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Neurocognitive testing is a critical tool in the management of sport-related concussions. Adversity during childhood and adolescence affects cognitive tasks, behavioral outcomes, and academic performance. Adversity may be important in baseline concussion test validity as well; however, the influence of these experiences is not well understood. To examine the relationship between individual-level experiences of adversity and baseline test validity of Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). We hypothesized that experiences of poverty, maltreatment, or extreme neighborhood deprivation would be associated with lower odds of baseline test validity. Case-control study. Cuyahoga County, Ohio. A total of 6495 student-athletes born from 1995 through 2005 who completed a baseline ImPACT test between 10 and 18 years old and were identified in the Child-Household Integrated Longitudinal Data system, a comprehensive data system with demographic and social service usage outcomes for children in Cuyahoga County, Ohio. Baseline concussion test validity was determined using the ImPACT built-in validity measure. Experiences of adversity during the sensitive developmental periods of early childhood and adolescence were key independent variables. Our findings suggested that social mobility may play an important role in baseline validity. Youth with upward social mobility (ie, poverty or neighborhood deprivation in early childhood only) were not different from youth without such experiences (odds ratio [OR] = 0.91, P =.74). Youth with persistent adversity across childhood or downward social mobility (ie, poverty or high neighborhood deprivation in adolescence only) had 50% to 72% lower odds of achieving a valid baseline test (persistent poverty, OR = 0.59, P =.05; adolescent poverty only, OR = 0.50, P =.004; adolescent neighborhood deprivation only, OR = 0.28, P <.001). Maltreatment had no significant effect on test validity. These findings indicated that certain patterns of adversity may predispose youth to invalid baseline testing scores, potentially increasing their risk of inappropriate injury management and poor outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE‐BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset. Design/Methods: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601). Results: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning. Conclusions: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning. Key points: With the global population of older adults increasing rapidly, it is important to understand how older adults with bipolar disorder (BD) differ from younger adults.This replication analysis using a large global dataset focused on older‐age bipolar disorder (OABD) and examined associations of older age, BD symptoms, somatic burden and functioning.Older age was associated with less severe mania and more somatic burden but there was no association of depression with age.Worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning. [ABSTRACT FROM AUTHOR]

Objects: Studies of older age bipolar disorder (OABD) have mostly focused on "younger old" individuals. Little is known about the oldest OABD (OOABD) individuals aged ≥70 years old. The Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE‐BD) project provides an opportunity to evaluate the OOABD group to understand their characteristics compared to younger groups. Methods: We conducted cross‐sectional analyses of the GAGE‐BD database, an integrated, harmonized dataset from 19 international studies. We compared the sociodemographic and clinical characteristics of those aged <50 (YABD, n = 184), 50–69 (OABD, n = 881), and ≥70 (OOABD, n = 304). To standardize the comparisons between age categories and all characteristics, we used multinomial logistic regression models with age category as the dependent variable, with each characteristic as the independent variable, and clustering of standard errors to account for the correlation between observations from each of the studies. Results: OOABD and OABD had lower severity of manic symptoms (Mean YMRS = 3.3, 3.8 respectively) than YABD (YMRS = 7.6), and lower depressive symptoms (% of absent = 65.4%, and 59.5% respectively) than YABD (18.3%). OOABD and OABD had higher physical burden than YABD, especially in the cardiovascular domain (prevalence = 65% in OOABD, 41% in OABD and 17% in YABD); OOABD had the highest prevalence (56%) in the musculoskeletal domain (significantly differed from 39% in OABD and 31% in YABD which didn't differ from each other). Overall, OOABD had significant cumulative physical burden in numbers of domains (mean = 4) compared to both OABD (mean = 2) and YABD (mean = 1). OOABD had the lowest rates of suicidal thoughts (10%), which significantly differed from YABD (26%) though didn't differ from OABD (21%). Functional status was higher in both OOABD (GAF = 63) and OABD (GAF = 64), though only OABD had significantly higher function than YABD (GAF = 59). Conclusions: OOABD have unique features, suggesting that (1) OOABD individuals may be easier to manage psychiatrically, but require more attention to comorbid physical conditions; (2) OOABD is a survivor cohort associated with resilience despite high medical burden, warranting both qualitative and quantitative methods to better understand how to advance clinical care and ways to age successfully with BD. Key points: Limited knowledge of older and oldest older age bipolar disorder derived from limited sample sizes.The Global Aging and Geriatric Experiments in Bipolar Disorder consortium provided international data to compare younger age, older age, and oldest older age people with BDInternational sites (n = 14) provided data on patients aged <50 (n = 184 YABD), 50–69 (n = 881 OABD), and ≥70 (n = 304 OOABD) to assess differences among three groupsOABD and OOABD represent distinct cohorts within BD and differ in sociodemographic and clinical characteristics from YABD in general. OOABD individuals may be easier to manage psychiatrically but require more attention to their comorbid physical conditions. OOABD likely is a survivor cohort associated with resilience despite high medical burden, warranting future study using both qualitative and quantitative methods to better understand what makes OOABD resilient, how to advance clinical care and age successfully with BD. [ABSTRACT FROM AUTHOR]

BACKGROUND: We previously reported more rapid accrual of ambulatory impairments in Black compared to White individuals with relapsing remitting multiple sclerosis (RRMS) and higher body mass index (BMI). Hypertension and lower neighborhood socioeconomic status (SES) were associated with greater impairment, irrespective of race. We hypothesize that these common social and health inequities may explain a substantial portion of the racial differences in ambulation in American individuals with RRMS. METHODS: Causal mediation analyses investigated baseline and change-over-time mediators of ambulatory impairment differences between 1795 Black and White individuals with RRMS using a retrospective cohort study comprised of electronic health record data from 8491 clinical encounters between 2008 and 2015 where Timed 25-Foot Walk (T25FW) speeds without assistive devices were recorded. The hypothesis was that BMI, neighborhood SES, and hypertension were possible mediators. RESULTS: At baseline, Black individuals with RRMS (n = 175) had significantly slower T25FW speeds (5.78 vs 5.27 ft/s), higher BMI, a higher prevalence of hypertension, and they were more likely to live in lower-income neighborhoods than White individuals (n = 1,620). At baseline, a significant proportion (33.7%; 95% CI, 18.9%-59.4%) of the T25FW difference between Black and White individuals was indirectly due to a higher BMI (12.5%), hypertension burden (9.5%), and living in lower-income neighborhoods (11.2%). Once baseline mediation relationships were accounted for, there were no significant longitudinal mediation relationships. CONCLUSIONS: The findings implicate social and health disparities as prominent drivers of ambulatory differences between Black and White individuals with RRMS, suggesting that wellness and health promotion are essential components of MS care, particularly for Black individuals. [ABSTRACT FROM AUTHOR]

Objective: The current literature on employment in older adults with bipolar disorder (OABD) is limited. Using the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE‐BD), we examined the relationship of occupational status in OABD to other demographic and clinical characteristics. Methods: Seven hundred and thirty‐eight participants from 11 international samples with data on educational level and occupational status were included. Employment status was dichotomized as employed versus unemployed. Generalized linear mixed models with random intercepts for the study cohort were used to examine the relationship between baseline characteristics and employment. Predictors in the models included baseline demographics, education, psychiatric symptom severity, psychiatric comorbidity, somatic comorbidity, and prior psychiatric hospitalizations. Results: In the sample, 23.6% (n = 174) were employed, while 76.4% were unemployed (n = 564). In multivariable logistic regression models, less education, older age, a history of both anxiety and substance/alcohol use disorders, more prior psychiatric hospitalizations, and higher levels of BD depression severity were associated with greater odds of unemployment. In the subsample of individuals less than 65 years of age, findings were similar. No significant association between manic symptoms, gender, age of onset, or employment status was observed. Conclusion: Results suggest an association between educational level, age, psychiatric severity and comorbidity in relation to employment in OABD. Implications include the need for management of psychiatric symptoms and comorbidity across the lifespan, as well as improving educational access for people with BD and skills training or other support for those with work‐life breaks to re‐enter employment and optimize the overall outcome. [ABSTRACT FROM AUTHOR]

Food banks served a record of 60 million people in 2020, but little is known regarding sources and quality of foods distributed, especially with the COVID-19 pandemic's widespread disruptions. This mixed-methods study examined changes in food bank sourcing in 2020 relative to prior years. Findings highlight food bank-led purchases and federal commodities were used to meet increased food needs. While the inventory of fresh produce decreased proportionally in 2020 versus 2019, it increased in overall poundage by over a million pounds (p < 0.01). These findings have implications for nutritional food ranking across and within food banks. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF–ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3–PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.A genome-wide association study including 22,389 cases of multiple sclerosis finds an association with disease progression at the DYSF–ZNF638 and DNM3–PIGC loci and identifies a potential of higher educational attainment in slowing disease progression. [ABSTRACT FROM AUTHOR]

Objectives: Late-onset bipolar disorder (LOBD) represents a significant subgroup of bipolar disorder (BD). However, knowledge for this group is mostly extrapolated from small studies in subjects with early/mixed age of illness onset. In this global sample of older adults with BD (OABD: ≥50 years old) we aim to characterize the sociodemographic and clinical presentation of LOBD (≥40 years at BD onset) compared to early-onset BD (EOBD: <40 years at BD onset).Methods: The Global Aging and Geriatric Experiments in Bipolar Disorder consortium provided international data on 437 older age bipolar disorder participants. We compared LOBD versus EOBD on depression, mania, functionality, and physical comorbidities. Exploratory analyses were performed on participants with BD onset ≥50 years old.Results: LOBD (n = 105) did not differ from EOBD (n = 332) on depression, mania, global functioning, nor employment status (p > 0.05). Late-onset bipolar disorder was associated with higher endocrine comorbidities (odds ratio = 1.48, [95%CI = 1.0,12.1], p = 0.03). This difference did not remain significant when subjects with BD onset ≥50 years old were analyzed.Limitations: This study is limited by the retrospective nature of the variable age of onset and the differences in evaluation methods across studies (partially overcame by harmonization processes).Conclusion: The present analysis is in favor of the hypothesis that LOBD might represent a similar clinical phenotype as classic EOBD with respect to core BD symptomatology, functionality, and comorbid physical conditions. Large-scale global collaboration to improve our understanding of BD across the lifespan is needed. [ABSTRACT FROM AUTHOR]

Objectives: There is limited information on the characteristics of older adults with bipolar disorder (OABD) treated with lithium, along with safety concerns about its use by older adults. The aim of the present study is to describe the demographic and clinical characteristics of OABD receiving lithium therapy, using data from the Global Ageing & Geriatric Experiments in Bipolar Disorder (GAGE‐BD). Experimental Procedures: Cross‐sectional analysis of the GAGE‐BD dataset to determine differences and similarities between lithium users and non‐users. We analysed data from 986 participants aged 50 years or older (mean age 63.5 years; 57.5% females) from 12 study sites. Two subgroups ('Lithium'; 'Non‐lithium') were defined according to the current prescription of lithium. We compared several outcomes between these groups, controlling for age, gender, and study site. Results: OABD treated with lithium had lower scores on depression rating scales and were less likely to be categorised as with moderate or severe depression. There was a lower proportion of lithium users than non‐users among those with evidence of rapid cycling and non‐bipolar psychiatric diagnoses. Assessment of global cognitive state and functionality indicated better performance among lithium users. The current use of antipsychotics was less frequent among lithium users, who also reported fewer cardiovascular comorbidities than non‐users. Conclusion: We found several potentially relevant differences in the clinical profile of OABD treated with lithium compared with those treated with other mood stabilisers. However, the interpretation of the present results must take into account the methodological limitations inherent to the cross‐sectional approach and data harmonisation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although persons with multiple sclerosis (MS) are encouraged to engage in physical activity, they are less active than the general population and experience poorer emotional/cognitive health, underscoring the need for increased understanding of the factors independently associated with exercise in MS. METHODS: Six hundred forty people with MS completed a detailed demographic survey, the Godin Leisure-Time Exercise Questionnaire, and Quality of Life in Neurological Disorders short forms. The average number of weekly sessions of exercise was examined as a count, as a binary variable (a weekly minimum of 4 sessions of physical activity), and as an ordinal variable of being active using multivariable zero-inflated negative binomial, logistic, and ordered logistic regression models, respectively. Primary predictors of interest included depression, cognitive function, positive affect, and lower extremity functioning as measured by the Quality of Life in Neurological Disorders short forms. RESULTS: The study sample was 91% White race, 83% female, 65% with a relapsing-remitting MS diagnosis. The mean participant age was 52 years. Across analyses, body mass index and disability were inversely associated with exercising. Greater lower extremity impairment was associated with decreased odds of exercising and being active. A greater burden of depression symptoms was correlated with lower odds of engaging in physical activity. People with MS with higher self-reported cognitive functioning were less likely to engage in any exercise, but it was not associated with frequency of activities. CONCLUSIONS: These results demonstrate associations between exercise and cognitive and emotional health in people with MS, underscoring the need to consider these factors when designing MS-targeted physical activity recommendations. [ABSTRACT FROM AUTHOR]

Objective: Literature on older‐age bipolar disorder (OABD) is limited. This first‐ever analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE‐BD) investigated associations among age, BD symptoms, comorbidity, and functioning. Methods: This analysis used harmonized, baseline, cross‐sectional data from 19 international studies (N = 1377). Standardized measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM‐D), Montgomery‐Asberg Depression Rating Scale (MADRS), and Global Assessment of Functioning (GAF). Results: Mean sample age was 60.8 years (standard deviation [SD] 12.2 years), 55% female, 72% BD I. Mood symptom severity was low: mean total YMRS score of 4.3 (SD 5.4) and moderate‐to‐severe depression in only 22%. Controlled for sample effects, both manic and depressive symptom severity appeared lower among older individuals (p's < 0.0001). The negative relationship between older age and symptom severity was similar across sexes, but was stronger among those with lower education levels. GAF was mildly impaired (mean =62.0, SD = 13.3) and somatic burden was high (mean =2.42, SD = 1.97). Comorbidity burden was not associated with GAF. However, higher depressive (p < 0.0001) and manic (p < 0.0001) symptoms were associated with lower GAF, most strongly among older individuals. Conclusions: Findings suggest an attenuation of BD symptoms in OABD, despite extensive somatic burden. Depressive symptom severity was strongly associated with worse functioning in older individuals, underscoring the need for effective treatments of BD depression in older people. This international collaboration lays a path for the development of a better understanding of aging in BD. [ABSTRACT FROM AUTHOR]

Background: Tobacco smoke plays a pathogenic role in multiple sclerosis (MS) and may accelerate disease progression, yet, some people with MS continue to smoke after disease onset. The average smoker reports diminished health-related quality of life (HRQOL) across many populations. Objectives: To describe the relationships between smoking status and HRQOL, disease activity, and global disability in a US population with MS. Methods: We compared smokers to non-smokers in 950 responders to the Spring 2014 update survey completed by North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants. HRQOL was assessed using Short Form-12 version 2 (SF-12v2), disease activity was investigated using eight Performance Scales (PS) and three Functionality Scales (FS). Global disability was evaluated using Patient Determined Disease Steps (PDDS) and an item response theory (IRT) summed score based on the PS and FS. Results: Smokers had lower HRQOL (p < 0.0001), reported more disease activity (p < 0.05) and greater deficits in all PS and FS (p = 6 × 10-7 to 0.05), except mobility. Smokers and non-smokers did not differ by PDDS but had substantially greater IRT global disability (p = 2 × 10-7). Conclusion: Active smoking is meaningfully associated with deficits across multiple domains in people with MS and adds to the growing literature of the need for MS-tailored smoking cessation programs. [ABSTRACT FROM AUTHOR]

Comparing the relative fit of competing models can be used to address many different scientific questions. In classical statistics one can, if appropriate, use likelihood ratio tests and information based criterion, whereas clinical medicine has tended to rely on comparisons of fit metrics like C-statistics. However, for many data adaptive modelling procedures such approaches are not suitable. In these cases, statisticians have used cross-validation, which can make inference challenging. In this paper we propose a general approach that focuses on the 'conditional' risk difference (conditional on the model fits being fixed) for the improvement in prediction risk. Specifically, we derive a Wald-type test statistic and associated confidence intervals for cross-validated test sets utilizing the independent validation within cross-validation in conjunction with a test for multiple comparisons. We show that this test maintains proper Type I Error under the null fit, and can be used as a general test of relative fit for any semi-parametric model alternative. We apply the test to a candidate gene study to test for the association of a set of genes in a genetic pathway. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system with a strong genetic component. Several lines of evidence support a strong role for genetic factors influencing both disease susceptibility and clinical outcome in MS. Identification of genetic variants that distinguish particular disease subgroups and/or predict a severe clinical outcome is critical to further our understanding of disease mechanisms and guide development of effective therapeutic approaches. We studied 1470 MS cases and performed a genome-wide association study of more than 2.5 million single-nucleotide polymorphisms to identify loci influencing disease severity, measured using the MS severity score (MSSS), a measure of clinical disability. Of note, no single result achieved genome-wide significance. Furthermore, variants within previously confirmed MS susceptibility loci do not appear to influence severity. Although bioinformatic analyses highlight certain pathways that are over-represented in our results, we conclude that the genetic architecture of disease severity is likely polygenic and comprised of modest effects, similar to what has been described for MS susceptibility, to date. However, a role for major effects of rare variants cannot be excluded. Importantly, our results also show the MSSS, when considered as a binary or continuous phenotype variable is by comparison a stable outcome. [ABSTRACT FROM AUTHOR]

The Random Forests (RF) algorithm has become a commonly used machine learning algorithm for genetic association studies. It is well suited for genetic applications since it is both computationally efficient and models genetic causal mechanisms well. With its growing ubiquity, there has been inconsistent and less than optimal use of RF in the literature. The purpose of this review is to breakdown the theoretical and statistical basis of RF so that practitioners are able to apply it in their work. An emphasis is placed on showing how the various components contribute to bias and variance, as well as discussing variable importance measures. Applications specific to genetic studies are highlighted. To provide context, RF is compared to other commonly used machine learning algorithms. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system with a prominent genetic component. The primary genetic risk factor is the human leukocyte antigen (HLA)-DRB1*1501 allele; however, much of the remaining genetic contribution to MS has not been elucidated. The authors investigated the relation between variation in DNA repair pathway genes and risk of MS. Single-locus association testing, epistatic tests of interactions, logistic regression modeling, and nonparametric Random Forests analyses were performed by using genotypes from 1,343 MS cases and 1,379 healthy controls of European ancestry. A total of 485 single nucleotide polymorphisms within 72 genes related to DNA repair pathways were investigated, including base excision repair, nucleotide excision repair, and double-strand breaks repair. A single nucleotide polymorphism variant within the general transcription factor IIH, polypeptide 4 gene, GTF2H4, on chromosome 6p21.33 was significantly associated with MS (odds ratio = 0.7, P = 3.5 × 10−5) after accounting for multiple testing and was not due to linkage disequilibrium with HLA-DRB1*1501. Although other candidate genes examined here warrant further follow-up studies, collectively, these results derived from a well-powered study do not support a strong role for common variation within DNA repair pathway genes in MS. [ABSTRACT FROM PUBLISHER]

This commentary is on the original article by Brenton et al. on pages 1289–1294 of this issue. [ABSTRACT FROM AUTHOR]

Objectives: To compare the prevalence of physical morbidities between older aged patients with bipolar disorder (OABD) and non-psychiatric comparisons (NC), and to analyze sex differences in prevalence., Methods: OABD was defined as bipolar disorder among adults aged ≥50 years. Outcomes analyzed were the prevalence of diseases affecting the cardiovascular, respiratory, gastrointestinal, genitourinary, renal, musculoskeletal, and endocrine systems. The analysis used cross-sectional data of OABD participants (n = 878; mean age 60.9 ± 8.0 years, n = 496 (56%) women) from the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) dataset and NC participants recruited at the same sites (n = 355; mean age 64.4 ± 9.7 years, n = 215 (61%) women)., Results: After controlling for sex, age, education, and smoking history, the OABD group had more cardiovascular (odds ratio [95% confidence interval]: 2.12 [1.38-3.30]), renal (5.97 [1.31-43.16]), musculoskeletal (2.09 [1.30-3.43]) and endocrine (1.90 [1.20-3.05]) diseases than NC. Women with OABD had more gastrointestinal (1.56 [0.99-2.49]), genitourinary (1.72 [1.02-2.92]), musculoskeletal (2.64 [1.66-4.37]) and endocrine (1.71 [1.08-2.73]) comorbidities than men with OABD, when age, education, smoking history, and study site were controlled., Conclusions: This replication GAGE-BD study confirms previous findings indicating that OABD present more physical morbidities than matched comparison participants, and that this health burden is significantly greater among women., Competing Interests: Declaration of competing interest VB-M has received honoraria from Angelini, unrelated to the present work. JBL has received grant funding from NIH, AHA, and Merck. EV has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Biohaven, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, HMNC, Idorsia, Johnson & Johnson, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris, outside the submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Social determinants of health and adversity, including poverty, maltreatment, and neighborhood deprivation, are individual-level factors that may significantly affect baseline neurocognitive testing and management that have yet to be thoroughly explored within the computerized neurocognitive assessment. Objectives: Examine individual-level experiences of poverty, abuse, neighborhood deprivation, and social mobility on computerized cognitive testing. Methods: The sample included 3,845 student-athletes who completed a baseline Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) and were enrolled in the Child-Household Integrated Longitudinal Data database. Multivariable linear regressions were used to assess independent variables of Supplemental Nutrition Assistance Program enrollment, abuse or neglect cases, Area Deprivation Index scores, and other demographic factors on four baseline ImPACT composite scores: verbal and visual memory, visuomotor, and reaction time. Results: Individual-level factors of persistent poverty and neighborhood deprivation were associated with lower composite scores; however, upward social mobility was not significantly associated with cognitive performance. The effects of mother's race on computerized cognitive testing performance were attenuated when accounting for measures of adversity. Conclusion: Findings highlight the importance of social determinants of health in computerized neurocognitive testing to ensure more culturally sensitive and precise understanding of athletic baselines.

Objective: Sex-specific research in adult bipolar disorder (BD) is sparse and even more so among those with older age bipolar disorder (OABD). Knowledge about sex differences across the bipolar lifespan is urgently needed to target and improve treatment. To address this gap, the current study examined sex differences in the domains of clinical presentation, general functioning, and mood symptoms among individuals with OABD., Methods: This Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) study used data from 19 international studies including BD patients aged ≥50 years (N = 1,185: 645 women, 540 men).A comparison of mood symptoms between women and men was conducted initially using two-tailed t tests and then accounting for systematic differences between the contributing cohorts by performing generalized linear mixed models (GLMMs). Associations between sex and other clinical characteristics were examined using GLMM including: age, BD subtype, rapid cycling, psychiatric hospitalization, lifetime psychiatric comorbidity, and physical health comorbidity, with study cohort as a random intercept., Results: Regarding depressive mood symptoms, women had higher scores on anxiety and hypochondriasis items. Female sex was associated with more psychiatric hospitalizations and male sex with lifetime substance abuse disorders., Conclusion: Our findings show important clinical sex differences and provide support that older age women experience a more severe course of BD, with higher rates of psychiatric hospitalization. The reasons for this may be biological, psychological, or social. These differences as well as underlying mechanisms should be a focus for healthcare professionals and need to be studied further., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Epidemiologic studies have established obesity as a risk factor for multiple sclerosis (MS). These studies relied on body-mass index (BMI) and body size silhouettes as the primary measures of obesity. Unfortunately, the causal mechanisms through which obesity confers MS risk are not yet known., Objectives: To investigate the causal effects of multiple specific measures of body fat on MS risk in populations of European descent, using Mendelian randomization (MR)., Methods: MR is a genetic instrumental variable analysis utilizing genome-wide association (GWA) summary statistics to infer causality between phenotypes. MR analyses were performed to investigate the relationships between seven measures of body fat (BMI, waist-hip ratio, visceral adipose tissue [VAT], subcutaneous adipose tissue, and arm-, leg-, and trunk-fat to total body fat ratio) and MS risk., Results: Only BMI and VAT were significantly associated with MS risk in separate MR analyses (β BMI =0.27, p BMI <0.001; β VAT =0.28, p VAT =0.006). High correlation between BMI and VAT instruments suggest that two-sample MR associations for BMI and VAT likely capture the same causal mechanisms., Conclusions: BMI and VAT were causally associated with MS risk in European populations, though their effects do not appear independent, suggesting overlap in the role of overall body mass and visceral obesity in MS pathogenesis., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Genes associated with increased susceptibility to multiple sclerosis (MS) have been identified, but their functions are incompletely understood. One of these genes codes for the RNA helicase DExD/H-Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with interleukin-7 receptor-α gene ( IL7R ) in MS-risk. Based on evolutionary and functional arguments, we postulated that DDX39B enhances immune tolerance thereby decreasing MS risk. Consistent with such a role we show that DDX39B controls the expression of many MS susceptibility genes and important immune-related genes. Among these we identified Forkhead Box P3 ( FOXP3 ), which codes for the master transcriptional factor in CD4 + /CD25 + T regulatory cells. DDX39B knockdown led to loss of immune-regulatory and gain of immune-effector expression signatures. Splicing of FOXP3 introns, which belong to a previously unrecognized type of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as an important guardian of immune tolerance., Competing Interests: MH, CN, GS, LW, AA, VJ, XY, SW, FB, SG, DK, WF, SB No competing interests declared, GG, MG I acknowledge that I have significant ownership in Autoimmunity Biologic Solutions, Inc (Galveston, TX), which is commercializing therapies that target the IL7R pathway in autoimmune diseases. While I do not believe this represents a conflict of interest it can lead to the perception of said conflict, (© 2023, Hirano, Galarza-Muñoz et al.)

Objective: The Managing Epilepsy Well (MEW) Network conducts epilepsy self-management (ESM) intervention development, testing, and archival clinical trials data analyses in the MEW Network Integrated Database (MEW-DB). However, not all trial participants fully benefit from ESM due to prematurely discontinuing program participation. This analysis sought to identify demographic and clinical predictors of premature discontinuation (PD) of ESM interventions available in the MEW-DB., Methods: Data from prior studies were included if: 1) they were prospective trials testing an ESM intervention, 2) included baseline assessment and at least one post-intervention assessment, and 3) included data on PD. Dependent variables were all-cause PD, categorized as a binary variable (yes/no) and time to PD for the intervals between baseline and follow-up visit 1 (V1; approximately week 12) and visit two (V2; approximately week 24). Multivariable Cox proportional hazard models were used to identify factors affecting PD time-point. Explanatory variables included age, gender, race/ethnicity, education, employment, income, marital status, psychiatric comorbidities, depressive severity, anxiety symptoms, self-efficacy, number of anti-seizure medications (ASMs), health status, seizure frequency, and study design., Results: Six prior MEW-DB studies were included, consisting of 627 people, where 624 were assigned to ESM or to control. PD among randomized individuals was 14.3 % by V1 and 15.7 % by V2. Predictors for V1 PD were treatment (ESM) vs. control arm, more severe depressive symptoms and having schizophrenia. Predictors for V2 PD were younger age, white race, more severe depressive symptoms and having schizophrenia., Significance: While ESM approaches can improve multiple health outcomes among people with epilepsy, nearly one in six individuals prematurely discontinues their program. These findings suggest that ESM interventionists need to be particularly attentive to program retention over the first 3 months after ESM initiation. Younger people with epilepsy, those who self-identify as white, those with schizophrenia, and/or more severe depressive symptoms may need additional support for engagement., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Some individuals with bipolar disorder (BD) experience manic and depressive symptoms concurrently, but data are limited on symptom mixity in older age bipolar disorder (OABD). Using the Global Aging & Geriatric Experiments in Bipolar Disorder Database, we characterized mixity in OABD and associations with everyday function., Methods: The sample (n = 805), from 12 international studies, included cases with both mania and depression severity ratings at a single timepoint. Four mixity groups were created: asymptomatic (A), mixed (Mix), depressed only (Dep), and manic only (Man). Generalized linear mixed models used mixity group as the predictor variable; cohort was included as a random intercept. Everyday function was assessed with the Global Assessment of Functioning score., Results: Group proportions were Mix (69.6%; n = 560), followed by Dep (18.4%; n = 148), then A (7.8%; n = 63), then Man (4.2%; n= 34); levels of depression and mania were similar in Mix compared to Dep and Man, respectively. Everyday function was lowest in Mix, highest in A, and intermediate in Man and Dep. Within Mix, severity of depression was the main driver of worse functioning. Groups differed in years of education, with A higher than all others, but did not differ by age, gender, employment status, BD subtype, or age of onset., Conclusions: Mixed features predominate in a cross-sectional, global OABD sample and are associated with worse everyday function. Among those with mixed symptoms, functional status relates strongly to current depression severity. Future studies should include cognitive and other biological variables as well as longitudinal designs to allow for evaluation of causal effects., (Published by Elsevier Inc.)

Introduction: Pain is a common and complex symptom in Parkinson's disease. The underlying mechanisms and longitudinal patterns are not well understood, which impedes therapeutic decision making. The objectives of this study were to characterize longitudinal pain trajectories, identify clusters (subgroups) with similar patterns, and examine associations with sociodemographic and clinical characteristics., Methods: Latent class growth analysis was applied to 16,863 people with Parkinson's disease stratified by early (N = 8612; <3 years), mid (N = 6181; 3-10 years) and later (N = 2070; >10 years) disease duration over ∼4.5 years (2017-2021) using the Fox Insight Data Exploration Network, to discern clusters of individuals with similar longitudinal patterns of self-reported pain. Associations were evaluated between cluster membership and sociodemographic and clinical factors., Results: Across the disease duration strata, five clusters were identified. The clusters ranged from none to moderate pain, with a small cluster of subjects with severe pain. The percentage of subjects with moderate (early = 17.3%, mid = 24.2%, later = 34.4%) and severe (early = 2.3%, mid = 4.4%, later = 6.5%) pain at baseline increased across disease duration groups. The trajectories tended to be variable or slightly worsening in the early duration group, more stable in the mid duration group, and improving in the later duration group. Across strata, the clusters with moderate to severe pain were associated with more severe impairment, depression, anxiety and arthritis, higher body mass index, lower income, and lower education., Conclusion: This latent class growth analysis, applied to people with Parkinson's disease, provides a template for using self-reported outcomes to improve our understanding of pain trajectories., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To compare the prevalence of physical morbidities among men and women with older adult bipolar disorder (OABD), and men with and without OABD., Methods: Cross-sectional analysis of the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) database and non-OABD data from the Health in Men Study. OABD defined as bipolar disorder among adults aged greater than or equal to 50 years. Outcomes of interest were diseases affecting the cardiovascular, respiratory, gastrointestinal, renal, musculoskeletal and endocrinological systems., Results: We examined 1407 participants with OABD aged 50-95 years, of whom 787 were women. More women than men showed evidence of morbidities affecting the respiratory, gastrointestinal, musculoskeletal and endocrinological systems. More men with than without OABD showed evidence of cardiovascular, renal and endocrinological diseases., Conclusion: GAGE-BD data showed that physical morbidities affect more women than men with OABD, and more men with than without OABD. The underlying reasons for these differences require clarification., (Copyright © 2021 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Aims: Self-management for people with epilepsy and a history of negative health events (SMART) is a behavioral intervention that has been demonstrated to reduce epilepsy-related complications and improve physical and mental health functioning among people with epilepsy (PWE) [1]. The Community-SMART (C-SMART) initiative was a 4-month prospective implementation of feasibility and pre/post outcomes of SMART in a community setting and in collaboration with key epilepsy service stakeholders., Methods: Self-management for people with epilepsy and a history of negative health events is a group-format, entirely virtual intervention delivered in eight 60-90 sessions over the course of 8-10 weeks. The C-SMART initiative used research staff to guide intervention performance evaluation and staff of a regional epilepsy advocacy agency to assist with community engagement. Process evaluations included outreach and engagement efforts needed to reach PWE, the barriers and facilitators to roll-out, and participant retention and satisfaction. Outcomes included depressive symptoms and epilepsy self-management competency., Results: Thirty individuals were enrolled in 3 "cohorts" of approximately 10 PWE per cohort. Mean age of participants was 48.50 (standard deviation 16.15) years, 60% were female and 53.3% were African-American. Individuals had epilepsy, on average, for over 2 decades, were on approximately 2 prescribed antiepileptic drugs (AEDs) and had an average of just over 6 seizures in the last 30 days. Over 63% had a comorbid mental health condition. There were 23 individuals (76.7%) who were retained at the 4-month follow-up. Baseline to 4-month outcomes for depression and epilepsy self-management were significantly improved. Most (90%) of participants reported high levels of satisfaction with the program., Conclusions: The SMART epilepsy self-management program can be successfully implemented in partnership with epilepsy-focused community partners, is acceptable to participants and associated with improved outcomes. Future work might consider how to make virtual epilepsy self-management available to the full spectrum of PWE., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Although psychiatric disorders are more common among people with epilepsy, 2 depression and suicidal ideation among Hispanics with epilepsy remain understudied. We examined the prevalence and correlates of depression and suicidal ideation among Hispanic adults with epilepsy who participated in self-management studies in the Managing Epilepsy Well 3 Network., Methods: This cross-sectional analysis of pooled data from ten studies used the Patient Health Questionnaire-9 4 or Neurological Disease Depression Inventory-Epilepsy 5 to examine the prevalence of elevated depressive symptoms (PHQ ≥ 10, NDDI-E ≥ 15) and suicidal ideation (PHQ-9 item 9 ≥ 1, NDDI-E item 4 ≥ 2). Multilevel mixed-effects logistic regression models examined associations between ethnicity, elevated depressive symptoms, and suicidal ideation among PWE. Secondary analyses examined correlates of elevated depressive symptoms and suicidal ideation among Hispanic PWE., Results: Of 559 participants, 49.6% (n = 277) were Hispanic. Elevated depressive symptoms were endorsed by 38.1% (n = 213) of all participants (32.5% of Hispanics); suicidal ideation was endorsed by 18.4% (n = 103) of all participants (16.3% of Hispanics). After adjustment for sociodemographic and health attributes, Hispanic PWE had a 44% lower prevalence of elevated depressive symptoms (OR = 0.56, CI 0.37-0.84, p = 0.0056) compared to non-Hispanics but similar rates of suicidal ideation (OR = 0.84, CI 0.45-1.58, p = 0.59). Acculturation measures were available for 256 (92.4%) of Hispanic PWE: language preference was Spanish for 62.9%, 46.1% were foreign-born. Spanish-speaking Hispanics were less likely than English-speaking Hispanics to report elevated depressive symptoms (OR = 0.43, CI 0.19-0.97, p = 0.041); however, Hispanics who reported fair or poor health status had a four-fold higher depression prevalence compared to those who reported excellent or very good health status [reference group] (OR = 4.44, CI 1.50-13.18, p = 0.0071). Of the Hispanics who provided prior 30-day seizure data, ≥1 monthly seizure was independently associated with higher depression prevalence (OR = 3.11, CI 1.29-7.45, p = 0.01). Being foreign-born was not associated with elevated depressive symptoms or suicidal ideation prevalence., Conclusions: In a large, geographically diverse sample of PWE, elevated depressive symptoms were significantly lower in Hispanics compared to non-Hispanics. Spanish language preference was associated with a lower prevalence of elevated depressive symptoms among Hispanic PWE. Future studies should include acculturation data to better screen for depression and suicidal ideation risk and optimize interventions for Hispanic PWE., Competing Interests: Declaration of Competing Interest Susanna S. O’Kula, Farren B.S. Briggs, Brittany Brownrigg, Kaylee Sarna, Omar Rosales, Ross Shegog, Erica K. Johnson, Robert T. Fraser, Rakale Quarells, and Tanya M. Spruill have no conflicts of interest to disclose. Daniel Friedman receives salary support for consulting and clinical trial related activities performed on behalf of The Epilepsy Study Consortium, a non-profit organization. Dr. Friedman receives no personal income for these activities. NYU receives a fixed amount from the Epilepsy Study Consortium towards Dr. Friedman’s salary. Within the past two years, The Epilepsy Study Consortium received payments for research services performed by Dr. Friedman from: Biogen, Cerevel, Cerebral, Crossject, Engage Pharmaceuticals, Eisai, Lundbeck, Pfizer, SK Life Science, and Xenon. He has also served as a paid consultant for Neurelis Pharmaceuticals and Receptor Life Sciences. He has received research support from Epitel. He serves on the scientific advisory board for Receptor Life Sciences. He holds equity interests in Neuroview Technology. He received royalty income from Oxford University Press. Martha Sajatovic has served as a paid consultant for Alkermes, Otsuka, Janssen, Myriad, Health Analytics, Frontline Medical Communications. She collected royalties from Springer Press, Johns Hopkins University Press, Oxford Press, UpToDate. She has received compensation for preparation of CME activities from American Physician’s Institute, MCM Education, CMEology, Potomac Center for Medical Education, Global Medical Education, Creative Educational Concepts, Psychopharmacology Institute., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Hypertension, hyperlipidemia, and asthma are common in multiple sclerosis (MS) patients and adversely impact physical and mental health independent of sociodemographic and clinical attributes. Characterizing MS patients with these comorbidities is necessary for informing comorbidity screening and managed care in vulnerable patient subgroups; however, there is sparse data currently available., Methods: We conducted cross-sectional analyses of 2,012 relapsing remitting (RR) MS patients. Separate multivariable logistic regression models were conducted for the presence of hypertension, hyperlipidemia, and asthma. Independent variables included age, sex, race, MS duration, body mass index classification, insurance payer, smoking status, median income by residence ZIP code, disease modifying therapies, and the other comorbidities., Results: Hypertension was more common in RRMS patients who were older, obese/severely obese, had hyperlipidemia, were asthmatics, living in neighborhoods with the lowest income, and who were Black Americans. RRMS patients with hyperlipidemia were more likely to be male, older, overweight/obese/severely obese, hypertensive, asthmatics, and White American. Asthmatic RRMS patients were more likely to be female, obese, hypertensive, and living in neighborhood of medium/low income, and less likely to be on interferons or glatiramer acetate., Conclusion: We identified factors independently associated with common comorbidity burden in RRMS patients, which will inform risk-stratification efforts aimed at mitigating the adverse impact of these conditions in MS patients. Our results are consistent with what is known about the determinants of hypertension, hyperlipidemia, and asthma in the non-MS patient population, and therefore disparities that exist in screening and management in the general U.S. population may likely exist in U.S. MS patients. It is also possible that there may be unique differences in specific MS patient subgroups, which warrants further investigation and detailed characterization., (Copyright © 2021. Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) patients experience wide-ranging symptoms with varied severity, and approaches that integrate patient-reported outcomes and objective quantitative measures will present opportunities for advancing clinical profiling. The primary objective of the current study was to conduct exploratory data analysis using latent variable modeling to empirically identify clusters of relapsing remitting (RR) MS patients with shared impairment patterns across three patient-reported outcomes and two timed task measures., Methods: Latent profile analyses and impairment data for 2,012 RRMS patients identified distinct patient clusters using timed task measures of upper and lower limb performance, and patient-reported outcomes measuring quality of life, depression symptom severity, and perceived global disability. Multinomial logistic regression models were used to characterize associations between socio-demographic attributes and assignment to the patient clusters., Results: There were 6 distinct clusters of RRMS patients that differed by symptom patterns, and by their socio-demographic attributes. Most notable were were no differences in age, sex, or disease duration between the least and most impaired classes, representing 14% and 4% of patients, respectively. Patients in the most impaired class were much more likely to be Black American, have a history of smoking, have a higher body mass index, and be of lower socioeconomic status than the least impaired class. There were positive relationships between age and classification to clusters of increasing moderately severe impairment but not the most severe clusters., Conclusion: We present a framework for discerning phenotypic impairment clusters in RRMS. The results demonstrate opportunities for advancing clinical profiling, which is necessary for optimizing personalized MS care models and clinical research., Competing Interests: Declaration of Conflicting Interests The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Significance: Health literacy, the ability to understand necessary health information to make proper health decisions, has been linked to greater frequency of hospitalizations. However, there is limited literature on the associations between health literacy and outcomes in patients with epilepsy, and thus, this secondary analysis investigates the associations between health literacy and outcomes in patients with epilepsy enrolled in the self-management intervention "Self-management for people with epilepsy and a history of negative events" (SMART). We examined the associations between higher health literacy and higher education level and outcomes of the SMART trial., Methods: This is a secondary analysis of data from the SMART self-management intervention, where individuals were randomized to the SMART intervention or a 6-month waitlist (WL) control. Health literacy was assessed at baseline before randomization using the Rapid Estimate of Adult Literacy in Medicine (REALM-R). Education level was self-reported by participants at baseline. Pearson correlations between REALM-R scores and continuous demographic and clinical variables were conducted. Point-biserial Pearson correlations were computed for REALM-R and dichotomous variables. The effect of education on change in negative health events (NHEs) counts from baseline to six months was conducted using a linear regression. A logistic regression with health literacy and randomization arm as predictors and improvement in NHE (1 = improvement, 0 = no change or increased NHEs at 6 months) as the outcome was conducted., Results: Lower education and lower income were significantly correlated with lower health literacy (p < 0.001 and p = 0.03). Higher education level was associated with a greater improvement in 6-month seizure counts (r s (105) = 0.29, p = 0.002), and a greater improvement in total 6-month NHEs (r s (95) = 0.20, p = 0.045). Health literacy was not associated with change in NHEs or with study retention., Conclusions: The SMART intervention appears effective for individuals regardless of health literacy competency. Nevertheless, individuals with higher levels of education have fewer epilepsy complications, and thus, those with limited education may still require additional support while participating in epilepsy self-management programs., Competing Interests: Declaration of competing interest The author has no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: People with epilepsy frequently experience negative health events (NHEs), such as emergency room visits or hospitalizations for epilepsy-related complications despite significant advances in care. We developed a novel remotely delivered group-format epilepsy self-management program ("Self-management for people with epilepsy and a history of negative health events"; SMART). In a 6-month randomized controlled trial (RCT), SMART participants had significant decreases in NHEs, as well changes in attitudes and behaviors compared to a wait-list (Sajatovic et al., 2018). This secondary analysis from the RCT characterizes the indirect causal effects of SMART on NHE improvements that may be mediated by specific improvements in self-management, self-efficacy, social support, quality of life, and depression symptom severity., Methods: Participants were adults with epilepsy and a NHE in the prior 6 months. There were 60 participants in each RCT arm (SMART versus wait-list) and assessments were conducted at baseline, 10 weeks and 24 weeks. The outcome was a binary variable measuring NHE improvement at week 24. A counterfactual-based mediation framework was used to determine whether improvements or changes in attitudes and behaviors at specific time points or across the study period, mediated the impact of SMART on NHE improvements., Results: At week 24, SMART contributed to significant improvements in NHEs compared to those in wait-list (odds ratio = 3.2, p = 0.015). SMART was significantly associated with improvements and changes in aspects of self-management, self-efficacy, quality of life, and depression symptom severity at week 10, and significant improvements between baseline and week 24 in overall self-management and quality of life. Mediation analyses demonstrated that a portion of the effect (∼20-30 %; p < 0.05) of SMART on NHE improvement was also indirectly mediated by early improvements in depression symptom severity and quality of life., Conclusions: This mediation analysis of the SMART intervention demonstrates that in addition to its direct effect on improving NHEs in people with epilepsy, early improvements in depression symptom severity and quality of life indirectly mediated ∼20-30 % of the intervention's effect. These results demonstrate the promise of self-management approaches as a key component of an optimal healthcare model for people with epilepsy, particularly those with a recent history of NHEs., Competing Interests: Declaration of Competing Interest Dr. Sajatovic has research grants from Otsuka, Alkermes, Merck, Janssen, Reuter Foundation, Woodruff Foundation, Reinberger Foundation, National Institute of Health (NIH), and the Centers for Disease Control and Prevention (CDC). Dr. Sajatovic is a consultant to Bracket, Otsuka, Supernus, Neurocrine, Health Analytics and Sunovion and has received royalties from Springer Press, Johns Hopkins University Press, Oxford Press, and UpToDate., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The clinical manifestation of multiple sclerosis (MS) is highly variable. Factors influencing phenotypic heterogeneity are not well known since most studies have relied on the Expanded Disability Status Scale which has modest inter/intra-rater reliability. We therefore sought to investigate other reliable and valid measures of impairment., Methods: We constructed a retrospective cohort of 2083 relapsing remitting MS patients using electronic health records to identify prognostic factors of Timed 25-Foot Walk (lower limb disability), Performance Scales Sum (perceived global disability), and Patient Health Questionnaire 9 (a depression tool). Patients had a clinical visit between 1/1/2008 and 5/29/2012, and at least one additional visit within approximately 3 years; the cohort consisted of 16,538 visits. The outcomes and predictors were extracted from the records. Longitudinal models were conducted, and sex- and race-specific differences were explored., Results: Walking speeds were slower in females, black patients, ever smokers, and Medicaid/Medicare beneficiaries. Higher body mass index (BMI), older age, longer disease duration, lower median income, and higher depression scores also predicted slower walking speeds. Older age, higher BMI, lower median income, higher depression scores, ever smokers and Medicaid/Medicare beneficiaries were associated with higher global disability. Those who were of younger age, higher BMI, lower median income, ever smoked, and on Medicaid had higher depressive scores. The effect of age and BMI on depressive scores were restricted to female and white patients, respectively., Conclusion: We identified multiple longitudinal predictors of disability in relapsing remitting patients. Modifiable factors (including smoking and BMI) and adverse socioeconomic conditions were independently, and negatively associated with walking speed, global disability, and depression., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The phenotypic presentation of multiple sclerosis (MS) may predict long-term outcomes and little is known about factors contributing to heterogeneity at MS onset. Given temporality, it is likely MS risk factors also influence presentation of the disease near onset., Methods: Using a retrospective cross-sectional study of MS cases, we investigated: age of onset (AOO), number of impaired functional domains (NIFDs), time to second relapse (TT2R), and early relapse activity (ERA). Machine learning variable selection was applied to epidemiologic data for each outcome, followed by multivariable regression models. The models were further adjusted for HLA-DRB1*15:01 carrier status and a MS genetic risk score (GRS). The TT2R and ERA analyses were restricted to relapsing remitting MS cases., Results: HLA-DRB1*15:01, GRS, and smoking were associated with earlier AOO. Cases who were male, obese, had lower education, or had primary progressive MS were older at onset. For NIFDs, those with relapsing remitting MS and of lower SES had increased NIFDs. Among relapsing remitting cases, those who were older at onset, obese, and had polyfocal presentation had shorter TT2R, while ERA was greater among those younger at onset and who were obese., Conclusion: Individual characteristics including age, genetic profiles, obesity, and smoking status contribute to heterogeneity in disease presentation and modulate early disease course evolution., (Copyright © 2018 Elsevier B.V. All rights reserved.)