TARGETED HIV AND STI SCREENING STRATEGIES AMONGST MSM IN BALTIMORE, AND THE IMPACT ON THE HIV EPIDEMIC: Using Agent Based Models to Study STI- HIV Co-infection Dynamics

Co-infection of men who have sex with men who have sex with men (MSM) with HIV and and Neisseria gonorrhoeae/Chlamydia trachomatis (NG/CT) remains a significant public health problem in the United States due to co-infection dynamics creating an epidemiologic phenomenon whereby co-epidemics of HIV and NG/CT (along with other STIs) help propagate each other. One of the key components of the US National AIDS Strategy revolves around the HIV Care Continuum, in which HIV-infected persons are diagnosed, linked to care, retained in care and virally suppressed to prevent transmission. Screening for HIV is the entry point for the care continuum and various understanding the most efficacious strategies for this is of utmost importance to help identify HIV-infected persons and link them to care. We used an agent-based model to test three screening strategies for efficacy: targeting high-risk MSM, increased general HIV screening, and improved NG/CT screening amongst HIV-infected MSM. Targeting high-risk MSM and increased general HIV screening produced significant decreases in the HIV and NG/CT incidence relative to baseline, but the former produced steeper declines while simultaneously testing thousands less persons. Improved NG/CT screening amongst HIV-infected MSM has no impact on the incidence rate of either. The targeting high-risk MSM strategy produced steep declines in HIV incidence, and efficiently achieved this in less HIV tests given per year compared to the general HIV screening. This suggests that targeting high-risk MSM may be a more effective approach to achieve a reduction in HIV incidence. Furthermore, it suggests that the HIV epidemic amongst MSM in Baltimore may be concentrated amongst a subset of the MSM population

Population genomics of Plasmodium vivax in Panama to assess the risk of case importation on malaria elimination

Malaria incidence in Panama has plateaued in recent years in spite of elimination efforts, with almost all cases caused by Plasmodium vivax. Notwithstanding, overall malaria prevalence remains low (fewer than 1 case per 1000 persons). We used selective whole genome amplification to sequence 59 P. vivax samples from Panama. The P. vivax samples were collected from two periods (2007–2009 and 2017–2019) to study the population structure and transmission dynamics of the parasite. Imported cases resulting from increased levels of human migration could threaten malaria elimination prospects, and four of the samples evaluated came from individuals with travel history. We explored patterns of recent common ancestry among the samples and observed that a highly genetically related lineage (termed CL1) was dominant among the samples (47 out of 59 samples with good sequencing coverage), spanning the entire period of the collection (2007–2019) and all regions of the country. We also found a second, smaller clonal lineage (termed CL2) of four parasites collected between 2017 and 2019. To explore the regional context of Panamanian P. vivax we conducted principal components analysis and constructed a neighbor-joining tree using these samples and samples collected worldwide from a previous study. Three of the four samples with travel history clustered with samples collected from their suspected country of origin (consistent with importation), while one appears to have been a result of local transmission. The small number of Panamanian P. vivax samples not belonging to either CL1 or CL2 clustered with samples collected from Colombia, suggesting they represent the genetically similar ancestral P. vivax population in Panama or were recently imported from Colombia. The low diversity we observe in Panama indicates that this parasite population has been previously subject to a severe bottleneck and may be eligible for elimination. Additionally, while we confirmed that P. vivax is imported to Panama from diverse geographic locations, the lack of impact from imported cases on the overall parasite population genomic profile suggests that onward transmission from such cases is limited and that imported cases may not presently pose a major barrier to elimination

Hormonal milieu at time of B cell activation controls duration of autoantibody response

A strong gender bias is seen in many autoimmune diseases including systemic lupus erythematosus (SLE). To investigate the basis for the female preponderance in SLE, we have been studying BALB/c mice in which B cells express the R4A heavy chain of an anti-DNA antibody in association with an endogenous light chain repertoire (R4Atg mice). In unmanipulated mice, approximately 5% of B cells express the R4A transgene. R4Atg mice do not spontaneously develop elevated serum titers of anti-DNA antibodies. Administration of either estradiol (E2) or prolactin (Pr) results in escape from tolerance of autoreactive B cells, expressed as an increase in transgene-expressing B cells and elevated serum titers of anti-DNA antibodies. We previously demonstrated that autoreactive B cells maturing in an estrogenic milieu develop as marginal zone (MZ) B cells; when these same B cells mature in the presence of increased prolactin, they develop as follicular (Fo) B cells. To determine the long term consequence of this differential maturation of DNA-reactive B cells, we treated R4Atg BALB/c mice with E2 or Pr for 6 weeks until serum titers of anti-DNA antibody were high, at which time hormonal exposure was discontinued. In E2-treated mice, the anti-DNA titers remained high even 3 months after discontinuation of hormone exposure. Nascent B cells underwent normal tolerance induction, but existing autoreactive MZ B cells persisted and continued to secrete autoantibody. In contrast, Pr caused only a short-term increase in anti-DNA antibody titers. By 3 months after cessation of hormone treatment, serum anti-DNA antibody titers and B cell subsets were indistinguishable from those in placebo (P) treated mice. These findings suggest that autoantibody responses are sustained for variable lengths of time depending on the B cell subset producing the autoantibodies. This observation may be relevant to understanding the heterogeneous presentation of patients with SLE and to the design of therapies targeting specific B-cell populations in autoimmune disease. (C) 2014 Elsevier Ltd. All rights reserved

The molecular basis of antimalarial drug resistance in Plasmodium vivax

Plasmodium vivax is the most geographically widespread cause of human malaria and is responsible for the majority of cases outside of the African continent. While great progress has been made towards eliminating human malaria, drug resistant parasite strains pose a threat towards continued progress. Resistance has arisen to multiple antimalarials in P. vivax, including to chloroquine, which is currently the first line therapy for P. vivax in most regions. Despite its importance, an understanding of the molecular mechanisms of drug resistance in this species remains elusive, in large part due to the complex biology of P. vivax and the lack of in vitro culture. In this review, we will cover the extent and challenges of measuring clinical and in vitro drug resistance in P. vivax. We will consider the roles of candidate drug resistance genes. We will highlight the development of molecular approaches for studying P. vivax biology that provide the opportunity to validate the role of putative drug resistance mutations as well as identify novel mechanisms of drug resistance in this understudied parasite. Validated molecular determinants and markers of drug resistance are essential for the rapid and cost-effective monitoring of drug resistance in P. vivax, and will be useful for optimizing drug regimens and for informing drug policy in control and elimination settings

A central role of plasmin in cardiac injury initiated by fetal exposure to maternal anti-Ro autoantibodies

Objective. Cardiac neonatal lupus (cardiac-NL), initiated by surface binding of anti-Ro60 autoantibodies to apoptotic cardiocytes during development, activates the urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) system. Subsequent accumulation of apoptotic cells and plasmin generation facilitates increased binding of anti-Ro60 by disrupting and cleaving circulating β2-glycoprotein I (β2GPI) thereby eliminating its protective effect. The association of soluble levels of components of the uPA/uPAR system with cardiac-NL was examined. Methods. Levels of the uPA/uPAR system were assessed by ELISA in cord blood and immunohistological evaluation of autopsies. Results. uPA, uPAR and plasminogen levels were each significantly higher in cord blood from cardiac-NL (n = 35) compared with non-cardiac-NL (n = 26) anti-Ro-exposed neonates: 3.3 ± 0.1 vs 1.9 ± 0.05 ng/ml (P < 0.0001), 6.6 ± 0.3 vs 2.1 ± 0.2 ng/ml (P < 0.0001) and 435 ± 34 vs 220 ± 19 ng/ml (P < 0.0001), respectively. In three twin pairs discordant for cardiac-NL, the twin with cardiac-NL had higher levels of uPA, uPAR and plasminogen than the unaffected twin (3.1 ± 0.1 vs 1.9 ± 0.05 ng/ml; P = 0.0086, 6.2 ± 1.4 vs 2.2 ± 0.7 ng/ml; P = 0.147 and 412 ± 61 vs 260 ± 27 ng/ml; P = 0.152, respectively). Immunohistological evaluation of three hearts from fetuses dying with cardiac-NL revealed macrophages and giant cells expressing uPA and plasminogen in the septal region. Conclusion. Increased soluble uPA, uPAR and plasminogen in cord blood and expression in affected tissue of fetuses with cardiac-NL supports the hypothesis that fetal cardiac injury is in part mediated by plasmin generation initiated by anti-Ro binding to the apoptotic cardiocyte.We thank the support of the Australian National Health and Medical Research Council Postgraduate Training Fellowship Grant 595989 and AHA Award #12POST9830005 (to J.H.R.) and the Clinician Scientist Award from the Doris Duke Charitable Foundation, Grant #2009040 (to M.K.H.). This work was supported by National Institutes of Health grants 1K01AR060302 (to P.B), RO1 AR42455- 16 and N01-AR-4-2271 (to J.P.B. and R.M.C.)

Achieving the endgame: Integrated NTD case searches.

Trachoma and Guinea Worm Disease (GWD) are neglected tropical diseases (NTD) slated for elimination as a public health problem and eradication respectively by the World Health Organization. As these programs wind down, uncovering the last cases becomes an urgent priority. In 2010, Ghana Health Services, along with The Carter Center, Sightsavers, and other partners, conducted integrated case searches for both GWD and the last stage of trachoma disease, trachomatous trichiasis (TT), as well as providing surgical treatment for TT to meet elimination (and eradication targets). House to house case searches for both diseases were conducted and two case management strategies were explored: a centralized referral to services method and a Point of Care (POC) delivery method. 835 suspected TT cases were discovered in the centralized method, of which 554 accepted surgery. 482 suspected TT cases were discovered in the POC method and all TT cases accepted surgery. The cost per TT case examined was lower in the POC searches compared to the centralized searches ($19.97 in the POC searches and$20.85 in the centralized searches). Both strategies resulted in high surgical uptake for TT surgery, with average uptakes of 72.4% and 83.9% for the centralized and POC searches respectively. We present here that house to house case searches offering services at POC are feasible and a potential tool for elimination and eradication programs nearing their end

The Impact of Onchocerciasis Control and Elimination Programs on the MDGs

<p>The Impact of Onchocerciasis Control and Elimination Programs on the MDGs</p