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OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. METHODS: A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. RESULTS: Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. CONCLUSION: These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations.

Although evidence exists for a causal association between 25-hydroxyvitamin D (25(OH)D) serum levels, and multiple sclerosis (MS), the role of variation in vitamin D receptor (VDR) binding in MS is unknown. Here, we leveraged previously identified variants associated with allele imbalance in VDR binding (VDR-binding variant; VDR-BV) in ChIP-exo data from calcitriol-stimulated lymphoblastoid cell lines and 25(OH)D serum levels from genome-wide association studies to construct genetic instrumental variables (GIVs). GIVs are composed of one or more genetic variants that serve as proxies for exposures of interest. Here, GIVs for both VDR-BVs and 25(OH)D were used in a two-sample Mendelian Randomization study to investigate the relationship between VDR binding at a locus, 25(OH)D serum levels, and MS risk. Data for 13,598 MS cases and 38,887 controls of European ancestry from Kaiser Permanente Northern California, Swedish MS studies, and the UK Biobank were included. We estimated the association between each VDR-BV GIV and MS. Significant interaction between a VDR-BV GIV and a GIV for serum 25OH(D) was evidence for a causal association between VDR-BVs and MS unbiased by pleiotropy. We observed evidence for associations between two VDR-BVs (rs2881514, rs2531804) and MS after correction for multiple tests. There was evidence of interaction between rs2881514 and a 25(OH)D GIV, providing evidence of a causal association between rs2881514 and MS. This study is the first to demonstrate evidence that variation in VDR binding at a locus contributes to MS risk. Our results are relevant to other autoimmune diseases in which vitamin D plays a role.

ObjectiveWe undertook this study to estimate changes in cell-specific DNA methylation (DNAm) associated with methotrexate (MTX) response using whole blood samples collected from rheumatoid arthritis (RA) patients before and after initiation of MTX treatment.MethodsPatients included in this study were from the Rheumatoid Arthritis Medication Study (n = 66) and the University of California San Francisco Rheumatoid Arthritis study (n = 11). All patients met the American College of Rheumatology RA classification criteria. Blood samples were collected at baseline and following treatment. Disease Activity Scores in 28 joints using the C-reactive protein level were collected at baseline and after 3-6 months of treatment with MTX. Methylation profiles were generated using the Illumina Infinium HumanMethylation450 and MethylationEPIC v1.0 BeadChip arrays using DNA from whole blood. MTX response was defined using the EULAR response criteria (responders showed good/moderate response; nonresponders showed no response). Differentially methylated positions were identified using the Limma software package and Tensor Composition Analysis, which is a method for identifying cell-specific differential DNAm at the CpG level from tissue-level ("bulk") data. Differentially methylated regions were identified using Comb-p software.ResultsWe found evidence of differential global methylation between treatment response groups. Further, we found patterns of cell-specific differential global methylation associated with MTX response. After correction for multiple testing, 1 differentially methylated position was associated with differential DNAm between responders and nonresponders at baseline in CD4+ T cells, CD8+ T cells, and natural killer cells. Thirty-nine cell-specific differentially methylated regions associated with MTX treatment response were identified. There were no significant findings in analyses of whole blood samples.ConclusionWe identified cell-specific changes in DNAm that were associated with MTX treatment response in RA patients. Future studies of DNAm and MTX treatment response should include measurements of DNAm from sorted cells.

BackgroundWe previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis.MethodsUsing a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090).Results490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p

BackgroundWe previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure.ObjectivesTo examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86, and HLA-DRB1*15, the strongest genetic variant associated with POMS.MethodsCases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC's Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86, and the presence of DRB1*15:01 (DRB1*15) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother's education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated.ResultsA total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69-3.59 and 1.95, 95% CI: 1.32-2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15, with a RERI of 2.21 (95% CI: 0.83-3.59) and an AP of 0.56 (95% CI: 0.33-0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14-3.06) and an AP of 0.37 (95% CI: 0.001-0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype.ConclusionsIn addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene-environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

Gene therapy offers great promise in addressing neuropathologies associated with the central and peripheral nervous systems (CNS and PNS). However, genetic access remains difficult, reflecting the critical need for the development of effective and non-invasive gene delivery vectors across species. To that end, we evolved adeno-associated virus serotype 9 (AAV9) capsid in mice and validated two capsids, AAV-MaCPNS1 and AAV-MaCPNS2, across rodent species (mice and rats) and non-human primate (NHP) species (marmosets and rhesus macaques). Intravenous administration of either AAV efficiently transduced the PNS in rodents and both the PNS and CNS in NHPs. Furthermore, we used AAV-MaCPNS1 in mice to systemically deliver the following: (1) the neuronal sensor jGCaMP8s to record calcium signal dynamics in nodose ganglia and (2) the neuronal actuator DREADD to dorsal root ganglia to mediate pain. This conclusively demonstrates the translatability of these two systemic AAVs across four species and their functional utility through proof-of-concept studies in mice.

Serological surveillance studies of infectious diseases provide population-level estimates of infection and antibody prevalence, generating crucial insight into population-level immunity, risk factors leading to infection, and effectiveness of public health measures. These studies traditionally rely on detection of pathogen-specific antibodies in samples derived from venipuncture, an expensive and logistically challenging aspect of serological surveillance. During the COVID-19 pandemic, guidelines implemented to prevent the spread of SARS-CoV-2 infection made collection of venous blood logistically difficult at a time when SARS-CoV-2 serosurveillance was urgently needed. Dried blood spots (DBS) have generated interest as an alternative to venous blood for SARS-CoV-2 serological applications due to their stability, low cost, and ease of collection; DBS samples can be self-generated via fingerprick by community members and mailed at ambient temperatures. Here, we detail the development of four DBS-based SARS-CoV-2 serological methods and demonstrate their implementation in a large serological survey of community members from 12 cities in the East Bay region of the San Francisco metropolitan area using at-home DBS collection. We find that DBS perform similarly to plasma/serum in enzyme-linked immunosorbent assays and commercial SARS-CoV-2 serological assays. In addition, we show that DBS samples can reliably detect antibody responses months postinfection and track antibody kinetics after vaccination. Implementation of DBS enabled collection of valuable serological data from our study population to investigate changes in seroprevalence over an 8-month period. Our work makes a strong argument for the implementation of DBS in serological studies, not just for SARS-CoV-2, but any situation where phlebotomy is inaccessible. IMPORTANCE Estimation of community-level antibody responses to SARS-CoV-2 from infection or vaccination is critical to inform public health responses. Traditional studies of antibodies rely on collection of blood via venipuncture, an invasive procedure not amenable to pandemic-related social-distancing measures. Dried blood spots (DBS) are an alternative to venipuncture, since they can be self-collected by study participants at home and do not require refrigeration for shipment or storage. However, DBS-based assays to measure antibody levels to SARS-CoV-2 have not been widely utilized. Here, we show that DBS are comparable to blood as a sampling method for antibody responses to SARS-CoV-2 infection and vaccination over time measured using four distinct serological assays. The DBS format enabled antibody surveillance in a longitudinal cohort where study participants self-collected samples, ensuring the participants' safety during an ongoing pandemic. Our work demonstrates that DBS are an excellent sampling method for measuring antibody responses whenever venipuncture is impractical.

Comprehensive data on transmission mitigation behaviors and both SARS-CoV-2 infection and serostatus are needed from large, community-based cohorts to identify COVID-19 risk factors and the impact of public health measures. We conducted a longitudinal, population-based study in the East Bay Area of Northern California. From July 2020-March 2021, approximately 5,500 adults were recruited and followed over three data collection rounds to investigate the association between geographic and demographic characteristics and transmission mitigation behavior with SARS-CoV-2 prevalence. We estimated the populated-adjusted prevalence of antibodies from SARS-CoV-2 infection and COVID-19 vaccination, and self-reported COVID-19 test positivity. Population-adjusted SARS-CoV-2 seroprevalence was low, increasing from 1.03% (95% CI: 0.50-1.96) in Round 1 (July-September 2020), to 1.37% (95% CI: 0.75-2.39) in Round 2 (October-December 2020), to 2.18% (95% CI: 1.48-3.17) in Round 3 (February-March 2021). Population-adjusted seroprevalence of COVID-19 vaccination was 21.64% (95% CI: 19.20-24.34) in Round 3, with White individuals having 4.35% (95% CI: 0.35-8.32) higher COVID-19 vaccine seroprevalence than individuals identifying as African American or Black, American Indian or Alaskan Native, Asian, Hispanic, two or more races, or other. No evidence for an association between transmission mitigation behavior and seroprevalence was observed. Despite >99% of participants reporting wearing masks individuals identifying as African American or Black, American Indian or Alaskan Native, Asian, Hispanic, two or more races, or other, as well as those in lower-income households, and lower-educated individuals had the highest SARS-CoV-2 seroprevalence and lowest vaccination seroprevalence. Results demonstrate that more effective policies are needed to address these disparities and inequities.

Background: The COVID‐19 pandemic underscored the need for rapid and accurate diagnostic tools. In August 2020, the Abbott BinaxNOW COVID‐19 Antigen Card test became available as a timely and affordable alternative for SARS‐CoV‐2 molecular testing, but its performance may vary due to factors including timing and symptomatology. This study evaluates BinaxNOW diagnostic performance in diverse epidemiological contexts. Methods: Using RT‐PCR as reference, we assessed performance of the BinaxNOW COVID‐19 test for SARS‐CoV‐2 detection in anterior nasal swabs from participants of two studies in Puerto Rico from December 2020 to May 2023. Test performance was assessed by days post symptom onset, collection strategy, vaccination status, symptomatology, repeated testing, and RT‐PCR cycle threshold (Ct) values. Results: BinaxNOW demonstrated an overall sensitivity of 84.1% and specificity of 98.8%. Sensitivity peaked within 1–6 days after symptom onset (93.2%) and was higher for symptomatic (86.3%) than asymptomatic (67.3%) participants. Sensitivity declined over the course of infection, dropping from 96.3% in the initial test to 48.4% in testing performed 7–14 days later. BinaxNOW showed 99.5% sensitivity in participants with low Ct values (≤ 25) but lower sensitivity (18.2%) for participants with higher Cts (36–40). Conclusions: BinaxNOW demonstrated high sensitivity and specificity, particularly in early‐stage infections and symptomatic participants. In situations where test sensitivity is crucial for clinical decision‐making, nucleic acid amplification tests are preferred. These findings highlight the importance of considering clinical and epidemiological context when interpreting test results and emphasize the need for ongoing research to adapt testing strategies to emerging SARS‐CoV‐2 variants. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) is a positive sense RNA virus of the Flaviviridae family, which includes several medically notable arboviruses such as dengue (DENV), yellow fever, Japanese encephalitis virus, and West [...]

The 4 serotypes of dengue virus (DENV1-4) are mosquito-borne flaviviruses that infect humans. Live attenuated tetravalent DENV vaccines are at different phases of clinical testing. DENV vaccine developers have relied on neutralizing antibodies (NAbs) as a correlate of protection. A leading tetravalent vaccine (Dengvaxia) stimulated NAbs to the 4 DENV serotypes, yet overall vaccine efficacy was low in children who were DENV seronegative at baseline before vaccination. We compared the properties of (a) NAbs induced by WT DENV1 or DENV3 infections, which are strongly correlated with protection from repeat infections, and (b) NAbs induced by Dengvaxia in individuals who subsequently experienced DENV1 or DENV3 breakthrough infections. WT infections induced NAbs that recognized epitopes unique (type specific) to each serotype, whereas the vaccine stimulated qualitatively different NAbs that recognized epitopes conserved (crossreactive) between serotypes. Our results indicate that, among children who were DENV-seronegative at baseline, unbalanced replication of the DENV type 4 vaccine component in the tetravalent vaccine stimulates Abs capable of crossneutralizing DENV1 and DENV3 in vitro, but not protecting in vivo. In DENV-seronegative individuals who are vaccinated, we propose that type-specific NAbs are a better correlate of protection than total levels of NAbs., Introduction The 4 dengue virus serotypes (DENV1-4) are mosquito-transmitted flaviviruses estimated to infect over 100 million people every year. (1) DENV infections stimulate neutralizing antibodies (NAbs) that are correlated with [...]

As the green movement grows, studies provide conclusive evidence about the benefits of environmentally conscious practices indoors and outdoors. Schools are no exception. Many of these studies demonstrate how poor indoor air quality (IAQ) in schools adversely affects many of the nation's 55 million students with health problems such as asthma and flu. These IAQ-related health issues can result in sick days, reduced performance and lower test scores. In this article, the author discusses the benefits of improving air quality in schools and offers a few green steps on how facility managers can improve IAQ and student health.