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Background: Disease progression is observed across the spectrum of people with multiple sclerosis (MS) and identification of effective treatment strategies to halt progression remains one of the greatest unmet clinical needs. Objectives: The Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) was designed to evaluate a wide range of factors associated with the onset and rate of clinical disease progression in MS and to describe the interplay between these factors. Design: A prospective cohort study. Methods: CanProCo is a national, prospective, observational cohort study that has recruited 944 individuals from 5 large academic MS centers in Canada. Participants include people with radiologically isolated syndrome (RIS), early relapsing-remitting and primary progressive MS (RRMS, PPMS), and healthy controls (HCs). Annually, participants complete self-reported questionnaires, undergo clinical evaluation and, if clinically indicated, magnetic resonance images (MRIs) of the brain and cervical spinal cord; in a subset of participants ( n = 399), blood, and research MRIs of the brain and cervical spinal cord are collected. Linkages to health administrative databases are available at three sites. Results: Overall, 944 participants were recruited (53 HCs, 63 RIS, 751 RRMS, 77 PPMS). RIS and MS participants had a mean age of 39.0 years and 70.5% female. The mean time since diagnosis was 2.7 years. There were differences observed in the Expanded Disability Status Scale score and components of the MS performance test (walking speed test, manual dexterity test, processing speed test, and low-contrast visual acuity) between RIS and MS subtypes. Questionnaires revealed more symptoms of depression and anxiety and impaired physical and mental quality of life in people with RIS/MS versus HCs and differences across RIS/MS subtypes. Conclusion: Physical and mental neurological disability is prevalent even in the earliest stages of MS. Transdisciplinary approaches such as those used in CanProCo are needed to better characterize clinical progression in MS. Additional CanProCo results, including MRI, biological, and pharmaco-economic data will be forthcoming. Going forward, CanProCo’s data sharing and collaborative vision will facilitate numerous global collaborations, which will inform the development and implementation of effective interventions for people with MS around the world.

Abstract Background A growing body of literature investigated childhood exposure to environmental chemicals in association with attention-deficit/hyperactivity disorder (ADHD) symptoms, but limited studies considered urinary mixtures of multiple chemical classes. This study examined associations of concurrent exposure to non-persistent chemicals with ADHD symptoms in children diagnosed with autism spectrum disorder (ASD), developmental delay (DD), and typical development (TD). Methods A total of 549 children aged 2–5 years from the Childhood Autism Risks from Genetics and Environment (CHARGE) case-control study were administered the Aberrant Behavior Checklist (ABC). This study focused on the ADHD/noncompliance subscale and its two subdomains (hyperactivity/impulsivity, inattention). Sixty-two chemicals from four classes (phenols/parabens, phthalates, organophosphate pesticides, trace elements) were quantified in child urine samples, and 43 chemicals detected in > 70% samples were used to investigate their associations with ADHD symptoms. Negative binomial regression was used for single-chemical analysis, and weighted quantile sum regression with repeated holdout validation was applied for mixture analysis for each chemical class and all chemicals. The mixture analyses were further stratified by diagnostic group. Results A phthalate metabolite mixture was associated with higher ADHD/noncompliance scores (median count ratio [CR] = 1.10; 2.5th, 97.5th percentile: 1.00, 1.21), especially hyperactivity/impulsivity (median CR = 1.09; 2.5th, 97.5th percentile: 1.00, 1.25). The possible contributors to these mixture effects were di-2-ethylhexyl phthalate (DEHP) metabolites and mono-2-heptyl phthalate (MHPP). These associations were likely driven by children with ASD as these were observed among children with ASD, but not among TD or those with DD. Additionally, among children with ASD, a mixture of all chemicals was associated with ADHD/noncompliance and hyperactivity/impulsivity, and possible contributors were 3,4-dihydroxy benzoic acid, DEHP metabolites, MHPP, mono-n-butyl phthalate, and cadmium. Conclusions Early childhood exposure to a phthalate mixture was associated with ADHD symptoms, particularly among children with ASD. While the diverse diagnostic profiles limited generalizability, our findings suggest a potential link between phthalate exposure and the comorbidity of ASD and ADHD.

BackgroundDisability progression is a key milestone in the disease evolution of people with multiple sclerosis (PwMS). Prediction models of the probability of disability progression have not yet reached the level of trust needed to be adopted in the clinic. A common benchmark to assess model development in multiple sclerosis is also currently lacking.MethodsData of adult PwMS with a follow-up of at least three years from 146 MS centers, spread over 40 countries and collected by the MSBase consortium was used. With basic inclusion criteria for quality requirements, it represents a total of 15, 240 PwMS. External validation was performed and repeated five times to assess the significance of the results. Transparent Reporting for Individual Prognosis Or Diagnosis (TRIPOD) guidelines were followed. Confirmed disability progression after two years was predicted, with a confirmation window of six months. Only routinely collected variables were used such as the expanded disability status scale, treatment, relapse information, and MS course. To learn the probability of disability progression, state-of-the-art machine learning models were investigated. The discrimination performance of the models is evaluated with the area under the receiver operator curve (ROC-AUC) and under the precision recall curve (AUC-PR), and their calibration via the Brier score and the expected calibration error. All our preprocessing and model code are available at https://gitlab.com/edebrouwer/ms_benchmark, making this task an ideal benchmark for predicting disability progression in MS.FindingsMachine learning models achieved a ROC-AUC of 0⋅71 ± 0⋅01, an AUC-PR of 0⋅26 ± 0⋅02, a Brier score of 0⋅1 ± 0⋅01 and an expected calibration error of 0⋅07 ± 0⋅04. The history of disability progression was identified as being more predictive for future disability progression than the treatment or relapses history.ConclusionsGood discrimination and calibration performance on an external validation set is achieved, using only routinely collected variables. This suggests machine-learning models can reliably inform clinicians about the future occurrence of progression and are mature for a clinical impact study.

Introduction Multiple sclerosis (MS) is an immune-mediated demyelinating disease with a significant burden of neuropsychiatric sequelae. These symptoms, including depression and anxiety, are predictors of morbidity and mortality in people with MS. Despite a high prevalence of obsessive-compulsive disorder in MS, potentially shared pathophysiological mechanisms and overlap in possible treatments, no review has specifically examined the clinical dimensions of people with obsessive-compulsive and related disorders (OCRD) and MS. In this scoping review, we aim to map the available knowledge on the clinical dimensions of people with co-occurring OCRD and MS. Understanding the characteristics of this population in greater detail will inform more patient-centred care and create a framework for future studies.Methods and analysis We developed a search strategy to identify all articles that include people with co-occurring OCRD and MS. The search strategy (extending to the grey literature) was applied to MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, Web of Science and ProQuest Dissertations & Theses. Records will undergo title and abstract screening by two independent reviewers. Articles meeting inclusion criteria based on title and abstract screening will go on to full-text review by the two independent reviewers. After reaching a consensus about articles for inclusion in the final review, data will be extracted using a standardised extraction form. The extracted data will include clinical characteristics of patients such as age, gender, medication use and severity of MS, among others.Ethics and dissemination This scoping review does not require research ethics approval. Results will be shared at national and/or international conferences, in a peer-reviewed journal publication, in a plain language summary and in a webinar for the general public.

Abstract Floodlight Open was a global, open-access, digital-only study designed to understand the drivers and barriers in deployment and use of a smartphone app in a naturalistic setting and broad study population of people with and without multiple sclerosis (MS). The study utilised the Floodlight Open app: a ‘bring-your-own-device’ solution that remotely measures a user’s mood, cognition, hand motor function, and gait and postural stability via smartphone sensor-based tests requiring active user input (‘active tests’). Levels of mobility of study participants (‘life-space measurement’) were passively measured. Study data from these tests were made available via an open-access platform. Data from 1350 participants with self-declared MS and 1133 participants with self-declared non-MS from 17 countries across four continents were included in this report. Overall, MS participants provided active test data for a mean duration of 5.6 weeks or a mean duration of 19 non-consecutive days. This duration increased among MS participants who persisted beyond the first week to a mean of 10.3 weeks or 36.5 non-consecutive days. Passively collected life-space measurement data were generated by MS participants for a mean duration of 9.8 weeks or 50.6 non-consecutive days. This duration increased to 16.3 weeks/85.1 non-consecutive days among MS participants who persisted beyond the first week. Older age, self-declared MS disease status, and clinical supervision as part of concomitant clinical research were all significantly associated with higher persistence of the use of the Floodlight Open app. MS participants performed significantly worse than non-MS participants on four out of seven active tests. The findings from this multinational study inform future research to improve the dynamics of persistence of use of digital monitoring tools and further highlight challenges and opportunities in applying them to support MS clinical care.

Significant advances have been made in the diagnosis and treatment of multiple sclerosis in recent years yet challenges remain. The current classification of MS phenotypes according to disease activity and progression, for example, does not adequately reflect the underlying pathophysiological mechanisms that may be acting in an individual with MS at different time points. Thus, there is a need for clinicians to transition to a management approach based on the underlying pathophysiological mechanisms that drive disability in MS. A Canadian expert panel convened in January 2023 to discuss priorities for clinical discovery and scientific exploration that would help advance the field. Five key areas of focus included: identifying a mechanism-based disease classification system; developing biomarkers (imaging, fluid, digital) to identify pathologic processes; implementing a data-driven approach to integrate genetic/environmental risk factors, clinical findings, imaging and biomarker data, and patient-reported outcomes to better characterize the many factors associated with disability progression; utilizing precision-based treatment strategies to target different disease processes; and potentially preventing disease through Epstein-Barr virus (EBV) vaccination, counselling about environmental risk factors (e.g. obesity, exercise, vitamin D/sun exposure, smoking) and other measures. Many of the tools needed to meet these needs are currently available. Further work is required to validate emerging biomarkers and tailor treatment strategies to the needs of individual patients. The hope is that a more complete view of the individual’s pathobiology will enable clinicians to usher in an era of truly personalized medicine, in which more informed treatment decisions throughout the disease course achieve better long-term outcomes.

Key unmet needs in multiple sclerosis (MS) include detection of early pathology, disability worsening independent of relapses, and accurate monitoring of treatment response. Collaborative approaches to address these unmet needs have been driven in part by industry–academic networks and initiatives such as the Grant for Multiple Sclerosis Innovation (GMSI) and Multiple Sclerosis Leadership and Innovation Network (MS-LINK™) programs. We review the application of recent advances, supported by the GMSI and MS-LINK™ programs, in neuroimaging technology to quantify pathology related to central pathology and disease worsening, and potential for their translation into clinical practice/trials. GMSI-supported advances in neuroimaging methods and biomarkers include developments in magnetic resonance imaging, positron emission tomography, ocular imaging, and machine learning. However, longitudinal studies are required to facilitate translation of these measures to the clinic and to justify their inclusion as endpoints in clinical trials of new therapeutics for MS. Novel neuroimaging measures and other biomarkers, combined with artificial intelligence, may enable accurate prediction and monitoring of MS worsening in the clinic, and may also be used as endpoints in clinical trials of new therapies for MS targeting relapse-independent disease pathology.

Autism spectrum disorder (ASD), with its high economic and societal costs, is a growing public health concern whose prevalence has risen steadily over the last two decades. Although actual increased incidence versus improved diagnosis remains controversial, the increased prevalence of ASD suggests non-inherited factors as likely contributors. There is increasing epidemiologic evidence that abnormal maternal thyroid function during pregnancy is associated with increased risk of child ASD and other neurodevelopmental disorders. Prenatal exposure to endocrine-disrupting chemicals such as per- and polyfluoroalkyl substances (PFAS) is known to disrupt thyroid function and can affect early brain development; thus, thyroid dysfunction is hypothesized to mediate this relationship. The concept of a potential pathway from prenatal PFAS exposure through thyroid dysfunction to ASD etiology is not new; however, the extant literature on this topic is scant. The aim of this review is to evaluate and summarize reports with regard to potential mechanisms in this pathway.

A comparative analysis on resting-state magnetoencephalography data from healthy controls and patients with chronic pain reveals spectral frequency-specific dysregulation and a temporal imbalance of brain microstates in chronic neuropathic pain.

ObjectiveThe 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.MethodsA 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.ResultsCurrently, 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.ConclusionTo 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.

Purpose This study explored the prevalence of prenatal and postpartum depression in Korea and its influencing factors from 20 weeks of pregnancy to 12 weeks postpartum. Methods Using a prospective cohort study design, data on women’s depression and its influencing factors were collected at 20, 28, and 36 weeks of pregnancy and at 2, 6, and 12 weeks postpartum. The participants were 219 women and 181 spouses during pregnancy; and 183 mothers and 130 spouses after childbirth. Depressive symptoms were assessed by the Edinburgh Postnatal Depression Scale and influencing factors were measured by the Postpartum Depression Predictors Inventory-Revised, parity, and spousal depression. Results The prevalence of maternal depression was 10.5% to 21.5% before birth, and it was 22.4% to 32.8% postpartum. The prevalence slightly decreased during the prenatal period but peaked at 2 weeks postpartum. Antenatal depression was influenced by low socioeconomic status, lower self-esteem, having experienced prenatal depression, having experienced prenatal anxiety, a previous history of depression, lower social support, lower marital satisfaction, and higher life stress. The factors influencing postpartum depression were lower self-esteem, having experienced prenatal depression, having experienced prenatal anxiety, lower social support, lower marital satisfaction, and higher life stress, as well as infant temperament and maternal blues. Parity and spousal depression had no impacts. Conclusion The prevalence and influencing factors of maternal depression changed over time. Nurses need to screen women accordingly during the perinatal period and should provide education or counseling to prevent depression and promote adjustment to parenthood.

Purpose: Implementation of nurse navigators during cancer screening to the first treatment visit may facilitate early diagnosis and treatment. This study aims to demonstrate the evidence of the effects of nurse navigators during cancer screening in the first treatment phase. Methods: Eleven electronic databases were searched, including PubMed, CINAHL, Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, Web of Science, ScienceDirect, PsycINFO, KoreaMed, KISS, RISS, and DBPIA. The final search was completed in August 2021. Two reviewers independently screened and selected studies, extracted data, and conducted a quality assessment. Data to evaluate the effects of nurse navigators was analyzed through meta-analysis and narrative summary. Subgroup analyses were performed. Results: A total of 16 studies was included. With low to moderate quality of evidence, nurse navigators had favorable effects on improving the timeliness of care during screening during the first treatment visits (MD = 20.42, 95% CI = 8.74 to 32.10, p = .001). Additionally, 13.0% to 45.0% of nurse navigated patients were more likely to complete cancer care services, although insignificant effects were observed. Study participants from individual studies reported a high satisfaction to the nurse navigators. Subgroup analyses indicated that nurse navigators working as key members in multidisciplinary programs had the greatest effect on reducing waiting times. Conclusion: Nurse navigators improve cancer patient outcomes by providing more timely care. Additionally, nurse navigators have the substantial potential to increase completion rates to cancer care services and patient satisfaction. For facilitating multidisciplinary care, the use of nurse navigators is highly recommended in the future.

Abstract Background Neurological disability progression occurs across the spectrum of people living with multiple sclerosis (MS). Although there are a handful of disease-modifying treatments approved for use in progressive phenotypes of MS, there are no treatments that substantially modify the course of clinical progression in MS. Characterizing the determinants of clinical progression can inform the development of novel therapeutic agents and treatment approaches that target progression in MS, which is one of the greatest unmet needs in clinical practice. Canada, having one of the world’s highest rates of MS and a publicly-funded health care system, represents an optimal country to achieve in-depth analysis of progression. Accordingly, the overarching aim of the Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) is to evaluate a wide spectrum of factors associated with the clinical onset and rate of disease progression in MS, and to describe how these factors relate to one another to influence progression. Methods CanProCo is a prospective, observational cohort study with investigators specializing in epidemiology, neuroimaging, neuroimmunology, health services research and health economics. CanProCo’s study design was approved by an international review panel, comprised of content experts and key stakeholders. One thousand individuals with radiologically-isolated syndrome, relapsing-remitting MS, and primary-progressive MS within 10–15 years of disease onset will be recruited from 5 academic MS centres in Canada. Participants will undergo detailed clinical evaluation annually over 5 years (including advanced, app-based clinical data collection). In a subset of participants within 5–10 years of disease onset (n = 500), blood, cerebrospinal fluid, and research MRIs will be collected allowing an integrated, in-depth evaluation of factors contributing to progression in MS from multiple perspectives. Factors of interest range from biological measures (e.g. single-cell RNA-sequencing), MRI-based microstructural assessment, participant characteristics (self-reported, performance-based, clinician-assessed, health-system based), and micro and macro-environmental factors. Discussion Halting the progression of MS remains a fundamental need to improve the lives of people living with MS. Achieving this requires leveraging transdisciplinary approaches to better characterize why clinical progression occurs. CanProCo is a pioneering multi-dimensional cohort study aiming to characterize these determinants to inform the development and implementation of efficacious and effective interventions.

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been shown to affect offspring behaviors in laboratory animals. Several epidemiological studies investigated associations between prenatal PFAS exposure and child neurodevelopment, but results were inconclusive. We examined associations between cord blood concentrations of perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) and cognitive development in children from 4 to 40 months of age. Methods: This study included 598 mother–child pairs who participated in the Hamamatsu Birth Cohort Study for Mothers and Children (HBC Study), a prospective birth cohort study in Japan. PFOA and PFOS were quantified in cord blood. The Mullen Scales of Early Learning (MSEL) was used to assess child cognitive function at 4, 6, 10, 14, 18, 24, 32, and 40 months of age. For each of log 2-transformed PFOA and PFOS concentrations, we examined: 1) associations with the scores of MSEL Early Learning Composite (Composite) and four subscales (Fine Motor, Visual Reception, Receptive Language, Expressive Language) at each assessment time point; and 2) associations with longitudinal changes in the Composite and subscale scores. Results: MSEL Composite scores were inversely associated with PFOA at 18 months of age (per 2-fold increase in concentration: β = -2.23, 95% CI: -3.91, -0.56), but not at other ages. When accounting for changes in scores from 4 to 40 months of age, PFOA and PFOS were positively associated with Composite as well as Receptive and Expressive Language scores. Child’s sex modified associations between PFOA and Composite scores at 14, 18, and 40 months and those between PFOS and Composite scores at 14 months, showing negative associations among females. Conclusions: In this study, cord blood PFOA and PFOS concentrations showed mixed associations with child cognitive functions at specific age but had positive associations with longitudinal changes in cognitive development from 4 to 40 months of age.

ObjectiveLittle 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.MethodsWe 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.ResultsOf 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.ConclusionCanadian 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.

Abstract Objective To report initial results of a planned multicenter year‐long prospective study examining the risk and impact of COVID‐19 among persons with neuroinflammatory disorders (NID), particularly multiple sclerosis (MS). Methods In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID‐19 in persons with NID (PwNID) and change in their neurological care. Results Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID‐19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID‐19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID‐19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID‐19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID‐19 (ORadj = 1.45, 1.17–1.84). Interpretations Our study of real‐time, patient‐reported experience during the COVID‐19 pandemic complements physician‐reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID‐19 similar to the reference population.

Abstract Background Mesenchymal stem cells (MSCs) are used for the treatment of osteoarthritis (OA), and MSC genetic engineering is expected to enhance cartilage repair. Here, we aimed to investigate the effect of MSCs overexpressing platelet-derived growth factor (PDGF) or heme oxygenase-1 (HO-1) in chondrocytes and synovial cells with an OA phenotype and assess the in vivo efficacy of intra-articular injections of these MSCs in canine OA models. Methods Canine adipose-derived MSCs were transfected with canine PDGF (PDGF-MSCs) or HO-1 (HO-1-MSCs) using lentiviral vectors. Canine chondrocytes or synovial cells were stimulated with lipopolysaccharide (LPS) to mimic the inflammatory OA model and then co-cultured with MSCs, PDGF-MSCs, or HO-1-MSCs for 24 h and 72 h. The mRNA levels of pro-inflammatory, extracellular matrix-degradative/synthetic, or pain-related factors were measured after co-culture by real-time PCR. Furthermore, a surgery-induced canine OA model was established and the dogs were randomized into four groups: normal saline (n = 4), MSCs (n = 4), PDGF-MSCs (n = 4), and HO-1-MSCs (n = 4). The OA symptoms, radiographic OA severity, and serum matrix metallopeptidase (MMP)-13 levels were assessed before and 10 weeks after treatment, to evaluate the safety and efficacy of the modified MSCs. Results PDGF or HO-1 overexpression significantly reduced the expression of pro-inflammatory factors, MMP-13, and nerve growth factor elicited by LPS and increased that of aggrecan and collagen type 2 in chondrocytes (P

BackgroundThe Expanded Disability Status Scale (EDSS) score is a widely used measure to monitor disability progression in people with multiple sclerosis (MS). However, extracting and deriving the EDSS score from unstructured electronic health records can be time-consuming. ObjectiveWe aimed to compare rule-based and deep learning natural language processing algorithms for detecting and predicting the total EDSS score and EDSS functional system subscores from the electronic health records of patients with MS. MethodsWe studied 17,452 electronic health records of 4906 MS patients followed at one of Canada’s largest MS clinics between June 2015 and July 2019. We randomly divided the records into training (80%) and test (20%) data sets, and compared the performance characteristics of 3 natural language processing models. First, we applied a rule-based approach, extracting the EDSS score from sentences containing the keyword “EDSS.” Next, we trained a convolutional neural network (CNN) model to predict the 19 half-step increments of the EDSS score. Finally, we used a combined rule-based–CNN model. For each approach, we determined the accuracy, precision, recall, and F-score compared with the reference standard, which was manually labeled EDSS scores in the clinic database. ResultsOverall, the combined keyword-CNN model demonstrated the best performance, with accuracy, precision, recall, and an F-score of 0.90, 0.83, 0.83, and 0.83 respectively. Respective figures for the rule-based and CNN models individually were 0.57, 0.91, 0.65, and 0.70, and 0.86, 0.70, 0.70, and 0.70. Because of missing data, the model performance for EDSS subscores was lower than that for the total EDSS score. Performance improved when considering notes with known values of the EDSS subscores. ConclusionsA combined keyword-CNN natural language processing model can extract and accurately predict EDSS scores from patient records. This approach can be automated for efficient information extraction in clinical and research settings.

Extreme weather events caused by climate change affect the growth of crops, requiring reliable weather forecasts. In order to provide day-to-season seamless forecasting data for the agricultural sector, improving the forecasting performance of the S2S period is necessary. A number of studies have been conducted to improve prediction performance based on the bias correction of systematic errors in GCM or by producing high-resolution data via dynamic detailing. In this study, a daily simple mean bias correction technique is applied on CFSv2 (∼100 km) data. We then use case studies to evaluate how beneficial the precision of the high-resolution RCM simulation is in improving S2S prediction performance using the bias-corrected lateral boundary. Based on our examination of 45-day sequences of WRF simulations with 27–9–3 km resolution, it can be concluded that a higher resolution is correlated with better prediction in the case of the extreme heatwave in Korea in 2018. However, the effect of bias correction in improving predictive performances is not significant, suggesting that further studies on more cases are necessary to obtain more solid conclusions in the future.

Background: Evidence suggests that efficacy and safety of disease-modifying treatments for multiple sclerosis may differ with age. We evaluate efficacy and safety of teriflunomide across age subgroups of patients from pooled clinical trials and real-world studies. Methods: Post hoc analyses of patients who received teriflunomide 14 mg in the pooled phase II and III TEMSO, TOWER, TENERE, and TOPIC core and extension studies (n = 1978), and the real-world Teri-PRO (n = 928) and TAURUS-MS I (n = 1126) studies were conducted. Data were stratified by age at study entry: ⩽25, >25 to ⩽35, >35 to ⩽45, and >45 years. In Teri-PRO and TAURUS-MS I, an additional group, >55 years, was assessed. Results: In the pooled core studies, teriflunomide reduced annualized relapse rate (ARR) versus placebo across all ages. Unadjusted ARRs remained low across age groups in pooled extensions (0.18-0.30), Teri-PRO (0.10-0.35), and TAURUS-MS I (0.14-0.35). Baseline Expanded Disability Status Scale scores were higher with age, but stable through core and extension studies (mean increases over 7 years: ⩽25 years, +0.59; >25 to ⩽35 years, +0.46; >35 to ⩽45 years, +0.35; >45 years, +0.81). Across age groups, adverse event (AE) incidences were 78.4% to 90.7% in pooled core and extension studies and Teri-PRO, and 29.2% to 37.7% in TAURUS-MS I; serious AE incidences were ⩽21.3% in all studies. In pooled phase III and Teri-PRO studies, lymphocyte count decreases over 1 year after initiating teriflunomide, and proportions of patients developing lymphopenia, were small across age groups. Conclusions: Teriflunomide efficacy was demonstrated regardless of age. Safety was generally consistent across age groups.

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, inflammatory disease of the central nervous system marked by relapses often associated with poor recovery and long-term disability. Magnetic resonance imaging (MRI) is recognized as an important tool for timely diagnosis of NMOSD as, in combination with serologic testing, it aids in distinguishing NMOSD from possible mimics. Although the role of MRI for disease monitoring after diagnosis is not as well established, MRI may provide important prognostic information and help differentiate between relapses and pseudorelapses. Increasing evidence of subclinical disease activity and the emergence of newly approved, highly effective immunotherapies for NMOSD adjure us to re-evaluate MRI as a tool to guide optimal treatment selection and escalation throughout the disease course. In this article we review the role of MRI in NMOSD diagnosis, prognostication, disease monitoring, and treatment selection.

PURPOSE: The objective of this study was to investigate the prevalence of antenatal depression in pregnant women and its influencing factors. METHODS: With a cross-sectional survey design, a total of 396 pregnant women were recruited from a local obstetrics and gynecology clinic. Measurements included antenatal depression, perceived stress, predictors of depression during pregnancy, and demographic and obstetric characteristics. RESULTS: Mean antenatal depression score was 8.20 (standard deviation=4.95) out of 30, falling into its normal range. However, the prevalence of antenatal depression was 35.9% when cut-point of 9/10 was used. The prevalence of antenatal depression among women in the first trimester was 31.4%. It was slightly increased to 34.9% in the second trimester but significantly increased to 40.5% in the third trimester. In multiple logistic regression analysis, experiencing prenatal anxiety (odds ratio [OR], 4.16), having no job (OR, 2.90), lower self-esteem (OR, 1.62), and higher perceived stress (OR, 1.32) were significant factors influencing antenatal depression. CONCLUSION: Negative feeling such as feeling anxious, lower self-esteem, and higher perceived stress during pregnancy are key factors affecting antenatal depression. Thus, antenatal nursing intervention focusing on pregnant women's feeling upon their job status is necessary to improve their antenatal psychological well-being.

Background: Prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has shown potential to adversely affect child brain development, but epidemiologic evidence remains inconsistent. We examined whether prenatal exposure to PFAS was associated with increased risk of autism spectrum disorder (ASD). Methods: Participants were 173 mother–child pairs from MARBLES (Markers of Autism Risk in Babies – Learning Early Signs), a high-risk ASD cohort. At 3 years old, children were clinically confirmed for ASD and classified into ASD (n = 57) and typical development (TD, n = 116). We quantified nine PFAS in maternal serum collected during pregnancy. We examined associations of ASD with individual PFAS as well as the combined effect of PFAS on ASD using scores of the first principal component (PC-1) accounting for the largest variance. Results: Prenatal perfluorooctanoate (PFOA) and perfluorononanoate (PFNA) showed positive associations (per 2 nanogram per milliliter increase: relative risk (RR) = 1.20, 95% CI: 0.90, 1.61 [PFOA]; RR = 1.24, 95% CI: 0.91, 1.69 [PFNA]), while perfluorohexane sulfonate (PFHxS) showed a negative association (RR = 0.88, 95% CI: 0.77, 1.01) with ASD risk. When examining associations of ASD with untransformed PFAS concentrations, PFOA, PFNA, and PC-1 were associated with increased ASD risk (per nanogram per milliliter increase: RR = 1.31, 95% CI: 1.04, 1.65; RR = 1.79, 95% CI: 1.13, 2.85; RR = 1.10, 95% CI: 0.97, 1.25, respectively), while the RR of PFHxS moved toward the null. Conclusions: From this high-risk ASD cohort, we observed increased risk of ASD in children exposed to PFOA and PFNA. Further studies should be conducted in the general population because this population may have a larger fraction of cases resulting from genetic sources.

Six new β-resorcylic acid derivatives (1–5 and 7) were isolated from a halophyte-associated fungus, Colletotrichum gloeosporioides JS0419, together with four previously reported β-resorcylic acid lactones (RALs). The relative and absolute stereochemistry of 1 was completely established by a combination of spectroscopic data and chemical reactions. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR data. Notably, compounds 1–3 had a β-resorcylic acid harboring a long unesterified aliphatic side chain, whereas the long aliphatic chains were esterified to form macrolactones in 4–9. Among the isolated compounds, monocillin I and radicicol showed potent antifungal activities against Cryptococcus neoformans, comparable to clinically available antifungal agents and radicicol showed weak antifungal activity against Candida albicans. These findings provide insight into the chemical diversity of fungal RAL-type compounds and their pharmacological potential.

Sensory perceptions are coded by complex neural dynamics of regional communication in the brain. Thus, sensory abnormalities such as chronic pain may occur when neural dynamics go awry. Previous studies of cross-network dynamic functional connectivity in chronic pain identified abnormalities but were based on functional MRI which only captures slow temporal features. Here we conducted a magnetoencephalography (MEG) study to investigate fine temporal dynamics of aberrant cross-regional and cross-network communication of the dynamic pain connectome in patients with chronic pain. We also introduced a novel measure, dynamic functional coupling, to quantify the variability of brain communication. The study was performed in 33 people who had chronic pain associated with multiple sclerosis and 30 healthy controls. We found that patients with chronic pain exhibited abnormalities in cross-network functional coupling across multiple frequency bands (theta, alpha, beta, gamma), between the salience network and 3 other networks: the ascending nociceptive pathway, descending anti-nociceptive pathway, and the default mode network. However, these cross-network abnormalities involved different frequency bands in patients with neuropathic versus non-neuropathic chronic pain. Furthermore, cross-network abnormalities were linked to pain severity and pain interference. Our findings implicate broadband cross-network abnormalities as hallmark features of chronic pain in multiple sclerosis.

PURPOSE: This study was conducted among older women to (1) identify their levels of knowledge, self-efficacy, and health behavior in dealing with osteoporosis and falls and (2) explore the relationships between the study variables based on a health-beliefs model. METHODS: With a cross-sectional survey design, we recruited 94 older women of ages from 65 to 74 at a community setting via convenience sampling. The study participants completed two sets of structured questionnaires (on osteoporosis and fall prevention). RESULTS: The general characteristics of the study participants demonstrated that the women were at high risk for osteoporosis and falls. Overall, the levels of knowledge about osteoporosis and falls, their self-efficacy, and their preventive behaviors were average or slightly above. The relationships between the study variables showed that self-efficacy and healthy behavior, such as doing osteoporosis exercise, eating an osteoporosis diet, and avoiding falls, were related (r=38, p < .001; r=.33, p < .05; r=.26, p < .05). In addition, there were statistically significant relationships between osteoporosis and fall prevention knowledge (r=.37~.46, p < .001), self-efficacy (r=.50~.53, p < .001), and preventive behaviors (r=.50, p < .001). CONCLUSION: The women's scores on osteoporosis and fall knowledge, self-efficacy, and preventive behaviors suggest an urgent need for the implementation of educational programs for older women. A close relationship between self-efficacy and health behaviors implies a need for transformation of a traditional one-way lecture form.

Background: Nuclear protein-1 (NUPR1, also known as p8/Com-1) is a transcription factor involved in the regulation of cellular stress responses, including serum starvation and drug stimulation. Methods: We investigated the mechanism of NUPR1 nuclear translocation involving karyopherin β1 (KPNB1), using a single-molecule binding assay and confocal microscopy. The cellular effects associated with NUPR1–KPNB1 inhibition were investigated by gene expression profiling and cell cycle analysis. Results: The single-molecule binding assay revealed that KPNB1 bound to NUPR1 with a binding affinity of 0.75 nM and that this binding was blocked by the aminothiazole ATZ-502. Following doxorubicin-only treatment, NUPR1 was translocated to the nucleus in more than 90% and NUPR1 translocation was blocked by the ATZ-502 combination treatment in MDA-MB-231 with no change in NUPR1 expression, providing strong evidence that NUPR1 nuclear translocation was directly inhibited by the ATZ-502 treatment. Inhibition of KPNB1 and NUPR1 binding was associated with a synergistic anticancer effect (up to 19.6-fold) in various cancer cell lines. NUPR1-related genes were also downregulated following the doxorubicin–ATZ-502 combination treatment. Conclusion: Our current findings clearly demonstrate that NUPR1 translocation into the nucleus requires karyopherin β1 binding. Inhibition of the KPNB1 and NUPR1 interaction may constitute a new cancer therapeutic approach that can increase the drug efficacy while reducing the side effects.

In this work, loess-based materials were designed based on a multicomponent composite materials system for ecofriendly natural three-dimensional (3D) printing involving quick lime, gypsum, and water. The 3D printing process was monitored as a function of gypsum content; in terms of mechanical strength and electrical resistance, in the cube-shaped bulk form. After initial optimization, the 3D printing composition was refined to provide improved printability in a 3D printing system. The optimal 3D fabrication allowed for reproducible printing of rectangular columns and cubes. The development of 3D printing materials was scrutinized using a multitude of physicochemical probing tools, including X-ray diffraction for phase identification, impedance spectroscopy to monitor setting behaviors, and mercury intrusion porosimetry to extract the pore structure of loess-based composite materials. Additionally, the setting behavior in the loess-based composite materials was analyzed by investigating the formation of gypsum hydrates induced by chemical reaction between quick lime and water. This setting reaction provides reasonable mechanical strength that is sufficient to print loess-based pastes via 3D printing. Such mechanical strength allows utilization of robotic 3D printing applications that can be used to fabricate ecofriendly structures.

Protein glycosylation is a post-translational modification that impacts on protein activity, stability, and interactions. It was sensitively altered by the cellular state and, therefore, is now used for a diagnostic or prognostic indicator of various human diseases such as cancer. To evaluate the clinical feasibility in the veterinary area, the N-glycan biomarkers were discovered from canine serum for the diagnosis of osteoarthritis (OA), which is one of the most common diseases of dogs. N-glycome was obtained from 20 μL of canine serum by the enzymatic cleavage followed by the purification and enrichment using solid-phase extraction. Independent compositions of 163 and 463 N-glycans were found from healthy control (n = 41) and osteoarthritis patients (n = 92), respectively. Initially, 31 of the potential biomarkers were screened by the p-values below 1.0 × 10−10 from ANOVA. Then, the area under the curve (AUC) and the intensity ratio between OA patient and healthy control (P/C ratio) were calculated. Considering the diagnostic efficacy, the AUC bigger than 0.9 and the P/C ratio larger than 3.0 were used to discover 16 N-glycans as diagnostic biomarkers. Particularly, five of the diagnostic biomarkers were AUC above 0.99 and three of N-glycans had AUC 1.0. The results suggest a clear possibility for N-glycan biomarkers to be used as a clinical tool in the veterinary medical area enabling to provide objective and non-invasive diagnostic information.

Introduction: According to previous studies, therapeutic inertia (TI) may affect 7 out of 10 physicians who care for MS patients, particularly in countries where clinical guidelines are not widely used. Limited information is available on the prevalence of TI and its associated factors across Canada.Objectives: (i) To evaluate factors associated with TI amongst neurologists caring for MS patients across Canada; (ii) to compare the prevalence of TI observed in Canadian neurologists to the prevalence of TI observed in Argentinean, Chilean, and Spanish neurologists (historical controls from prior studies).Design: One hundred and eight neurologists with expertise in MS were invited to participate in an online study in Canada. Participants answered questions regarding their clinical practice, risk preferences, management of 10 simulated case-scenarios. The design of that study was similar to that of the prior studies completed in Argentina and Chile (n = 115). TI was defined as lack of treatment initiation or escalation when there was clear evidence of clinical and radiological disease activity (8 case-scenarios, 440 individual responses). A TI score was created & defined as the number of case-scenarios that fit the TI criteria over the total number of presented cases (score range from 0 to 8), with a higher score corresponding to a higher TI. TI scores observed in the Canadian study were compared with those observed in Argentina and Chile, as both studies followed the same design, case-scenarios and methodologies. Predictors of TI included demographic data, MS specialist vs. general neurologist, practice setting, years of practice, volume of MS patients and risk preferences.Results: Fifty-five Canadian neurologists completed the study (completion rate: 50.9%). The mean age (±SD) was 38.3 (±15) years; 47.3% of the participants were female and 56.4% self-identified as MS specialists. Overall, 54 of 440 (12.3%) individual responses were classified as TI. 60% of participants displayed TI in at least one case-scenario. The mean TI score across Canada [0.98 (SD = 1.15)] was significantly lower than the TI score observed in the Argentinean-Chilean [1.82 (SD = 1.47); p < 0.001] study. The multivariable analysis revealed that older age (p = 0.018), years of experience (p = 0.04) and willingness to risk further disease progression by avoiding treatment initiation or treatment change (p = 0.043) were independent predictors of TI.Conclusions: TI in Canada was observed in 6 out of 10 neurologists, affecting on average 1 in 8 therapeutic decisions in MS care. TI in Canada is significantly lower than in the other studied countries. Factors associated with TI include older age, lower years of experience, and willingness to risk disease progression by avoiding treatment initiation or treatment change. Differences in clinical practice patterns and adherence/access to accepted MS guidelines may explain how TI in Canada differs significantly from TI in Argentina-Chile.

Background: Educational interventions are needed to overcome knowledge-to-action gaps in clinical care. We previously tested the feasibility and potential efficacy of an educational intervention that facilitates treatment decisions in multiple sclerosis care. A demonstration of the usability of such an intervention is crucial prior to demonstration of efficacy in a large trial.Objectives: To evaluate the usability of a novel, pilot-tested intervention aimed at neurologists to improve therapeutic decisions in multiple sclerosis (MS) care.Methods: We surveyed 50 neurologists from Chile, Argentina, and Canada randomized to an educational intervention arm of a pilot feasibility study using the System Usability Score (SUS) to assess the usability of a traffic light system (TLS)-based educational intervention. The TLS facilitates therapeutic decisions, allowing participants to easily recognize high-risk scenarios requiring treatment escalation. The SUS is a validated 10-item questionnaire with five response options. The primary outcome was the average and 95% confidence interval (CI) of the SUS score. Values above 68 are considered highly usable.Results: Of 50 neurologists invited to be part of the study, all completed the SUS scale and the study. For the primary outcome, the average usability score was 74.7 (95%CI 70.1–79.2). There was one outlier with a score of 35. The usability score excluding the outlier was 76.8 (95%CI 72.7–80.8). Multivariate analysis revealed no association between participants' characteristics and the SUS score.Conclusions: Our educational intervention has shown high usability among neurologists. The next step is to evaluate the effectiveness of this educational intervention in facilitating treatment decisions for the management of multiple sclerosis in a large trial.

Hepatocyte growth factor receptor (HGFR, c-Met) is an essential member of the receptor tyrosine kinase (RTK) family that is often dysregulated during tumor progression, driving a malignant phenotypic state and modulating important cellular functions including tumor growth, invasion, metastasis, and angiogenesis, providing a strong rationale for targeting HGF/c-Met signaling axis in cancer therapy. Based on its protumorigenic potentials, we developed IRCR201, a potent antagonistic antibody targeting the plexin-semaphorin-integrin (PSI) domain of c-Met, using synthetic human antibody phage libraries. We characterized and evaluated the biochemical properties and tumor inhibitory effect of IRCR201 in vitro and in vivo. IRCR201 is a novel fully-human bivalent therapeutic antibody that exhibits cross-reactivity against both human and mouse c-Met proteins with high affinity and specificity. IRCR201 displayed low agonist activity and rapidly depleted total c-Met protein via the lysosomal degradation pathway, inhibiting c-Met-dependent downstream activation and attenuating cellular proliferation in various c-Met-expressing cancer cells. In vivo tumor xenograft models also demonstrated the superior tumor inhibitory responsiveness of IRCR201. Taken together, IRCR201 provides a promising therapeutic agent for c-Met-positive cancer patients through suppressing the c-Met signaling pathway and tumor growth.

A number of novel oral agents are now approved for use in relapsing multiple sclerosis (MS). Among these agents, teriflunomide has shown promise with respect to clinical efficacy and safety in relapsing MS patients. In this review we aim to clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing relevant points on the use of teriflunomide in MS, with a discussion of teriflunomide’s pharmacologic properties, pivotal clinical trials, and safety and tolerability.

BACKGROUND:Implementing semi-automated processes to efficiently match patients to clinical trials at the point of care requires both detailed patient data and authoritative information about open studies. OBJECTIVE:To evaluate the utility of the ClinicalTrials.gov registry as a data source for semi-automated trial eligibility screening. METHODS:Eligibility criteria and metadata for 437 trials open for recruitment in four different clinical domains were identified in ClinicalTrials.gov. Trials were evaluated for up to date recruitment status and eligibility criteria were evaluated for obstacles to automated interpretation. Finally, phone or email outreach to coordinators at a subset of the trials was made to assess the accuracy of contact details and recruitment status. RESULTS:24% (104 of 437) of trials declaring on open recruitment status list a study completion date in the past, indicating out of date records. Substantial barriers to automated eligibility interpretation in free form text are present in 81% to up to 94% of all trials. We were unable to contact coordinators at 31% (45 of 146) of the trials in the subset, either by phone or by email. Only 53% (74 of 146) would confirm that they were still recruiting patients. CONCLUSION:Because ClinicalTrials.gov has entries on most US and many international trials, the registry could be repurposed as a comprehensive trial matching data source. Semi-automated point of care recruitment would be facilitated by matching the registry's eligibility criteria against clinical data from electronic health records. But the current entries fall short. Ultimately, improved techniques in natural language processing will facilitate semi-automated complex matching. As immediate next steps, we recommend augmenting ClinicalTrials.gov data entry forms to capture key eligibility criteria in a simple, structured format.

Neuromyelitis optica (NMO) is a recurrent inflammatory disease that preferentially targets the optic nerves and spinal cord leading to blindness and paralysis. The hallmarks of NMO include bilateral optic neuritis and longitudinally extensive transverse myelitis. Woman and African Americans are overrepresented in the US patient population. NMO is associated with the NMO-IgG biomarker, which targets the aquaporin-4 water channel on astrocytes. The humoral pathology of NMO lesions include IgG and IgM deposits and infiltration by granulocytes suggesting that the NMO-IgG may be involved in the pathogenesis of disease. This review of the recent NMO literature covers the clinical features, epidemiology, radiology and pathology of disease and includes discussion of the important basic science research work in the field.

Purpose: This study investigated the scope of patient navigation studies on women's health care for maternal health and noncancerous gynecologic conditions and aimed to report the characteristics of the identified patient navigation programs. Methods: A scoping review was conducted following Arksey and O'Malley's framework. Five electronic databases were searched for relevant studies published in English: PubMed, Embase, Cochrane Library, CINAHL, and PsycInfo. There were no restrictions on the publication date and the search was completed in July 2023. Results: This scoping review included 14 studies, which collectively examined seven patient navigation programs. All selected studies were related to maternal health issues (e.g., perinatal health problems and contraception for birth spacing). Close to two-thirds of the patient navigation services were provided by women (n=9, 64.3%) and half by lay navigators (n=7, 50.0%). The majority incorporated the use of mobile health technologies (n=11, 78.6%). All of the patient navigation programs included in the review coordinated the necessary clinical and social support services to improve women's access to care. Conclusion: Patient navigation appears to be in its nascent phase in the field of maternal health. The results of this study suggest that the implementation of patient navigation services could potentially improve access to care for socially disadvantaged women and families. Furthermore, providing patient navigation services that are specifically tailored to meet women's needs could improve the quality of maternity care. [ABSTRACT FROM AUTHOR]