelin water measures are associated with cognitive performance. MWI offers an in vivo biomarker feasible for use in clinical trials investigating cognition, providing a means for monitoring changes in myelination and its association with symptom worsening or improvement.

Standardized magnetic resonance imaging (MRI) protocols are important for the diagnosis and monitoring of patients with multiple sclerosis (MS). The Consortium of Multiple Sclerosis Centers (CMSC) convened an international panel of MRI experts to review and update the current guidelines. The objective was to update the standardized MRI protocol and clinical guidelines for diagnosis and follow-up of MS and develop strategies for advocacy, dissemination, and implementation. Conference attendees included neurologists, radiologists, technologists, and imaging scientists with expertise in MS. Representatives from the CMSC, Magnetic Resonance Imaging in MS (MAGNIMS), North American Imaging in Multiple Sclerosis Cooperative, US Department of Veteran Affairs, National Multiple Sclerosis Society, Multiple Sclerosis Association of America, MRI manufacturers, and commercial image analysis companies were present. Before the meeting, CMSC members were surveyed about standardized MRI protocols, gadolinium use, need for diffusion-weighted imaging, and the central vein sign. The panel worked to make the CMSC and MAGNIMS MRI protocols similar so that the updated guidelines could ultimately be accepted by international consensus. Advocacy efforts will promote the importance of standardized MS MRI protocols. Dissemination will include publications, meeting abstracts, educational programming, webinars, "meet the expert" teleconferences, and examination cards. Implementation will require comprehensive and coordinated efforts to make the protocol easy to access and use. The ultimate vision, and goal, is for the guidelines to be universally useful, usable, and used as the standard of care for patients with MS., Competing Interests: Financial Disclosures: Dr Li has received grant/research support from the Multiple Sclerosis Society of Canada; is a consultant for Biogen, EMD Serono, Genzyme, Novartis, Nuron Biotech, Opexa, and Vertex Pharmaceuticals; is on the speakers’ bureaus for Genzyme, Novartis, and the CMSC; and is emeritus director of The University of British Columbia MS/MRI Research Group, which has been contracted to perform central analysis of MRIs for therapeutic trials with Chugai, Genzyme, Hoffmann-LaRoche, EMD Serono, Nuron Biotech, Perceptive Analytics, and Sanofi Aventis. Dr Banwell is a consultant for Novartis, UCB, and Roche Pharmaceuticals; has served as a nonremunerated advisor to Biogen and Teva Neuroscience; and receives grant funding from the NMSS, Multiple Sclerosis Society of Canada, and National Institutes of Health. Dr Barkhof reports financial relationships with Neurology, Brain, Radiology, Multiple Sclerosis Journal, and Neuroradiology Journal; personal fees from Springer, Biogen, Roche, IXICO Ltd, and Combinostics; personal fees and other from Bayer and GeNeuro; grants from Novartis, Teva Pharmaceutical, Merck, Biogen, IMI-EU, GE Healthcare, UK Multiple Sclerosis Society, Dutch MS Research Foundation, NWO, and the National Institute for Health Research. Dr Dunn holds a patent (USPTO # 10054588) for biomarker of MS treatment responsiveness; has ownership interest in Scientific Advisory Board and Progentec Diagnostics Inc; and received honoraria for consulting or lectures from Bristol Myers Squibb, Alexion, Novartis, Genzyme, and Roche Genentech. Dr Giri is an employee of Siemens Healthineers. Ms Maes is an employee of CorTechs Labs Inc. Dr Newsome receives consulting fees for scientific and board meetings from Biogen, Genentech, Celgene, EMD Serono, and Novartis; is an advisor for BioIncept and Autobahn Therapeutics; is a clinical adjudication committee member for a MedDay trial; and received research funding (paid directly to institution) from Biogen, Genentech, NMSS, Department of Defense, and Patient-Centered Outcomes Research Institute. Dr Paul receives honoraria for lecturing and travel expenses for attending meetings from Guthy-Jackson Charitable Foundation, Sanofi Genzyme, Novartis, Alexion, Viela Bio, Roche, UCB, Mitsubishi Tanabe, and Celgene, and his research is funded by the German Ministry for Education and Research, Deutsche Forschungsgemeinschaft, Einstein Foundation, Guthy-Jackson Charitable Foundation, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Biogen, Genzyme, Merck Serono, Novartis, Bayer, Teva Pharmaceutical, Alexion, Roche Parexel, and Almirall. Mr Quarterman is an employee of GE Healthcare. Dr Reich receives personal fees from Bounds Law Group LLC and Leventhal and Puga LLC and has a patent on system and method of automatically detecting tissue abnormalities (US Patent 9,607,392) issued, a patent on method of analyzing multisequence MRI data for analyzing brain abnormalities in a subject (US Patent 9,888,876) issued, a patent on automatic identification of subjects at risk of MS (US Patent application 16/254,710) pending, and a patent on high-resolution cerebrospinal fluid–suppressed T2*- weighted MRI of cortical lesions (US Patent application 62/838,578) pending. Dr Shinohara receives consulting fees from the American Medical Association/Emerson Collective for reviewership duties. Dr Van Hecke has ownership interest in icometrix. Dr van de Ven is an employee of Philips Healthcare. Dr Wallin has received grant funding from the NMSS, the VA Merit Review grant system, and Genentech; is a consultant for the RAND Corporation, the Centers for Disease Control and Prevention, and the Multiple Sclerosis International Federation. Dr Wolinsky receives royalties for out-licensed monoclonal antibodies through University of Texas Health from Millipore Corp; is the intellectual property rights/patent holder of US010363245B2 (Methods for Treating CNS Lesions/Board of Regents UT System); and receives consulting fees from Alkermes, Brainstorm Cell Therapeutics, EMD Serono, GW Pharmaceuticals, MedDay, NervGen, Novartis, Roche/Genentech, and Sanofi Genzyme. Dr Traboulsee receives consulting fees from Genzyme, Roche, and Novartis; is on the speakers’ bureaus for Genzyme and Roche; and is the principal investigator (contracted research) for clinical trials with Genzyme and Roche. The other authors declare no conflicts of interest., (© 2020 Consortium of Multiple Sclerosis Centers.)

People with ataxia-telangiectasia (A-T) display phenotypic variability with regard to progression of immunodeficiency, sino-pulmonary disease, and neurologic decline. To determine the association between differential gene expression, epigenetic state, and phenotypic variation among people with A-T, we performed transcriptional and genome-wide DNA methylation profiling in patients with mild and classic A-T progression as well as healthy controls. RNA and genomic DNA were isolated from peripheral blood mononuclear cells for transcriptional and DNA methylation profiling with RNA-sequencing and modified reduced representation bisulfite sequencing, respectively. We identified 555 genes that were differentially expressed among the control, mild A-T, and classic A-T groups. Genome-wide DNA methylation profiling revealed differential promoter methylation in cis with 146 of these differentially expressed genes. Functional enrichment analysis identified significant enrichment in immune, growth, and apoptotic pathways among the methylation-regulated genes. Regardless of clinical phenotype, all A-T participants exhibited downregulation of critical genes involved in B cell function (PAX5, CD79A, CD22, and FCRL1) and upregulation of several genes associated with senescence and malignancy, including SERPINE1. These findings indicate that gene expression differences may be associated with phenotypic variability and suggest that DNA methylation regulates expression of critical immune response genes in people with A-T.

Background and Purpose: Our aims were the following: 1) to compare multicontrast cortical lesion detection using 3T and 7T MR imaging, 2) to compare cortical lesion type frequency in relapsing-remitting and secondary-progressive MS, and 3) to assess whether detectability is related to the magnetization transfer ratio, an imaging marker sensitive to myelin content., Materials and Methods: Multicontrast 3T and 7T MR images from 10 participants with relapsing-remitting MS and 10 with secondary-progressive MS. We used the following 3T contrast sequences: 3D-T1-weighted, quantitative T1, FLAIR, magnetization-transfer, and 2D proton-density- and T2-weighted. We used the following 7T contrast sequences: 3D-T1-weighted, quantitative T1, and 2D-T2*-weighted., Results: Cortical lesion counts at 7T were the following: 720 total cortical lesions, 420 leukocortical lesions (58%), 27 intracortical lesions (4%), and 273 subpial lesions (38%). Cortical lesion counts at 3T were the following: 424 total cortical, 393 leukocortical (93%), zero intracortical, and 31 subpial (7%) lesions. Total, intracortical, and subpial 3T lesion counts were significantly lower than the 7T counts ( P < .002). Leukocortical lesion counts were not significantly different between scanners. Total and leukocortical lesion counts were significantly higher in secondary-progressive MS, at 3T and 7T ( P ≤ .02). Subpial lesions were significantly higher in secondary-progressive MS at 7T ( P = .006). The magnetization transfer ratio values of leukocortical lesions visible on both scanners were significantly lower than the magnetization transfer ratio values of leukocortical lesions visible only at 3T. No significant difference was found in magnetization transfer ratio values between subpial lesions visible only at 7T and subpial lesions visible on both 3T and 7T., Conclusions: Detection of leukocortical lesions at 3T is comparable with that at 7T MR imaging. Imaging at 3T is less sensitive to intracortical and subpial lesions. Leukocortical lesions not visible on 7T T2*-weighted MRI may be associated with less demyelination than those that are visible. Detectability of subpial lesions does not appear to be related to the degree of demyelination., (© 2019 by American Journal of Neuroradiology.)

Background: Pathological laughing and crying (PLC) encompasses episodes of involuntary laughing, crying, or both that are contextually incongruous with the individual's subjective mood. Despite a 10% to 46% prevalence in people with multiple sclerosis (MS) and reduced quality of life, localization of neuroanatomical lesions associated with PLC remains poorly delineated., Methods: The relationship between posterior fossa lesions and PLC in people with MS was examined using a retrospective medical record review of people with MS (2012-2016) who had completed the Center for Neurologic Study-Liability Scale (CNS-LS) and had undergone 1.5-T magnetic resonance imaging within 6 months of each other., Results: Medical record review identified 80 potential cases, with 77 included. Brainstem and cerebellar lesions were counted, measured, and compared between people with MS who had positive results on the CNS-LS (scores ≥17, n = 22) with those who had negative results on the CNS-LS (scores ≤16, n = 55). Initial χ 2 analysis showed no significant difference in lesion numbers in people with MS without (CNS-LS score ≤16) versus with (CNS-LS score ≥17) PLC. When analyzing only people with MS without evidence of depression, a significant inverse relationship was identified such that fewer posterior fossa lesions on automated magnetic resonance imaging was associated with the presence of PLC., Conclusions: Posterior fossa lesion load is not indicative of which individuals could develop PLC. Further investigations to delineate the primary source of PLC symptoms would aid in diagnosis and treatment of this condition., Competing Interests: Dr. Menon has disclosed relationships with Roche, EMD Serono, Sanofi (consulting fee); and Roche (contracted research). Dr. Morrow has disclosed relationships with Biogen, EMD Serono, Novartis, Roche, and Sanofi Genzyme (consulting fee, speakers' bureau, contracted research). The other authors declare no conflicts of interest.

Background: Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures., Methods: This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes., Discussion: If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD., Trial Registration: ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.

Emerging evidence suggests that adverse early life events can affect long-term health trajectories throughout life. Preterm birth, in particular, is a significant early life event that affects approximately 10% of live births. Worldwide, prematurity is the number one cause of death in children less than 5 years of age and has been shown to disrupt normal lung development with lasting effects into adult life. Along with impaired lung development, interventions used to support gas exchange and other sequelae of prematurity can lead to the development of bronchopulmonary dysplasia (BPD). BPD is a chronic respiratory disease of infancy characterized by alveolar simplification, small airways disease, and pulmonary vascular changes. Although many survivors of BPD improve with age, survivors of BPD often have chronic lung disease characterized by airflow obstruction and intermittent pulmonary exacerbations. Long-term lung function trajectories as measured by FEV1 can be lower in children and adults with a history BPD. In this review, we discuss the epidemiology and manifestations of BPD and its long-term consequences throughout childhood and into adulthood. Available evidence suggests that disrupted lung development, genetic susceptibility and subsequent environment and infectious events that occur in prenatal and postnatal life likely increase the predisposition of children with BPD to develop early onset chronic obstructive pulmonary disease (COPD). The reviews of this paper are available via the supplemental material section.

Introduction: Classic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid malignancies and telangiectasias. Prior studies have suggested that chronic inflammation and premature aging may contribute to the development of malignancy and pulmonary disease in people with A-T. To further examine the link between A-T and inflammation, we hypothesized that subjects with classic A-T would have greater enrichment of inflammatory pathways in peripheral blood mononuclear cells (PBMCs) compared to non A-T age-matched controls. To test this hypothesis we used RNAseq as an unsupervised approach to identify biological processes altered in people with classic A-T., Methods: PBMCs were isolated from subjects with classic A-T and compared to non-A-T age-matched healthy controls. RNAseq with differential gene expression analyses was then performed. Selected genes were validated by RT-qPCR using cohorts of subjects consisting of classic A-T, mild A-T or non-A-T controls. Subjects with mild A-T were characterized by later onset/mild neurologic features and normal/near normal immune status., Results: RNAseq revealed 310 differentially expressed genes (DEGs) including genes involved in inflammation, immune regulation, and cancer. Using gene set enrichment analysis, A-T subjects were found to have biological processes enriched for inflammatory and malignancy pathways. In examining a cohort of A-T subjects in which baseline serum IL8 and IL6 levels were measured previously, an association was found between higher serum IL8 levels and higher likelihood of developing malignancy and/or death in a subsequent 4-6 year period., Conclusion: RNAseq using PBMCs from subjects with classic A-T uncovered differential expression of immune response genes and biological processes associated with inflammation, immune regulation, and cancer. Follow-up of A-T subjects over a 4-6 year period revealed an association between higher baseline serum IL8 levels and malignancy/death. These findings support a role for inflammation as a contributing factor in A-T phenotypes., Competing Interests: The authors have declared that no competing interests exist.

Multiple sclerosis (MS) is characterized by chronic inflammation in conjunction with neurodegeneration within the central nervous system. Most individuals with MS begin with a relapsing remitting course that later transitions to secondary progressive MS. Currently available disease-modifying therapies (DMTs) for relapsing MS have been demonstrated to reduce disease activity, however most patients require a change in therapy over the course of their disease. Treatment goals include the prevention of relapses and disability accumulation and to achieve this objective requires careful planning. Sequencing of DMTs for individual patients should be designed in such a way to maximize disease control and minimize risk based on the mechanism of action, pharmacokinetic and pharmacodynamic properties of each therapy. This includes the DMT patients are being switched from to those they are being switched to. The reversibility of immune system effects should be a key consideration for DMT sequence selection. This feature varies across DMTs and should factor more prominently in decision making as newer treatments become available for the prevention of disability accumulation in patients with progressive MS. In this short review, we discuss the landscape of existing therapies with an eye to the future when planning for optimal DMT sequencing. While no cure exists for MS, efforts are being directed toward research in neuroregeneration with the hope for positive outcomes., Competing Interests: FG has disclosed that he has received grant funding from Novartis, Chugai, Opexa, Serono, Biogen, Roche, Genzyme, Abbott and Actelion. MY has disclosed that he has received consultation fees from EMD Serono, Genzyme and Novartis, and the Canadian Agency for Drugs and Technologies in Health (CADTH)/Health Canada, and research support from Biogen Idec, Genzyme, Hoffmann-La Roche, Novartis, and Teva Canada Innovation. SAM has disclosed that she has received honoraria for speaking, consulting and advisory board participation from Biogen Idec, EMD Serono, Genzyme, Novartis and Roche; she has acted as site principal investigator for clinical trials for Novartis, Genzyme and Roche; she has received investigator initiated trial funding from Genzyme. LL has disclosed that he has served on advisory boards, received honoraria, conducted clinical trials with and received research funding from Allergan, Biogen Canada, Serono Canada, Teva Neurosciences, Schering (Berlex), BioMS, Bayer Canada, Novartis Canada, Sanofi-Aventis, Genzyme Canada and Roche Canada. FE has disclosed that he has received honoraria as a speaker, consultant/advisor or received educational/CME grant or a research grant from Biogen Idec, EMD Serono, Genzyme, Novartis, Teva Innovation and Hoffman-La Roche. BJW has disclosed that he received compensation from Novartis for work related to infectious complications of DMTs. PL has disclosed that he has served as a consultant in an advisory board related to fingolimod; he has received honoraria as a speaker on the immunological effects of DMTs in MS from Novartis and Sanofi; he has also received reimbursement of travel and lodging expenses to give presentations on the immunological effects of DMTs in MS from Novartis. RS has disclosed that she is an employee of Novartis Pharmaceuticals Canada Inc

Introduction: The purpose of this study was to examine the relationships between screening questions for secondhand smoke (SHS) exposure and biomarker results using hair nicotine levels. Our ultimate goal was to develop sensitive and valid screening tools in pediatric clinical settings for SHS exposure., Methods: Investigators developed a core set of questions regarding exposure. Data from two separate ongoing studies of well children and those with bronchopulmonary dysplasia (BPD) were used to assess the concordance between responses and hair nicotine levels. Sensitivity, a positive predictive value, and accuracy were examined., Results: There was no single question with similar sensitivity in both populations. The question with the highest positive predictive value (90.8% well-cohort and 84.6% BPD cohort) for both the groups was whether the child had been exposed to in-home smoking in the last 7 days. The question with the highest accuracy for both groups was the number of smokers at home (0 vs ≥ 1), with an accuracy of 72.4% for well children and 79.0% for the BPD cohort., Conclusions: There was a wide variability in the performance of specific questions. These data demonstrate that a "one-size-fits-all" approach to screening for secondhand tobacco smoke exposure may not be appropriate for all pediatric populations.

Objective: Longer initial hospitalizations for preterm infants with bronchopulmonary dysplasia (BPD) can delay family bonding and attainment of developmental milestones, increase the risk for hospital acquired complications, and increase healthcare costs. The goal of the study was to identify the characteristics associated with longer lengths of hospitalization in this high-risk population., Study Design: A retrospective analysis was performed on 660 children (born ≤32 weeks gestation) discharged from 13 Maryland NICUs recruited into an outpatient BPD registry., Result: The mean age of discharge was 4.3 ± 2.9 months (median: 3.7 months). Subjects born with lower birthweights and covered by public insurance had longer lengths of hospitalization. Clinical characteristics at discharge associated with longer initial hospitalizations included gastrostomy tube, mechanical ventilation, tracheostomy, pulmonary hypertension, and supplemental oxygen., Conclusion: Identifying the risk factors associated with longer lengths of stay could prompt the implementation of personalized in-hospital interventions to improve outcomes and minimize length of stay in infants with BPD.

Pediatric acute lung injury, usually because of pneumonia, has a mortality rate of more than 20% and an incidence that rivals that of all childhood cancers combined. CD4 + T-cells coordinate the immune response to pneumonia but fail to function robustly among the very young, who have poor outcomes from lung infection. We hypothesized that DNA methylation represses a mature CD4 + T-cell transcriptional program in neonates with pneumonia. Here, we found that neonatal mice (3-4 days old) aspirated with Escherichia coli bacteria had a higher mortality rate than juvenile mice (11-14 days old). Transcriptional profiling with an unsupervised RNA-Seq approach revealed that neonates displayed an attenuated lung CD4 + T-cell transcriptional response to pneumonia compared with juveniles. Unlike neonates, juveniles up-regulated a robust set of canonical T-cell immune response genes. DNA methylation profiling with modified reduced representation bisulfite sequencing revealed 44,119 differentially methylated CpGs, which preferentially clustered around transcriptional start sites and CpG islands. A methylation difference-filtering algorithm detected genes with a high likelihood of differential promoter methylation regulating their expression; these 731 loci encoded important immune response and tissue-protective T-cell pathway components. Disruption of DNA methylation with the hypomethylating agent decitabine induced plasticity in the lung CD4 + T-cell marker phenotype. Altogether, multidimensional profiling suggested that DNA methylation within the promoters of a core set of CD4 + T-cell pathway genes contributes to the hyporesponsive neonatal immune response to pneumonia. These findings also suggest that DNA methylation could serve as a mechanistic target for disease-modifying therapies in pediatric lung infection and injury., (© 2018 McGrath-Morrow et al.)

Background: Cognitive impairment is common in multiple sclerosis (MS) and can manifest early in the disease process, sometimes as early as the first demyelinating event. However, the frequency of cognitive impairment in a newly diagnosed MS population has not been evaluated comprehensively in a clinical population. We sought to examine the prevalence of cognitive impairment in relapsing-remitting MS (RRMS) within a year of diagnosis in a clinic where cognitive testing at diagnosis is part of routine practice., Methods: A retrospective medical record review of persons with RRMS assessed in a cognitive MS clinic identified 107 patients assessed by the Minimal Assessment of Cognitive Function in Multiple Sclerosis battery within 1 year of a confirmed RRMS diagnosis., Results: The cohort was predominantly female (n = 82 [76.6%]) and white (n = 93 [86.9%]). Only 36 patients (33.6%) were diagnosed as having RRMS based on a second clinical event. Processing speed was the most frequently impaired domain (n = 38 [35.5%]). Only 37 patients (34.6%) were within normal limits on all cognitive domains. Regarding mood symptoms, 25 patients (23.4%) were positive for depressive symptoms; 59 (55.1%), for anxiety. Severe fatigue was correlated with a lower score on the Symbol Digit Modalities Test (SDMT) (r = -0.380, P < .001), and higher depressive scores were correlated with lower performance on the SDMT (r = -0.397, P < .001) and the Paced Auditory Serial Addition Test (r = -0.254, P = .009)., Conclusions: Cognitive impairment, specifically processing speed, and mood symptoms are frequently present in persons with newly diagnosed RRMS.

Background: Physical activity (PA) is beneficial for all people, yet people affected by multiple sclerosis (MS) find regular PA challenging. These people may include individuals with the disease who have moderate-to-severe disability and their family caregivers. For researchers and clinicians to effectively promote PA among caregiver/care-recipient dyads with moderate-to-severe MS, a comprehensive understanding of the shared PA experiences of these dyads would be beneficial., Objective: We explored shared experiences of caregiver/care-recipient dyads affected by moderate-to-severe MS about PA and directions for intervention., Methods: Six focus groups with 23 people with moderate-to-severe MS and 12 family caregivers were conducted. Data were analysed using a constant comparative approach., Results: Three major themes emerged as follows: (i) PA is a continuum, (ii) cycle of disengagement and (iii) cycle of adjustment. The first theme captured the dyads understanding that PA falls along a continuum ranging from highly structured to unstructured activities. Cycle of disengagement captured the experiences of dyads engaging in little or no PA. These dyads perceived internal and external issues as drivers of the cycle of disengagement, while availability of supportive programmes and services or people helped the dyads to break out of the cycle. When the cycle of disengagement was broken, the dyads described moving towards the cycle of adjustment, where they were able to learn skills and take action to incorporate PA into daily routines., Conclusion: This research highlights the need to adopt an integrative approach that acknowledges the caregiver/care-recipient dyad with moderate-to-severe MS as a focus for PA intervention., (© 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.)

Prior limited research indicates that children with pulmonary hypertension (PH) have higher rates of adverse perioperative outcomes when undergoing non-cardiac procedures and cardiac catheterizations. We examined a single-center retrospective cohort of children with active or pharmacologically controlled PH who underwent cardiac catheterization or non-cardiac surgery during 2006-2014. Preoperative characteristics and perioperative courses were examined to determine relationships between the severity or etiology of PH, type of procedure, and occurrence of major and minor events. We identified 77 patients who underwent 148 procedures at a median age of six months. The most common PH etiologies were bronchopulmonary dysplasia (46.7%), congenital heart disease (29.9%), and congenital diaphragmatic hernia (14.3%). Cardiac catheterizations (39.2%), and abdominal (29.1%) and central venous access (8.9%) were the most common procedures. Major events included failed planned extubation (5.6%), postoperative cardiac arrest (4.7%), induction or intraoperative cardiac arrest (2%), and postoperative death (1.4%). Major events were more frequent in patients with severe baseline PH ( P = 0.006) and the incidence was associated with procedure type ( P = 0.05). Preoperative inhaled nitric oxide and prostacyclin analog therapies were associated with decreased incidence of minor events (odds ratio [OR] = 0.32, P = 0.046 and OR = 0.24, P = 0.008, respectively), but no change in the incidence of major events. PH etiology was not associated with events ( P = 0.24). Children with PH have increased risk of perioperative complications; cardiac arrest and death occur more frequently in patients with severe PH and those undergoing thoracic procedures. Risk may be modified by using preoperative pulmonary vasodilator therapy and lends itself to further prospective studies.

Neonates have greater morbidity/mortality from lower respiratory tract infections (LRTI) compared to older children. Lack of conditioning of the pulmonary immune system due to limited environmental exposures and/or infectious challenges likely contributes to the increase susceptibility in the neonate. In this study, we sought to gain insights into the nature and dynamics of the neonatal pulmonary immune response to LRTI using a murine model., Methods: Wildtype (WT) and Ccr2 -/- C57BL/6 neonatal and juvenile mice received E. coli or PBS by direct pharyngeal aspiration. Flow cytometry was used to measure immune cell dynamics and identify cytokine-producing cells. Real-time PCR and ELISA were used to measure cytokine/chemokine expression., Results: Innate immune cell recruitment in response to E. coli-induced LRTI was delayed in the neonatal lung compared to juvenile lung. Lung clearance of bacteria was also significantly delayed in the neonate. Ccr2 -/- neonates, which lack an intact CCL2-CCR2 axis, had higher mortality after E. coli challenged than Ccr2 +/+ neonates. A greater percentage of CD8 + T cells and monocytes from WT neonates challenged with E. coli produced TNF compared to controls., Conclusion: The pulmonary immune response to E. coli-induced LRTI differed significantly between neonatal and juvenile mice. Neonates were more susceptible to increasing doses of E. coli and exhibited greater mortality than juveniles. In the absence of an intact CCL2-CCR2 axis, susceptibility to LRTI-induced mortality was further increased in neonatal mice. Taken together these findings underscore the importance of age-related differences in the innate immune response to LRTI during early stages of postnatal life., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Definition of the Disease: Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome., Epidemiology: The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births., Clinical Description: A-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations., Etiology: A-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress., Diagnosis: The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene., Differential Diagnosis: There are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing., Antenatal Diagnosis: Antenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis., Genetic Counseling: Genetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted., Management and Prognosis: Treatment of the neurologic problems associated with A-T is symptomatic and supportive, as there are no treatments known to slow or stop the neurodegeneration. However, other manifestations of A-T, e.g. immunodeficiency, pulmonary disease, failure to thrive and diabetes can be treated effectively.