Platelet Factor 4 Regulation of Monocyte KLF4 in Experimental Cerebral Malaria

Cerebral malaria continues to be a difficult to treat complication of Plasmodium falciparum infection in children. We have shown that platelets can have major deleterious immune functions in experimental cerebral malaria (ECM). One of the platelet derived mediators we have identified as particularly important is platelet factor 4/CXCL4. Our prior work demonstrated that PF4−/− mice are protected from ECM, have reduced plasma cytokines, and have reduced T-cell trafficking to the brain. We now show that PF4 drives monocyte cytokine production in a Kruppel like factor 4 (KLF4) dependent manner. Monocyte depleted Plasmodium berghei infected mice have improved survival, and KLF4 is greatly increased in control, but not monocyte depleted mice. PF4−/− mice have less cerebral monocyte trafficking and no change in KLF4 expression. These data indicate that PF4 induction of monocyte KLF4 expression may be an important step in the pathogenesis of ECM

Survival time and its predictors among preterms in the neonatal period post-discharge in Busoga region-Uganda June – July 2017

Introduction: Globally, out of 15 million babies born preterm each year, one million die. In Uganda, preterm deaths contribute 30% of the neonatal mortality rate. There is a paucity of information on the most critical time to conduct high impact interventions among neonate born preterm especially post-discharge from hospital. We determined the survival time to mortality and its predictors among preterm infants in the neonatal period post-discharge from hospital. Methods: We conducted a prospective cohort study in which 128 preterm infants were recruited from six hospitals including Jinja Regional Referral, St. Francis Buluba, Kamuli mission, Iganga, Kamuli and Bugiri district hospitals were prematurity was confirmed using gestation age and birth weight. Initially, background characteristics of the participants were assessed and then followed prospectively until 28 days. Kaplan-Meier survival analysis was used to estimate survival probabilities while time to preterm mortality was described using the 5thpercentile. Cox proportional hazards regression was used to determine predictors of survival. Results: Overall, 8% (10/128) of the preterm infants died; the 5th percentile survival time was 17 days. There was a 6-fold increase in hazard to mortality among preterm infants who had Kangaroo Mother Care (KMC) compared to those who did not (adjusted HR: 6.4, 95%CI: 1.7 – 24.5), a 5-fold increase in the hazard to preterm mortality among preterm infants born to HIV positive mothers compared to their counterparts who had HIV negative mothers (adjusted HR: 4.9, 95%CI: 1.1 – 22.2); and a 4-fold increase in the hazard to preterm mortality among preterm infants who were not exclusively breastfed compared to those who were exclusively breastfed (adjusted HR: 4.4, 95%CI: 1.1 – 18.3). Conclusion: Among babies who died, death occurred in the first 17 days while factors negatively associated with preterm survival included; not practicing Kangaroo Mother Care, not being breastfed exclusively and being born to an HIV positive mother. We recommend follow-up care for preterm infants following hospital discharge, implementation of prevention of mother to child transmission of HIV and exclusive breastfeeding of preterm babies

RESTORE-IMI 1: A Multicenter, Randomized, Doubleblind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections

Background. The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections. Methods. Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilatorassociated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenemnonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5–21 days imipenem/ relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment. Results. Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, –27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, –46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drugrelated deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively. Conclusions. Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infection

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p

A Novel Protective Role for Platelet-Mediated Immune Responses in Murine Experimental Cerebral Malaria

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pathology & Laboratory Medicine, 2013.Cerebral malaria is caused by complications from Plasmodium falciparum infection and claims hundreds of thousands of lives of young children in endemic countries annually. Platelets enhance infected red blood cell and immune cell vascular adhesion and platelets are thought to be a major driving factor in the microvascular pathology associated with cerebral malaria. Furthermore, platelets directly contribute to leukocyte recruitment and activation. Recently it has been suggested that platelets may have direct parasitocidal activity and limit parasite burden in some experimental settings. In this work, we evaluate the pleiotropic effects of platelet activation during Plasmodium infection. We have found that platelet inhibition or depletion pre-infection is not survival protective; however platelet inhibition or depletion post-infection confers protection from murine experimental cerebral malaria. These intriguing observations led us to explore the early effects of platelet activation. We found that platelets are activated very early post P berghei infection and induce the activation of the acute phase response. We found that platelets induce acute phase responses in both an indirect cytokine and direct contact dependent manner that leads to reduced parasitemia. Platelet mediated induction of the acute phase response leads to focused complement activation in the murine experimental cerebral malaria (ECM) model, thereby decreasing parasitemia and increasing survival. In summary, the data presented in these studies describe a novel protective innate immune role for platelets in ECM. These results warrant further considerations of the diverse roles for platelets in immune responses, including those to Plasmodium infection

Early infant diagnosis testing for HIV in a hard-to-reach fishing community in Uganda.

BackgroundInfants born to HIV-infected mothers are at a high risk of acquiring the infection. The World Health Organization recommends early diagnosis of HIV-exposed infants (HEIs) through deoxyribonucleic acid polymerase chain reaction (DNA PCR) and rapid HIV testing. Early detection of paediatric HIV is critical for access to antiretroviral therapy (ART) and child survival. However, there is limited evidence of the factors associated with receiving early infant diagnosis (EID) tests of the HIV testing protocol among HEIs in fishing communities in Uganda. This study established the factors associated with receiving EID tests of the HIV testing protocol among HEIs in a hard-to-reach fishing community in Uganda.MethodsA cross-sectional study was conducted among HEIs in selected healthcare facilities in Buvuma islands, Buvuma district. We obtained secondary data from mother-infant pair files enrolled in the EID program using a data extraction tool. Data were analysed using STATA Version 14. A modified Poisson regression analysis was used to determine the factors associated with not receiving the 1st DNA PCR test among HEIs enrolled in care.ResultsNone of the HEIs had received all the EID tests prescribed by the HIV testing protocol within the recommended time frame for the period of January 2014-December 2016. The proportion of infants that had received the 1st and 2nd DNA PCR, and rapid HIV tests was 39.5%, 6.1%, and 81.0% respectively. Being under the care of a single mother (PR = 1.11, 95% CI: 1.01-1.23, p = 0.023) and cessation of breastfeeding (PR = 0.90, 95% CI: 0.83-0.98, p = 0.025) were significantly associated with not receiving the 1st DNA PCR.ConclusionOur study revealed that none of the HEIs had received all the EID tests of the HIV diagnosis testing protocol. Receiving the 1st DNA PCR was positively associated with being an infant born to a single mother, and exclusive breastfeeding. Our findings highlight the need for the creation of an enabling environment for mothers and caregivers in order to increase the uptake of early diagnosis services for HEIs. Awareness-raising on the importance of EID should be scaled up in fishing communities. Demographic characteristics such as marital and breastfeeding status should be used as an entry point to increase the proportion of HEIs who receive EID tests

Sentinel Research Network (SRN) of IeDEA: Study Protocol

BACKGROUND The global scale up of antiretroviral therapy (ART) has significantly improved the immune recovery and life expectancy of people living with HIV (PLHIV). However, PLHIV on long-term ART now face health challenges related to non-communicable diseases (NCDs). We know that exposures such as tobacco, alcohol, diet and exercise are associated with the risk of NCDs. In addition, alcohol is one of the most commonly used substances globally and unhealthy drinking commonly co-occurs with mental health disorders. However, limited data are available in low- and middle-income country (LMIC) settings on the intersection between HIV, NCDs, mental health, and use of alcohol and other substances. As the population of PLHIV increases and ages, it is imperative that we understand the burden of NCDs and risk factors for NCD development as well as their impact on long-term health outcomes. AIMS To establish a network of research sites, the Sentinel Research Network (SRN), and to capture and analyze standardized data among PLHIV in LMICs. Through this network, we further seek to implement studies on cardiovascular risk factors, mental health, alcohol and other substance use disorders, as well as liver disease prevalence/incidence and associated factors among PLHIV accessing care in LMICs. METHODS Create a “sentinel” cohort nested in the pre-existing regional networks of the International epidemiologic Databases to Evaluate AIDS (IeDEA) cohorts based in LMICs. A total of 2, 925 people living with HIV (PLHIV) ≥40 years old and on ART ≥6 months are expected to be recruited at 12 HIV clinics participating in the IeDEA SRN project from the four African regions (East, Central, Southern and Western Africa), Asia-Pacific and Southern America. These participants will be assessed at baseline for various chronic conditions and their risk factors, including diabetes, dyslipidemia, hypertension, drug and alcohol abuse, as well as chronic liver diseases, through standardized questionnaires and non-to-minimally invasive “bedside” screening tests. Follow-up visits are planned at month six, month twelve, month twenty-four and month thirty-six for reassessment of these chronic conditions and also document incident cardiovascular outcomes. Data prospectively collected through the SRN will be merged with pre-existing HIV-related data routinely collected through IeDEA cohorts. EXPECTED RESULTS To date, the IeDEA consortium houses data on nearly 1.5 million adults and 150,000 children and adolescents living with HIV and has been studying treatment and other HIV-related outcomes since 2006. The establishment of the SRN will allow IeDEA investigators to better evaluate additional risk factors and co-morbidities associated with aging and HIV in standardized ways. Through the SRN, IeDEA will also develop the research infrastructure needed to enhance the design and validation of data collection tools related to these co-morbidities