Intrathecal IgM Synthesis Is Associated with Spinal Cord Manifestation and Neuronal Injury in Early MS.

OBJECTIVE: Intrathecal Immunoglobulin M synthesis (IgMIntrathecal Fraction (IF) + ) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgMIF + is associated with spinal cord manifestation and higher neuroaxonal damage in early MS. METHODS: In 122 patients with a first demyelinating event associations between (1) spinal versus (vs) non-spinal clinical syndrome (2) spinal vs cerebral T2-weighted (T2w) and (3) contrast-enhancing (CE) lesion counts with IgGIF + (vs IgGIF - ) or IgMIF + (vs IgMIF - ) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgGIF and IgMIF (>0% vs 0%, respectively): (1) OCGB- /IgGIF - /IgMIF - ; (2) OCGB+ /IgGIF - /IgMIF - ; (3) OCGB+ /IgGIF + /IgMIF - ; and (4) OCGB+ /IgGIF + /IgMIF + . Associations between categories 2 to 4 vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters. RESULTS: Patients with a spinal syndrome had a 8.36-fold higher odds of IgMIF + (95%CI 3.03-23.03; p < 0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02-1.90; p = 0.037) and CE lesion (OR 2.73; 1.22-6.09; p = 0.014) was associated with an increased risk of IgMIF + (but not of IgGIF + ); this was not the case for cerebral lesions. OCGB+ /IgGIF + /IgMIF + category patients showed highest sNfL levels (estimate:1.80; 0.55-3.06; p < 0.01). INTERPRETATION: Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. ANN NEUROL 2022;91:814-820.

Granulocyte activation markers in cerebrospinal fluid differentiate acute neuromyelitis spectrum disorder from multiple sclerosis.

BACKGROUND: Granulocyte invasion into the brain is a pathoanatomical feature differentiating neuromyelitis optica spectrum disorder (NMOSD) from multiple sclerosis (MS). We aimed to determine whether granulocyte activation markers (GAM) in cerebrospinal fluid (CSF) can be used as a biomarker to distinguish NMOSD from MS, and whether levels associate with neurological impairment. METHODS: We quantified CSF levels of five GAM (neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin, matrixmetalloproteinase-8, tissue inhibitor of metalloproteinase-1), as well as a set of inflammatory and tissue-destruction markers, known to be upregulated in NMOSD and MS (neurofilament light chain, glial fibrillary acidic protein, S100B, matrix metalloproteinase-9, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1), in two cohorts of patients with mixed NMOSD and relapsing-remitting multiple sclerosis (RRMS). RESULTS: In acute NMOSD, GAM and adhesion molecules, but not the other markers, were higher than in RRMS and correlated with actual clinical disability scores. Peak GAM levels occurred at the onset of NMOSD attacks, while they were stably low in MS, allowing to differentiate the two diseases for ≤21 days from onset of clinical exacerbation. Composites of GAM provided area under the curve values of 0.90-0.98 (specificity of 0.76-1.0, sensitivity of 0.87-1.0) to differentiate NMOSD from MS, including all anti-aquaporin-4 protein (aAQP4)-antibody-negative patients who were untreated. CONCLUSIONS: GAM composites represent a novel biomarker to reliably differentiate NMOSD from MS, including in aAQP4- NMOSD. The association of GAM with the degree of concurrent neurological impairment provides evidence for their pathogenic role, in turn suggesting them as potential drug targets in acute NMOSD.

Serum neurofilament light chain in functionally relevant coronary artery disease and adverse cardiovascular outcomes.

Background: Functionally relevant coronary artery disease (fCAD), causing symptoms of myocardial ischemia, can currently only be reliably detected with advanced cardiac imaging. Serum neurofilament light chain (sNfL) is a biomarker for neuro-axonal injury known to be elevated by cardiovascular (CV) risk factors and cerebrovascular small-vessel diseases. Due to their pathophysiological similarities with fCAD and the link to CV risk factors, we hypothesised that sNfL may have diagnostic and prognostic value for fCAD and adverse cardiovascular outcomes.Methods: Of the large prospective Basel VIII study (NCT01838148), 4'016 consecutive patients undergoing cardiac work-up for suspected fCAD were included (median age 68 years, 32.5% women, 46.9% with history of CAD). The presence of fCAD was adjudicated using myocardial perfusion imaging single-photon emission tomography (MPI-SPECT) and coronary angiography. sNfL was measured using a high-sensitive single-molecule array assay. All-cause and cardiovascular death, myocardial infarction (MI), and stroke/transient ischaemic attack (TIA) during 5-year follow-up were the prognostic endpoints.Results: The diagnostic accuracy of sNfL for fCAD as quantified by the area under the curve (AUC) was low (0.58, 95%CI 0.56-0.60). sNfL was strongly associated with age, renal dysfunction, and body mass index and was a strong and independent predictor of all-cause death, cardiovascular death, and stroke/TIA but not MI. Time-dependent AUC for cardiovascular-death at 1-year was 0.85, 95%CI 0.80-0.89, and 0.81, 95%CI 0.77-0.86 at 2-years.Conclusion: While sNfL concentrations did not show a diagnostic role for fCAD, in contrast, sNfL was a strong and independent predictor of cardiovascular outcomes, including all-cause death, cardiovascular death and stroke/TIA.

The role of community healthcare professionals in discussing sexual assault experiences during obstetrics and gynecological healthcare appointments.

BACKGROUND: Nearly half of adult women in the US report experiencing sexual assault, with almost one-fifth reporting rape. For many sexual assault survivors, healthcare professionals are the first point of contact and disclosure. This study aimed to understand how healthcare professionals working in community settings perceived their role in discussing sexual violence experiences with women during obstetrical and gynecological healthcare appointments. The secondary purpose was to compare healthcare professionals' perspectives with the patients' to determine how sexual violence conversations should occur in these environments. METHODS: Data were collected in two phases. Phase 1 consisted of 6 focus groups (Sept-Dec, 2019) with women aged 18-45 (n = 22) living in Indiana who sought community-based or private healthcare for women's reproductive healthcare needs. Phase 2 included 20 key-informant interviews with non-physician healthcare professionals (i.e., NP, RN, CNM, doula, pharmacist, chiropractor) living in Indiana (September 2019-May 2020) who provided community-based women's reproductive healthcare. Focus groups and interviews were audio-recorded, transcribed, and analyzed using thematic analyses. HyperRESEARCH assisted in data management and organization. RESULTS: There were three resulting themes: (1) healthcare professionals' approaches to screening for a history of sexual violence varied depending on how they ask, what setting they work in, and type of professional asking; (2) healthcare experiences can compound traumatic experiences and create distrust with survivors; and (3) sexual violence impacts patient healthcare experiences through what services they seek, how professionals may interact with them, and what professionals they are willing to utilize. CONCLUSIONS: Findings offered insight into actionable and practical strategies for enhancing sexual violence screening and discussions in community-based women's reproductive health settings. The findings offer strategies to address barriers and facilitators among community healthcare professionals and the people they serve. Incorporating healthcare professional and patient experiences and preferences for violence-related discussions during obstetrical and gynecological healthcare appointments can assist in violence prevention efforts, improve patient-professional rapport, and yield better health outcomes.

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis.

OBJECTIVE: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgMIF < median. Dose-dependent associations were also found for IgMIF but not for IgGIF with magnetic resonance imaging-defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.

Diabetes, Glycated Hemoglobin (HbA1c), and Neuroaxonal Damage in Parkinson's Disease (MARK-PD Study).

BACKGROUND: Diabetes is associated with incidence and prevalence of Parkinson's disease (PD). Furthermore, glycated hemoglobin (HbA1c) levels have been linked with motor function and progression. OBJECTIVES: We evaluated the relationship between prevalent diabetes and HbA1c levels with serum neurofilament light chain (NfL) levels as marker of neuroaxonal damage. METHODS: NfL concentrations were analyzed with Simoa in serum of 195 PD patients with available HbA1c values. Motor (MDS-UPDRS III, Hoehn & Yahr [H&Y]) and cognitive (Montreal Cognitive Assessment [MoCA]) function was assessed and vascular comorbidities were documented from medical records. RESULTS: PD patients with prevalent diabetes had higher serum NfL levels and lower MoCA scores independent of age, body mass index (BMI), and vascular risk factors. Furthermore, diabetes was associated with higher H&Y stages in unadjusted and age/BMI-adjusted models. Higher HbA1c levels were associated with increased NfL in unadjusted and age/BMI-adjusted models. CONCLUSIONS: In PD patients, diabetes and high HbA1c are associated with increased neuroaxonal damage and cognitive impairment. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

Cross-border reproductive healthcare attitudes and behaviours among women living in Florence, Italy.

BACKGROUND: The number of women living in Italy and seeking cross-border reproductive care (CBRC), especially for medically assisted reproduction (MAR), has increased. The purpose of this study was to explore CBRC attitudes and behaviours among a cohort of reproductive-aged women who have never engaged in CBRC to gauge social and cultural perceptions and gain a deeper understanding of family planning discourse. METHODS: In-depth interviews were conducted during May - June 2018 with 30 women aged 18-50 living in or around Florence, Italy and enrolled in the Italian healthcare system. Interviews offered in-depth insight into CBRC attitudes, behaviours, and experiences among a cohort of women living in Italy who had never engaged in CBRC. Researchers used an expanded grounded theory through open and axial coding. Emergent themes were identified via a constant comparison approach. RESULTS: Three themes and two subthemes emerged from the data. Participants discussed how limitations in Italy's access to MAR can lead women to seek reproductive healthcare in other countries. Women had mixed feelings about the effect of religion on legislation and reproductive healthcare access, with many views tied to religious and spiritual norms impacting MAR treatment-seeking in-country and across borders. Participants perceived infertility and CBRC-seeking as socially isolating, as the motherhood identity was highly revered. The financial cost of traveling for CBRC limited access and exacerbated emotional impacts. CONCLUSIONS: Findings offered insight into CBRC perceptions and intentions, presenting a deeper understanding of the existing family planning discourse among reproductive-aged women. This may allow policymakers and practitioners to address social and cultural perceptions, increase access to safe and effective local care, and empower women in their family planning decisions.

Messaging and access strategies for improving emergency contraceptive knowledge and uptake among Italians.

OBJECTIVES: Over-the-counter emergency contraception (EC) purchase was legalised in Italy in 2015. Knowledge and access gaps, however, remain. The goal of this study was to explore women's and men's EC informational and access needs. METHODS: As part of a larger reproductive study, researchers conducted 42 in-depth interviews (May-June 2019) with English-speaking women and men aged 18-50 years (mean ± standard deviation, 29.1 ± 7.9 years) living in or near Florence, Italy, and using the Italian health care system. Researchers completed qualitative data analysis to identify emergent themes related to EC knowledge, attitudes and access. HyperRESEARCH aided data organisation and analysis. Researchers used a comparative method to contextualise data and identify emergent themes. RESULTS: Findings demonstrated that peer communication and experiences served as influential factors in others' EC use. This propagated misinformation, reducing participants' confidence in EC efficacy and safety. Women described the relevance of relationship type in whether to engage men in EC discussion, while men desired an active supportive role. Finally, participants described various messaging and access channels to increase EC knowledge and access. CONCLUSION: Findings offer practical recommendations to guide social marketing and behaviour change interventions to increase EC access among women and men in Italy. The utility of pharmacists to individuals wishing to access EC is explored.

Measurement of neurofilaments improves stratification of future disease activity in early multiple sclerosis.

BACKGROUND: The added value of neurofilament light chain levels in serum (sNfL) to the concept of no evidence of disease activity-3 (NEDA-3) has not yet been investigated in detail. OBJECTIVE: To assess whether combination of sNfL with NEDA-3 status improves identification of patients at higher risk of disease activity during the following year. METHODS: We analyzed 369 blood samples from 155 early relapsing-remitting MS patients on interferon beta-1a. We compared disease activity, including the rate of brain volume loss in subgroups defined by NEDA-3 status and high or low sNfL (> 90th or < 90th percentile). RESULTS: In patients with disease activity (EDA-3), those with higher sNFL had higher odds of EDA-3 in the following year than those with low sNFL (86.5% vs 57.9%; OR = 4.25, 95% CI: [2.02, 8.95]; p = 0.0001) and greater whole brain volume loss during the following year (ß = -0.36%; 95% CI = [-0.60, -0.13]; p = 0.002). Accordingly, NEDA-3 patients with high sNfL showed numerically higher disease activity (EDA-3) in the following year compared with those with low sNfL (57.1% vs 31.1%). CONCLUSION: sNfL improves the ability to identify patients at higher risk of future disease activity, beyond their NEDA-3 status. Measurement of sNfL may assist clinicians in decision-making by providing more sensitive prognostic information.

"Nobody's Ever Told Me That:" Women's Experiences with Shared Decision-making when Accessing Contraception.

Half of all pregnancies in the United States are unintended. Contraceptive methods are effective in reducing unintended pregnancy burden. The shared decision-making model serves as best practice when choosing among healthcare options, and may be appropriate when considering contraceptive options. This study examined women's experiences with shared decision-making in contraceptive use dynamics. Researchers analyzed 38 interviews with women of reproductive age (range: 19-50 years) living in South Carolina (May-November 2016). Researchers completed a constant comparative method of data analysis using HyperRESEARCH 3.7.3 to explore reproductive-aged women's contraceptive decision-making. Shared decision-making provided a conceptual framework for analysis. Gaps in contraceptive knowledge, especially method effectiveness, impacted participants' experiences with contraception. Although participants believed they had adequate information, findings suggest they may not be fully informed about existing contraceptive options. Participants wanted options; however, results indicated women may not be actively involved in choosing contraception. Nuanced beliefs about contraception demonstrated preferences for patient-provider communication within the broader context of reproductive health and individual lifestyle needs. Findings from this study offer theoretical and practical recommendations to guide shared decision-making during contraceptive consultations to empower women in making informed and lifestyle-appropriate contraceptive choices.