Search

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.

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.

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.

BackgroundVirtual activities, hybrid work and virtual mentoring have become part of the ongoing milieu of academic medicine. As the shift to remote mentoring continues to evolve, it is now possible to adapt, refine, and improve tools to support thriving mentoring relationships that take place virtually. This study explores strategies for virtual mentoring as a cornerstone for effective training programs among senior mentors participating in an ongoing mentoring program.MethodsWe conducted a qualitative study among prior and current participants of an ongoing "Mentoring the Mentors" program about key strategies for optimizing virtual mentoring. Data were coded and analyzed following a thematic analysis approach.ResultsRespondents were mostly female (62%), white (58%), and associate (39%) or full professors (32%). We found that, with the expansion of hybrid and fully remote work, there are now fewer opportunities for informal but important chance meetings between mentors and mentees; however, virtual mentoring provides opportunities to compensate for reduced interactivity normally experienced in the workplace. The heightened need to plan and be more deliberate in the virtual sphere was woven throughout narratives and was the foundation of most recommendations. Specifically, a central obstacle for respondents was that spontaneous conversations were harder to initiate because virtual conversations are expected to have set agendas.ConclusionsDeveloping new ways to maintain meaningful interpersonal relationships in a virtual training environment, including opportunities for serendipitous and informal engagement, is critical to the success of virtual mentoring programs.

BackgroundIntellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM-5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two year period in a large sample of children, adolescents and young adults with IDD.MethodsThree groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (mage = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid Cognition, Crystallized Cognition, Total Cognition) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization).ResultsOver a two year period, change in cognition (both Crystallized and Total Composites) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model.ConclusionsThe present study demonstrated that developmental changes in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in DLS emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.

There is growing need to distinguish between sex and gender. While sex is assigned at birth, gender is socially constructed and may not correspond to one's assigned sex. However, in most research studies, sex or gender is assessed in isolation or the terms are used interchangeably, which has implications for research accuracy and inclusivity. We used data from the UK Biobank to quantify the prevalence of disagreement between chromosomal and self-reported sex and identify potential reasons for discordance. Among approximately 200 individuals with sex discordance, 71% of discordances were potentially explained by the presence of intersex traits or transgender identity. The findings indicate that when describing sex- and/or gender-specific differences in health, researchers may be limited in their ability to draw conclusions regarding specific sex and/or gender health information.

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

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

BackgroundSex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk.MethodsWe conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH.ResultsAcross disorders, genome-wide significant single nucleotide polymorphism-by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10-8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10-6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10-7; rs73033497, p = 8.8 × 10-7; rs7914279, p = 6.4 × 10-7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10-7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10-7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05).ConclusionsIn the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections were rising during early summer 2021 in many countries as a result of the Delta variant. We assessed reverse transcription polymerase chain reaction swab positivity in the Real-time Assessment of Community Transmission–1 (REACT-1) study in England. During June and July 2021, we observed sustained exponential growth with an average doubling time of 25 days, driven by complete replacement of the Alpha variant by Delta and by high prevalence at younger, less-vaccinated ages. Prevalence among unvaccinated people [1.21% (95% credible interval 1.03%, 1.41%)] was three times that among double-vaccinated people [0.40% (95% credible interval 0.34%, 0.48%)]. However, after adjusting for age and other variables, vaccine effectiveness for double-vaccinated people was estimated at between ~50% and ~60% during this period in England. Increased social mixing in the presence of Delta had the potential to generate sustained growth in infections, even at high levels of vaccination.

ObjectivesThis study was aimed to describe the interviewer-assessed measures present in the 2015/2016 Round of National Social Life, Health, and Aging Project (NSHAP), outline strengths of interviewer-assessed measures, and explore how interviewer assessments in the domains of home environment and personal characteristics are associated with older adult health.MethodData come from the 2015/2016 Round of the NSHAP.ResultsWe provide descriptive results from the interviewer assessments of personal attributes, indoor home environment, and outdoor residential context. We present an illustrative analysis of reports of falls, a health outcome that might be predicted by characteristics assessed by the interviewer, and we suggest directions for further research.DiscussionInterviewer assessments collected in NSHAP are useful as proxy measures and can be used in combination with respondent's reports and ecological measures to generate insights into healthy aging.

OBJECTIVE: The purpose of this study was to compare the results of a biphasic synthetic scaffold (TruFit, Smith & Nephew) to microfracture for the treatment of knee cartilage defects and identify patient- and lesion-specific factors that influence outcomes. DESIGN: Prospectively collected data from 132 patients (mean age, 41.8 years; 69% male) with isolated chondral or osteochondral femoral defects treated with biphasic synthetic scaffolds (n = 66) or microfracture (n = 66) were reviewed. Clinical outcomes were evaluated longitudinally over 5 years with the Short Form-36 (SF-36), Activities of Daily Living of the Knee Outcome Survey (KOS-ADL), International Knee Documentation Committee (IKDC), and Marx Activity Scale. Cartilage-sensitive magnetic resonance imaging (MRI) was performed to evaluate osseous integration and cartilage fill in a subgroup of patients. Multivariate regression analysis was used to identify predictors of clinical outcomes within the scaffold group. RESULTS: Both groups demonstrated clinically significant improvements in knee clinical scores over 5 years (P < 0.01). There were no significant differences in KOS-ADL and IKDC scores between groups up to 5 years postoperatively. Marx activity level scores in the microfracture group declined over time, while significant improvements in activity level scores were observed in the scaffold group over 5 years (P < 0.01). Good-quality tissue fill and cartilage isointensity were more often observed in the scaffold group compared with the microfracture group, particularly with longer time intervals. Increasing age, high body mass index, prior microfracture, and traumatic etiology were predictors for inferior outcomes in the scaffold group. CONCLUSIONS: Activity level and MRI appearance following treatment of cartilage lesions with the biphasic synthetic scaffold were superior to microfracture over time in this nonrandomized, retrospective comparison.

ObjectiveThe purpose of this study was to compare the results of a biphasic synthetic scaffold (TruFit, Smith & Nephew) to microfracture for the treatment of knee cartilage defects and identify patient- and lesion-specific factors that influence outcomes.DesignProspectively collected data from 132 patients (mean age, 41.8 years; 69% male) with isolated chondral or osteochondral femoral defects treated with biphasic synthetic scaffolds (n = 66) or microfracture (n = 66) were reviewed. Clinical outcomes were evaluated longitudinally over 5 years with the Short Form-36 (SF-36), Activities of Daily Living of the Knee Outcome Survey (KOS-ADL), International Knee Documentation Committee (IKDC), and Marx Activity Scale. Cartilage-sensitive magnetic resonance imaging (MRI) was performed to evaluate osseous integration and cartilage fill in a subgroup of patients. Multivariate regression analysis was used to identify predictors of clinical outcomes within the scaffold group.ResultsBoth groups demonstrated clinically significant improvements in knee clinical scores over 5 years (P < 0.01). There were no significant differences in KOS-ADL and IKDC scores between groups up to 5 years postoperatively. Marx activity level scores in the microfracture group declined over time, while significant improvements in activity level scores were observed in the scaffold group over 5 years (P < 0.01). Good-quality tissue fill and cartilage isointensity were more often observed in the scaffold group compared with the microfracture group, particularly with longer time intervals. Increasing age, high body mass index, prior microfracture, and traumatic etiology were predictors for inferior outcomes in the scaffold group.ConclusionsActivity level and MRI appearance following treatment of cartilage lesions with the biphasic synthetic scaffold were superior to microfracture over time in this nonrandomized, retrospective comparison.

BackgroundIndividuals who are unsheltered or experiencing homelessness are more likely to smoke than those in the general population and have a higher prevalence of tobacco-related illnesses. Those who are unhoused make quit attempts at rates similar to the general population, however rates of successful quitting are much lower. Women bear a higher burden of smoking-related diseases and are less successful in their cessation efforts than men. Despite these increased risks and challenges, cessation programs specifically designed to meet the needs of women experiencing homelessness are extremely rare.MethodsTo examine perceptions of smoking cessation programs among women who are unstably housed, we conducted in-depth, semi-structured interviews with twenty-nine women experiencing homelessness or unstable housing who had histories of tobacco and substance use. Interviews explored the social context of smoking, as well as interest in, barriers to, and facilitators of quitting. We used a grounded theory approach to analyze the transcripts.ResultsParticipants reported a number of structural barriers to cessation. They reported obstacles to participating in existing cessation programs, including chronic stress related to experiences of being unsheltered and fear of being exposed to neighborhood violence. These conditions were paired with a strong need to self-isolate in order to maintain personal safety, which runs counter to traditional group-based cessation programs.ConclusionA dissonance exists between current smoking cessation programs and the needs of women who are unsheltered or unstably housed. Alternative cessation treatment delivery models that address extremely high levels of chronic stress violence, and avoidance of group settings are needed, as are programs that provide options for safe participation.

Hepatic failure is an important risk factor for poor outcome in septic patients. Using a chemical tagging workflow and high-resolution mass spectrometry, we demonstrate that rapid proteome remodeling of the vascular surfaces precedes hepatic damage in a murine model of Staphylococcus aureus sepsis. These early changes include vascular deposition of neutrophil-derived proteins, shedding of vascular receptors, and altered levels of heparin/heparan sulfate-binding factors. Modification of endothelial heparan sulfate, a major component of the vascular glycocalyx, diminishes neutrophil trafficking to the liver and reduces hepatic coagulopathy and organ damage during the systemic inflammatory response to infection. Modifying endothelial heparan sulfate likewise reduces neutrophil trafficking in sterile hepatic injury, reflecting a more general role of heparan sulfate contribution to the modulation of leukocyte behavior during inflammation. IMPORTANCE Vascular glycocalyx remodeling is critical to sepsis pathology, but the glycocalyx components that contribute to this process remain poorly characterized. This article shows that during Staphylococcus aureus sepsis, the liver vascular glycocalyx undergoes dramatic changes in protein composition associated with neutrophilic activity and heparin/heparan sulfate binding, all before organ damage is detectable by standard circulating liver damage markers or histology. Targeted manipulation of endothelial heparan sulfate modulates S. aureus sepsis-induced hepatotoxicity by controlling the magnitude of neutrophilic infiltration into the liver in both nonsterile and sterile injury. These data identify an important vascular glycocalyx component that impacts hepatic failure during nonsterile and sterile injury.

AbstractThe COVID-19 pandemic disrupted almost all sectors of academic training and research, but the impact on human immunodeficiency virus (HIV) research mentoring has yet to be documented. We present the perspectives of diverse, experienced mentors in a range of HIV research disciplines on the impact of COVID-19 on mentoring the next generation of HIV researchers.In November to December, 2020, we used an online data collection platform to cross-sectionally query previously-trained HIV mentors on the challenges related to mentoring during the pandemic, surprising/positive aspects of mentoring in that context, and recommendations for other mentors. Data were coded and analyzed following a thematic analysis approach.Respondents (180 of 225 mentors invited [80% response]) reported challenges related to relationship building/maintenance, disruptions in mentees' training and research progress, and mentee and mentor distress, with particular concerns regarding mentees who are parents or from underrepresented minority backgrounds. Positive/surprising aspects included logistical ease of remote mentoring, the relationship-edifying result of the shared pandemic experience, mentee resilience and gratitude, and increased enjoyment of mentoring. Recommendations included practical tips, encouragement for patience and persistence, and prioritizing supporting mentees' and one's own mental well-being.Findings revealed gaps in HIV mentors' competencies, including the effective use of remote mentoring tools, how to work with mentees in times of distress, and the prioritization of mentor well-being. Mentors are in a unique position to identify and potentially address factors that may lead to mentees leaving their fields, especially parents and those from underrepresented backgrounds. We discuss implications beyond the COVID-19 pandemic.

ObjectiveTo identify preoperative imaging-based indicators of knee degeneration that correlate with graft failure risk and postoperative clinical outcome scores after osteochondral graft treatment for chondral defects of the knee.DesignProspectively collected data from 113 patients (mean age, 34 years; 65% male) treated with mosaicplasty or osteochondral allograft transplantation (OCA) was reviewed. Four different aspects of knee degeneration were examined based on preoperative radiographs or magnetic resonance imaging: (1) Osteoarthritis using the Kellgren-Lawrence (KL) grading system, (2) meniscus volume, (3) meniscus quality, and (4) synovitis. Primary outcomes included graft failure, defined by removal/revision of the graft or conversion to arthroplasty, and patient responses to clinical outcome scores.ResultsForty-one knees (36%) underwent mosaicplasty, and 72 knees (64%) underwent OCA. Mean duration of follow-up was 4.5 years (range, 2-14 years). A preoperative KL grade of ≥3 was correlated with increased failure rates (P = 0.01), lower postoperative International Knee Documentation Committee form (IKDC), Activities of Daily Living of the Knee Outcome Survey (KOS-ADL), and Overall Condition scores (P < 0.01), and decreased improvement in Overall Condition scores (P = 0.01). Within an individual tibiofemoral compartment, a preoperative meniscus volume grade of ≥3 (indicating

Despite increased awareness of the lack of gender equity in academia and a growing number of initiatives to address issues of diversity, change is slow, and inequalities remain. A major source of inequity is gender bias, which has a substantial negative impact on the careers, work-life balance, and mental health of underrepresented groups in science. Here, we argue that gender bias is not a single problem but manifests as a collection of distinct issues that impact researchers' lives. We disentangle these facets and propose concrete solutions that can be adopted by individuals, academic institutions, and society.

BackgroundThe appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy.MethodsUsing an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis.ResultsA total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]).ConclusionsIn this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

Secreted polypeptides are a fundamental axis of intercellular and endocrine communication. However, a global understanding of the composition and dynamics of cellular secretomes in intact mammalian organisms has been lacking. Here, we introduce a proximity biotinylation strategy that enables labeling, detection and enrichment of secreted polypeptides in a cell type-selective manner in mice. We generate a proteomic atlas of hepatocyte, myocyte, pericyte and myeloid cell secretomes by direct purification of biotinylated secreted proteins from blood plasma. Our secretome dataset validates known cell type-protein pairs, reveals secreted polypeptides that distinguish between cell types and identifies new cellular sources for classical plasma proteins. Lastly, we uncover a dynamic and previously undescribed nutrient-dependent reprogramming of the hepatocyte secretome characterized by the increased unconventional secretion of the cytosolic enzyme betaine-homocysteine S-methyltransferase (BHMT). This secretome profiling strategy enables dynamic and cell type-specific dissection of the plasma proteome and the secreted polypeptides that mediate intercellular signaling.

ObjectiveRetirement is a potential trigger for cognitive aging as it may be a stressful life event accompanied by changes in everyday activities. However, the consequences of retirement may differ across institutional contexts which shape retirement options. Comparing memory trajectories before and after retirement in 17 European countries, this study aims to identify cross-national differences in the association between retirement and memory decline.MethodRespondents to the longitudinal Survey of Health, Aging, and Retirement in Europe (SHARE; N = 8,646) aged 50+ who were in paid work at baseline and retired during the observation period completed up to 6 memory assessments (immediate and delayed word recall) over 13 years. Three-level (time points, individuals, and countries) linear mixed models with country-level random slopes for retirement were estimated to evaluate whether memory decline accelerated after retirement and if this association differed between countries.ResultsOn average, retirement was associated with a moderate decrement in word recall (b = -0.273, 95% CI -0.441, -0.104) and memory decline accelerated after retirement (b = -0.044, 95% CI -0.070, -0.018). Significant between-country heterogeneity in memory decline after retirement existed (variance = 0.047, 95% CI (0.013, 0.168). Memory decline after retirement was more rapid in Italy, Greece, Czech Republic, Poland, Portugal, and Estonia compared to Northern and Central European countries.DiscussionMemory decline postretirement was faster in Mediterranean and eastern European countries, which are characterized by less generous welfare systems with comparatively low pension benefits. Evaluation of resources that could protect retirees from memory decline would be valuable.

The majority of research on the physiological effects of dietary resistant starch type 2 (RS2) has focused on sources derived from high-amylose maize. In this study, we conduct a double-blind, randomized, placebo-controlled, crossover trial investigating the effects of RS2 from wheat on glycemic response, an important indicator of metabolic health, and the gut microbiota. Overall, consumption of RS2-enriched wheat rolls for one week resulted in reduced postprandial glucose and insulin responses relative to conventional wheat when participants were provided with a standard breakfast meal containing the respective treatment rolls (RS2-enriched or conventional wheat). This was accompanied by an increase in the proportions of bacterial taxa Ruminococcus and Gemmiger in the fecal contents, reflecting the composition in the distal intestine. Additionally, fasting breath hydrogen and methane were increased during RS2-enriched wheat consumption. However, although changes in fecal short-chain fatty acid (SCFA) concentrations were not significant between control and RS-enriched wheat roll consumption, butyrate and total SCFAs were positively correlated with relative abundance of Faecalibacterium, Ruminoccocus, Roseburia, and Barnesiellaceae. These effects show that RS2-enriched wheat consumption results in a reduction in postprandial glycemia, altered gut microbial composition, and increased fermentation activity relative to wild-type wheat.

BackgroundThough SARS-CoV-2 outbreaks have been documented in occupational settings and in-person essential work has been suspected as a risk factor for COVID-19, occupational differences in excess mortality have, to date, not been examined. Such information could point to opportunities for intervention, such as vaccine prioritization or regulations to enforce safer work environments.Methods and findingsUsing autoregressive integrated moving average models and California Department of Public Health data representing 356,188 decedents 18-65 years of age who died between January 1, 2016 and November 30, 2020, we estimated pandemic-related excess mortality by occupational sector and occupation, with additional stratification of the sector analysis by race/ethnicity. During these first 9 months of the COVID-19 pandemic, working-age adults experienced 11,628 more deaths than expected, corresponding to 22% relative excess and 46 excess deaths per 100,000 living individuals. Sectors with the highest relative and per-capita excess mortality were food/agriculture (39% relative excess; 75 excess deaths per 100,000), transportation/logistics (31%; 91 per 100,000), manufacturing (24%; 61 per 100,000), and facilities (23%; 83 per 100,000). Across racial and ethnic groups, Latino working-age Californians experienced the highest relative excess mortality (37%) with the highest excess mortality among Latino workers in food and agriculture (59%; 97 per 100,000). Black working-age Californians had the highest per-capita excess mortality (110 per 100,000), with relative excess mortality highest among transportation/logistics workers (36%). Asian working-age Californians had lower excess mortality overall, but notable relative excess mortality among health/emergency workers (37%), while White Californians had high per-capita excess deaths among facilities workers (70 per 100,000).ConclusionsCertain occupational sectors are associated with high excess mortality during the pandemic, particularly among racial and ethnic groups also disproportionately affected by COVID-19. In-person essential work is a likely venue of transmission of coronavirus infection and must be addressed through vaccination and strict enforcement of health orders in workplace settings.

Regular surveillance testing of asymptomatic individuals for SARS-CoV-2 has been center to SARS-CoV-2 outbreak prevention on college and university campuses. Here we describe the voluntary saliva testing program instituted at the University of California, Berkeley during an early period of the SARS-CoV-2 pandemic in 2020. The program was administered as a research study ahead of clinical implementation, enabling us to launch surveillance testing while continuing to optimize the assay. Results of both the testing protocol itself and the study participants' experience show how the program succeeded in providing routine, robust testing capable of contributing to outbreak prevention within a campus community and offer strategies for encouraging participation and a sense of civic responsibility.

Diabetes mellitus (DM) is associated with a dysfunctional intestinal barrier and an increased risk for systemic infection and inflammation in people, though the pathogenic mechanisms leading to this are poorly understood. Using a canine model of DM, we showed that the peroxisomal proliferator-activated receptor-α agonist fenofibrate modulates plasma lipid profiles and markers of intestinal barrier function. A 3-week course of fenofibrate reduced fasting interstitial glucose and inflammatory cytokine IL-8 and TNF-α concentrations, which correlated with reduced triglyceride levels. The lipidomic profile exhibited significantly lower levels of triacylglycerols, phosphatidylethanolamines, diacylglycerols, and ceramides following fenofibrate administration. On histopathological analysis, we observed an aberrant amount of intraepithelial CD3+ T lymphocytes (IEL) in the small intestine of dogs with spontaneous and induced-DM. Fenofibrate reduced IEL density in the duodenum of dogs with DM and enhanced markers of intestinal barrier function in vivo and in vitro. There were minimal changes in the intestinal microbial composition following fenofibrate administration, suggesting that repair of intestinal barriers can be achieved independently of the resident microbiota. Our findings indicate that lipid metabolism is critical to functionality of the intestinal epithelium, which can be rescued by PPARα activation in dogs with DM.

The earliest and most prevalent sensory experience includes tactile, thermal, and olfactory stimulation delivered to the young via contact with the mother, and in some mammals, the father. Prairie voles (Microtus ochrogaster), like humans, are biparental and serve as a model for understanding the impact of parent/offspring interactions on the developing brain. Prairie voles also exhibit natural variation in the level of tactile stimulation delivered by the parents to the offspring, and this has been well documented and quantified. Previous studies revealed that adult prairie vole offspring who received either high (HC) or low (LC) tactile contact from their parents have differences in the size of cortical fields and the connections of somatosensory cortex. In the current investigation, we examined gene expression, intraneocortical connectivity, and cortical thickness in newborn voles to appreciate when differences in HC and LC offspring begin to emerge. We observed differences in developmentally regulated genes, as well as variation in prelimbic and anterior cingulate cortical thickness at postnatal Day 1 (P1) in HC and LC voles. Results from this study suggest that parenting styles, such as those involving high or low physical contact, impact the developing neocortex via very early sensory experience as well as differences in epigenetic modifications that may emerge in HC and LC voles.

Background: The aim of this study was to quantify the stabilizing properties of a 3-dimensional (3D)-printed short-arm cast and compare those properties with traditional fiberglass casts in a cadaveric subacute distal radius fracture model. Methods: A cadaveric subacute fracture model was created in 8 pairs of forearms. The specimens were equally allocated to a fiberglass cast or 3D-printed cast group. All specimens were subjected to 3 biomechanical testing modalities simulating daily life use: flexion and extension of digits, pronation and supination of the hand, and 3-point bending. Between each loading modality, radiological evaluation of the specimens was performed to evaluate possible interval displacement. Interfragmentary motion was quantified using a 3D motion-tracking system. Results: Radiographic assessment did not reveal statistically significant differences in radiographic parameters between the 2 groups before and after biomechanical testing. A statistically significant difference in interfragmentary motion was calculated with the 3-point bending test, with a mean difference of 0.44 (±0.48) mm of motion. Conclusions: A statistically significant difference in interfragmentary motion between the 2 casting groups was only identified in 3-point bending. However, the clinical relevance of this motion remains unclear as the absolute motion is less than 1 mm. The results of this study show noninferiority of the 3D-printed casts compared with the traditional fiberglass casts in immobilizing a subacute distal radius fracture model. These results support the execution of a prospective randomized clinical trial comparing both casting techniques.

PurposePembrolizumab improved survival in patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this study were to determine if pembrolizumab would be safe, result in pathologic tumor response (pTR), and lower the relapse rate in patients with resectable human papillomavirus (HPV)-unrelated HNSCC.Patients and methodsNeoadjuvant pembrolizumab (200 mg) was administered and followed 2 to 3 weeks later by surgical tumor ablation. Postoperative (chemo)radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) received adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (

Central nervous system B cells have several potential roles in multiple sclerosis (MS): secretors of proinflammatory cytokines and chemokines, presenters of autoantigens to T cells, producers of pathogenic antibodies, and reservoirs for viruses that trigger demyelination. To interrogate these roles, single-cell RNA sequencing (scRNA-Seq) was performed on paired cerebrospinal fluid (CSF) and blood from subjects with relapsing-remitting MS (RRMS; n = 12), other neurologic diseases (ONDs; n = 1), and healthy controls (HCs; n = 3). Single-cell immunoglobulin sequencing (scIg-Seq) was performed on a subset of these subjects and additional RRMS (n = 4), clinically isolated syndrome (n = 2), and OND (n = 2) subjects. Further, paired CSF and blood B cell subsets (RRMS; n = 7) were isolated using fluorescence activated cell sorting for bulk RNA sequencing (RNA-Seq). Independent analyses across technologies demonstrated that nuclear factor kappa B (NF-κB) and cholesterol biosynthesis pathways were activated, and specific cytokine and chemokine receptors were up-regulated in CSF memory B cells. Further, SMAD/TGF-β1 signaling was down-regulated in CSF plasmablasts/plasma cells. Clonally expanded, somatically hypermutated IgM+ and IgG1+ CSF B cells were associated with inflammation, blood-brain barrier breakdown, and intrathecal Ig synthesis. While we identified memory B cells and plasmablast/plasma cells with highly similar Ig heavy-chain sequences across MS subjects, similarities were also identified with ONDs and HCs. No viral transcripts, including from Epstein-Barr virus, were detected. Our findings support the hypothesis that in MS, CSF B cells are driven to an inflammatory and clonally expanded memory and plasmablast/plasma cell phenotype.

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction.

Previous studies measuring the health-related quality of life (HRQoL) of individuals with dengue focused on treatment seeking populations. However, the vast majority of global dengue cases are unlikely to be detected by health systems. Representative measurements of HRQoL should therefore include patients with disease not likely to trigger treatment-seeking behavior. This study based in Iquitos, Peru used the Quality of Wellbeing Scale-Self Administered, a survey that enquires about not only physical health, but also psychological health, self-care, mobility, and usual social activities, and rates HRQoL between 0 (death) and 1 (optimum function), to evaluate the impact of dengue on HRQoL. In order to enroll treatment and non treatment-seeking participants, three modalities of participant recruitment were used. In addition to clinic and community-based febrile surveillance, a contact-cluster methodology was also employed to identify infected individuals less likely to seek treatment. We measured changes in HRQoL and identified common areas of health impairment in 73 virologically confirmed dengue cases at 3 time points during the participant's illness; the early-acute (days 0-6 post symptom onset), late-acute (days 7-20), and convalescent illness phases (days 21 +). Participants reported HRQoL related impairments at significantly higher frequency during the early-acute versus convalescent illness phase (Fisher's exact: P

BackgroundAtrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described.MethodsWe assessed factors associated with a 1-year increase in the Atrial Fibrillation Effect on Quality-of-Life score of 1 SD (≥18 points; 3× clinically important difference), among outpatients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation I registry.ResultsOverall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 versus 74, P=0.3), equally likely to be female (44% versus 48%, P=0.3), but more likely to have newly diagnosed AF at baseline (18% versus 8%; P=0.0004), prior antiarrhythmic drug use (52% versus 40%, P=0.005), baseline antiarrhythmic drug use (34.8% versus 26.8%, P=0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% versus 2.0%, P=0.003; cardioversion: 12.2% versus 5.9%, P=0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR, 2.41; P=0.01) and increased baseline diastolic blood pressure (adjusted OR, 1.23 per 10-point increase and >65 mm Hg; P=0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/transient ischemic attack, chronic obstructive pulmonary disease, and peripheral arterial disease were less likely to improve (P

BackgroundBenzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups.MethodsIn this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group (65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075.FindingsBetween Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group.InterpretationChildren, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus.FundingNational Institute of Neurological Disorders and Stroke, National Institutes of Health.

ObjectiveTo advance the science of cognitive outcome measurement for individuals with intellectual disability (ID), we established administration guidelines and evaluated the psychometric properties of the NIH-Toolbox Cognitive Battery (NIHTB-CB) for use in clinical research.MethodsWe assessed feasibility, test-retest reliability, and convergent validity of the NIHTB-CB (measuring executive function, processing speed, memory, and language) by assessing 242 individuals with fragile X syndrome (FXS), Down syndrome (DS), and other ID, ages 6 through 25 years, with retesting completed after 1 month. To facilitate accessibility and measurement accuracy, we developed accommodations and standard assessment guidelines, documented in an e-manual. Finally, we assessed the sensitivity of the battery to expected syndrome-specific cognitive phenotypes.ResultsAbove a mental age of 5.0 years, all tests had excellent feasibility. More varied feasibility across tests was seen between mental ages of 3 and 4 years. Reliability and convergent validity ranged from moderate to strong. Each test and the Crystallized and Fluid Composite scores correlated moderately to strongly with IQ, and the Crystallized Composite had modest correlations with adaptive behavior. The NIHTB-CB showed known-groups validity by detecting expected executive function deficits in FXS and a receptive language deficit in DS.ConclusionThe NIHTB-CB is a reliable and valid test battery for children and young adults with ID with a mental age of ≈5 years and above. Adaptations for very low-functioning or younger children with ID are needed for some subtests to expand the developmental range of the battery. Studies examining sensitivity to developmental and treatment changes are now warranted.

Background Patients with Eisenmenger syndrome are known to have a high incidence of sudden cardiac death (SCD), yet the underlying causes are not well understood. We sought to define the predictors of SCD in this population. Methods and Results A retrospective analysis of all patients with Eisenmenger syndrome from 2 large tertiary referral centers was performed. ECGs, prolonged ambulatory recordings, echocardiograms, and clinical histories were reviewed; and the cause of death was identified. A total of 246 patients (85 [34.6%] men) with a mean age of 37.3 (±14.2) years were followed up for a median of 7 years. Over the study period, 136 patients died, with 40 experiencing SCD and 74 experiencing cardiac death (sudden and nonsudden). Age, atrial fibrillation, prolonged QRS duration, complete heart block, right atrial enlargement, right bundle branch block, increased right atrial pressure, impaired biventricular function, and the presence of a pacemaker were associated with increased risk of SCD, whereas advanced pulmonary hypertension therapies were protective. Atrial fibrillation (11.45-fold increased risk; P

BackgroundNitric oxide (NO) plays an important role in normal postnatal transition. Our aims were to determine whether adding inhaled NO (iNO) decreases supplemental oxygen exposure in preterm infants requiring positive pressure ventilation (PPV) during resuscitation and to study iNO effects on heart rate (HR), oxygen saturation (SpO2), and need for intubation during the first 20 min of life.MethodsThis was a pilot, double-blind, randomized, placebo-controlled trial. Infants 25 0/7-31 6/7 weeks' gestational age requiring PPV with supplemental oxygen during resuscitation were enrolled. PPV was initiated with either oxygen (FiO2-0.30) + iNO at 20 ppm (iNO group) or oxygen (FiO2-0.30) + nitrogen (placebo group). Oxygen was titrated targeting defined SpO2 per current guidelines. After 10 min, iNO/nitrogen was weaned stepwise per protocol and terminated at 17 min.ResultsTwenty-eight infants were studied (14 per group). The mean gestational age in both groups was similar. Cumulative FiO2 and rate of exposure to high FiO2 (>0.60) were significantly lower in the iNO group. There were no differences in HR, SpO2, and need for intubation.ConclusionsAdministration of iNO as an adjunct during neonatal resuscitation is feasible without side effects. It diminishes exposure to high levels of supplemental oxygen.

BackgroundClinical research in Parkinson's disease (PD) faces practical and ethical challenges due to two interrelated problems: participant under-recruitment and lack of diversity. Fox Insight (FI) is a web-based longitudinal study collecting patient-reported outcomes and genetic data worldwide to inform therapeutic studies. FI's online platform provides an opportunity to evaluate online strategies for recruiting large, diverse research cohorts.ObjectiveThis project aimed to determine 1) whether FI's digital marketing was associated with increased enrollment overall and from under-represented patient groups, compared to traditional recruitment methods; 2) the clinical and demographic characteristics of samples recruited online, and 3) the cost of this online recruitment.MethodFI recruitment during a 6-week baseline period without digital promotion was compared to recruitment during several periods of digital outreach. Separate online recruiting intervals included general online study promotion and unique Facebook and Google ad campaigns targeting under-represented subgroups: early PD, late/advanced PD, and residents of underrepresented/rural geographic areas.ResultsEarly PD, late PD, and geotargeting campaigns enrolled more individuals in their respective cohorts compared to baseline. All online campaigns also yielded greater total FI enrollment, attracting more participants who were non-White, Hispanic, older, female, and had lower educational attainment and income, and more medical comorbidities. Cost per new participant ranged from $21 (Facebook) to $108 (Google).ConclusionDigital marketing may allow researchers to increase, accelerate, and diversify recruitment for PD clinical studies, by tailoring digital ads to target PD cohort characteristics.

An unhealthy gut microbial community may act as a barrier to improvement in growth and health outcomes in response to nutritional interventions. The objective of this analysis was to determine whether the infant microbiota modified the effects of a randomized controlled trial of lipid-based nutrient supplements (LNS) in Malawi on growth and inflammation at 12 and 18 months, respectively. We characterized baseline microbiota composition of fecal samples at 6 months of age (n = 506, prior to infant supplementation, which extended to 18 months) using 16S rRNA gene sequencing of the V4 region. Features of the gut microbiota previously identified as being involved in fatty acid or micronutrient metabolism or in outcomes relating to growth and inflammation, especially in children, were investigated. Prior to correction for multiple hypothesis testing, the effects of LNS on growth appeared to be modified by Clostridium (p-for-interaction = 0.02), Ruminococcus (p-for-interaction = 0.007), and Firmicutes (p-for-interaction = 0.04) and effects on inflammation appeared to be modified by Faecalibacterium (p-for-interaction = 0.03) and Streptococcus (p-for-interaction = 0.004). However, after correction for multiple hypothesis testing these findings were not statistically significant, suggesting that the gut microbiota did not alter the effect of LNS on infant growth and inflammation in this cohort.

BackgroundOnline tools for data collection could be of value in patient-oriented research. The Fox Insight (FI) study collects data online from individuals with self-reported Parkinson's disease (PD). Comparing the FI cohort to other cohorts assessed through more traditional (in-person) observational research studies would inform the representativeness and utility of FI data.ObjectiveTo compare self-reported demographic characteristics, symptoms, medical history, and PD medication use of the FI PD cohort to other recent observational research study cohorts assessed with in-person visits.MethodsThe FI PD cohort (n = 12,654) was compared to 3 other cohorts, selected based on data accessibility and breadth of assessments: Parkinson's Progression Markers Initiative (PPMI; PD n = 422), Parkinson's Disease Biomarker Program (PDBP; n = 700), and PD participants in the LRRK2 consortium without LRRK2 mutations (n = 508). Demographics, motor and non-motor assessments, and medications were compared across cohorts. Where available, identical items on surveys and assessments were compared; otherwise, expert opinion was used to determine comparable definitions for a given variable.ResultsThe proportion of females was significantly higher in FI (45.56%) compared to PPMI (34.36%) and PDBP (35.71%). The FI cohort had greater educational attainment as compared to all other cohorts. Overall, prevalence of difficulties with motor experiences of daily living and non-motor symptoms in the FI cohort was similar to other cohorts, with only a few significant differences that were generally small in magnitude. Missing data were rare for the FI cohort, except on a few variables.DiscussionPatterns of responses to patient-reported assessments obtained online on the PD cohort of the FI study were similar to PD cohorts assessed in-person.

BackgroundWell-tolerated, highly effective HCV treatment, known as direct-acting antivirals (DAAs), is now recommended for all people living with HCV, providing the tools for HCV elimination. We sought to understand treatment barriers among low-income HIV/HCV coinfected patients and providers with the goal of increasing uptake.MethodsIn 2014, we conducted 26 interviews with HIV/HCV co-infected patients and providers from a San Francisco clinic serving underinsured and publically-insured persons to explore barriers impacting treatment engagement and completion. Interview transcripts were coded, and a thematic analysis was conducted to identify emerging patterns.ResultsConditions of poverty-specifically, meeting basic needs for food, shelter, and safety-undermined patient perceptions of self-efficacy to successfully complete HCV treatment programs. While patient participants expressed interest in HCV treatment, the perceived burden of taking daily medications without strong social support was an added challenge. This need for support contradicted provider assumptions that, due to the shorter-course regimens, support is unnecessary in the DAA era.ConclusionsInterferon-free treatments alone are not sufficient to overcome social-structural barriers to HCV treatment and care among low-income HIV/HCV co-infected patients. Support for patients with unmet social needs may facilitate treatment initiation and completion, particularly among those in challenging socioeconomic situations.

The gut microbiota regulates levels of serotonin (5-hydroxytryptamine (5-HT)) in the intestinal epithelium and lumen1-5. However, whether 5-HT plays a functional role in bacteria from the gut microbiota remains unknown. We demonstrate that elevating levels of intestinal lumenal 5-HT by oral supplementation or genetic deficiency in the host 5-HT transporter (SERT) increases the relative abundance of spore-forming members of the gut microbiota, which were previously reported to promote host 5-HT biosynthesis. Within this microbial community, we identify Turicibacter sanguinis as a gut bacterium that expresses a neurotransmitter sodium symporter-related protein with sequence and structural homology to mammalian SERT. T. sanguinis imports 5-HT through a mechanism that is inhibited by the selective 5-HT reuptake inhibitor fluoxetine. 5-HT reduces the expression of sporulation factors and membrane transporters in T. sanguinis, which is reversed by fluoxetine exposure. Treating T. sanguinis with 5-HT or fluoxetine modulates its competitive colonization in the gastrointestinal tract of antibiotic-treated mice. In addition, fluoxetine reduces the membership of T. sanguinis in the gut microbiota of conventionally colonized mice. Host association with T. sanguinis alters intestinal expression of multiple gene pathways, including those important for lipid and steroid metabolism, with corresponding reductions in host systemic triglyceride levels and inguinal adipocyte size. Together, these findings support the notion that select bacteria indigenous to the gut microbiota signal bidirectionally with the host serotonergic system to promote their fitness in the intestine.

BackgroundStaphylococcus aureus and beta-hemolytic streptococci (BHS) diseases disproportionately affect populations in middle/low-income countries. To assess if this disparity is reflected in colonization by these organisms, we compared their colonization frequency among children from different socioeconomic status (SES) communities in a city with high income inequality.MethodsBetween May-August 2014, we collected nasal and throat swabs to investigate S. aureus and BHS colonization among children who attended private and public pediatric clinics. Patients were classified as high SES, middle/low SES, and slum residents. We investigated the antimicrobial resistance profile, the SCCmec types and the presence of PVL genes among methicillin-resistant S. aureus (MRSA). We also examined the antimicrobial resistance profile and serogroups of BHS.ResultsOf 598 children, 221 (37%) were colonized with S. aureus, of which 49 (22%) were MRSA. MRSA colonization was higher in middle/low SES (n = 18; 14%) compared with high SES (n = 17; 6%) and slum (n = 14; 8%) residents (p = 0.01). All MRSA strains were susceptible to clindamycin, nitrofurantoin, and rifampin. The highest non-susceptibility frequency (42.9%) was observed to erythromycin. SCCmec type V was only found in isolates from high SES children; types I and II were found only in middle/low SES children. Ten (20%) MRSA isolates carried PVL genes. Twenty-four (4%) children were BHS carriers. All BHS (n = 8) found in high SES children and six (67%) isolates from slum patients belonged to group A. All group B streptococci were from middle/low SES children, corresponding to five (71%) of the seven BHS isolated in this group. BHS isolates were susceptible to all drugs tested.ConclusionsChildren from different SES communities had distinct bacterial colonization profiles, including MRSA carriage. Public health officials/researchers should consider SES when assessing disease transmission and control measures.

HIV/HCV coinfected patients are a priority for direct acting antiretroviral (DAA) treatment, yet barriers to treating vulnerable patients persist. This study surveyed safety net clinic patients and providers to quantify their preferences for DAA treatment and prioritize modifiable barriers. Preferences were assessed using best-worst scaling. General linear mixed models were used to determine whether attributes differed in importance and whether patients and providers valued attributes differently. 158 HIV/HCV coinfected patients and 49 providers participated. Patients and providers had strong preferences for treatment within the medical homes where patients receive HIV care. Support such as reminders and advice numbers were also important, but were more important to providers than patients. Providers identified lack of insurance coverage for DAA as the most significant barrier. Providers rated HIV primary care providers as best suited to deliver DAA to HIV+ patients. Addressing structural barriers is essential for increasing DAA treatment in safety net settings.

BACKGROUND: Single room occupancy (SRO) buildings, also known as residential hotels, are a form of affordable housing common to cities in North America, and residents of these buildings face elevated rates of substance use, physical and mental multimorbidity, and mortality. Identifying distinct populations at greater risk of overdose death is crucial to the planning of interventions aiming to reduce drug-related mortality, yet no studies have assessed the population burden of overdose mortality among SRO residents. The present study quantifies and characterizes drug overdose mortality among residents of SRO buildings in a large U.S. city. METHODS: We used mortality records and a database of SRO buildings to calculate rate ratios comparing overdose mortality due to opioids, cocaine, and methamphetamine among SRO residents and non-SRO residents in San Francisco, CA 2010-2017 and assessed bivariate differences in decedent and death location characteristics between SRO resident and other overdose decedents. RESULTS: There were 1,551 overdose deaths during the study period, with an overall rate of 21.3 per 100,000 residents (95%CI = 20.2-22.6). The rate among SRO residents (278.7, 95%CI = 252.9-306.5) was 19.3 (95%CI = 17.1-21.7) times that of non-SRO residents (21.3, 95%CI = 20.2-22.6). An additional 79 (5%) deaths among non-residents occurred in SRO buildings, and 86% of SRO resident decedents died at home compared to 64% of non-SRO residents (p

Since 2012, the United States of America has experienced a biennial spike in pediatric acute flaccid myelitis (AFM)1-6. Epidemiologic evidence suggests non-polio enteroviruses (EVs) are a potential etiology, yet EV RNA is rarely detected in cerebrospinal fluid (CSF)2. CSF from children with AFM (n = 42) and other pediatric neurologic disease controls (n = 58) were investigated for intrathecal antiviral antibodies, using a phage display library expressing 481,966 overlapping peptides derived from all known vertebrate and arboviruses (VirScan). Metagenomic next-generation sequencing (mNGS) of AFM CSF RNA (n = 20 cases) was also performed, both unbiased sequencing and with targeted enrichment for EVs. Using VirScan, the viral family significantly enriched by the CSF of AFM cases relative to controls was Picornaviridae, with the most enriched Picornaviridae peptides belonging to the genus Enterovirus (n = 29/42 cases versus 4/58 controls). EV VP1 ELISA confirmed this finding (n = 22/26 cases versus 7/50 controls). mNGS did not detect additional EV RNA. Despite rare detection of EV RNA, pan-viral serology frequently identified high levels of CSF EV-specific antibodies in AFM compared with controls, providing further evidence for a causal role of non-polio EVs in AFM.

INTRODUCTION:Delamination of the chondral surface of an osteochondral allograft (OCA) from the underlying cancellous bone has been described as a mode of failure after implantation in the knee. Our hypothesis was that increased storage time of the OCA is associated with increased risk of graft delamination after implantation. METHODS:Prospective data on 13 patients with evidence of OCA delamination identified on magnetic resonance imaging or during subsequent surgery from 2000 to 2015 were reviewed. A cohort of 33 patients without evidence of graft delamination were then matched to the delamination group based on recipient age, sex, body mass index (BMI), and chondral defect location. The matched cohort size was established based on a power calculation for determining differences in OCA storage times. All patients had a minimum 2-year follow-up. RESULTS:There was no difference in donor age, donor sex, and graft storage time between groups (30 vs. 31 days, P = 0.78). There were no differences between number of previous ipsilateral knee surgeries (1.8 vs. 0.84, P = 0.26), BMI (26.8 vs. 25.0 kg/m2, P = 0.31), total chondral defect size (6.5 vs. 5.8 cm2, P = 0.41) or preoperative Marx activity scores between groups. CONCLUSION:There is no association between OCA storage time, activity level scores, or number of previous ipsilateral knee surgeries and graft delamination in our patient population. Further work is needed to identify the etiology for this mode of failure of OCAs.

The Toxicology Investigators Consortium (ToxIC) Registry was established by the American College of Medical Toxicology (ACMT) in 2010. The Registry collects data from participating sites with the agreement that all bedside medical toxicology consultation will be entered. The objective of this ninth annual report is to summarize the Registry's 2018 data and activity with its additional 7043 cases. Cases were identified for inclusion in this report by a query of the ToxIC database for any case entered from 1 January to 31 December 2018. Detailed data was collected from these cases and aggregated to provide information which included demographics, reason for medical toxicology evaluation, agent and agent class, clinical signs and symptoms, treatments and antidotes administered, mortality, and whether life support was withdrawn. A total of 51.5% of cases were female, 48% were male, and 0.6% transgender. Non-opioid analgesics were the most commonly reported agent class, followed by antidepressants and opioids. Acetaminophen was once again the most common agent reported. There were 106 fatalities, comprising 1.5% of all registry cases. Major trends in demographics and exposure characteristics remained similar to past years' reports. Sub-analyses were conducted to describe exposures in elderly patients, addiction consultation practices, and risk factors for bupropion-induced seizures. The launch of the ToxIC Qualified Clinical Data Registry (TQCDR) is also described.

BackgroundWe have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (PAE). Results of the present study provided some support for this hypothesis.MethodsWe conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from 3 separate cohorts of patients: (i) pregnant women who consumed moderate-to-high levels of alcohol or low/unexposed controls, (ii) children with PAE and non-alcohol-exposed controls, and (iii) children with PAE treated with or without choline.ResultsWe found pregnant women who consumed moderate-to-high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone. Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE.ConclusionsThese data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.

Background. Proprioception of fingers is essential for motor control. Reduced proprioception is common after stroke and is associated with longer hospitalization and reduced quality of life. Neural correlates of proprioception deficits after stroke remain incompletely understood, partly because of weaknesses of clinical proprioception assessments. Objective. To examine the neural basis of finger proprioception deficits after stroke. We hypothesized that a model incorporating both neural injury and neural function of the somatosensory system is necessary for delineating proprioception deficits poststroke. Methods. Finger proprioception was measured using a robot in 27 individuals with chronic unilateral stroke; measures of neural injury (damage to gray and white matter, including corticospinal and thalamocortical sensory tracts), neural function (activation of and connectivity of cortical sensorimotor areas), and clinical status (demographics and behavioral measures) were also assessed. Results. Impairment in finger proprioception was present contralesionally in 67% and bilaterally in 56%. Robotic measures of proprioception deficits were more sensitive than standard scales and were specific to proprioception. Multivariable modeling found that contralesional proprioception deficits were best explained (r2 = 0.63; P = .0006) by a combination of neural function (connectivity between ipsilesional secondary somatosensory cortex and ipsilesional primary motor cortex) and neural injury (total sensory system injury). Conclusions. Impairment of finger proprioception occurs frequently after stroke and is best measured using a quantitative device such as a robot. A model containing a measure of neural function plus a measure of neural injury best explained proprioception performance. These measurements might be useful in the development of novel neurorehabilitation therapies.

IntroductionHDL is associated with increased longevity and protection from multiple chronic diseases. The major HDL protein ApoA-I has a half-life of about 4 days, however, the effects of diet on the composition of HDL particles at this time scale have not been studied.ObjectivesThe objective of this study is to investigate the short term dietary effect on HDL lipidomic composition.MethodsIn this randomized order cross-over study, ten healthy subjects consumed a Mediterranean (Med) and a fast food (FF) diet for 4 days, with a 4-day wash-out between treatments. Lipidomic composition was analyzed in isolated HDL fractions by an untargeted LC-MS method with 15 internal standards.ResultsHDL phosphatidylethanolamine (PE) content was increased by FF diet, and 41 out of 170 lipid species were differentially affected by diet. Saturated fatty acids (FAs) and odd chain FA were enriched after FF diet, while very-long chain FA and unsaturated FA were enriched after Med diet. The composition of phosphatidylcholine (PC), triacylglycerol (TG) and cholesteryl ester (CE) were significantly altered to reflect the FA composition of the diet whereas the composition of sphingomyelin (SM) and ceramides were generally unaffected.ConclusionResults from this study indicate that the HDL lipidome is widely remodeled within 4 days of diet change and that certain lipid classes are more sensitive markers of diet whereas other lipid classes are better indicators of non-dietary factors.