Lower Microscopy Sensitivity with Decreasing Malaria Prevalence in the Urban Amazon Region, Brazil, 2018-2021.

Malaria is increasingly diagnosed in urban centers across the Amazon Basin. In this study, we combined repeated prevalence surveys over a 4-year period of a household-based random sample of 2,774 persons with parasite genotyping to investigate the epidemiology of malaria in Mâncio Lima, the main urban transmission hotspot in Amazonian Brazil. We found that most malarial infections were asymptomatic and undetected by point-of-care microscopy. Our findings indicate that as malaria transmission decreases, the detection threshold of microscopy rises, resulting in more missed infections despite similar parasite densities estimated by molecular methods. We identified genetically highly diverse populations of Plasmodium vivax and P. falciparum in the region; occasional shared lineages between urban and rural residents suggest cross-boundary propagation. The prevalence of low-density and asymptomatic infections poses a significant challenge for routine surveillance and the effectiveness of malaria control and elimination strategies in urbanized areas with readily accessible laboratory facilities.

Changing Clinical Epidemiology of Plasmodium vivax Malaria as Transmission Decreases: Population-Based Prospective Panel Survey in the Brazilian Amazon.

BACKGROUND: Malarial infections are often missed by microscopy, and most parasite carriers are asymptomatic in low-endemicity settings. Whether parasite detectability and its ability to elicit symptoms change as transmission declines remains unclear. METHODS: We performed a prospective panel survey with repeated measurements on the same participants over 12 months to investigate whether Plasmodium vivax detectability by microscopy and risk of symptoms upon infection varied during a community-wide larviciding intervention in the Amazon basin of Brazil that markedly reduced vector density. We screened 1096 to 1400 residents in the intervention site for malaria by microscopy and quantitative TaqMan assays at baseline and twice during intervention. RESULTS: We found that more P vivax infections than expected from their parasite densities measured by TaqMan assays were missed by microscopy as transmission decreased. At lower transmission, study participants appeared to tolerate higher P vivax loads without developing symptoms. We hypothesize that changes in the ratio between circulating parasites and those that accumulate in the bone marrow and spleen, by avoiding peripheral blood microscopy detection, account for decreased parasite detectability and lower risk of symptoms under low transmission. CONCLUSIONS: P vivax infections are more likely to be subpatent and remain asymptomatic as malaria transmission decreases.

Malaria Resilience in South America: Epidemiology, Vector Biology, and Immunology Insights from the Amazonian International Center of Excellence in Malaria Research Network in Peru and Brazil.

The 1990s saw the rapid reemergence of malaria in Amazonia, where it remains an important public health priority in South America. The Amazonian International Center of Excellence in Malaria Research (ICEMR) was designed to take a multidisciplinary approach toward identifying novel malaria control and elimination strategies. Based on geographically and epidemiologically distinct sites in the Northeastern Peruvian and Western Brazilian Amazon regions, synergistic projects integrate malaria epidemiology, vector biology, and immunology. The Amazonian ICEMR's overarching goal is to understand how human behavior and other sociodemographic features of human reservoirs of transmission-predominantly asymptomatically parasitemic people-interact with the major Amazonian malaria vector, Nyssorhynchus (formerly Anopheles) darlingi, and with human immune responses to maintain malaria resilience and continued endemicity in a hypoendemic setting. Here, we will review Amazonian ICEMR's achievements on the synergies among malaria epidemiology, Plasmodium-vector interactions, and immune response, and how those provide a roadmap for further research, and, most importantly, point toward how to achieve malaria control and elimination in the Americas.

Epidemiology of COVID-19 after Emergence of SARS-CoV-2 Gamma Variant, Brazilian Amazon, 2020-2021.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Gamma variant has been hypothesized to cause more severe illness than previous variants, especially in children. Successive SARS-CoV-2 IgG serosurveys in the Brazilian Amazon showed that age-specific attack rates and proportions of symptomatic SARS-CoV-2 infections were similar before and after Gamma variant emergence.

A novel risk assessment tool for bovine respiratory disease in preweaned dairy calves.

Due to the increased morbidity and mortality of bovine respiratory disease (BRD) in dairy calves, as well as an increasing urgency for the judicious use of antimicrobials in farm animals, a comprehensive risk assessment tool for BRD in preweaned dairy calves has been designed based on a longitudinal and a cross-sectional study. As a multifactorial disease complex in which immune function stressors increase susceptibility to respiratory pathology, risk management programs for environmental and husbandry practices may be an effective approach for BRD control. Practices of known or suspected effect on BRD in preweaned calves have been explored in 2 large studies correlating management factors to BRD prevalence (BRD 100 study) and incidence (BRD 10K study) and forming the scores presented here. Priority was given to results from multivariable over univariable model estimates. However, when used, univariable model estimates were adjusted for confounders or stratified by effect modifiers if necessary. Regression coefficients were translated into scores, which are presented in a field-ready tool consisting of (1) a risk assessment questionnaire, which identifies the herd-specific risk factors and the risk scores associated with each; (2) the California BRD scoring system to estimate the BRD prevalence at the time of risk assessment for future comparison with the prevalence after interventions; and (3) the BRD control and prevention herd management plan, which can be used to plan and track the interventions identified. Scores for 100 dairies across California were used to benchmark a dairy's risk on a spectrum. With the help of the risk assessment tool, dairy producers, calf managers, and veterinarians may be able to adjust management factors that affect BRD risk on a farm and objectively monitor BRD prevalence before and after management interventions. As a result, the BRD risk assessment tool described here is the first comprehensive effort for herd-specific BRD control and prevention.

Management factors associated with bovine respiratory disease in preweaned calves on California dairies: The BRD 100 study.

The objective of this cross-sectional study was to determine how management practices on California dairies may be associated with bovine respiratory disease (BRD) in preweaned calves. A convenience sample of 100 dairies throughout California, providing a study population of 4,636 calves, were visited between May 2014 and April 2016. During each farm visit, in-person interviews with the herd manager or calf caretaker were conducted to collect information about herd demographics, maternity pen, colostrum and calf management, herd vaccinations, and dust abatement. A random sample of preweaned calves was identified and evaluated for the presence of BRD using a standardized tool. A survey-adjusted generalized linear mixed model with a logit link function was fitted with calf as the unit of analysis and dairy as the random effect. Mean study herd size (±SE) was 1,718 (±189.9) cows. Survey-adjusted estimates of breed types in the sample were 81.6% (±0.6) Holstein, 13.1% (±0.4) Jersey, and 5.3% (±0.5) crossbred or other purebred breeds, and calf sex proportions were 73.8% (±1.0) female and 26.2% (±1.0) male. Overall survey-adjusted BRD prevalence in the study herds was 6.91% (±0.69). Housing factors positively associated with BRD were metal hutches compared with wood hutches [odds ratio (OR) = 11.19; 95% confidence interval (CI) = 2.80-44.78], calf-to-calf contact in calves >75 d of age (OR = 9.95, 95% CI = 1.50-65.86), feeding Holstein calves <2.84 L of milk or replacer per day (OR = 7.16, 95% CI = 1.23-41.68), and lagoon water used for flushing manure under hutches compared with no flush (OR = 12.06, 95% CI = 1.93-75.47). Providing extra shade over hutches (OR = 0.08; 95% CI = 0.02-0.37), feeding calves at least 90% saleable milk (OR = 0.27, 95% CI = 0.13-0.54) or pasteurized milk (OR = 0.10; 95% CI = 0.03-0.36), and feeding >5.68 L of milk or replacer per day to Jersey calves (OR = 0.04; 95% CI = 0.01-0.28) were negatively associated with BRD. Our study identified management practices on California dairies with variability and that may contribute to differences in BRD prevalence, which will be incorporated into a risk-assessment tool to control and prevent BRD in preweaned dairy calves.

Multivariate MR biomarkers better predict cognitive dysfunction in mouse models of Alzheimer's disease.

To understand multifactorial conditions such as Alzheimer's disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between pathology affected brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD, while being raised in uniform environments and with known genotype alterations. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI traditional voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included hippocampus, olfactory areas, entorhinal cortex and cerebellum, as well as the frontal association area. The properties of these regions, extracted from each of the imaging markers, were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning, allowing the detection of associations between context, location, and responses. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, expected to play a role in memory dysfunction, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our cross-sectional results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.

Regional management practices and prevalence of bovine respiratory disease in California's preweaned dairy calves.

The objective of this cross-sectional study was to estimate the prevalence of bovine respiratory disease (BRD) in California preweaned dairy calves and identify management practices that are associated with BRD. A convenience sample of 100 dairies in the 3 distinct dairy regions of California was surveyed. Regions evaluated were Northern California (NCA), northern San Joaquin Valley (NSJV), and greater Southern California (GSCA). A questionnaire on calf management practices and demographic information was administered via in-person interviews at each dairy and a random sample of preweaned calves was evaluated using the California BRD scoring system on the same day. Prevalence of BRD varied between the 3 dairy regions: 9.30% in NCA, 4.51% in NSJV, and 7.35% in GSCA. Breed was not associated with BRD prevalence at the statewide level, but differences in prevalence were observed between breeds across the regions with a higher prevalence in NCA for Jerseys and in GSCA for Holsteins, compared with NSJV. Prevalence of BRD was not different between organic and conventional dairies. Colostrum management practices, including heat treatment and feeding colostrum from multiparous cows, varied by region and were associated with lower BRD prevalence. Calves housed in group pens, a practice observed primarily in NCA, had a higher BRD prevalence than those in individual housing. Feeding salable milk was also more common in NCA and was associated with lower BRD prevalence. Ground and road surfaces adjacent to the calf raising area were also variable by region, and paved surfaces were associated with lower BRD prevalence. Management practices associated with BRD varied across the state and may be addressed to inform the adoption and implementation of potentially protective management decisions on California dairies and other regions with similar dairy systems.

Glycolipid-peptide conjugate vaccines enhance CD8+ T cell responses against human viral proteins.

An important goal of vaccination against viruses and virus-driven cancers is to elicit cytotoxic CD8+ T cells specific for virus-derived peptides. CD8+ T cell responses can be enhanced by engaging help from natural killer T (NKT) cells. We have produced synthetic vaccines that induce strong peptide-specific CD8+ T cell responses in vivo by incorporating an NKT cell-activating glycolipid. Here we examine the effect of a glycolipid-peptide conjugate vaccine incorporating an NKT cell-activating glycolipid linked to an MHC class I-restricted peptide from a viral antigen in human peripheral blood mononuclear cells. The vaccine induces CD1d-dependent activation of human NKT cells following enzymatic cleavage, activates human dendritic cells in an NKT-cell dependent manner, and generates a pool of activated antigen-specific CD8+ T cells with cytotoxic potential. Compared to unconjugated peptide, the vaccine upregulates expression of genes encoding interferon-γ, CD137 and granzyme B. A similar vaccine incorporating a peptide from the clinically-relevant human papilloma virus (HPV) 16 E7 oncoprotein induces cytotoxicity against peptide-expressing targets in vivo, and elicits a better antitumor response in a model of E7-expressing lung cancer than its unconjugated components. Glycolipid-peptide conjugate vaccines may prove useful for the prevention or treatment of viral infections and tumors that express viral antigens.

Temporal summation of second pain: variability in responses to a fixed protocol.

BACKGROUND: Temporal summation of second pain (TSSP) is relevant for the study of central sensitization, and refers to increased pain evoked by repetitive stimuli at a constant intensity. While the literature reports on participants whose pain ratings increase with successive stimuli, response to a TSSP protocol can be variable. The aim of this study was to characterize the full range of responses to a TSSP protocol in pain-free adults. METHOD: Three hundred twelve adults received a train of brief, repetitive heat stimuli at a fixed temperature and rated the intensity of second pain after each pulse. TSSP response (Δ in pain ratings) was quantified using the most common methods in the literature, and response groups were formed: TSSP (Δ > 0), no change (Δ = 0), and temporal decrease in second pain (TDSP) (Δ < 0). A cluster analysis was performed on the Δ values to empirically derive response groups. RESULTS: Depending on how TSSP response was quantified, 61-72% of the sample demonstrated TSSP, 11-28% had no change in pain ratings and 0-20% demonstrated TDSP. The cluster analysis found that the majority (59%) of participants fell in the no change cluster, 29% clustered into the TSSP group and 12% in the TDSP cluster. CONCLUSIONS: Using a fixed thermal paradigm, pain-free adults exhibit substantial variability in response to a TSSP protocol not well characterized by group-mean slopes. Studies are needed to determine TSSP response patterns in clinical samples, identify predictors of response and determine the clinical implications of response variability.