Early Clinical Features of Dengue Virus Infection in Nicaraguan Children: A Longitudinal Analysis

Dengue virus causes an estimated 50 million dengue cases and approximately 500,000 life-threatening complications annually. New tools are needed to distinguish dengue from other febrile illnesses. In addition, the natural history of pediatric dengue early in illness in a community-based setting has not been well-defined. Here, we describe the clinical spectrum of pediatric dengue over the course of illness in a community setting by using five years of data from an ongoing prospective cohort study of children in Managua, Nicaragua. Day-by-day analysis of clinical signs and symptoms together with longitudinal statistical analysis showed significant associations with testing dengue-positive and important differences during the early phase of illness compared to the entire course of illness. These findings are important for clinical practice since outside of the hospital setting, clinicians may see dengue patients toward the beginning of their illness and utilize that information to decide whether their patient has dengue or another febrile illness. The results of these models should be extended for the development of prediction algorithms to aid clinicians in diagnosing suspected dengue

Risk Factors for African Tick-Bite Fever in Rural Central Africa

African tick-bite fever is an emerging infectious disease caused by the spotted fever group Rickettsia, Rickettsia africae, and is transmitted by ticks of the genus Amblyomma. To determine the seroprevalence of exposure to R. africae and risk factors associated with infection, we conducted a cross-sectional study of persons in seven rural villages in distinct ecological habitats of Cameroon. We examined 903 plasma samples by using an indirect immunofluorescence assay for antibodies to R. africae and analyzed demographic and occupational data collected from questionnaires. Of the 903 persons tested, 243 (26.9%) had IgG/IgM/IgA reactive with R. africae. Persons from four of the seven village sites were significantly more likely to be seropositive (P < 0.05), and lowland forest sites tended to have higher seroprevalences. These results suggest that African tick-bite fever is common in adults in rural areas of Cameroon and that ecological factors may play a role in the acquisition of R. africae infection

HIV gp41 Engages gC1qR on CD4+ T Cells to Induce the Expression of an NK Ligand through the PIP3/H2O2 Pathway

CD4+ T cell loss is central to HIV pathogenesis. In the initial weeks post-infection, the great majority of dying cells are uninfected CD4+ T cells. We previously showed that the 3S motif of HIV-1 gp41 induces surface expression of NKp44L, a cellular ligand for an activating NK receptor, on uninfected bystander CD4+ T cells, rendering them susceptible to autologous NK killing. However, the mechanism of the 3S mediated NKp44L surface expression on CD4+ T cells remains unknown. Here, using immunoprecipitation, ELISA and blocking antibodies, we demonstrate that the 3S motif of HIV-1 gp41 binds to gC1qR on CD4+ T cells. We also show that the 3S peptide and two endogenous gC1qR ligands, C1q and HK, each trigger the translocation of pre-existing NKp44L molecules through a signaling cascade that involves sequential activation of PI3K, NADPH oxidase and p190 RhoGAP, and TC10 inactivation. The involvement of PI3K and NADPH oxidase derives from 2D PAGE experiments and the use of PIP3 and H2O2 as well as small molecule inhibitors to respectively induce and inhibit NKp44L surface expression. Using plasmid encoding wild type or mutated form of p190 RhoGAP, we show that 3S mediated NKp44L surface expression on CD4+ T cells is dependent on p190 RhoGAP. Finally, the role of TC10 in NKp44L surface induction was demonstrated by measuring Rho protein activity following 3S stimulation and using RNA interference. Thus, our results identify gC1qR as a new receptor of HIV-gp41 and demonstrate the signaling cascade it triggers. These findings identify potential mechanisms that new therapeutic strategies could use to prevent the CD4+ T cell depletion during HIV infection and provide further evidence of a detrimental role played by NK cells in CD4+ T cell depletion during HIV-1 infection

Track A Basic Science

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138319/1/jia218438.pd

The dominant Anopheles vectors of human malaria in the Asia-Pacific region: occurrence data, distribution maps and bionomic précis

<p>Abstract</p> <p>Background</p> <p>The final article in a series of three publications examining the global distribution of 41 dominant vector species (DVS) of malaria is presented here. The first publication examined the DVS from the Americas, with the second covering those species present in Africa, Europe and the Middle East. Here we discuss the 19 DVS of the Asian-Pacific region. This region experiences a high diversity of vector species, many occurring sympatrically, which, combined with the occurrence of a high number of species complexes and suspected species complexes, and behavioural plasticity of many of these major vectors, adds a level of entomological complexity not comparable elsewhere globally. To try and untangle the intricacy of the vectors of this region and to increase the effectiveness of vector control interventions, an understanding of the contemporary distribution of each species, combined with a synthesis of the current knowledge of their behaviour and ecology is needed.</p> <p>Results</p> <p>Expert opinion (EO) range maps, created with the most up-to-date expert knowledge of each DVS distribution, were combined with a contemporary database of occurrence data and a suite of open access, environmental and climatic variables. Using the Boosted Regression Tree (BRT) modelling method, distribution maps of each DVS were produced. The occurrence data were abstracted from the formal, published literature, plus other relevant sources, resulting in the collation of DVS occurrence at 10116 locations across 31 countries, of which 8853 were successfully geo-referenced and 7430 were resolved to spatial areas that could be included in the BRT model. A detailed summary of the information on the bionomics of each species and species complex is also presented.</p> <p>Conclusions</p> <p>This article concludes a project aimed to establish the contemporary global distribution of the DVS of malaria. The three articles produced are intended as a detailed reference for scientists continuing research into the aspects of taxonomy, biology and ecology relevant to species-specific vector control. This research is particularly relevant to help unravel the complicated taxonomic status, ecology and epidemiology of the vectors of the Asia-Pacific region. All the occurrence data, predictive maps and EO-shape files generated during the production of these publications will be made available in the public domain. We hope that this will encourage data sharing to improve future iterations of the distribution maps.</p

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Epidemiologic, clinical and laboratory features of pediatric dengue in Nicaragua

Dengue virus is a flavivirus of worldwide importance, with approximately 4 billion people across 128 countries at risk of dengue virus infection. Most cases present as classic dengue fever, a debilitating, but self-limited illness that manifests with high fever, retro-orbital pain, severe myalgia or arthralgia, and rash. However, in some cases, illness progresses to life-threatening dengue hemorrhagic fever or dengue shock syndrome. The identification of distinguishing clinical and laboratory features that occur during the early febrile phase of illness is important for developing a clinical prediction algorithm to differentiate dengue from other febrile illnesses, and severe dengue from mild dengue. In addition, the success of community-based programs for preventing dengue indicates that identifying environments that could benefit from intervention at a community level is critical in order to have the greatest impact and to target limited resources.This dissertation focuses on data from two ongoing studies in order to investigate the epidemiologic, clinical and laboratory features of pediatric dengue in Nicaragua. Chapter 1 reports on the clinical and laboratory features of dengue virus infection in Nicaraguan children. The aims of the study were to examine the frequency of clinical signs and symptoms by day of dengue illness and to analyze the association of signs and symptoms with dengue virus infection during the early febrile phase of illness and over the course of illness.Chapter 2 reports on the association of lower low-density lipoprotein cholesterol levels with severe dengue outcome. The aim of the study was to delineate the trajectories of cholesterol levels over time by dengue virus infection status in order to understand the effect of dengue virus infection on cholesterol metabolism. We also sought to delineate their trajectories by dengue severity and to assess the effect of cholesterol level at presentation on development of severe dengue.Chapter 3 reports on individual-, household- and neighborhood-level determinants of dengue virus seropositivity in a community-based cohort. The aim of the study was to identify risk factors for DENV infection among children living in urban neighborhoods in Managua, Nicaragua. We also sought to determine the seroprevalence of dengue virus infection and identify individual- and household-level risk factors for dengue virus infection in neighborhood groups categorized by similar socioeconomic, infrastructural and ecological characteristics.Together, these studies present important findings on the natural history of pediatric dengue in Nicaragua and provide the basis for future research to develop clinical prediction algorithms to discriminate dengue from other febrile illnesses, and severe dengue from mild dengue. They also reveal the importance of understanding neighborhood-level factors in targeting community-based programs to prevent dengue

Factors Associated with Antenatal Influenza Vaccination in a Medically Underserved Population

Influenza infection in pregnant women is associated with increased risk of morbidity and mortality. Despite recommendations for all women to receive the seasonal influenza vaccine during pregnancy, vaccination rates among pregnant women in the U.S. have remained around 50%. The objective of this study was to evaluate clinical and demographic factors associated with antenatal influenza vaccination in a medically underserved population of women. We conducted a retrospective cohort study at Grady Memorial Hospital, a large safety-net hospital in Atlanta, Georgia, from July 1, 2016, to June 30, 2018. Demographic and clinical characteristics were abstracted from the electronic medical record. The Kotelchuck index was used to assess prenatal care adequacy. Relative risks and 95% confidence intervals for associations between receipt of influenza vaccine and prenatal care adequacy, demographic characteristics, and clinical characteristics were calculated using multivariable log-binominal models. Among 3723 pregnant women with deliveries, women were primarily non-Hispanic black (68.4%) and had Medicaid as their primary insurance type (87.9%). The overall vaccination rate was 49.8% (1853/3723). Inadequate prenatal care adequacy was associated with a lower antenatal influenza vaccination rate (43.5%), while intermediate and higher levels of prenatal care adequacy were associated with higher vaccination rates (66.9–68.3%). Hispanic ethnicity, non-Hispanic other race/ethnicity, interpreter use for a language other than Spanish, and preexisting diabetes mellitus were associated with higher vaccination coverage in multivariable analyses. Among medically underserved pregnant women, inadequate prenatal care utilization was associated with a lower rate of antenatal influenza vaccination. Socially disadvantaged women may face individual and structural barriers when accessing prenatal care, suggesting that evidenced-based, tailored approaches may be needed to improve prenatal care utilization and antenatal influenza vaccination rates