SwissGenVar: A Platform for Clinical-Grade Interpretation of Genetic Variants to Foster Personalized Healthcare in Switzerland.

Large-scale next-generation sequencing (NGS) germline testing is technically feasible today, but variant interpretation represents a major bottleneck in analysis workflows. This includes extensive variant prioritization, annotation, and time-consuming evidence curation. The scale of the interpretation problem is massive, and variants of uncertain significance (VUSs) are a challenge to personalized medicine. This challenge is further compounded by the complexity and heterogeneity of the standards used to describe genetic variants and the associated phenotypes when searching for relevant information to support clinical decision making. To address this, all five Swiss academic institutions for Medical Genetics joined forces with the Swiss Institute of Bioinformatics (SIB) to create SwissGenVar as a user-friendly nationwide repository and sharing platform for genetic variant data generated during routine diagnostic procedures and research sequencing projects. Its aim is to provide a protected environment for expert evidence sharing about individual variants to harmonize and upscale their significance interpretation at the clinical grade according to international standards. To corroborate the clinical assessment, the variant-related data will be combined with consented high-quality clinical information. Broader visibility will be achieved by interfacing with international databases, thus supporting global initiatives in personalized healthcare.

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression. METHODS: CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient. RESULTS: CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001). DISCUSSION: CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

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.

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 Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis.

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS). Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression. Design, Setting, and Participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab). Exposures: Patients received standard immunotherapies or were untreated. Main Outcomes and Measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally. Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001). Conclusions and Relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

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.

Neurofilament light chain plasma levels are associated with area of brain damage in experimental cerebral malaria.

Neurofilament light chain (NfL), released during central nervous injury, has evolved as a powerful serum marker of disease severity in many neurological disorders, including infectious diseases. So far NfL has not been assessed in cerebral malaria in human or its rodent model experimental cerebral malaria (ECM), a disease that can lead to fatal brain edema or reversible brain edema. In this study we assessed if NfL serum levels can also grade disease severity in an ECM mouse model with reversible (n = 11) and irreversible edema (n = 10). Blood-brain-barrier disruption and brain volume were determined by magnetic resonance imaging. Neurofilament density volume as well as structural integrity were examined by electron microscopy in regions of most severe brain damage (olfactory bulb (OB), cortex and brainstem). NfL plasma levels in mice with irreversible edema (317.0 ± 45.01 pg/ml) or reversible edema (528.3 ± 125.4 pg/ml) were significantly increased compared to controls (103.4 ± 25.78 pg/ml) by three to five fold, but did not differ significantly in mice with reversible or irreversible edema. In both reversible and irreversible edema, the brain region most affected was the OB with highest level of blood-brain-barrier disruption and most pronounced decrease in neurofilament density volume, which correlated with NfL plasma levels (r = - 0.68, p = 0.045). In cortical and brainstem regions neurofilament density was only decreased in mice with irreversible edema and strongest in the brainstem. In reversible edema NfL plasma levels, MRI findings and neurofilament volume density normalized at 3 months' follow-up. In conclusion, NfL plasma levels are elevated during ECM confirming brain damage. However, NfL plasma levels fail short on reliably indicating on the final outcomes in the acute disease stage that could be either fatal or reversible. Increased levels of plasma NfL during the acute disease stage are thus likely driven by the anatomical location of brain damage, the olfactory bulb, a region that serves as cerebral draining pathway into the nasal lymphatics.

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.

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.

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study.

BACKGROUND: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies. METHODS: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry. FINDINGS: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1-2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0-8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35-4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08-6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry. INTERPRETATION: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials. FUNDING: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche.

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.

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.

Shared decision-making among non-physician healthcare professionals: Enhancing patient involvement in women's reproductive health in community healthcare settings.

OBJECTIVE: Shared decision-making (SDM) is an important approach to patient-centered care in women's reproductive healthcare. This study explored SDM experiences and perceptions among non-physician healthcare professionals. METHODS: We completed 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. Interviews were audio-recorded, transcribed, and analyzed using an expanded grounded theory framework. Constant comparative analysis identified emergent themes. RESULTS: Professionals noted community-based healthcare required contextualized decision-making approaches. Results identified listening, decisional ownership, and engagement strategies that enhanced SDM involvement. Findings suggested outcome-oriented SDM concepts, including decisional ownership and investigative listening to enhance SDM. Providers redefined 'challenging' patients as engaged in their healthcare and discussed ways SDM improved healthcare experience beyond one visit. CONCLUSION: Findings offered insight into actionable and practical strategies for enhancing SDM in community-based women's reproductive healthcare. The findings offer strategies to improve SDM by addressing barriers and facilitators among professionals. This extends SDM beyond the patient-physician dyad and supports broader application of SDM. PRACTICE IMPLICATIONS: Incorporating professionals' experiences into SDM concepts can enhance SDM in community-based women's healthcare practice, offering opportunities to support a culture of SDM across settings.

You Have Options: Implementing and evaluating a contraceptive choice social marketing campaign.

Background: Up to two-thirds of pregnancies among young, unmarried women in the United States are unintended, despite increased access to highly effective contraceptive options. Aim: This study implemented and evaluated a social marketing campaign designed to increase access to a full range of contraceptive methods among women aged 18-24 years on a southeastern university campus. Methods: Researchers partnered with Choose Well and Student Health Services to design, implement, and evaluate You Have Options, a 10-week multi-media social marketing campaign. The campaign aimed to raise awareness, increase knowledge, and improve access to contraceptive options, including long-acting reversible contraception (LARC) methods among college women. A pretest-posttest web-based survey design measured campaign awareness and recognition, as well as attitudes, subjective norms, and behavior. Results: Participants demonstrated a significant increase in knowledge about intrauterine devices (IUDs) between pretest (M = 2.66, SD = 1.30) and posttest (M = 3.06; SD = 1.96); t(671) = -2.60, p < .01). Analysis revealed that frequent exposure to the campaign prompted participants to engage in discussions about LARC with friends (p < .05). In addition, 20- to 24-year-olds who reported seeing the campaign messages were more likely to seek out information (p < .01) and adopt a LARC method (p = .001) than 18- or 19-year-olds who saw the campaign messages. Conclusion: Findings from the study offer practical recommendations for implementing social marketing campaigns aimed at increasing access to LARC and reducing unintended pregnancy.

"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.

"I'm More Open to Talking About It": Women's Experiences With Sexual Abuse and Reproductive Health.

Approximately one in three women experience sexual abuse, which can result in negative reproductive health consequences. A history of sexual abuse may negatively impact health care seeking and experience. The purposes of this article were to understand how women perceived their sexual abuse experiences and how these experiences integrated into their overall reproductive health, reproductive planning, and health care access. As part of a larger study about women's reproductive health, researchers analyzed 16 in-depth interviews with women aged 18 years and older (range = 18-78) living in South Carolina (May-November 2016). A constant comparative method of data analysis was completed to explore women's sexual abuse experiences as they related to reproductive health and health care experiences. HyperRESEARCH 3.7.3 assisted in data organization and management. Limited bodily agency impacted women's ability to engage in family planning, particularly when partners utilized sexual coercion to maintain desired relationships and attain desired family size, regardless of women's preferences. In addition, limited sexual violence and abuse discussion in health care contexts impacted women's autonomy in reproductive health decision-making despite participants' desire to engage in these discussions with providers. Participants expressed a desire for communication about their sexual abuse experiences; however, results indicated women had to navigate stigma within families and communities, which deterred disclosure and open discussion. Negative health outcomes and desire to discuss these experiences within the health care context highlighted a need for patient-provider communication about sexual abuse history as one aspect of gynecologic care. Findings from this study offer practical recommendations to guide communication about sexual abuse within reproductive health care experiences to empower women in their reproductive health choices. As these experiences may impact overall health and reproductive choices, provider-initiated conversations with adolescents and women may improve care and assist in prevention efforts, including the prevention of negative health outcomes.

"You have to be clean:" a qualitative study of pubic hair grooming behaviours among women living in Italy.

The majority of pubic hair and genital self-image research describes women living in the USA, UK and Australia. This may leave attitudes and behaviours across other cultures and geographic regions ambiguous. The purpose of this study was to describe pubic hair removal attitudes and behaviours among reproductive-age women living in Italy. Individual interviews were conducted with 46 women aged 18-45 years between June and July 2017, living in Florence, Italy and currently utilising the Italian healthcare system. Pubic hair removal was popular among participants. Women mainly removed pubic hair by waxing. Sexual partners influenced removal, as did cultural norms and the desire for cleanliness. Most participants indicated pubic hair removal onset during adolescence, often upon puberty. However, most participants had never discussed removal complications with providers. Pubic hair removal often related to a more positive genital self-image because of social norms surrounding hairlessness. Removal among this sample appears to differ from the literature in other contexts, with women living in Italy engaging in more frequent and earlier waxing. Findings offer opportunities for clinicians to proactively address safe pubic hair practices and women's genital concerns during consultations.

Condom-vending machines in Italy: a qualitative exploration of gender differences to improve promotion and use.

OBJECTIVES: The purposes of this study were to explore gender differences in condom purchasing from condom-vending machines (CVMs) and identify ways to improve CVM promotion. METHODS: Semi-structured interviews with 42 men and women aged 18-50 years (mean ± standard deviation, 29.1 ± 7.9) and living in or near Florence, Italy, were conducted between May and June 2019. Techniques from expanded grounded theory-guided data analysis allowed for a constant comparative approach to contextualise data and identify emergent themes. RESULTS: Three themes emerged: (1) attitudes and barriers towards CVMs; (2) gender-specific purchasing influences and behaviours; and (3) CVM improvement and promotion. Women and men described varied concerns surrounding CVM purchasing, illuminating reasons for hesitancy. Focussing on CVM quality and improving product offerings were suggested by participants to increase use. CONCLUSION: Findings offer practical recommendations to guide CVM messaging to increase access to and use of condoms and other personal care items. Men were cited as primary CVM users, expressing practical concerns surrounding CVMs, while, for women, CVM visibility was as much an advantage as a drawback. Reflecting consumer needs via diversified product offerings should be considered a priority for increased CVM use. Working to promote CVMs requires clear messaging that attends to gender norm limitations, details product safety and establishes CVMs as a reliable condom purchase outlet.