Factors influencing fever care-seeking for children under five years of age in The Gambia: a secondary analysis of 2019-20 DHS data.

BACKGROUND: Malaria contributes to excess child mortality in The Gambia. Children under five are at risk of severe malaria and death if not treated promptly and appropriately. It is crucial that a child with fever receive appropriate care from a trained provider. The aim was to identify influences on child fever care-seeking in The Gambia to inform malaria control strategies. METHODS: This cross-sectional analysis of The Gambia 2019-20 Demographic and Health Survey used logistic regression analysis to identify associations between source of care for a child with fever (public or private healthcare provider, other, or no treatment) and mother, child, and household characteristics. RESULTS: Only 52.0% of mothers sought care from a trained healthcare provider for a child with fever-45.1% from a public facility and 7.0% from the private sector. 35.2% of mothers did not seek treatment. Mothers in urban households were 2.67 times as likely (aOR, 95% CI 1.504-4.736) as mothers in rural households to seek care from an informal source (e.g., pharmacy) versus not seeking treatment, and 0.29 times as likely (aOR, 95% CI 0.165-0.515) as mothers in rural households to seek care from a public provider versus informal source. Mothers in wealthier households were 2.30 times as likely (aOR, 95% CI 1.274-4.164) as mothers in poorer households to seek care from an informal source versus no treatment and half as likely as mothers in poorer households to seek care from a public provider versus informal source (aOR 0.53, 95% CI 0.291-0.959). CONCLUSIONS: Maintaining The Gambia's malaria control achievements will require the active engagement and oversight of private pharmacies along with continued integrated community case management to reach mothers who do not seek care for a child with fever, and remove challenges to seeking appropriate care from trained providers. Whether influenced by convenience, costs, perceived urgency, or other factors, given the likelihood of urban mothers and mothers in wealthier households to seek care from private pharmacies, it will be necessary to incorporate private pharmacies into malaria control strategies while building public sector capacity and workforce, and initiating more effective attitude and behavioural change among mothers and households.

Representative Public Health Surveys Pose Several Challenges: Lessons Learned Across 9 Communities During the COVID-19 Pandemic.

Community surveillance surveys offer an opportunity to obtain important and timely public health information that may help local municipalities guide their response to public health threats. The objective of this paper is to present approaches, challenges, and solutions from SARS-CoV-2 surveillance surveys conducted in different settings by 2 research teams. For rapid assessment of a representative sample, a 2-stage cluster sampling design was developed by an interdisciplinary team of researchers at Oregon State University between April 2020 and June 2021 across 6 Oregon communities. In 2022, these methods were adapted for New York communities by a team of veterinary, medical, and public health practitioners. Partnerships were established with local medical facilities, health departments, COVID-19 testing sites, and health and public safety staff. Field staff were trained using online modules, field manuals describing survey methods and safety protocols, and in-person meetings with hands-on practice. Private and secure data integration systems and public awareness campaigns were implemented. Pilot surveys and field previews revealed challenges in survey processes that could be addressed before surveys proceeded. Strong leadership, robust trainings, and university-community partnerships proved critical to successful outcomes. Cultivating mutual trust and cooperation among stakeholders is essential to prepare for the next pandemic.

Trends and Factors Affecting Knowledge of and Stigma and Violence Towards Female Sex Workers in Morocco.

BACKGROUND: We investigate factors affecting HIV knowledge, stigma, and violence among female sex workers (FSW) in Agadir, Rabat, Fes, and Tangier, Morocco, over three rounds of HIV surveillance surveys (2012, 2016, and 2019) conducted using respondent-driven sampling (RDS). Multivariable analyses from RDS studies examining the relationships between variables are under-utilized, particularly analyses that combine multiple locations and years of data together in a principled manner. METHOD: We fit three weighted logistic regression models for HIV transmission knowledge, having been denied service (experienced stigma), and having been hit (experienced violence) in the last 12 months, and perform model selection using 41 possible explanatory variables. RESULTS: Variables significantly associated with higher risk included reasons for sex work, how FSW solicit clients, if female family members are also involved in sex work, ever being forced to have sex, and ever being arrested or jailed. There were also significant differences between cities and in trends over time, with HIV transmission knowledge increasing and having been denied health services and having been hit decreasing. CONCLUSION: We found associations indicating that some particularly vulnerable FSW may be subject to multiple intersecting risks related to HIV knowledge, stigma, and violence which may decrease their agency to receive proper HIV testing, care, and treatment. Although Morocco has made excellent progress in providing HIV services to vulnerable populations, this additional analysis will be useful as Morocco makes programmatic decisions related to ending HIV by 2030.

Hidden population size estimation and diagnostics using two respondent-driven samples with applications in Armenia.

Estimating the size of hidden populations is essential to understand the magnitude of social and healthcare needs, risk behaviors, and disease burden. However, due to the hidden nature of these populations, they are difficult to survey, and there are no gold standard size estimation methods. Many different methods and variations exist, and diagnostic tools are needed to help researchers assess method-specific assumptions as well as compare between methods. Further, because many necessary mathematical assumptions are unrealistic for real survey implementation, assessment of how robust methods are to deviations from the stated assumptions is essential. We describe diagnostics and assess the performance of a new population size estimation method, capture-recapture with successive sampling population size estimation (CR-SS-PSE), which we apply to data from 3 years of studies from three cities and three hidden populations in Armenia. CR-SS-PSE relies on data from two sequential respondent-driven sampling surveys and extends the successive sampling population size estimation (SS-PSE) framework by using the number of individuals in the overlap between the two surveys and a model for the successive sampling process to estimate population size. We demonstrate that CR-SS-PSE is more robust to violations of successive sampling assumptions than SS-PSE. Further, we compare the CR-SS-PSE estimates to population size estimations using other common methods, including unique object and service multipliers, wisdom of the crowd, and two-source capture-recapture to illustrate volatility across estimation methods.

Evaluation of a Wastewater-Based Epidemiological Approach to Estimate the Prevalence of SARS-CoV-2 Infections and the Detection of Viral Variants in Disparate Oregon Communities at City and Neighborhood Scales.

BACKGROUND: Positive correlations have been reported between wastewater SARS-CoV-2 concentrations and a community's burden of infection, disease or both. However, previous studies mostly compared wastewater to clinical case counts or nonrepresentative convenience samples, limiting their quantitative potential. OBJECTIVES: This study examined whether wastewater SARS-CoV-2 concentrations could provide better estimations for SARS-CoV-2 community prevalence than reported cases of COVID-19. In addition, this study tested whether wastewater-based epidemiology methods could identify neighborhood-level COVID-19 hotspots and SARS-CoV-2 variants. METHODS: Community SARS-CoV-2 prevalence was estimated from eight randomized door-to-door nasal swab sampling events in six Oregon communities of disparate size, location, and demography over a 10-month period. Simultaneously, wastewater SARS-CoV-2 concentrations were quantified at each community's wastewater treatment plant and from 22 Newport, Oregon, neighborhoods. SARS-CoV-2 RNA was sequenced from all positive wastewater and nasal swab samples. Clinically reported case counts were obtained from the Oregon Health Authority. RESULTS: Estimated community SARS-CoV-2 prevalence ranged from 8 to 1,687/10,000 persons. Community wastewater SARS-CoV-2 concentrations ranged from 2.9 to 5.1 log10 gene copies per liter. Wastewater SARS-CoV-2 concentrations were more highly correlated (Pearson's r=0.96; R2=0.91) with community prevalence than were clinically reported cases of COVID-19 (Pearson's r=0.85; R2=0.73). Monte Carlo simulations indicated that wastewater SARS-CoV-2 concentrations were significantly better than clinically reported cases at estimating prevalence (p<0.05). In addition, wastewater analyses determined neighborhood-level COVID-19 hot spots and identified SARS-CoV-2 variants (B.1 and B.1.399) at the neighborhood and city scales. DISCUSSION: The greater reliability of wastewater SARS-CoV-2 concentrations over clinically reported case counts was likely due to systematic biases that affect reported case counts, including variations in access to testing and underreporting of asymptomatic cases. With these advantages, combined with scalability and low costs, wastewater-based epidemiology can be a key component in public health surveillance of COVID-19 and other communicable infections. https://doi.org/10.1289/EHP10289.

The Impact of an Integrated Care Management Program on Acute Care Use and Outpatient Appointment Attendance Among High-Risk Patients With Lupus.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) often struggle with high acute care use (emergency department [ED] visits and hospitalizations) and missed appointments. A nurse-led integrated care management program (iCMP) at our multihospital system coordinates care for patients at high risk for frequent acute care use due to comorbidities, demographics, and prior use patterns. We studied whether iCMP enrollment was associated with decreased acute care use and missed appointment rates among patients with SLE. METHODS: We used a validated electronic health record (EHR) machine learning algorithm to identify adults with SLE and then determined which patients were enrolled in the iCMP from January 2012 to February 2019. We then used EHR data linked to insurance claims to compare the incidence rates of ED visits, hospitalizations, potentially avoidable ED visits and hospitalizations, and missed appointments during iCMP enrollment versus the 12 months prior to iCMP enrollment. We used Poisson regression to compare incidence rate ratios (IRRs) during the iCMP versus pre-iCMP for each use measure, adjusted for age, sex, race and ethnicity, number of comorbidities, and calendar year, accounting for within-patient clustering. RESULTS: We identified 67 iCMP enrollees with SLE and linked EHR claims data. In adjusted analyses, iCMP enrollment was associated with reduced rates of ED visits (IRR 0.63, 95% confidence interval [CI] 0.47-0.85), avoidable ED visits (IRR 0.50, 95% CI 0.28-0.88), and avoidable hospitalizations (IRR 0.37, 95% CI 0.21-0.65). CONCLUSION: A nurse-led iCMP was effective at decreasing the rate of all ED visits and potentially avoidable ED visits and hospitalizations among high-risk patients with SLE. Further studies are needed to confirm these findings in other patient populations.

Populations size estimations using SS-PSE among MSM in four European cities: how many MSM are living with HIV?

BACKGROUND: Although men who have sex with men (MSM) are considered at high risk for transmission of sexually transmitted infections, including HIV, there are few studies estimating the population size of MSM in Europe. We used network data from a survey of MSM in four cities to perform successive sampling-population size estimations (SS-PSE) to estimate MSM population sizes. METHODS: Data were collected in 2013-14 in Bratislava, Bucharest, Verona and Vilnius using respondent-driven sampling (RDS). SS-PSE uses a Bayesian framework to approximate the RDS sampling structure via a successive sampling model and uses the selection order of the sample to provide information about the distribution of network sizes over the population members of MSM. RESULTS: We estimate roughly 4600 MSM in Bratislava, 25 300 MSM in Bucharest, 7200 in Verona and 2900 in Vilnius. This represents 2.9% of the estimated adult male population in Bratislava, 2.3% in Bucharest, 2.7% in Verona and 1.5% in Vilnius. The number of MSM living with HIV would roughly be 200 in Bratislava, 4554 in Bucharest, 690 in Verona and 100 in Vilnius. CONCLUSIONS: Benefits of this method are that no additional information from an RDS survey needs to be collected, that the sizes can be calculated ex post facto a survey and that there is a software programme that can run the SS-PSE models. However, this method relies on having reliable priors. Although many countries are estimating the sizes of their vulnerable populations, European countries have yet to incorporate similar and novel methods.

Use of an Integrated Care Management Program to Uncover and Address Social Determinants of Health for Individuals With Lupus.

OBJECTIVE: We studied patients with systemic lupus erythematosus (SLE) enrolled in a nurse-led, multihospital, primary care-based integrated care management program (iCMP) for complex patients with chronic conditions to understand whether social determinants of health (SDoH), including food insecurity, housing instability, and financial constraints, were prevalent in this population. METHODS: The academic hospital-based iCMP enrolls the top 2% of medically and psychosocially complex patients identified on the basis of clinical complexity health care use, and primary care provider referral. A nurse conducts needs assessments and coordinates care. We reviewed the electronic medical records of enrolled patients with SLE to identify SDoH needs and corresponding actions taken 1 year prior to iCMP enrollment using physicians' and social workers' notes, and during enrollment using iCMP team members' notes. RESULTS: Among 69 patients with SLE in the iCMP, in the year prior to enrollment, 57% had documentation of one or more SDoH challenges, compared with 94% during enrollment. iCMP nurses discussed and addressed one or more SDoH issues for 81% of the patients; transportation challenges, medication access, mental health care access, and financial insecurity were the most prevalent. Nurses connected 75% of these patients with related resources and support. CONCLUSION: Although SDoH-related issues were not used to identify patients for the iCMP, the vast majority of enrolled medically and psychosocially complex patients with SLE had these needs. The iCMP team uncovered and addressed SDoH-related concerns not documented prior to iCMP participation. Expansion of care management programs like the iCMP would help identify, document, and address these barriers that contribute to disparities in chronic disease care and outcomes.

Linking subsistence harvest diversity and productivity to adaptive capacity in an Alaskan food sharing network.

BACKGROUND: Although anthropogenic climate change poses existential challenges for Indigenous communities in the Arctic, these challenges are not entirely unprecedented. Over many generations, Arctic peoples have developed a wide range of behavioral strategies to navigate environmental change and uncertainty, and these strategies provide a foundation for contemporary adaptation. AIMS: In this article, we focus on mixed cash-subsistence economies and the social networks that underlie them in Alaska. The patterns of food production, labor exchange, and food sharing in subsistence-oriented communities throughout Alaska are driven by the productivity of keystone households who regularly harvest and share resources within and between communities. MATERIALS & METHODS: Building on previous research suggesting the critical importance of these networks to community resilience, we use network analysis to investigate whether patterns in resource transfers between households are associated with subsistence harvest diversity-the diversity of species harvested by a household unit. We use exponential random graph models to describe the structure of a sharing network from Aniak, Alaska, and model the links between harvest productivity, harvest diversity, and household position in this network. RESULTS: Our results indicate that both productivity and diversity are positively associated with network connections, and that productivity alone provides an incomplete model of network structure. DISCUSSION: We suggest that subsistence harvest diversity may play a unique role in supporting adaptive capacity and resilience by maintaining the productivity of keystone households despite changing environments and sustaining social network structures that circulate resources throughout the community. Harvest diversity may also serve as a broad indicator of Indigenous ecological knowledge and a tangible representation of cultural practices, values, and worldviews that underlie subsistence in Alaska. CONCLUSION: Greater attention to harvest diversity is important for understanding how subsistence networks adapt to environmental change and uncertainty linked to social and ecological dynamics of anthropogenic climate change.

Population Dynamics of Wheat Root Pathogens Under Different Tillage Systems in Northeast Oregon.

No-till or direct seeding can be described as seeding directly into the crop stubble from the previous season without use of tillage. A reduction in tillage can result in many benefits, including increased soil organic matter, increased water holding capacity, and reduced fuel costs. However, the effect of no-till and reduced tillage on crop root disease profiles is poorly understood. To study the effect of tillage on disease dynamics, soil samples were collected from commercial wheat fields representing a wide range of tillage strategies in fall 2016 and fall 2017. Because precipitation might affect soilborne diseases, wheat fields located across a diverse gradient of precipitation zones of the dryland Pacific Northwest were selected. Fusarium spp., Pythium spp., and Rhizoctonia spp. were quantified from soil samples using soil dilution plating and quantitative PCR (qPCR) assays. Results of dilution plating showed that the colony counts of Fusarium, Pythium, and Rhizoctonia at the genus level were negatively associated with tillage. However, the same patterns were not observed when specific causal agents of Fusarium, Pythium, and Rhizoctonia that are known to be pathogenic on wheat were quantified with qPCR. Furthermore, precipitation affected the population density of some fungal pathogens (F. culmorum, P. ultimum, and R. solani AG 8). Within the scope of inference of this study, results of this study indicate that the benefits of adopting reduced tillage likely outweigh potential risk for increased root disease.

Association Between "Unacceptable Condition" Expressed in Palliative Care Consultation Before Left Ventricular Assist Device Implantation and Care Received at the End of Life.

CONTEXT: Palliative care consultation before left ventricular assist device (LVAD) surgery (PreVAD) has been recommended, but its impact on goal-concordant care is unknown. OBJECTIVES: To describe the association between patients' unique unacceptable condition articulated during PreVAD with the actual care provided at the end of life. METHODS: Among 308 patients who had PreVAD between 2014 and 2019, 72 patients died before December 31, 2019. Based on the answers to the question, "Is there any condition you would find unacceptable?" patients were divided into ARTICULATE (those who could articulate their unacceptable condition clearly, n = 58) and non-ARTICULATE (those who could not, n = 14). Circumstances at death and end-of-life care were compared between groups. RESULTS: Mean age at death was 63.2 years (SD ±13.1), 56 patients (77.8%) were males, and median duration of LVAD was 167.5 days (interquartile range 682). ARTICULATE patients died less frequently in the intensive care unit than non-ARTICULATE patients (33 patients, 57.9% vs. 13 patients, 92.9%; P = 0.014) and had ethics consultation less frequently (four patients, 6.9% vs. five patients, 35.7%; P = 0.011). Frequency of LVAD withdrawal was similar in both groups. Among ARTICULATE cohort, the unacceptable condition articulated in PreVAD did not seem to influence decisions at the end of life. CONCLUSION: Patients who articulated their unacceptable condition clearly before LVAD surgery had less frequent ethics consultations and received less intensive care at the end of life, but it did not seem to affect the decision of LVAD withdrawal. It may be more important to engage in discussions around their unacceptable conditions, rather than the specific condition articulated. The question of an unacceptable condition should be part of any routine palliative care consultation before LVAD surgery.

Population Size Estimations Among Hidden Populations Using Respondent-Driven Sampling Surveys: Case Studies From Armenia.

BACKGROUND: Estimates of the sizes of hidden populations, including female sex workers (FSW), men who have sex with men (MSM), and people who inject drugs (PWID), are essential for understanding the magnitude of vulnerabilities, health care needs, risk behaviors, and HIV and other infections. OBJECTIVE: This article advances the successive sampling-population size estimation (SS-PSE) method by examining the performance of a modification allowing visibility to be jointly modeled with population size in the context of 15 datasets. Datasets are from respondent-driven sampling (RDS) surveys of FSW, MSM, and PWID from three cities in Armenia. We compare and evaluate the accuracy of our imputed visibility population size estimates to those found for the same populations through other unpublished methods. We then suggest questions that are useful for eliciting information needed to compute SS-PSE and provide guidelines and caveats to improve the implementation of SS-PSE for real data. METHODS: SS-PSE approximates the RDS sampling mechanism via the successive sampling model and uses the order of selection of the sample to provide information on the distribution of network sizes over the population members. We incorporate visibility imputation, a measure of a person's propensity to participate in the study, given that inclusion probabilities for RDS are unknown and social network sizes, often used as a proxy for inclusion probability, are subject to measurement errors from self-reported study data. RESULTS: FSW in Yerevan (2012, 2016) and Vanadzor (2016) as well as PWID in Yerevan (2014), Gyumri (2016), and Vanadzor (2016) had great fits with prior estimations. The MSM populations in all three cities had inconsistencies with expert prior values. The maximum low prior value was larger than the minimum high prior value, making a great fit impossible. One possible explanation is the inclusion of transgender individuals in the MSM populations during these studies. There could be differences between what experts perceive as the size of the population, based on who is an eligible member of that population, and what members of the population perceive. There could also be inconsistencies among different study participants, as some may include transgender individuals in their accounting of personal network size, while others may not. Because of these difficulties, the transgender population was split apart from the MSM population for the 2018 study. CONCLUSIONS: Prior estimations from expert opinions may not always be accurate. RDS surveys should be assessed to ensure that they have met all of the assumptions, that variables have reached convergence, and that the network structure of the population does not have bottlenecks. We recommend that SS-PSE be used in conjunction with other population size estimations commonly used in RDS, as well as results of other years of SS-PSE, to ensure generation of the most accurate size estimation.

Measuring a hidden population: A novel technique to estimate the population size of women with sexual violence-related pregnancies in South Kivu Province, Democratic Republic of Congo.

Successive sampling (SS)-population size estimation (PSE) is a technique used to estimate the sizes of hidden populations using data collected in respondent-driven sampling (RDS) surveys. We assess past estimations and use new data from an RDS survey to calculate a new PSE. In 2012, 852 adult women in South Kivu Province, Democratic Republic of Congo, who self-identified as survivors of sexual violence, resulting in a pregnancy, since the start of the war (in 1996) were sampled using RDS. We used imputed visibility, enrollment order, and prior estimates for PSE using SS-PSE in RDS Analyst. Prior estimates varied between Congolese local experts and researchers. We calculated the PSE of women with a sexual violence-related pregnancy in South Kivu using researchers' priors to be approximately 17,400. SS-PSE is an effective method for estimating the population sizes of hidden populations, useful for providing evidence for services and resource allocation. SS-PSE is beneficial because population sizes can be calculated after conducting the survey and do not rely on separate studies or additional data (as in network scale-up, multiplier, and capture-recapture methods).

Clinical and MRI phenotype of children with MOG antibodies.

OBJECTIVE: To investigate the clinical and magnetic resonance imaging (MRI) features of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-seropositive pediatric demyelinating syndromes. METHODS: Serum samples collected from 74 children with suspected demyelinating disorders whom were being followed at Massachusetts General Hospital were incubated with control green fluorescent protein (GFP)- and MOG-GFP-transfected Jurkat cell clones. The binding ratios were calculated using flow cytometry. Using statistical analyses, we compared the demographic, clinical and radiological features in our seropositive and seronegative patients. RESULTS: We found that 13 out of 74 (17.5%) patients were seropositive for MOG. The MOG-seropositive patients were younger than the seronegative patients (p = 0.049). No single disease category predominated among the seropositive patients, nor was one group more likely to have a polyphasic course. There were two out of four neuromyelitis optica (NMO) patients who had MOG antibodies; both were seronegative for aquaporin -4 (AQP4) antibodies. One had monophasic disease and the other had frequent relapses. There was a bimodal distribution of the MOG-seropositive patients by age at onset, with a distinct younger group (4-8 years) having a high prevalence of encephalopathy and an older group (13-18 years), whom presented almost exclusively with optic neuritis. MRI analysis demonstrated the absence of corpus callosum lesions in the seropositive patients (p = 0.012). The annualized relapse rate (ARR) and the Expanded Disability Status Scale (EDSS) results at 2 years did not differ between the seropositive and seronegative patients. CONCLUSION: MOG antibodies are found across a variety of pediatric demyelinating syndromes having some distinct clinical and MRI features.

Estimating the Size of Hidden Populations Using Respondent-driven Sampling Data: Case Examples from Morocco.

BACKGROUND: Respondent-driven sampling is used worldwide to estimate the population prevalence of characteristics, such as HIV/AIDS and associated risk factors in hard-to-reach populations. Estimating the total size of these populations is of great interest to national and international organizations; however, reliable measures of population size often do not exist. METHODS: Successive sampling-population size estimation (SS-PSE) along with network size imputation allows population size estimates to be made without relying on separate studies or additional data (as in network scale-up, multiplier, and capture-recapture methods), which may be biased. RESULTS: Ten population size estimates were calculated for people who inject drugs, female sex workers, men who have sex with other men, and migrants from sub-Saharan Africa in six different cities in Morocco. SS-PSE estimates fell within or very close to the likely values provided by experts and the estimates from previous studies using other methods. CONCLUSIONS: SS-PSE is an effective method for estimating the size of hard-to-reach populations that leverages important information within respondent-driven sampling studies. The addition of a network size imputation method helps to smooth network sizes allowing for more accurate results. However, caution should be used particularly when there is reason to believe that clustered subgroups may exist within the population of interest or when the sample size is small in relation to the population.

Assaying organochlorines in archived serum for a large, long-term cohort: implications of combining assay results from multiple laboratories over time.

Conserving irreplaceable, archived serum samples may sometimes conflict with the objective of minimizing measurement error due to laboratory effects. We sought to determine whether we could successfully combine assay results for DDT-related compounds and polychlorinated biphenyls (PCBs) in serum from the same birth cohort obtained from different laboratories over time. Using the Child Health and Development Studies (CHDS) serum archive, we compared variability for assays of a quality control pool to variability for assays of subject serum. The quality control pool was created from native archived serum samples that were pooled, then aliquoted, blinded and inserted pair-wise into assay batches along with the subject serum for 5 studies using CHDS samples conducted over a 13year period by three different laboratories. We found that the variability between laboratory and over time within laboratory was small relative to inter-individual variability for p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane), p,p'-DDE (1,1'-dichloro-2,2'-bis(p-chlorophenyl)ethylene) and o,p'-DDT (1,1,1-trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)-ethane). Results were also consistent for most PCB congeners which were detectable in 85% or more of samples. Our results suggest that it is possible to combine assays for DDT and PCB congeners measured at positive levels as they are accumulated for cohort subjects without risking meaningful misclassification due to variation stemming from laboratory or time period. This has significant implications for future study costs, conservation of irreplaceable archived samples and for leveraging past investments for future research. For PCB congeners with very low levels, findings caution against pooling of assays without further exploration.

Age-dependent B cell autoimmunity to a myelin surface antigen in pediatric multiple sclerosis.

Multiple sclerosis (MS) typically manifests in early to mid adulthood, but there is increasing recognition of pediatric-onset MS, aided by improvements in imaging techniques. The immunological mechanisms of disease are largely unexplored in pediatric-onset MS, in part because studies have historically focused on adult-onset disease. We investigated autoantibodies to myelin surface Ags in a large cohort of pediatric MS cases by flow cytometric labeling of transfectants that expressed different myelin proteins. Although Abs to native myelin oligodendrocyte glycoprotein (MOG) were uncommon among adult-onset patients, a subset of pediatric patients had serum Abs that brightly labeled the MOG transfectant. Abs to two other myelin surface Ags were largely absent. Affinity purification of MOG Abs as well as competition of binding with soluble MOG documented their binding specificity. Such affinity purified Abs labeled myelin and glial cells in human CNS white matter as well as myelinated axons in gray matter. The prevalence of such autoantibodies was highest among patients with a very early onset of MS: 38.7% of patients less than 10 years of age at disease onset had MOG Abs, compared with 14.7% of patients in the 10- to 18-year age group. B cell autoimmunity to this myelin surface Ag is therefore most common in patients with a very early onset of MS.

B cells and autoantibodies in the pathogenesis of multiple sclerosis and related inflammatory demyelinating diseases.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). The mainstream view is that MS is caused by an autoimmune attack of the CNS myelin by myelin-specific CD4 T cells, and this perspective is supported by extensive work in the experimental autoimmune encephalomyelitis (EAE) model of MS as well as immunological and genetic studies in humans. However, it is important to keep in mind that other cell populations of the immune system are also essential in the complex series of events leading to MS, as exemplified by the profound clinical efficacy of B cell depletion with Rituximab. This review discusses the mechanisms by which B cells contribute to the pathogenesis of MS and dissects their role as antigen-presenting cells (APCs) to T cells with matching antigen specificity, the production of proinflammatory cytokines and chemokines, as well as the secretion of autoantibodies that target structures on the myelin sheath and the axon. Mechanistic dissection of the interplay between T cells and B cells in MS may permit the development of B cell based therapies that do not require depletion of this important cell population.

Myelin-reactive type B T cells and T cells specific for low-affinity MHC-binding myelin peptides escape tolerance in HLA-DR transgenic mice.

Genes of the MHC show the strongest genetic association with multiple sclerosis (MS), but the underlying mechanisms have remained unresolved. In this study, we asked whether the MS-associated MHC class II molecules, HLA-DRB1*1501, HLA-DRB5*0101, and HLA-DRB1*0401, contribute to autoimmune CNS demyelination by promoting pathogenic T cell responses to human myelin basic protein (hMBP), using three transgenic (Tg) mouse lines expressing these MHC molecules. Unexpectedly, profound T cell tolerance to the high-affinity MHC-binding hMBP82-100 epitope was observed in all Tg mouse lines. T cell tolerance to hMBP82-100 was abolished upon back-crossing the HLA-DR Tg mice to MBP-deficient mice. In contrast, T cell tolerance was incomplete for low-affinity MHC-binding hMBP epitopes. Furthermore, hMBP82-100-specific type B T cells escaped tolerance in HLA-DRB5*0101 Tg mice. Importantly, T cells specific for low-affinity MHC-binding hMBP epitopes and hMBP82-100-specific type B T cells were highly encephalitogenic. Collectively, the results show that MS-associated MHC class II molecules are highly efficient at inducing T cell tolerance to high-affinity MHC-binding epitope, whereas autoreactive T cells specific for the low-affinity MHC-binding epitopes and type B T cells can escape the induction of T cell tolerance and may promote MS.

Induction of antigen-specific regulatory T cells in wild-type mice: visualization and targets of suppression.

Antigen-specific transplantation tolerance in the absence of immunosuppressive drugs is a rarely achieved goal. Immune responses to Y chromosome-encoded transplantation antigens (HY) can have life-threatening consequences in the clinic. Here, we have adopted a procedure developed in T cell antigen receptor (TCR)-transgenic mice to convert naïve T cells into male-specific Foxp3(+) regulatory T cells (Tregs) in WT female mice. For this purpose, female mice were infused by osmotic minipumps with a single class II MHC-presented HY peptide and Tregs visualized by tetramer staining. As a result, animals developed Treg-mediated long-term tolerance to all HY transplantation antigens, irrespective of whether they were recognized by CD4 or CD8 T cells, on skin or hematopoietic grafts from male donors.