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BACKGROUND AND OBJECTIVE: The impact of menopause on the brain is not well understood. Hormonal changes, including puberty and pregnancy, influence the onset and course of multiple sclerosis (MS). After menopause, a worsening of MS disease trajectory measured on the clinician-rated Expanded Disability Status Scale (EDSS) was reported in some, but not all, studies. Evaluating the association between menopause and more objective measures of CNS injury is warranted. This study sought to assess the trajectory of objective functional outcomes and disease biomarkers in women with MS before and after menopause in a longitudinal prospective observational cohort. METHODS: Data were collected prospectively from a longitudinally followed MS cohort, including the performance-based Multiple Sclerosis Functional Composite (MSFC) as the primary functional outcome and the paraclinical marker of neuronal injury serum neurofilament light chain (sNfL) as the primary biomarker outcome. Outcomes were analyzed using segmented linear mixed model regressions adjusted for age, BMI, and tobacco use, with a change in slope at the time of menopause, as the a priori inflection point. RESULTS: One hundred and eighty-four postmenopausal women met inclusion criteria. Participants were followed for a median of 13 years (interquartile range [IQR] = 4, range: 1-17). The median MS duration was 24 years (IQR = 13, range: 3-64), and the median EDSS score was 2.5 (IQR = 2, range: 0-8). The median age at natural menopause was 50 years (IQR = 5, range: 33-60); 17% of participants used any systemic menopausal hormone therapy. Menopause reflected an inflection point in MSFC worsening (slope difference 0.08, 95% CI 0.01, 0.14, p = 0.0163) and increase in serum neurofilament light chain (slope difference -0.95, 95% CI -1.74 to -0.16, p = 0.0194) while the opposite was found for EDSS (slope difference 0.05, 95% CI 0.01-0.09, p = 0.0200). Findings remained significant after adjustment for multiple covariates. When using additional nonlinear regression modeling, similar inflection points were found (within 3 years of the final menstrual period) for sNfL and EDSS but not MSFC. DISCUSSION: The menopausal transition may represent an inflection in accumulation of neuronal injury and functional decline in MS.

Coral persistence in the Anthropocene depends on interactions among holobiont partners (coral animals and microbial symbionts) and their environment. Cryptic coral lineages-genetically distinct yet morphologically similar groups-are critically important as they often exhibit functional diversity relevant to thermal tolerance. In addition, environmental parameters such as thermal variability may promote tolerance, but how variability interacts with holobiont partners to shape responses to thermal challenge remains unclear. Here, we identified three cryptic lineages of Siderastrea siderea in Bocas del Toro, Panamá that differ in distributions across inshore and offshore reefs, microbial associations, phenotypic traits of holobiont partners (i.e., phenomes), and skeleton morphologies. A thermal variability experiment failed to increase thermal tolerance, but subsequent thermal challenge and recovery revealed that one lineage maintained elevated energetic reserves, photochemical efficiency, and growth. Last, coral cores highlighted that this lineage also exhibited greater growth historically. Functional variation among cryptic lineages highlights their importance in predicting coral reef responses to climate change.

BACKGROUND AND OBJECTIVES: Ocrelizumab labeling advises contraception for women during treatment and for 6-12 months thereafter. Because pregnancies may occur during this time, it is critical to understand pregnancy and infant outcomes in women with multiple sclerosis (MS) after ocrelizumab exposure. METHODS: Pregnancy cases reported to Roche global pharmacovigilance until 12 July 2023 were analyzed. In utero exposure was defined if the last ocrelizumab infusion occurred in the 3 months before the last menstrual period or during pregnancy. Breastfeeding exposure was defined if at least one infusion occurred while breastfeeding. Fetal death was termed spontaneous abortion (SA) if < 22 complete gestational weeks (GWs) and stillbirth if later. Live births (LBs) were preterm if < 37 complete GWs. Major congenital anomalies (MCAs), infant outcomes, and maternal complications were also analyzed. RESULTS: In total, 3,244 pregnancies were reported in women with MS receiving ocrelizumab. The median maternal age was 32 years (Q1-Q3: 29-35 years), and most women had relapsing MS (65.6%). Of 2,444 prospectively reported pregnancies, 855 were exposed to ocrelizumab in utero (512 with a known outcome), 574 were nonexposed, and the remaining 1,015 had unknown timing of exposure. Most (83.6%; 956/1,144) of the pregnancies with a known outcome resulted in LBs (exposed, 84.2%; nonexposed, 88.3%). The exposed and nonexposed groups had similar proportions of other important pregnancy outcomes (preterm births, 9.5% vs 8.7%; SA, 7.4% vs 9.1%). Elective abortions were more frequent in the exposed group (7.4%, vs 1.7% in the nonexposed group). The proportion of LBs with MCAs was similar between the exposed and nonexposed groups (2.1% vs 1.9%) and within epidemiologic background rates. In the exposed group, one stillbirth and one neonatal death were prospectively reported. DISCUSSION: In this analysis of a large pregnancy outcome dataset for an anti-CD20 in MS, in utero exposure to ocrelizumab was not associated with an increased risk of adverse pregnancy or infant outcomes. These data will enable neurologists and women with MS to make more informed decisions around family planning, balancing safety risks to the fetus/infant against the importance of disease control in the mother.

Course-based undergraduate research experiences (CUREs) are an effective method of engaging large numbers of students in authentic research but are associated with barriers to adoption. Short CURE modules may serve as a low-barrier entryway, but their effectiveness in promoting expansion has not been studied. The Prevalence of Antibiotic Resistance in the Environment (PARE) project is a modular CURE designed to be a low-barrier gateway into CURE use. In a series of interviews, we track and characterize use of PARE in 19 PARE-interested instructors throughout the Innovation-Decision Process described by Rogers' Diffusion of Innovations theory. The majority (16/19) implement PARE at least once, and a majority of these implementers (11/16) expanded use by the final interview. Three of four cases of discontinuance were due to a disruption such as moving institutions or a change in course assignment and occurred for community college faculty. Expanders expressed fewer personal challenges than nonexpanders. Overall analysis shows that perception of barriers is nuanced and impacted by the innovation itself, the institutional context, and one's own experiences. These results suggest that a short duration, low barrier CURE can serve as a catalyst for implementation of a longer duration CURE.

One in three females with multiple sclerosis (MS) becomes pregnant after diagnosis. In the postpartum period, there is a risk of rebound inflammatory activity. This risk can likely be reduced with breastfeeding, as well as with early initiation of effective therapies that have low therapeutic lag. To guide patients in their choices surrounding breastfeeding and MS therapies, clinicians must be familiar with how best to protect against relapses, to ensure infant safety, and to support breastfeeding choices. This topical review provides a broad framework on lactation in women with MS. It seeks to reframe guidelines around caring for the maternal-infant dyad, and for diverse populations living with MS. It also provides updated data on the effects of lactation in women with MS and the limited data on transfer of disease-modifying therapies (DMTs) into breastmilk. The ultimate goal is to support informed shared decision-making between clinicians and patients regarding breastfeeding during the high-risk postpartum period.

BACKGROUND: Bladder dysfunction (BD) is common in people with multiple sclerosis (MS) and can reduce participation in daily life. Detecting BD early allows for effective prevention-focused treatments such as pelvic floor physical therapy. Pairing neurotechnology with patient-reported outcomes to remotely measure BD could significantly improve monitoring and treatment of BD. Therefore, we describe the process and findings of stakeholder engagement from a human-centered design process to assemble a wearables for the bladder (WeB) kit. METHODS: Four people with MS with varying BD severity, and 5 MS clinical/research experts had 4 virtual meetings. Commercially available bladder tools were graded for ability to evaluate, monitor, or treat BD. The Health Information Technology Usability Evaluation Scale (utility, usability, feasibility) was used for evaluation. Scoring was performed individually and as a group. RESULTS: Of the 11 devices, 5 obtained mean scores of greater than 6 of 10 for likability, usability, and device utility. The 2 highest scoring (9/10) devices were selected for the pilot. One device measures bladder urine levels, reporting the number/frequency of voids/leaks; the other guides pelvic floor exercises by pairing games on an app with biofeedback from intravaginal sensors. We uncovered critical differences in experts and patients appreciation of the tools, and the collaborative engagement led to substantial revisions of initial tool scores. CONCLUSIONS: This process underscores the critical role of stakeholder engagement in the selection of digital tools, especially in sensitive domains like pelvic function. Ongoing clinical validation of the selected tools will yield a validated, user-friendly WeB kit that is able to fill gaps in our ability to evaluate BD treatments in people with MS, ultimately reducing the impact of BD on quality of life.

BACKGROUND: Previous studies have suggested differences in multiple sclerosis (MS) severity according to ethnicity. METHODS: Data were obtained from the UK MS Register, a prospective longitudinal cohort study of persons with MS. We examined the association between self-reported ethnic background and age at onset, symptom of onset and a variety of participant-reported severity measures. We used adjusted multivariable linear regression models to explore the association between ethnicity and impact of MS, and Cox proportional hazards models to assess disability progression. RESULTS: We analysed data from 17,314 people with MS, including participants from self-reported Black (n = 157) or South Asian (n = 230) ethnic backgrounds. Age at MS onset and diagnosis was lower in those of South Asian (median 30.0) and Black (median 33.0) ethnicity compared with White ethnicity (median 35.0). In participants with online MS severity measures available, we found no statistically significant evidence for an association between ethnic background and physical disability in MS in both cross-sectional and longitudinal analyses. CONCLUSION: We found no association between ethnic background and MS severity in a large, diverse UK cohort. These findings suggest that other factors, such as socioeconomic status and structural inequalities, may explain previous findings.

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.

Opioid maintenance treatment (OMT) is the most widespread therapy for both females and males opioid addicts. While many studies have evaluated the OMT impact on men’s sexuality, the data collected about the change in women’s sexual functioning is still limited despite the fact that it is now well-known that opioids - both endogenous and exogenous - affect the endocrine system and play an important role in sexual functioning. The present study aims to determine how OMT with buprenorphine (BUP) or methadone (MTD) affects sexual health in women; examining also any possible emerging correlation between sexual dysfunction (SD), type of opioid and patients’ mental health. This multi-center study case recruited 258 female volunteers attending Italian public Addiction Outpatients Centers that were stabilized with OMT for at least 3 months. SD was assessed with the Arizona Sexual Experience Scale. The twelve-item General Health Questionnaire was used to assess participants’ mental health conditions. The results show that 56.6% of women receiving OMT for at least 3 months presented SD without significant differences between MTD e BUP groups. The majority of the subjects with SD have a poorer quality of intimate relationships and worse mental health than the average. To the best of our knowledge, the present study is the largest report on the presence of SDs in women as a side effects of MTD and BUP used in OMT. Since SDs cause difficulties in intimate relationships, lower patients’ quality of life and interfere with OMT beneficial outcomes, we recommend that women undertaking an opioid therapy have routine screening for SD and we highlight the importance to better examine opioid-endocrine interactions in future studies in order to provide alternative potential treatments such as the choice of opioid, opioid dose reduction and hormone supplementation.

Background Drinking water at US Marine Corps (USMC) Base Camp Lejeune, North Carolina, is sourced from groundwater supply wells. Eight treatment plants supplied drinking water to different areas of the [...], BACKGROUND: Drinking water at US Marine Corps Base Camp Lejeune, North Carolina, was contaminated with trichloroethylene and other industrial solvents from 1953 to 1985. METHODS: A cohort cancer incidence study was conducted of Marines/Navy personnel who began service and were stationed at Camp Lejeune (N = 154,821) or Camp Pendleton, California (N = 163,484) between 1975 and 1985 and civilian workers employed at Camp Lejeune (N = 6,494) or Camp Pendleton (N = 5,797) between October 1972 and December 1985. Camp Pendleton&apos;s drinking water was not contaminated with industrial solvents. Individual-level information on primary invasive cancers and in situ bladder cancer diagnosed between 1996 and 2017 was obtained from 54 US cancer registries. Proportional hazards regression was used to calculate adjusted hazard ratios (aHRs) comparing cancer incidence between the Camp Lejeune and Camp Pendleton cohorts, adjusted for sex, race, education, and rank (or blue-collar work), with age as the time variable. Precision of aHRs was evaluated using the 95% confidence interval (CI) ratio (CIR). RESULTS: Cancers among Camp Lejeune Marines/Navy personnel and civilian workers totaled 12,083 and 1,563, respectively. Cancers among Camp Pendleton Marines/Navy personnel and civilian workers totaled 12,144 and 1,416, respectively. Compared with Camp Pendleton, Camp Lejeune Marines/Navy personnel had aHRs [greater than or equal to]1:20 with CIRs [less than or equal to]3 for all myeloid cancers (HR = 1:24; 95% CI: 1.03, 1.49), acute myeloid leukemia (HR = 1:38; 95% CI: 1.03, 1.85), myelodysplastic and myeloproliferative syndromes (HR = 1:68; 95% CI: 1.07, 2.62), polycythemia vera (HR = 1:41; 95% CI: 0.94, 2.11), and cancers of the esophagus (HR = 1:27; 95% CI: 1.03, 1.56), larynx (HR = 1:21; 95% CI: 0.98, 1.50), soft tissue (HR = 1:21; 95% CI: 0.92, 1.59), and thyroid (HR = 1:22; 95% CI: 1.03, 1.45). Lymphoma subtypes mantle cell and marginal zone B-cell and lung cancer subtypes adenocarcinoma and non-small cell lung cancer also had aHRs [greater than or equal to]1:20 with CIRs [less than or equal to]3. Compared with Camp Pendleton, Camp Lejeune civilian workers had aHRs [greater than or equal to]1:20 with CIRs [less than or equal to]3 for all myeloid cancers (HR = 1:40; 95% CI: 0.83, 2.36), squamous cell lung cancer (HR = 1:63; 95% CI: 1.10, 2.41), and female breast (HR = 1:21; 95% CI: 0.97, 1.52) and ductal cancer (HR = 1:32; 95% CI: 1.02, 1.71). CONCLUSION: Increased risks of several cancers were observed among Marines/Navy personnel and civilian workers exposed to contaminated drinking water at Camp Lejeune compared with Camp Pendleton. https://doi.org/10.1289/EHP14966

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.