HIV infection drives IgM and IgG3 subclass bias in Plasmodium falciparum-specific and total immunoglobulin concentration in Western Kenya

BACKGROUND: HIV infection is associated with more frequent and severe episodes of malaria and may be the result of altered malaria-specific B cell responses. However, it is poorly understood how HIV and the associated lymphopenia and immune activation affect malaria-specific antibody responses. METHODS: HIV infected and uninfected adults were recruited from Bondo subcounty hospital in Western Kenya at the time of HIV testing (antiretroviral and co-trimoxazole prophylaxis naïve). Total and Plasmodium falciparum apical membrane antigen-1 (AMA1) and glutamate rich protein-R0 (GLURP-R0) specific IgM, IgG and IgG subclass concentrations was measured in 129 and 52 of recruited HIV-infected and uninfected individuals, respectively. In addition, HIV-1 viral load (VL), CD4+ T cell count, and C-reactive protein (CRP) concentration was quantified in study participants. Antibody levels were compared based on HIV status and the associations of antibody concentration with HIV-1 VL, CD4+ count, and CRP levels was measured using Spearman correlation testing. RESULTS: Among study participants, concentrations of IgM, IgG1 and IgG3 antibodies to AMA1 and GLURP-R0 were higher in HIV infected individuals compared to uninfected individuals (all p < 0.001). The IgG3 to IgG1 ratio to both AMA1 and GLURP-R0 was also significantly higher in HIV-infected individuals (p = 0.02). In HIV-infected participants, HIV-1 VL and CRP were weakly correlated with AMA1 and GLURP-R0 specific IgM and IgG1 concentrations and total (not antigen specific) IgM, IgG, IgG1, and IgG3 concentrations (all p < 0.05), suggesting that these changes are related in part to viral load and inflammation. CONCLUSIONS: Overall, HIV infection leads to a total and malaria antigen-specific immunoglobulin production bias towards higher levels of IgM, IgG1, and IgG3, and HIV-1 viraemia and systemic inflammation are weakly correlated with these changes. Further assessments of antibody affinity and function and correlation with risk of clinical malaria, will help to better define the effects of HIV infection on clinical and biological immunity to malaria

Prevalence and spectrum of illness among hospitalized adults with malaria in Blantyre, Malawi

Background As control interventions are rolled out, the burden of malaria may shift from young children to older children and adults as acquisition of immunity is slowed and persistence of immunity is short-lived. Data for malaria disease in adults are difficult to obtain because of co-morbid conditions and because parasitaemia may be asymptomatic. Regular surveys of adult admissions to a hospital in Malawi were conducted to characterize the clinical spectrum of malaria and to establish a baseline to monitor changes that occur in future. Methods In 2011–2012, at Queen Elizabeth Hospital, Blantyre, four separated one-week surveys in the peak malaria transmission period (wet season) and three one-week surveys in the low transmission period (dry season) were conducted using rapid diagnostic tests (RDT) with confirmation of parasitaemia by microscopy. All adults (aged ≥15) being admitted to the adult medical wards regardless of the suspected diagnosis, were enrolled. Participants with a positive malaria test underwent a standardized physical examination and laboratory tests. Malaria syndromes were characterized by reviewing charts and laboratory results on discharge. Results 765 adult admissions were screened. 63 (8.2%) were RDT-positive with 61 (8.0%) positive by microscopy. Over the course of the seven study weeks, two patients were judged to have incidental parasitaemia, 31 (4.1%) had uncomplicated malaria and 28 (3.7%) had severe malaria. Both uncomplicated and severe malaria cases were more common in the rainy season than the dry season. Prostration (22/28 cases) and hyperparasitaemia (>250,000 parasites/μl) (9/28) were the most common features of severe malaria. Jaundice (4/28), severe anaemia (2/28), hyperlactataemia (2/28), shock (1/28) and haemoglobinuria (1/28) were less commonly seen, and no patient had severe metabolic derangement or organ failure. There were no deaths attributable to malaria. Conclusion In this study of adults admitted to hospital in southern Malawi, an area with year-round transmission of Plasmodium falciparum, classical metabolic and organ complications of malaria were not encountered. Prostration and hyperparasitaemia were more common indicators of severity in patients admitted with malaria, none of whom died. These data will provide a baseline for monitoring trends in the frequency and clinical patterns of severe malaria in adults

Tau Oligomer–Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease

Importance: Factors associated with synapse loss beyond amyloid-β plaques and neurofibrillary tangles may more closely correlate with the emergence of cognitive deficits in Alzheimer disease (AD) and be relevant for early therapeutic intervention. // Objective: To investigate whether accumulation of tau oligomers in synapses is associated with excessive synapse elimination by microglia or astrocytes and with cognitive outcomes (dementia vs no dementia [hereinafter termed resilient]) of individuals with equal burdens of AD neuropathologic changes at autopsy. // Design, Setting, and Participants: This cross-sectional postmortem study included 40 human brains from the Massachusetts Alzheimer Disease Research Center Brain Bank with Braak III to IV stages of tau pathology but divergent antemortem cognition (dementia vs resilient) and cognitively normal controls with negligible AD neuropathologic changes. The visual cortex, a region without tau tangle deposition at Braak III to IV stages, was assessed after expansion microscopy to analyze spatial relationships of synapses with microglia and astrocytes. Participants were matched for age, sex, and apolipoprotein E status. Evidence of Lewy bodies, TDP-43 aggregates, or other lesions different from AD neuropathology were exclusion criteria. Tissue was collected from July 1998 to November 2020, and analyses were conducted from February 1, 2022, through May 31, 2023. // Main Outcomes and Measures: Amyloid-β plaques, tau neuropil thread burden, synapse density, tau oligomers in synapses, and internalization of tau oligomer–tagged synapses by microglia and astrocytes were quantitated. Analyses were performed using 1-way analysis of variance for parametric variables and the Kruskal-Wallis test for nonparametric variables; between-group differences were evaluated with Holm-Šídák tests. // Results: Of 40 included participants (mean [SD] age at death, 88 [8] years; 21 [52%] male), 19 had early-stage dementia with Braak stages III to IV, 13 had resilient brains with similar Braak stages III to IV, and 8 had no dementia (Braak stages 0-II). Brains with dementia but not resilient brains had substantial loss of presynaptic (43%), postsynaptic (33%), and colocalized mature synaptic elements (38%) compared with controls and significantly higher percentages of mature synapses internalized by IBA1-positive microglia (mean [SD], 13.3% [3.9%] in dementia vs 2.6% [1.9%] in resilient vs 0.9% [0.5%] in control; P < .001) and by GFAP-positive astrocytes (mean [SD], 17.2% [10.9%] in dementia vs 3.7% [4.0%] in resilient vs 2.7% [1.8%] in control; P = .001). In brains with dementia but not in resilient brains, tau oligomers more often colocalized with synapses, and the proportions of tau oligomer–containing synapses inside microglia (mean [SD] for presynapses, mean [SD], 7.4% [1.8%] in dementia vs 5.1% [1.9%] resilient vs 3.7% [0.8%] control; P = .006; and for postsynapses 11.6% [3.6%] dementia vs 6.8% [1.3%] resilient vs 7.4% [2.5%] control; P = .001) and astrocytes (mean [SD] for presynapses, 7.0% [2.1%] dementia vs 4.3% [2.2%] resilient vs 4.0% [0.7%] control; P = .001; and for postsynapses, 7.9% [2.2%] dementia vs 5.3% [1.8%] resilient vs 3.0% [1.5%] control; P < .001) were significantly increased compared with controls. Those changes in brains with dementia occurred in the absence of tau tangle deposition in visual cortex. // Conclusion and Relevance: The findings from this cross-sectional study suggest that microglia and astrocytes may excessively engulf synapses in brains of individuals with dementia and that the abnormal presence of tau oligomers in synapses may serve as signals for increased glial-mediated synapse elimination and early loss of brain function in AD

Developing a National-Scale Exposure Index for Combined Environmental Hazards and Social Stressors and Applications to the Environmental Influences on Child Health Outcomes (ECHO) Cohort

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0-1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a high exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context

Developing a National-Scale Exposure Index for Combined Environmental Hazards and Social Stressors and Applications to the Environmental Influences on Child Health Outcomes (ECHO) Cohort

Tools for assessing multiple exposures across several domains (e.g., physical, chemical, and social) are of growing importance in social and environmental epidemiology because of their value in uncovering disparities and their impact on health outcomes. Here we describe work done within the Environmental influences on Child Health Outcomes (ECHO)-wide Cohort Study to build a combined exposure index. Our index considered both environmental hazards and social stressors simultaneously with national coverage for a 10-year period. Our goal was to build this index and demonstrate its utility for assessing differences in exposure for pregnancies enrolled in the ECHO-wide Cohort Study. Our unitless combined exposure index, which collapses census-tract level data into a single relative measure of exposure ranging from 0-1 (where higher values indicate higher exposure to hazards), includes indicators for major air pollutants and air toxics, features of the built environment, traffic exposures, and social determinants of health (e.g., lower educational attainment) drawn from existing data sources. We observed temporal and geographic variations in index values, with exposures being highest among participants living in the West and Northeast regions. Pregnant people who identified as Black or Hispanic (of any race) were at higher risk of living in a "high" exposure census tract (defined as an index value above 0.5) relative to those who identified as White or non-Hispanic. Index values were also higher for pregnant people with lower educational attainment. Several recommendations follow from our work, including that environmental and social stressor datasets with higher spatial and temporal resolutions are needed to ensure index-based tools fully capture the total environmental context

Do small effects matter more in vulnerable populations? an investigation using Environmental influences on Child Health Outcomes (ECHO) cohorts

BackgroundA major challenge in epidemiology is knowing when an exposure effect is large enough to be clinically important, in particular how to interpret a difference in mean outcome in unexposed/exposed groups. Where it can be calculated, the proportion/percentage beyond a suitable cut-point is useful in defining individuals at high risk to give a more meaningful outcome. In this simulation study we compute differences in outcome means and proportions that arise from hypothetical small effects in vulnerable sub-populations.MethodsData from over 28,000 mother/child pairs belonging to the Environmental influences on Child Health Outcomes Program were used to examine the impact of hypothetical environmental exposures on mean birthweight, and low birthweight (LBW) (birthweight &lt; 2500g). We computed mean birthweight in unexposed/exposed groups by sociodemographic categories (maternal education, health insurance, race, ethnicity) using a range of hypothetical exposure effect sizes. We compared the difference in mean birthweight and the percentage LBW, calculated using a distributional approach.ResultsWhen the hypothetical mean exposure effect was fixed (at 50, 125, 167 or 250g), the absolute difference in % LBW (risk difference) was not constant but varied by socioeconomic categories. The risk differences were greater in sub-populations with the highest baseline percentages LBW: ranging from 3.1-5.3 percentage points for exposure effect of 125g. Similar patterns were seen for other mean exposure sizes simulated.ConclusionsVulnerable sub-populations with greater baseline percentages at high risk fare worse when exposed to a small insult compared to the general population. This illustrates another facet of health disparity in vulnerable individuals

What works with men? A systematic review of health promoting interventions targeting men

Peer reviewedPublisher PD

Hyperimmune immunoglobulin for hospitalised patients with COVID-19 (ITAC): a double-blind, placebo-controlled, phase 3, randomised trial

BACKGROUND: Passive immunotherapy using hyperimmune intravenous immunoglobulin (hIVIG) to SARS-CoV-2, derived from recovered donors, is a potential rapidly available, specific therapy for an outbreak infection such as SARS-CoV-2. Findings from randomised clinical trials of hIVIG for the treatment of COVID-19 are limited. METHODS: In this international randomised, double-blind, placebo-controlled trial, hospitalised patients with COVID-19 who had been symptomatic for up to 12 days and did not have acute end-organ failure were randomly assigned (1:1) to receive either hIVIG or an equivalent volume of saline as placebo, in addition to remdesivir, when not contraindicated, and other standard clinical care. Randomisation was stratified by site pharmacy; schedules were prepared using a mass-weighted urn design. Infusions were prepared and masked by trial pharmacists; all other investigators, research staff, and trial participants were masked to group allocation. Follow-up was for 28 days. The primary outcome was measured at day 7 by a seven-category ordinal endpoint that considered pulmonary status and extrapulmonary complications and ranged from no limiting symptoms to death. Deaths and adverse events, including organ failure and serious infections, were used to define composite safety outcomes at days 7 and 28. Prespecified subgroup analyses were carried out for efficacy and safety outcomes by duration of symptoms, the presence of anti-spike neutralising antibodies, and other baseline factors. Analyses were done on a modified intention-to-treat (mITT) population, which included all randomly assigned participants who met eligibility criteria and received all or part of the assigned study product infusion. This study is registered with ClinicalTrials.gov, NCT04546581. FINDINGS: From Oct 8, 2020, to Feb 10, 2021, 593 participants (n=301 hIVIG, n=292 placebo) were enrolled at 63 sites in 11 countries; 579 patients were included in the mITT analysis. Compared with placebo, the hIVIG group did not have significantly greater odds of a more favourable outcome at day 7; the adjusted OR was 1·06 (95% CI 0·77–1·45; p=0·72). Infusions were well tolerated, although infusion reactions were more common in the hIVIG group (18·6% vs 9·5% for placebo; p=0·002). The percentage with the composite safety outcome at day 7 was similar for the hIVIG (24%) and placebo groups (25%; OR 0·98, 95% CI 0·66–1·46; p=0·91). The ORs for the day 7 ordinal outcome did not vary for subgroups considered, but there was evidence of heterogeneity of the treatment effect for the day 7 composite safety outcome: risk was greater for hIVIG compared with placebo for patients who were antibody positive (OR 2·21, 95% CI 1·14–4·29); for patients who were antibody negative, the OR was 0·51 (0·29–0·90; pinteraction=0·001). INTERPRETATION: When administered with standard of care including remdesivir, SARS-CoV-2 hIVIG did not demonstrate efficacy among patients hospitalised with COVID-19 without end-organ failure. The safety of hIVIG might vary by the presence of endogenous neutralising antibodies at entry. FUNDING: US National Institutes of Health

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Decrease in Numbers of Naive and Resting B Cells in HIV-Infected Kenyan Adults Leads to a Proportional Increase in Total and Plasmodium falciparum-Specific Atypical Memory B Cells

Human immunodeficiency virus type 1 (HIV-1) infection is associated with B cell activation and exhaustion, and hypergammaglobulinemia. How these changes influence B cell responses to coinfections such as malaria is poorly understood. To address this, we compared B cell phenotypes and Abs specific for the Plasmodium falciparum vaccine candidate apical membrane Ag-1 (AMA1) in HIV-infected and uninfected adults living in Kenya. Surprisingly, HIV-1 infection was not associated with a difference in serum AMA1-specific Ab levels. HIV-infected individuals had a higher proportion of total atypical and total activated memory B cells (MBCs). Using an AMA1 tetramer to detect AMA1-specific B cells, HIV-infected individuals were also shown to have a higher proportion of AMA1-specific atypical MBCs. However, this proportional increase resulted in large part from a loss in the number of naive and resting MBCs rather than an increase in the number of atypical and activated cells. The loss of resting MBCs and naive B cells was mirrored in a population of cells specific for an Ag to which these individuals were unlikely to have been chronically exposed. Together, the data show that changes in P. falciparum Ag-specific B cell subsets in HIV-infected individuals mirror those in the overall B cell population, and suggest that the increased proportion of atypical MBC phenotypes found in HIV-1-infected individuals results from the loss of naive and resting MBCs