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BACKGROUND: Current guidance on the selection of appropriate contraception for people with multiple sclerosis (PwMS) is lacking. OBJECTIVE: To address this gap, an expert-led consensus program developed recommendations to support clinicians in discussing family planning and contraception with women and men with multiple sclerosis (MS). METHODS: A multidisciplinary steering committee (SC) of 13 international clinical experts led the program, supported by an extended faculty of 32 experts representing 18 countries. A modified Delphi methodology was used for decision-making and consensus-building. The SC drafted 15 clinical questions focused on patient-centered care, selection of contraception, and timing of stopping/starting contraception and disease-modifying therapies (DMTs). Statements addressing each question were drafted based on evaluation of published evidence and the experts clinical experience. Consensus was reached if ⩾75% of respondents agreed (scoring 7-9 on a 9-point scale) with each recommendation. RESULTS: Consensus was reached on 24 of 25 proposed recommendations, including how and when to discuss contraception, types and safety of contraceptives, and how to evaluate the most appropriate contraceptive options for specific patient groups, including those with significant disability or being treated with DMTs. CONCLUSION: These expert recommendations provide the first practical, relevant, and comprehensive guidance for clinicians on the selection of contraception in PwMS.

BackgroundTraumatic brain injury (TBI) and repetitive head impacts (RHI) have been linked to increased risk for multiple types of neurodegenerative disease, higher dementia risk, and earlier age of dementia symptom onset, suggesting transdiagnostic implications for later-life brain health. Frontotemporal dementia (FTD) and primary progressive aphasia (PPA) represent a spectrum of clinical phenotypes that are neuropathologically diverse. FTD/PPA diagnoses bring unique challenges due to complex cognitive and behavioral symptoms that disproportionately present as an early-onset dementia (before age 65). We performed a detailed characterization of lifetime head trauma exposure in individuals with FTD and PPA compared to healthy controls to examine frequency of lifetime TBI and RHI and associated clinical implications.MethodsWe studied 132 FTD/PPA (age 68.9 ± 8.1, 65% male) and 132 sex-matched healthy controls (HC; age 73.4 ± 7.6). We compared rates of prior TBI and RHI (contact/collision sports) between FTD/PPA and HC (chi-square, logistic regression, analysis of variance). Within FTD/PPA, we evaluated associations with age of symptom onset (analysis of variance). Within behavioral variant FTD, we evaluated associations with cognitive function and neuropsychiatric symptoms (linear regression controlling for age, sex, and years of education).ResultsYears of participation were greater in FTD/PPA than HC for any contact/collision sport (8.5 ± 6.7yrs vs. 5.3 ± 4.5yrs, p = .008) and for American football (6.2yrs ± 4.3yrs vs. 3.1 ± 2.4yrs; p = .003). Within FTD/PPA, there were dose-dependent associations with earlier age of symptom onset for TBI (0 TBI: 62.1 ± 8.1, 1 TBI: 59.9 ± 6.9, 2 + TBI: 57.3 ± 8.4; p = .03) and years of American football (0yrs: 62.2 ± 8.7, 1-4yrs: 59.7 ± 7.0, 5 + yrs: 55.9 ± 6.3; p = .009). Within bvFTD, those who played American football had worse memory (z-score: -2.4 ± 1.2 vs. -1.4 ± 1.6, p = .02, d = 1.1).ConclusionsLifetime head trauma may represent a preventable environmental risk factor for FTD/PPA. Dose-dependent exposure to TBI or RHI influences FTD/PPA symptom onset and memory function in bvFTD. Clinico-pathological studies are needed to better understand the neuropathological correlates linking RHI or TBI to FTD/PPA onset and symptoms.

The multifaceted nature of multiple sclerosis requires quantitative biomarkers that can provide insights related to diverse physiological pathways. To this end, proteomic analysis of deeply-phenotyped serum samples, biological pathway modeling, and network analysis were performed to elucidate inflammatory and neurodegenerative processes, identifying sensitive biomarkers of multiple sclerosis disease activity. Here, we evaluated the concentrations of > 1400 serum proteins in 630 samples from three multiple sclerosis cohorts for association with clinical and radiographic new disease activity. Twenty proteins were associated with increased clinical and radiographic multiple sclerosis disease activity for inclusion in a custom assay panel. Serum neurofilament light chain showed the strongest univariate correlation with gadolinium lesion activity, clinical relapse status, and annualized relapse rate. Multivariate modeling outperformed univariate for all endpoints. A comprehensive biomarker panel including the twenty proteins identified in this study could serve to characterize disease activity for a patient with multiple sclerosis.

PURPOSE OF REVIEW: Lack of consistent data and guidance have led to variations between clinicians in the management of pregnancy in women with multiple sclerosis (MS). Pregnant and/or lactating women are often excluded from clinical trials conducted in MS, and thus, the labeling for most disease-modifying therapies (DMTs) excludes use during pregnancy. This has led to heterogeneity in interpretation and labeling regarding the safety of DMTs during pregnancy and lactation and the required preconception washout periods. This review identifies key themes where there is conflicting information surrounding family planning and pregnancy in MS, focusing on the most common discussion points between physicians and patients during preconception planning, pregnancy, postpartum, and lactation. The goal was to inform the patient-physician conversation and provide best practice recommendations based on expert clinical expertise and experience. RECENT FINDINGS: We outline the latest evidence-based data for DMT use during pregnancy and lactation, the effect of MS on fertility and fertility treatments, the risk of adverse pregnancy and delivery outcomes, the risk of postpartum relapse, and immunization and clinical imaging safety during pregnancy and breastfeeding. SUMMARY: Management of family planning and pregnancy in patients with MS requires the most current information. Health care providers should discuss family planning early and frequently with patients with MS, and partners where practicable. Because management of pregnant people with MS will often require a risk/benefit analysis of their needs, shared decision-making in family planning discussions is emphasized. Additional data are needed for specific and underrepresented populations with MS (e.g., single parents or those from the LGBTQ+ community) and those at risk of racial and socioeconomic disparities in care. Pregnancy registries and the design and conduct of clinical trials focused on pregnant and lactating patients should provide additional data to guide the ongoing management of patients with MS.

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.

BackgroundPeople living with multiple sclerosis (MS) face a higher likelihood of being diagnosed with a depressive disorder than the general population. Although many low-cost screening tools and evidence-based interventions exist, depression in people living with MS is underreported, underascertained by clinicians, and undertreated.ObjectiveThis study aims to design a closed-loop tool to improve depression care for these patients. It would support regular depression screening, tie into the point of care, and support shared decision-making and comprehensive follow-up. After an initial development phase, this study involved a proof-of-concept pilot randomized controlled trial (RCT) validation phase and a detailed human-centered design (HCD) phase.MethodsDuring the initial development phase, the technological infrastructure of a clinician-facing point-of-care clinical dashboard for MS management (BRIDGE) was leveraged to incorporate features that would support depression screening and comprehensive care (Care Technology to Ascertain, Treat, and Engage the Community to Heal Depression in people living with MS [MS CATCH]). This linked a patient survey, in-basket messages, and a clinician dashboard. During the pilot RCT phase, a convenience sample of 50 adults with MS was recruited from a single MS center with 9-item Patient Health Questionnaire scores of 5-19 (mild to moderately severe depression). During the routine MS visit, their clinicians were either asked or not to use MS CATCH to review their scores and care outcomes were collected. During the HCD phase, the MS CATCH components were iteratively modified based on feedback from stakeholders: people living with MS, MS clinicians, and interprofessional experts.ResultsMS CATCH links 3 features designed to support mood reporting and ascertainment, comprehensive evidence-based management, and clinician and patient self-management behaviors likely to lead to sustained depression relief. In the pilot RCT (n=50 visits), visits in which the clinician was randomized to use MS CATCH had more notes documenting a discussion of depressive symptoms than those in which MS CATCH was not used (75% vs 34.6%; χ21=8.2; P=.004). During the HCD phase, 45 people living with MS, clinicians, and other experts participated in the design and refinement. The final testing round included 20 people living with MS and 10 clinicians including 5 not affiliated with our health system. Most scoring targets for likeability and usability, including perceived ease of use and perceived effectiveness, were met. Net Promoter Scale was 50 for patients and 40 for clinicians.ConclusionsCreated with extensive stakeholder feedback, MS CATCH is a closed-loop system aimed to increase communication about depression between people living with MS and their clinicians, and ultimately improve depression care. The pilot findings showed evidence of enhanced communication. Stakeholders also advised on trial design features of a full year long Department of Defense-funded feasibility and efficacy trial, which is now underway.Trial registrationClinicalTrials.gov NCT05865405; http://tinyurl.com/4zkvru9x.

BACKGROUND AND OBJECTIVES: Racial disparities exist in both neurologic and obstetric populations, underscoring the importance of evaluating pregnancy outcomes in diverse women with multiple sclerosis (MS). The objective of this multicenter retrospective study was to compare pregnancy care and outcomes between Black and Hispanic (underrepresented) and White women with MS. METHODS: Demographic and clinical data were extracted from medical records of 9 US MS centers for women with MS/clinically isolated syndrome who delivered live births between 2010 and 2021. Sites identified at last 15 consecutive Black/Hispanic women and a matching number of White women. Socioeconomic factors, pregnancy, and MS care/outcomes were compared between groups (underrepresented and White and then Black and Hispanic) using Wilcoxon rank sum (U statistic and effect size r reported), χ2, t tests and logistic regressions as appropriate to data type. Multiple imputation by chained equation was used to account for missing data. RESULTS: Overall, 294 pregnancies resulting in live births were analyzed ( 81 Black, 67 Hispanic, and 146 White mothers). Relative to underrepresented women, White women lived in areas of higher median (interquartile range [IQR]) Child Opportunity Index (79 [45.8] vs 22 [45.8], U = 3,824, r = 0.56, p < 0.0001) and were more often employed (84.9% vs 75%, odds ratio [OR] 2.57, CI 1.46-4.50, p = 0.0008) and privately insured (93.8% vs 56.8%, OR 11.6, CI 5.5-24.5, p < 0.0001) and more received a 14-week ultrasound (98.6% vs 93.9%, OR 4.66, CI 0.99-21.96, p = 0.027). Mode of delivery was significantly different between the three groups (X2(10,294) = 20.38, p = 0.03); notably, Black women had the highest rates of emergency cesarean deliveries, and Hispanic women highest rates of uncomplicated vaginal deliveries. Babies born to underrepresented women had lower median (IQR) birthweights than babies born to White women (3,198 g [435.3 g] vs 3,275 g [412.5 g], U = 9,255, r = 0.12, p = 0.04) and shorter median (IQR) breastfeeding duration (4.5 [3.3] vs 6.0 [4.2] months, U = 8,184, r = 0.21, p = 0.003). While underrepresented women were younger than White women (mean [SD] 30.9 [4.8] vs 33.8 [4.0], t = 1.97, CI 1.96-3.98, p < 0.0001), their median (Q1-Q3, IQR) Expanded Disability Status Scale was higher (1.5 [1-2.5, 1.5] vs 1 [0-1.5, 1.5], U = 7,260, r = 0.29, p < 0.0001) before pregnancy. Finally, medical records were missing more key data for Black women (19.7% missing vs 8.9% missing, OR 2.54, CI 1.25-5.06, p = 0.008). DISCUSSION: In this geographically diverse multicenter cohort, underrepresented women entered pregnancy with higher disability and fewer health care resources. Pregnancy represents a pivotal window where structural factors affect maternal and fetal health and neurologic trajectories; it is a critical period to optimize care and health outcomes.

INTRODUCTION: Depression occurs in over 50% of individuals living with multiple sclerosis (MS) and can be treated using many modalities. Yet, it remains: under-reported by patients, under-ascertained by clinicians and under-treated. To enhance these three behaviours likely to promote evidence-based depression care, we engaged multiple stakeholders to iteratively design a first-in-kind digital health tool. The tool, MS CATCH (Care technology to Ascertain, Treat, and engage the Community to Heal depression in patients with MS), closes the communication loop between patients and clinicians. Between clinical visits, the tool queries patients monthly about mood symptoms, supports patient self-management and alerts clinicians to worsening mood via their electronic health record in-basket. Clinicians can also access an MS CATCH dashboard displaying patients mood scores over the course of their disease, and providing comprehensive management tools (contributing factors, antidepressant pathway, resources in patients neighbourhood). The goal of the current trial is to evaluate the clinical effect and usability of MS CATCH in a real-world clinical setting. METHODS AND ANALYSIS: MS CATCH is a single-site, phase II randomised, delayed start, trial enrolling 125 adults with MS and mild to moderately severe depression. Arm 1 will receive MS CATCH for 12 months, and arm 2 will receive usual care for 6 months, then MS CATCH for 6 months. Clinicians will be randomised to avoid practice effects. The effectiveness analysis is superiority intent-to-treat comparing MS CATCH to usual care over 6 months (primary outcome: evidence of screening and treatment; secondary outcome: Hospital Anxiety Depression Scale-Depression scores). The usability of the intervention will also be evaluated (primary outcome: adoption; secondary outcomes: adherence, engagement, satisfaction). ETHICS AND DISSEMINATION: University of California, San Francisco Institutional Review Board (22-36620). The findings of the study are planned to be shared through conferences and publishments in a peer-reviewed journal. The deidentified dataset will be shared with qualified collaborators on request, provision of CITI and other certifications, and data sharing agreement. We will share the results, once the data are complete and analysed, with the scientific community and patient/clinician participants through abstracts, presentations and manuscripts. TRIAL REGISTRATION NUMBER: NCT05865405.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) commonly affects women in their childbearing years, necessitating discussion between patients and their MS treatment team around the issues of family planning, pregnancy, and postpartum experiences. This study assessed the impact of a diagnosis of MS on womens reproductive decision-making and on their perception of counseling received surrounding pregnancy. It also sought to evaluate trends in pregnancy and postpartum experiences and determine whether experiences differed by race, ethnicity, and zip code. METHODS: Women with an MS diagnosis seen at the University of Virginia MS Clinic or at Virginia Commonwealth University (VCU) MS Clinic were invited to participate in a survey study. MS disease and pregnancy history, and, when appropriate, reasons for pregnancy avoidance were collected. Respondents who had >1 pregnancy following MS diagnosis were asked to evaluate the counseling they received from medical professionals and to share their pregnancy experiences including complications during pregnancy, delivery outcomes, and postpartum experience including breastfeeding. RESULTS: Of the 280 respondents, 76.6% were currently receiving MS specialty care. Most of them (79.3%) had not been pregnant following MS diagnosis. Of them, 20.1% indicated that this decision was driven by MS-related concerns: MS worsening with pregnancy (47%); ability to care for child secondary to MS (35%); passing MS onto child (19%); stopping disease-modifying therapies to attempt pregnancy (14%); lack of knowledge about options for pregnancy and MS (9%). Women with a more recent estimated decade of pregnancy were more likely to report neurologist counseling regarding MS and pregnancy (pregnancy before 2000: 40%, 2000-2010: 64.7%, 2010- present: 83.3%; χ2 0.020). Breastfeeding initiation was reported in 71.4% of postdiagnosis pregnancies (median duration 6 months, interquartile range 1.75-11). DISCUSSION: Over the past few decades, women with MS have received a wide range of evolving guidance surrounding family planning, pregnancy, and postpartum care. Survey data suggest improvements in MS/pregnancy counseling and medical management in recent years, which may be driven by an increase in research in the field. There remains an important need and opportunity to improve counseling of women with MS who are considering pregnancy.

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 users 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.

BACKGROUND: Immune checkpoint inhibitors (ICIs) represent a novel class of agents approved for the treatment of several cancers and progressive multifocal leukoencephalopathy (PML). However, due to the risk of autoimmune side effects, their use in people with autoimmune diseases such as multiple sclerosis (MS) has been limited. OBJECTIVE: To characterize outcomes in a cohort of adults with MS who received ICIs. METHODS: A single-center retrospective review of medical record data was performed for people with MS treated with ICIs. RESULTS: Seven people with MS were identified, with a mean (SD) age at ICI use of 55.4 (13.7) years and a mean MS duration of 18.2 (12.2) years. Six were treated for cancer; 1 was treated for PML. After mean (SD) follow-up of 1.76 (2.15) years after ICI, outcomes are: no evidence of disease (2), residual metastatic disease (1), death due to cancer (1), death due to PML (1), and lost to follow-up (2). Notably, 0 out of 7 patients experienced an MS relapse; two out of six had new asymptomatic demyelinating magnetic resonance imaging lesions. In the three patients with expanded disability status scale (EDSS) scores at baseline and follow-up, EDSS remained stable (mean delta 0.13). CONCLUSION: In this cohort, no people with MS experienced clinical relapses and one-third experienced asymptomatic radiological activity following ICI treatment.

OBJECTIVE: Upper extremity function reflects disease progression in multiple sclerosis (MS). This study evaluated the feasibility, validity, and sensitivity to change of remote dexterity assessments applying human pose estimation to patient-uploaded videos. METHODS: A discovery cohort of 50 adults with MS recorded selfie videos of self-care tasks at home: buttoning, brushing teeth, and eating. Kinematic data were extracted using MediaPipe Hand pose estimation software. Clinical comparison tests were grip and pinch strength, 9 hole peg test (9HPT), and vibration, and patient-reported dexterity assessments (ABILHAND). Feasibility and acceptability were evaluated (Health-ITUES framework). A validation cohort (N = 35) completed 9HPT and videos. RESULTS: The modality was feasible: 88% of the 50 enrolled participants uploaded ≥3 videos, and 74% completed the study. It was also usable: assessments easy to access (95%), platform easy to use (97%), and tasks representative of daily activities (86%). The buttoning task revealed four metrics with strong correlations with 9HPT (nondominant: r = 0.60-0.69, dominant: r = 0.51-0.57, P  0.8). Cross-sectional correlations between video metrics and 9HPT were similar at 6 months, and in the validation cohort (nondominant: r = 0.46, dominant: r = 0.45, P

OBJECTIVE: Postpartum, patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) have increased risk for disease activity. Anti-CD20 IgG1 monoclonal antibodies (mAb) are increasingly used as disease-modifying therapies (DMTs). Patients may wish to both breastfeed and resume DMT postpartum. This study aimed to determine the transfer of anti-CD20 IgG1 mAbs, ocrelizumab, and rituximab (OCR/RTX), into mature breastmilk and describe maternal and infant outcomes. METHODS: Fifty-seven cis-women receiving OCR/RTX after 59 pregnancies and their infants were enrolled and followed up to 12M postpartum or 90 days post-infusion. Breastmilk was collected pre-infusion and serially up to 90 days and assayed for mAb concentration. Medical records and patients questionnaire responses were obtained to assess neurologic, breastfeeding, and infant development outcomes. RESULTS: The median average concentration of mAb in breastmilk was low (OCR: 0.08 μg/mL, range 0.05-0.4; RTX: 0.03 μg/mL, range 0.005-0.3). Concentration peaked 1-7 days post-infusion in most (77%) and was nearly undetectable after 90 days. Median average relative infant dose was  0.05) infants; neither did the proportion with normal development (breastfed: 37/41, non-breastfed: 11/13; p > 0.05). After postpartum infusion, two mothers experienced a clinical relapse. INTERPRETATION: These confirm minimal transfer of mAb into breastmilk. Anti-CD20 mAb therapy stabilizes MS activity before conception to the postpartum period, and postpartum treatments appears to be safe and well-tolerated for both mother and infant.

BACKGROUND: A majority of women with multiple sclerosis (MS) are diagnosed prior to menopause, yet their experiences during this transition are not well characterized. OBJECTIVES: To explore associations between mental health, sleep, and other quality of life metrics, and vasomotor symptoms (VMSs) in ambulatory, menopausal women with MS. METHODS: A secondary analysis was performed of baseline data from two trials enrolling ambulatory peri/postmenopausal women with MS: NCT02710214 (N = 24, bothersome VMS) and NCT04002934 (ongoing, N = 35, myelin repair). Measures analyzed were 36-Item Short-Form Survey (SF-36) (primary scale: general mental health), subjective sleep quality (Pittsburg Sleep Quality Index), VMS (daily diary, interference), mood (Center for Epidemiologist Studies-Depression Scale (CES-D)), walking impairment (timed 25-foot walk (T25FW)), and global disability (Expanded Disability Status Scale (EDSS)). RESULTS: Participants characteristics (N = 59) were: mean age 51.8 years (SD = 3.4), mean disease duration 11.3 years (SD = 7.6), median EDSS 3.0 (IQR = 2.0-4.0). Mental health was associated with better sleep quality (rho = -0.41, p = 0.019) and better mood (rho = -0.75, p < 0.001), but not with EDSS or T25FW (rho < 0.20, p > 0.10). Worse sleep quality also correlated with more frequent VMS (rho = 0.41, p = 0.02) and VMS interference (rho = 0.59, p < 0.001). CONCLUSIONS: Findings suggest that optimizing sleep quality, mood, and hot flash quantity/interference could substantially improve mental health in menopausal women with MS-and highlight an important care gap in this population.

PURPOSE OF REVIEW: Falls occur in more than half of all people with multiple sclerosis (MS) but tend to be underdiagnosed and underreported in clinical encounters. This narrative review aims to summarize evidence-based approaches for evaluating fall risk and proven treatment strategies to reduce falling in people with MS to improve care for people with MS and to enhance interprofessional care coordination between treating neurologic and physical therapy (PT) teams. RECENT FINDINGS: Screening not just for falls but for near-falls as well because fear of falling can improve fall assessment and identify patients who may benefit from fall prevention interventions. A number of barriers, including time constraints during visits and the fallacy that falling is inevitable in MS, can limit clinician awareness about patient falls and delay timely referral to PT. Consultation with physical therapists for individualized fall prevention treatment can reduce risk of falling. Interventional studies have also shown that PT-guided exercise programs improve balance confidence in people with MS. However, people with MS are often under-referred to PT by treating clinicians. SUMMARY: A clinical approach is provided to summarize practical, accessible, evidence-based, low-burden measurements and interventions likely to improve ascertainment of patients at risk of falling and optimize timely PT referral and treatment.

Knowledge representation and reasoning (KR&R) has been successfully implemented in many fields to enable computers to solve complex problems with AI methods. However, its application to biomedicine has been lagging in part due to the daunting complexity of molecular and cellular pathways that govern human physiology and pathology. In this article, we describe concrete uses of Scalable PrecisiOn Medicine Knowledge Engine (SPOKE), an open knowledge network that connects curated information from thirty-seven specialized and human-curated databases into a single property graph, with 3 million nodes and 15 million edges to date. Applications discussed in this article include drug discovery, COVID-19 research and chronic disease diagnosis, and management.

BACKGROUND: In clinical practice, females with MS often report menstrually-related symptom fluctuations. Hypothetically, use of oral contraceptives (OCs) could reduce these fluctuations, particularly continuous OCs (11+ weeks of consistent exogenous hormones followed by 1 week placebo). OBJECTIVES: To prospectively capture (1) whether neurologic and generalized symptoms vary with menstrual cycle phase and (2) whether type of contraception impacts symptom fluctuations. METHODS: In this two-center pilot study, females with MS and a regular menstrual cycle prospectively tracked their menstrual cycles and completed symptom surveys for up to 6 months. Participants were categorized as 1) users of oral contraceptives, either a) cyclic or b) continuous, or 2) endogenously cycling, either c) hormonal intrauterine device (IUD) users or d) none users (e.g. no hormonal contraception; included condoms, copper IUD, tubal ligation, fertility awareness methods). There was no correction for multiple analyses. RESULTS: Altogether, 47/70 participants (67%) provided >4 weeks of data and were included in the analyses. Mean (SD) age was 35.0 (0.9) years, median (IQR) EDSS was 1.5 (1-2) and mean (SD) SymptoMScreen score was 10.4 (9.6). For endogenously cycling patients (IUD and none users), fatigue (MFIS) was lower in the perimenstrual period than in the luteal period (p

BackgroundOver one-third of multiple sclerosis (MS) patients are post-menopausal women, the primary demographic affected by breast cancer. After breast cancer diagnosis, there is little information about patients' clinical experiences with both diseases.ObjectiveUtilize a case series of MS patients diagnosed with breast cancer to characterize oncologic and MS trajectories, and generate novel insights about clinical considerations using qualitative analysis.MethodsA single-center retrospective review was performed on medical record data of patients with MS and breast cancer. Thematic analysis was used to characterize experiences with the concurrent diagnoses.ResultsFor the 43 patients identified, mean age was 56.7 years at cancer diagnosis and MS duration was 16.5 years. Approximately half were treated with MS disease modifying therapy at cancer diagnosis, and half of these subsequently discontinued or changed therapy. Altogether 14% experienced MS relapse(s) during follow-up (with 2 relapses in the first 2 years), with mean annualized relapse rate of 0.03. Cohort Expanded Disability Status Scale (EDSS) scores remained stable during follow-up. Qualitative insights unique to this population were identified regarding immunosuppression use and neurologic symptoms.ConclusionsMS relapses were infrequent, and there was modest progression during breast cancer treatment. Oncologic outcomes were comparable to non-MS patients with similarly staged cancer.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.

Background and objectivesPatients with multiple sclerosis (MS) may seek fertility treatment (FT)-including in vitro fertilization (IVF). Variable relapse risk after IVF has been reported in small historical cohorts, with more recent studies suggesting no change in annualized relapse rate (ARR). The objective of this study was to evaluate ARR 12 months pre-FT and 3 months post-FT in a multicenter cohort and identify factors associated with an increased risk of relapse.MethodsPatients with clinically isolated syndrome (CIS) or MS aged 18-45 years with at least 1 FT from January 1, 2010, to October 14, 2021, were retrospectively identified at 4 large academic MS centers. The exposed period of 3 months after FT was compared with the unexposed period of 12 months before FT. FTs included controlled ovarian stimulation followed by fresh embryo transfer (COS-ET), COS alone, embryo transfer (ET) alone, and oral ovulation induction (OI). The Wilcoxon signed rank test and mixed Poisson regression models with random effects were used to compare ARR pre-FT vs post-FT, with the incidence rate ratio (IRR) and 95% CI reported.ResultsOne hundred twenty-four FT cycles among 65 patients with MS (n = 56) or CIS (n = 9) were included: 61 COS-ET, 19 COS alone, 30 ET alone, and 14 OI. The mean age at FT was 36.5 ± 3.8 years, and the mean disease duration was 8.2 ± 5.0 years. Across 80 cycles with COS, only 5 relapses occurred among 4 unique patients within 3 months of treatment. The mean ARR after COS and before was not different (0.26 vs 0.25, p = 0.37), and the IRR was 0.95 (95% CI: 0.52-1.76, p = 0.88). No cycles with therapeutic disease-modifying therapies (DMTs) during COS had 3 months relapse (ARR 0 post-COS vs 0.18 pre-COS, p = 0.02, n = 34). Relapse rates did not vary by COS protocol. Among COS-ET cycles that achieved pregnancy (n = 43), ARR decreased from 0.26 to 0.09 (p = 0.04) within the first trimester of pregnancy. There were no relapses 3 months after ET alone and 1 relapse after OI.DiscussionIn this modern multicenter cohort of patients with MS undergoing diverse FTs, which included 43% on DMTs, we did not observe an elevated relapse risk after FT.

BackgroundOur study investigated the rate of breakthrough SARS-CoV-2 infection and clinical outcomes in a cohort of multiple sclerosis (MS) patients who were treated with the anti-CD20 monoclonal antibody (Ab), ocrelizumab, before first, second and third BNT162b2 mRNA vaccinations. To correlate clinical outcomes with the humoral and cellular response.MethodsThe study was a prospective non-randomised controlled multicentre trial observational study. Participants with a diagnosis of MS who were treated for at least 12 months with ocrelizumab prior to the first BNT162b2 mRNA vaccination were prospectively followed up from January 2021 to June 2022.ResultsOut of 54 participants, 32 (59.3%) developed a positive SARS-CoV-2 PCR test in the study period. Mild infection was observed in all infected participants. After the third vaccination, the non-infected participants had higher mean Ab levels compared to the infected participants (54.3 binding antibody unit (BAU)/mL vs 26.5 BAU/mL, p=0.030). The difference in reactivity between spike-specific CD4+ and CD8+ T lymphocytes in the two groups was not significant.Conclusion and relevanceThe study results demonstrate rates of 59% in breakthrough infections after the third SARS-CoV-2 mRNA vaccination in ocrelizumab-treated patients with MS, without resulting in critical disease courses. These findings suggest the need for continuous development of prophylactic treatments when proved important in the protection of severe breakthrough infection.

BackgroundRemote activity monitoring has the potential to evaluate real-world, motor function, and disability at home. The relationships of daily physical activity with spinal cord white matter and gray matter (GM) areas, multiple sclerosis (MS) disability and leg function, are unknown.ObjectiveEvaluate the association of structural central nervous system pathology with ambulatory disability.MethodsFifty adults with progressive or relapsing MS with motor disability who could walk >2 minutes were assessed using clinician-evaluated, patient-reported outcomes, and quantitative brain and spinal cord magnetic resonance imaging (MRI) measures. Fitbit Flex2, worn on the non-dominant wrist, remotely assessed activity over 30 days. Univariate and multivariate analyses were performed to assess correlations between physical activity and other disability metrics.ResultsMean age was 53.3 years and median Expanded Disability Status Scale (EDSS) was 4.0. Average daily step counts (STEPS) were highly correlated with EDSS and walking measures. Greater STEPS were significantly correlated with greater C2-C3 spinal cord GM areas (ρ = 0.39, p = 0.04), total cord area (TCA; ρ = 0.35, p = 0.04), and cortical GM volume (ρ = 0.32, p = 0.04).ConclusionThese results provide preliminary evidence that spinal cord GM area is a neuroanatomical substrate associated with STEPS. STEPS could serve as a proxy to alert clinicians and researchers to possible changes in structural nervous system pathology.

Background and objectivesProspective, deeply phenotyped research cohorts monitoring individuals with chronic neurologic conditions, such as multiple sclerosis (MS), depend on continued participant engagement. The COVID-19 pandemic restricted in-clinic research activities, threatening this longitudinal engagement, but also forced adoption of televideo-enabled care. This offered a natural experiment in which to analyze key dimensions of remote research: (1) comparison of remote vs in-clinic visit costs from multiple perspectives and (2) comparison of the remote with in-clinic measures in cross-sectional and longitudinal disability evaluations.MethodsBetween March 2020 and December 2021, 207 MS cohort participants underwent hybrid in-clinic and virtual research visits; 96 contributed 100 "matched visits," that is, in-clinic (Neurostatus-Expanded Disability Status Scale [NS-EDSS]) and remote (televideo-enabled EDSS [tele-EDSS]; electronic patient-reported EDSS [ePR-EDSS]) evaluations. Clinical, demographic, and socioeconomic characteristics of participants were collected.ResultsThe costs of remote visits were lower than in-clinic visits for research investigators (facilities, personnel, parking, participant compensation) but also for participants (travel, caregiver time) and carbon footprint (p < 0.05 for each). Median cohort EDSS was similar between the 3 modalities (NS-EDSS: 2, tele-EDSS: 1.5, ePR-EDSS: 2, range 0.6.5); the remote evaluations were each noninferior to the NS-EDSS within ±0.5 EDSS point (TOST for noninferiority, p < 0.01 for each). Furthermore, year to year, the % of participants with worsening/stable/improved EDSS scores was similar, whether each annual evaluation used NS-EDSS or whether it switched from NS-EDSS to tele-EDSS.DiscussionAltogether, the current findings suggest that remote evaluations can reduce the costs of research participation for patients, while providing a reasonable evaluation of disability trajectory longitudinally. This could inform the design of remote research that is more inclusive of diverse participants.

Automated quantification of data acquired as part of an MRI exam requires identification of the specific acquisition of relevance to a particular analysis. This motivates the development of methods capable of reliably classifying MRI acquisitions according to their nominal contrast type, e.g., T1 weighted, T1 post-contrast, T2 weighted, T2-weighted FLAIR, proton-density weighted. Prior studies have investigated using imaging-based methods and DICOM metadata-based methods with success on cohorts of patients acquired as part of a clinical trial. This study compares the performance of these methods on heterogeneous clinical datasets acquired with many different scanners from many institutions. RF and CNN models were trained on metadata and pixel data, respectively. A combined RF model incorporated CNN logits from the pixel-based model together with metadata. Four cohorts were used for model development and evaluation: MS research (n = 11,106 series), MS clinical (n = 3244 series), glioma research (n = 612 series, test/validation only), and ADNI PTSD (n = 477 series, training only). Together, these cohorts represent a broad range of acquisition contexts (scanners, sequences, institutions) and subject pathologies. Pixel-based CNN and combined models achieved accuracies between 97 and 98% on the clinical MS cohort. Validation/test accuracies with the glioma cohort were 99.7% (metadata only) and 98.4 (CNN). Accurate and generalizable classification of MRI acquisition contrast types was demonstrated. Such methods are important for enabling automated data selection in high-throughput and big-data image analysis applications.

Background and aimsDetailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis.Approach and resultsA targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p

BackgroundAdequate response to the SARS-CoV-2 vaccine represents an important treatment goal in caring for patients with multiple sclerosis (MS) during the ongoing COVID-19 pandemic. Previous data so far have demonstrated lower spike-specific IgG responses following two SARS-CoV-2 vaccinations in MS patients treated with sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb) compared to other disease modifying therapies (DMTs). It is unknown whether subsequent vaccinations can augment antibody responses in these patients.ObjectivesThe goal of this observational study was to determine the effects of a third SARS-CoV-2 vaccination on antibody and T cell responses in MS patients treated with anti-CD20 mAb or S1P receptor modulators.MethodsVaccine responses in patients treated with anti-CD20 antibodies (ocrelizumab and ofatumumab) or S1P receptor modulators (fingolimod and siponimod) were evaluated before and after third SARS-CoV-2 vaccination as part of an ongoing longitudinal study. Total spike protein and spike receptor binding domain (RBD)-specific IgG responses were measured by Luminex bead-based assay. Spike-specific CD4+ and CD8+ T cell responses were measured by activation-induced marker expression.ResultsMS patients and healthy controls were enrolled before and following SARS-CoV-2 vaccination. A total of 31 MS patients (n = 10 ofatumumab, n = 13 ocrelizumab, n = 8 S1P) and 10 healthy controls were evaluated through three SARS-CoV-2 vaccinations. Compared to healthy controls, total spike IgG was significantly lower in anti-CD20 mAb-treated patients and spike RBD IgG was significantly lower in anti-CD20 mAb and S1P-treated patients following a third vaccination. While seropositivity was 100% in healthy controls after a third vaccination, total spike IgG and spike RBD IgG seropositivity were lower in ofatumumab (60% and 60%, respectively), ocrelizumab (85% and 46%, respectively), and S1P-treated patients (100% and 75%, respectively). Longer treatment duration, including prior treatment history, appeared to negatively impact antibody responses. Spike-specific CD4+ and CD8+ T cell responses were well maintained across all groups following a third vaccination. Finally, immune responses were also compared in patients who were vaccinated prior to or following ofatumumab treatment. Antibody responses were significantly higher in those patients who received their primary SARS-CoV-2 vaccination prior to initiating ofatumumab treatment.ConclusionsThis study adds to the evolving understanding of SARS-CoV-2 vaccine responses in people with MS treated with disease-modifying therapies (DMTs) known to suppress humoral immunity. Our findings provide important information for optimizing vaccine immunity in at-risk MS patient populations.

Introduction: Cognitive impairment is a debilitating symptom in people with multiple sclerosis (MS). Most of the neuropsychological tasks have little resemblance to everyday life. There is a need for ecologically valid tools for assessing cognition in real-life functional contexts in MS. One potential solution would involve the use of virtual reality (VR) to exert finer control over the task presentation environment; however, VR studies in the MS population are scarce. Objectives: To explore the utility and feasibility of a VR program for cognitive assessment in MS. Methods: A VR classroom embedded with a continuous performance task (CPT) was assessed in 10 non-MS adults and 10 people with MS with low cognitive functioning. Participants performed the CPT with distractors (i.e., WD) and without distractors (i.e., ND). The Symbol Digit Modalities Test (SDMT), California Verbal Learning Test-II (CVLT-II), and a feedback survey on the VR program was administered. Results: People with MS exhibited greater reaction time variability (RTV) compared to non-MS participants, and greater RTV in both WD and ND conditions was associated with lower SDMT. Conclusions: VR tools warrant further research to determine their value as an ecologically valid platform for assessing cognition and everyday functioning in people with MS.

Introduction: High-altitude pulmonary edema (HAPE) occurs as a result of rapid ascent to altitude faster than the acclimatization processes of the body. Symptoms can begin at an elevation of 2,500 meters above sea level. Our objective in this study was to determine the prevalence and trend of developing B-lines at 2,745 meters above sea level among healthy visitors over four consecutive days.Methods: We performed a prospective case series on healthy volunteers at Mammoth Mountain, CA, USA. Subjects underwent pulmonary ultrasound for B-lines over four consecutive days.Results: We enrolled 21 male and 21 female participants. There was an increase in the sum of B-lines at both lung bases from day 1 to day 3, with a subsequent decrease from day 3 to day 4 (P

ObjectiveExtremity venous aneurysms result in the risk of pulmonary embolism (PE) and chronic venous insufficiency. At present, owing to the rarity of these aneurysms, no consensus for their treatment has been established. The purpose of the present study was to review the presentation, natural history, and contemporary management of extremity venous aneurysms.MethodsWe performed a retrospective, multi-institutional review of all patients with extremity venous aneurysms treated from 2008 to 2018. A venous aneurysm was defined as saccular or fusiform with an aneurysm/vein ratio of >1.5.ResultsA total of 66 extremity aneurysms from 11 institutions were analyzed, 40 of which were in a popliteal location, 14 iliofemoral, and 12 in an upper extremity or a jugular location. The median follow-up was 27 months (range, 0-120 months). Of the 40 popliteal venous aneurysms, 8 (20%) had presented with deep vein thrombosis (DVT) or PE, 13 (33%) had presented with pain, and 19 had been discovered incidentally. The mean size of the popliteal venous aneurysms presenting with DVT or PE was larger than that of those presenting without thromboembolism (3.8 cm vs 2.5 cm; P = .003). Saccular aneurysm morphology in the lower extremity was associated with thromboembolism (30% vs 9%; P = .046) and fusiform aneurysm morphology with a thrombus burden >25% (45% vs 3%). Patients presenting with thromboembolism were more likely to have had a thrombus burden >25% in their lower extremity venous aneurysm compared with those who had presented without thromboembolism (70% vs 9%). Approximately half of all the patients underwent immediate intervention, and half were managed with observation or antithrombotic regimen. In the non-operative cohort, three patients subsequently developed a DVT. Eight patients in the medically managed cohort went on to require surgical intervention. Of the 12 upper extremity venous aneurysms, none had presented with DVT or PE, and only 2 (17%) had presented with pain. Of the 66 patients in the entire cohort, 41 underwent surgical intervention. The most common indication was the absolute aneurysm size. Nine patients had undergone surgery because of a DVT or PE, and 11 for pain or extremity swelling. The most common surgery was aneurysmorrhaphy in 21 patients (53%), followed by excision and ligation in 14 patients (35%). Five patients (12%) had undergone interposition bypass grafting. A postoperative hematoma requiring reintervention was the most common complication, occurring in three popliteal vein repairs and one iliofemoral vein repair. None of the patients, treated either surgically or medically, had reported post-thrombotic complications during the follow-up period.ConclusionsLarge lower extremity venous aneurysms and saccular aneurysms with thrombus >25% of the lumen are more likely to present with thromboembolic complications. Surgical intervention for lower extremity venous aneurysms is indicated to reduce the risk of venous thromboembolism (VTE) and the need for continued anticoagulation. Popliteal aneurysms >2.5 cm and all iliofemoral aneurysms should be considered for repair. Upper extremity aneurysms do not have a significant risk of VTE and warrant treatment primarily for symptoms other than VTE.

BackgroundThe influence of aldosterone breakthrough (ABT) on proteinuria reduction during renin-angiotensin system (RAS) inhibition for spontaneous proteinuric chronic kidney disease (CKDP ) has not been determined in dogs.ObjectivesDetermine whether ABT occurs in dogs with CKDP and if it is associated with decreased efficacy in proteinuria reduction during RAS inhibitor treatment.AnimalsFifty-six client-owned dogs with CKDP and 31 healthy client-owned dogs.MethodsProspective, multicenter, open-label clinical trial. Dogs were treated with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker alone or in combination at the attending clinician's discretion and evaluated at 5 time points over 6 months. Healthy dogs were used to determine the urine aldosterone-to-creatinine ratio cutoff that defined ABT. The relationship of ABT (present at ≥50% of visits) and proteinuria outcome (≥50% reduction in urine protein-to-creatinine ratio from baseline at ≥50% of subsequent visits) was evaluated. Mixed effects logistic regression was used to evaluate the relationship between clinical variables and outcomes (either successful proteinuria reduction or ABT).ResultsThirty-six percent (20/56) of dogs had successful proteinuria reduction. Between 34% and 59% of dogs had ABT, depending on the definition used. Aldosterone breakthrough was not associated with proteinuria outcome. Longer duration in the study was associated with greater likelihood of successful proteinuria reduction (P = .002; odds ratio, 1.6; 95% confidence interval [CI], 1.2-2.2).Conclusions and clinical importanceAldosterone breakthrough was common in dogs receiving RAS inhibitors for CKDp but was not associated with proteinuria outcome.

BackgroundIn multiple sclerosis (MS), telemedicine improves access to specialized medical care; however, barriers remain, including universal access and effective implementation. Focusing on telerehabilitation, ie, remotely delivered physical therapy, our goal was to identify barriers to telerehabilitation implementation and factors associated with patients completing telerehabilitation physical therapy treatment.MethodsQuantitative data included a review of electronic health records of patients with MS treated at the University of California San Francisco Physical Therapy Faculty Practice. We extracted demographic, clinical, and transit-related factors. For patients who scheduled an initial evaluation, we recorded the number of follow-ups, cancellations, completed physical therapy goals, and discharges. Qualitative data included interviews with 3 board-certified neurologic physical therapists and patients' perspectives recorded in the subjective portion of physical therapy notes.ResultsWe identified 111 patients with at least 1 visit (in-person or telerehabilitation) to physical therapy (82 women; mean ± SD age, 54.2 ± 12.7 years). Patients with no disability (Expanded Disability Status Scale [EDSS] score, 0) were 73% less likely to schedule a follow-up appointment (in-person or telerehabilitation) than those with some disability (EDSS score, >0) (odds ratio, 0.27; 95% CI, 0.09-0.75; P = .012). Neurologic physical therapists identified reduced travel burden and scheduling flexibility as benefits of telerehabilitation vs in-person visits. Barriers to telerehabilitation included low technological literacy, cognitive impairment, and fall risk. Patients described scheduling conflicts and pain/illness as barriers to telerehabilitation.ConclusionsPatients with no disability were least likely to complete physical therapy treatment via telerehabilitation. Although both benefits and barriers to completing physical therapy via telerehabilitation are present, the neurologic physical therapists were supportive of a hybrid model for physical therapy.

Background and objectivesPatients with multiple sclerosis (MS) transition from oral sphingosine-1-receptor (S1P) modulators to anti-CD20 therapies for several circumstances. Optimal timing of this transition is uncertain, given competing concerns of rebound disease activity and ensuring immune reconstitution. The objective of this study was to evaluate the relationship between inflammatory activity and the transition period from fingolimod to anti-CD20 therapies in a real-world MS cohort.MethodsMedical records were reviewed for all patients at our center transitioning from fingolimod to rituximab or ocrelizumab between 2010 and October 2020. Time periods reviewed were the following: before fingolimod discontinuation, interval between fingolimod and anti-CD20 treatments, and after the first anti-CD20 infusion. The primary outcome was clinical relapses; MRI activity, time to absolute lymphocyte count (ALC) recovery, and infections were secondary. Clinical and demographic factors significant in univariable analyses were included in multivariable analyses.ResultsTransition data were available for 108 patients (68.5% women, 68.5% relapsing-remitting MS, mean age 44.6 years). The median (interquartile range) interval between fingolimod and anti-CD20 therapy was 28 (1-115.2) days. Six of 51 patients (11.8%) with intervals >1 month and 0/57 patients with shorter intervals experienced a relapse (MRI confirmed) within 6 months of fingolimod discontinuation. In the year following anti-CD20 initiation, 4/108 patients (3.7%) experienced a relapse (median 214.5 days after infusion). An additional 7% of those undergoing contrast-enhanced MRIs developed Gd+ lesions. ALC normalized following treatment switch in 89/92; the interval between treatments was unrelated to ALC recovery or infection.DiscussionDelaying anti-CD20 start to monitor ALC after S1P modulator discontinuation may not be necessary and could increase rebound risk. ALC monitoring could instead occur after a rapid switch to anti-CD20 treatment.

Purpose of reviewThere is considerable heterogeneity in the use of B-cell depletion in women of childbearing age, likely driven at least in part by the discrepancy between the product labels and what is known about the physiology of IgG1, including breastmilk and placental transfer.Recent findingsWe provide practical considerations on the use of this medication class in women of childbearing potential. We discuss prepregnancy planning including vaccinations, safety of B-cell depletion during pregnancy, and postpartum considerations including breastfeeding.SummaryB-cell-depleting monoclonal antibodies have shown to be effective for prepregnancy and postpartum prevention of inflammatory activity in MS and neuromyelitis optica spectrum disorder. B-cell-depleting therapies are large IgG1 monoclonal antibodies, which have minimal transfer across the placenta and into breastmilk. Consideration of risks and benefits of these therapies should be considered in counseling women planning pregnancy and postpartum.

BackgroundThe effects of pregnancy on multiple sclerosis (MS) inflammatory activity are not well described in women with moderate to severe disabilities.ObjectiveTo quantify the peripartum annualized relapse rate (ARR) in women with MS with an Expanded Disability Status Scale (EDSS) ≥ 3.MethodsWe performed a retrospective cohort study of 85 pregnancies in 74 subjects with preconception EDSS ≥ 3. We quantified peripartum ARR and tested for risk factors predictive of peripartum relapses, postpartum brain magnetic resonance imaging activity (new T2 or gadolinium-enhancing lesions), and disability worsening.ResultsThere were 74 live births, with a 56% operative delivery rate. In subjects with relapsing-remitting MS, ARR decreased to 0.11 during the third trimester of pregnancy compared to 0.59 in the year preconception and increased to 1.22 in the 3 months postpartum. Women with a higher preconception EDSS had higher odds of postpartum relapses and clinically significant worsening of disability as compared to subjects with a lower EDSS.ConclusionsModerately to severely disabled women with MS have a lower risk of relapse during pregnancy as compared to preconception, followed by a marked increase postpartum. Further studies are needed to identify ways to reduce peripartum inflammatory activity and disability progression in women with MS with moderate to severe disability.

ObjectiveTo examine humoral and cellular response in multiple sclerosis patients on anti-CD20 therapy after third BNT162b2 mRNA SARS-CoV-2 vaccination.MethodsA prospective longitudinal study design from first throughout third vaccination in Danish and American MS centers. All participants were treated with ocrelizumab. Antibody (Ab) levels were assessed before and after third vaccination using SARS-CoV-2 IgG II Quant assay (Abbott Laboratories). B- and T-lymphocytes enumeration was done with BD Multitest™6-color TBNK reagent. Spike-specific T-cell responses were measured through PBMC stimulation with spike peptide pools (JPT Peptide Technologies).ResultsWe found that 14.0%, 37.7%, and 33.3% were seropositive after first, second and third vaccination. The median Ab-levels were 74.2 BAU/mL (range: 8.5-2427) after second vaccination, as well as 43.7 BAU/ml (range: 7.8-366.1) and 31.3 BAU/mL (range: 7.9-507.0) before and after third vaccination, respectively. No difference was found in levels after second and third vaccination (p = 0.1475). Seropositivity dropped to 25.0% of participants before the third vaccination, a relative reduction of 33.3% (p = 0.0020). No difference was found between frequencies of spike reactive CD4+and CD8+ T-cells after second (0.65 ± 0.08% and 0.95 ± 0.20%, respectively) and third vaccination (0.99 ± 0.22% and 1.3 ± 0.34%, respectively).ConclusionIn this longitudinal cohort we found no significant increased humoral or cellular response with administration of a third SARS-CoV-2 mRNA vaccination. These findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.

BackgroundFalling is common in people with multiple sclerosis (MS) but tends to be under-ascertained and under-treated.ObjectiveTo evaluate fall risk in people with MS.MethodsNinety-four people with MS, able to walk > 2 min with or without an assistive device (Expanded Disability Status Scale (EDSS ≤ 6.5) were recruited. Clinic-based measures were recorded at baseline and 1 year. Patient-reported outcomes (PROs), including a fall survey and the MS Walking Scale (MSWS-12), were completed at baseline, 1.5, 3, 6, 9, and 12 months. Average daily step counts (STEPS) were recorded using a wrist-worn accelerometer.Results50/94 participants (53.2%) reported falling at least once. Only 56% of participants who reported a fall on research questionnaires had medical-record documented falls. Fallers had greater disability [median EDSS 5.5 (IQR 4.0-6.0) versus 2.5 (IQR 1.5-4.0), p

BackgroundLoss of fine motor skills is observed in many neurological diseases, and remote monitoring assessments can aid in early diagnosis and intervention. Hand function can be regularly assessed to monitor loss of fine motor skills in people with central nervous system disorders; however, there are challenges to in-clinic assessments. Remotely assessing hand function could facilitate monitoring and supporting of early diagnosis and intervention when warranted.ObjectiveRemote assessments can facilitate the tracking of limitations, aiding in early diagnosis and intervention. This study aims to systematically review existing evidence regarding the remote assessment of hand function in populations with chronic neurological dysfunction.MethodsPubMed and MEDLINE, CINAHL, Web of Science, and Embase were searched for studies that reported remote assessment of hand function (ie, outside of traditional in-person clinical settings) in adults with chronic central nervous system disorders. We excluded studies that included participants with orthopedic upper limb dysfunction or used tools for intervention and treatment. We extracted data on the evaluated hand function domains, validity and reliability, feasibility, and stage of development.ResultsIn total, 74 studies met the inclusion criteria for Parkinson disease (n=57, 77% studies), stroke (n=9, 12%), multiple sclerosis (n=6, 8%), spinal cord injury (n=1, 1%), and amyotrophic lateral sclerosis (n=1, 1%). Three assessment modalities were identified: external device (eg, wrist-worn accelerometer), smartphone or tablet, and telerehabilitation. The feasibility and overall participant acceptability were high. The most common hand function domains assessed included finger tapping speed (fine motor control and rigidity), hand tremor (pharmacological and rehabilitation efficacy), and finger dexterity (manipulation of small objects required for daily tasks) and handwriting (coordination). Although validity and reliability data were heterogeneous across studies, statistically significant correlations with traditional in-clinic metrics were most commonly reported for telerehabilitation and smartphone or tablet apps. The most readily implementable assessments were smartphone or tablet-based.ConclusionsThe findings show that remote assessment of hand function is feasible in neurological disorders. Although varied, the assessments allow clinicians to objectively record performance in multiple hand function domains, improving the reliability of traditional in-clinic assessments. Remote assessments, particularly via telerehabilitation and smartphone- or tablet-based apps that align with in-clinic metrics, facilitate clinic to home transitions, have few barriers to implementation, and prompt remote identification and treatment of hand function impairments.

BACKGROUNDVaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of the effects of MS DMTs on SARS-CoV-2 vaccine-specific immunity is needed, including quantitative and functional B and T cell responses.METHODSSpike-specific Ab and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 study participants, including healthy controls and patients with MS in 6 DMT groups: untreated and treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 mAbs. Anti-spike-Ab responses were assessed by Luminex assay, VirScan, and pseudovirus neutralization. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker and cytokine expression and tetramer.RESULTSAnti-spike IgG levels were similar between healthy control participants and patients with untreated MS and those receiving GA, DMF, or NTZ but were reduced in anti-CD20 mAb- and S1P-treated patients. Anti-spike seropositivity in anti-CD20 mAb-treated patients was correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization were reduced in anti-CD20 mAb- and S1P-treated patients. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups, except in S1P-treated patients, in whom postvaccine CD4+ T cell responses were attenuated.CONCLUSIONThese findings from a large cohort of patients with MS exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines.FUNDINGNIH grants 1K08NS107619, K08NS096117, R01AI159260, R01NS092835, R01AI131624, and R21NS108159; NMSS grants TA-1903-33713 and RG1701-26628; Westridge Foundation; Chan Zuckerberg Biohub; Maisin Foundation.

ObjectiveA major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS).MethodsFrom a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion.ResultsPatients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p

ObjectiveEarly identification of chronic diseases is a pillar of precision medicine as it can lead to improved outcomes, reduction of disease burden, and lower healthcare costs. Predictions of a patient's health trajectory have been improved through the application of machine learning approaches to electronic health records (EHRs). However, these methods have traditionally relied on "black box" algorithms that can process large amounts of data but are unable to incorporate domain knowledge, thus limiting their predictive and explanatory power. Here, we present a method for incorporating domain knowledge into clinical classifications by embedding individual patient data into a biomedical knowledge graph.Materials and methodsA modified version of the Page rank algorithm was implemented to embed millions of deidentified EHRs into a biomedical knowledge graph (SPOKE). This resulted in high-dimensional, knowledge-guided patient health signatures (ie, SPOKEsigs) that were subsequently used as features in a random forest environment to classify patients at risk of developing a chronic disease.ResultsOur model predicted disease status of 5752 subjects 3 years before being diagnosed with multiple sclerosis (MS) (AUC = 0.83). SPOKEsigs outperformed predictions using EHRs alone, and the biological drivers of the classifiers provided insight into the underpinnings of prodromal MS.ConclusionUsing data from EHR as input, SPOKEsigs describe patients at both the clinical and biological levels. We provide a clinical use case for detecting MS up to 5 years prior to their documented diagnosis in the clinic and illustrate the biological features that distinguish the prodromal MS state.

Knowledge representation and reasoning (KR&R) has been successfully implemented in many fields to enable computers to solve complex problems with AI methods. However, its application to biomedicine has been lagging in part due to the daunting complexity of molecular and cellular pathways that govern human physiology and pathology. In this article we describe concrete uses of SPOKE, an open knowledge network that connects curated information from 37 specialized and human-curated databases into a single property graph, with 3 million nodes and 15 million edges to date. Applications discussed in this article include drug discovery, COVID-19 research and chronic disease diagnosis and management.

Fatigue is one of the most common multiple sclerosis (MS) symptoms. Despite this, monitoring and measuring fatigue (subjective lack of energy)- and fatigability (objectively measurable and quantifiable performance decline)- in people with MS have remained challenging. Traditionally, administration of self-report questionnaires during in-person visits has been used to measure fatigue. However, remote measurement and monitoring of fatigue and fatigability have become feasible in the past decade. Traditional questionnaires can be administered through the web in any setting. The ubiquitous availability of smartphones allows for momentary and frequent measurement of MS fatigue in the ecological home-setting. This approach reduces the recall bias inherent in many traditional questionnaires and demonstrates the fluctuation of fatigue that cannot be captured by standard measures. Wearable devices can assess patients' fatigability and activity levels, often influenced by the severity of subjective fatigue. Remote monitoring of fatigue, fatigability, and activity in real-world situations can facilitate quantifying symptom-severity in clinical and research settings. Combining remote measures of fatigue as well as objective fatigability in a single construct, composite score, may provide a more comprehensive outcome. The more granular data obtained through remote monitoring techniques may also help with the development of interventions aimed at improving fatigue and lowering the burden of this disabling symptom.

BackgroundAmbulatory disability is common in people with multiple sclerosis (MS). Remote monitoring using average daily step count (STEPS) can assess physical activity (activity) and disability in MS. STEPS correlates with conventional metrics such as the expanded disability status scale (Expanded Disability Status Scale; EDSS), Timed-25 Foot walk (T25FW) and timed up and go (TUG). However, while STEPS as a summative measure characterizes the number of steps taken over a day, it does not reflect variability and intensity of activity.ObjectivesNovel analytical methods were developed to describe how individuals spends time in various activity levels (e.g., continuous low versus short bouts of high) and the proportion of time spent at each activity level.Methods94 people with MS spanning the range of ambulatory impairment (unaffected to requiring bilateral assistance) were recruited into FITriMS study and asked to wear a Fitbit continuously for 1-year. Parametric distributions were fit to minute-by-minute step data. Adjusted R2 values for regressions between distributional fit parameters and STEPS with EDSS, TUG, T25FW and the patient-reported 12-item MS Walking scale (MSWS-12) were calculated over the first 4-weeks, adjusting for sex, age and disease duration.ResultsDistributional fits determined that the best statistically-valid model across all subjects was a 3-compartment Gaussian Mixture Model (GMM) that characterizes the step behavior within 3 levels of activity: high, moderate and low. The correlation of GMM parameters for baseline step count measures with clinical assessments was improved when compared with STEPS (adjusted R2 values GMM vs. STEPS: TUG: 0.536 vs. 0.419, T25FW: 0.489 vs. 0.402, MSWS-12: 0.383 vs. 0.378, EDSS: 0.557 vs. 0.465). The GMM correlated more strongly (Kruskal-Wallis: p = 0.0001) than STEPS and gave further information not included in STEPS.ConclusionsIndividuals' step distributions follow a 3-compartment GMM that better correlates with clinic-based performance measures compared with STEPS. These data support the existence of high-moderate-low levels of activity. GMM provides an interpretable framework to better understand the association between different levels of activity and clinical metrics and allows further analysis of walking behavior that takes step distribution and proportion of time at three levels of intensity into account.

BackgroundThe immunogenicity of COVID-19 vaccine among patients receiving anti-CD20 monoclonal antibody (Ab) treatment has not been fully investigated. Detectable levels of SARS-CoV-2 immunoglobulin G (IgG) are believed to have a predictive value for immune protection against COVID-19 and is currently a surrogate indicator for vaccine efficacy.ObjectiveTo determine IgG Abs in anti-CD20 treated patients with multiple sclerosis (MS).MethodIgG Abs against SARS-CoV-2 spike receptor-binding domain were measured with the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories) before and after vaccination (n = 60).Results36.7% of patients mounted a positive SARS-CoV-2 spike Ab response after the second dose of vaccine. Five patients (8.3%) developed Abs >264 BAU/mL, another 12 patients (20%) developed intermediate Abs between 54 BAU/mL and 264 BAU/mL and five patients (8.3%) had low levels

BackgroundSleep disturbances are commonly reported by people with multiple sclerosis (PwMS). However, optimal management of sleep disturbances is uncertain, and objective studies of sleep quality in PwMS are scarce.ObjectivesTo determine the effect of exogenous melatonin on sleep quality and sleep disturbances in PwMS.MethodsThirty adult PwMS reporting sleep difficulties were recruited in a randomized, controlled, double-blind cross-over study. They took either melatonin or placebo for 2 weeks, and the opposite for the following 2 weeks. During weeks 2 and 4, an actigraph was used to capture mean total sleep time and sleep efficiency. Patient-reported outcomes (PROs) were collected at weeks 0, 2 and 4.ResultsMelatonin use significantly improved mean total sleep time (p = 0.03), with a trend towards higher sleep efficiency (p = 0.06). No PROs were significantly different; there was a trend for melatonin use to decrease mean Insomnia Severity Index score (p = 0.07), improve Pittsburgh Sleep Quality Index sleep quality component (p = 0.07), and improve NeuroQoL-Fatigue (p = 0.06). No other PROs showed differences between melatonin and placebo; nor did step count measured by actigraphy (all p > 0.45).ConclusionThese results provide preliminary evidence that melatonin, a low-cost, over-the-counter supplement, could improve objective measures of sleep quality in PwMS.

BackgroundThe immunogenicity of COVID-19 vaccine among patients receiving anti-CD20 monoclonal antibody (Ab) treatment has not been fully investigated. Detectable levels of SARS-CoV-2 immunoglobulin G (IgG) are believed to have a predictive value for immune protection against COVID-19 and is currently a surrogate indicator for vaccine efficacy.ObjectiveTo determine IgG Abs in anti-CD20 treated patients with multiple sclerosis (MS).MethodIgG Abs against SARS-CoV-2 spike receptor-binding domain were measured with the SARS-CoV-2 IgG II Quant assay (Abbott Laboratories) before and after vaccination (n = 60).Results36.7% of patients mounted a positive SARS-CoV-2 spike Ab response after the second dose of vaccine. Five patients (8.3%) developed Abs >264 BAU/mL, another 12 patients (20%) developed intermediate Abs between 54 BAU/mL and 264 BAU/mL and five patients (8.3%) had low levels

Telehealth services complement in-person neurologic care. The American Academy of Neurology supports patient access to telehealth services regardless of location, coverage for telehealth services by all subscriber benefits and insurance, equitable provider reimbursement, simplified state licensing requirements easing access to virtual care, and expanding telehealth research and quality initiatives. The roles and responsibilities of providers should be clearly delineated in telehealth service models.

BackgroundFalling is common in people with multiple sclerosis (MS) but tends to be under-ascertained and under-treated.ObjectiveTo evaluate fall risk in people with MS.MethodsNinety-four people with MS, able to walk > 2 min with or without an assistive device (Expanded Disability Status Scale (EDSS ≤ 6.5) were recruited. Clinic-based measures were recorded at baseline and 1 year. Patient-reported outcomes (PROs), including a fall survey and the MS Walking Scale (MSWS-12), were completed at baseline, 1.5, 3, 6, 9, and 12 months. Average daily step counts (STEPS) were recorded using a wrist-worn accelerometer.Results50/94 participants (53.2%) reported falling at least once. Only 56% of participants who reported a fall on research questionnaires had medical-record documented falls. Fallers had greater disability [median EDSS 5.5 (IQR 4.0-6.0) versus 2.5 (IQR 1.5-4.0), p