Blood and body fluids exposure, post-exposure prophylaxis, and HIV self-testing among healthcare workers in northern Nigeria.

INTRODUCTION: In high-HIV burden settings, such as Nigeria, HIV self-testing and post-exposure prophylaxis (PEP) are often recommended, but not widely practiced. This study aims to identify the predictors of PEP utilization and preferences for HIV self-testing among healthcare workers in Nigeria. METHODS: A total of 403 healthcare workers from a tertiary hospital in Nigeria completed questionnaires. Adjusted odds ratios were derived from logistic regression models. RESULTS: Among the respondents, 141 (35.0%) reported experiencing at least one workplace exposure incident, with 72 (51.1%) of them receiving PEP. The majority of healthcare workers (n = 354, 87.8%) expressed a preference for HIV self-testing over traditional HIV testing and counseling. The occurrence of exposure incidents was predicted by the respondent's sex (adjusted odds ratio [aOR] = 1.25; 95% confidence interval [CI]: 1.15-3.08, female vs. male), age (aOR = 0. 16; 95% CI: 0.03-0.92, >40 vs. <30 years), profession (aOR = 1.88; 95% CI: 1.18-4.66, nurse/midwife vs. physician), work unit (aOR = 0.06; 95% CI: 0.02-0.23, obstetrics/gynecology vs. surgery), and previous HIV testing and counseling (aOR = 0.01; 95% Cl: 0.004-0.03, no vs. yes). Respondent's profession, work unit, and previous HIV testing and counseling independently predicted a preference for HIV self-testing. CONCLUSION: Further exploration of the feasibility of implementing HIV self-testing as an alternative to traditional HIV testing and counseling for workplace exposures is warranted.

Unravelling the utility of modern sulfonylureas from cardiovascular outcome trials and landmark trials: expert opinion from an international panel.

AIM: The primary objective of this review is to develop practice-based expert group opinions on the cardiovascular (CV) safety and utility of modern sulfonylureas (SUs) in cardiovascular outcome trials (CVOTs). BACKGROUND: The United States Food and Drug Administration issued new guidance to the pharmaceutical industry in 2008 regarding the development of new antihyperglycemic drugs. The guidance expanded the scope for the approval of novel antihyperglycemic drugs by mandating CVOTs for safety. A few long-term CVOTs on dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium-glucose cotransporter 2 inhibitors have been completed, while others are ongoing. SUs, which constitute one of the key antihyperglycemic agents used for the management of type 2 diabetes mellitus (T2DM), have been used as comparator agents in several CVOTs. However, the need for CVOTs on modern SUs remains debatable. In this context, a multinational group of endocrinologists convened for a meeting and discussed the need for CVOTs of modern SUs to evaluate their utility in the management of patients with T2DM. At the meeting, CVOTs of modern SUs conducted to date and the hypotheses derived from the results of these trials were discussed. REVIEW RESULTS: The expert group analyzed the key trials emphasizing the CV safety of modern SUs and also reviewed the results of various CVOTs in which modern SUs were used as comparators. Based on literature evidence and individual clinical insights, the expert group opined that modern SUs are cardiosafe and that since they have been used as comparators in other CVOTs, CVOTs of SUs are not required. CONCLUSION: Modern SUs can be considered a cardiosafe option for the management of patients with diabetes mellitus and CV disease; thus CVOTs among individuals with T2DM are not required.

Fixed-dose combination in management of type 2 diabetes mellitus: Expert opinion from an international panel.

Type 2 diabetes mellitus (T2DM) is a progressive disease with multifactorial etiology. The first-line therapy includes monotherapy (with metformin), which often fails to provide effective glycemic control, necessitating the addition of add-on therapy. In this regard, multiple single-dose agents formulated as a single-dose form called fixed-dose combinations (FDCs) have been evaluated for their safety, efficacy, and tolerability. The primary objective of this review is to develop practice-based expert group opinion on the current status and the causes of concern regarding the irrational use of FDCs, in Indian settings. After due discussions, the expert group analyzed the results from several clinical evidence in which various fixed combinations were used in T2DM management. The panel opined that FDCs (double or triple) improve patient adherence, reduce cost, and provide effective glycemic control and, thereby, play an important role in the management of T2DM. The expert group strongly recommended that the irrational metformin FDC's, banned by Indian government, should be stopped and could be achieved through active participation from the government, regulatory bodies, and health ministry, and through continuous education of primary care physicians and pharmacists. In T2DM management, FDCs play a crucial role in achieving glycemic targets effectively. However, understanding the difference between rational and irrational FDC combinations is necessary from the safety, efficacy, and tolerability perspective. In this regard, primary care physicians will have to use a multistep approach so that they can take informed decisions.

Repeated semen exposure decreases cervicovaginal SIVmac251 infection in rhesus macaques.

Semen is the vehicle for virion dissemination in the female reproductive tract (FRT) in male-to-female HIV transmission. Recent data suggests that higher frequency semen exposure is associated with activation of anti-HIV mechanisms in HIV negative sex workers. Here, we use a non-human primate (NHP) model to show that repeated vaginal exposure to semen significantly reduces subsequent infection by repeated low-dose vaginal SIVmac251 challenge. Repeated semen exposures result in lower CCR5 expression in circulating CD4+ T-cells, as well as higher expression of Mx1 (in correlation with IFNε expression) and FoxP3 in the cervicovaginal mucosa, and increased infiltration of CD4+ T-cells. Establishing in vivo evidence of competing effects of semen on transmission impacts our basic understanding of what factors may determine HIV infectivity in humans. Our results clearly indicate that repeated semen exposure can profoundly modulate the FRT microenvironment, paradoxically promoting host resistance against HIV acquisition.

Vaccine-Mediated Inhibition of the Transporter Associated with Antigen Processing Is Insufficient To Induce Major Histocompatibility Complex E-Restricted CD8+ T Cells in Nonhuman Primates.

Major histocompatibility complex E (MHC-E) is a highly conserved nonclassical MHC-Ib molecule that tightly binds peptides derived from leader sequences of classical MHC-Ia molecules for presentation to natural killer cells. However, MHC-E also binds diverse foreign and neoplastic self-peptide antigens for presentation to CD8+ T cells. Although the determinants of MHC-E-restricted T cell priming remain unknown, these cells are induced in humans infected with pathogens containing genes that inhibit the transporter associated with antigen processing (TAP). Indeed, mice vaccinated with TAP-inhibited autologous dendritic cells develop T cells restricted by the murine MHC-E homologue, Qa-1b. Here, we tested whether rhesus macaques (RM) vaccinated with viral constructs expressing a TAP inhibitor would develop insert-specific MHC-E-restricted CD8+ T cells. We generated viral constructs coexpressing SIVmac239 Gag in addition to one of three TAP inhibitors: herpes simplex virus 2 ICP47, bovine herpes virus 1 UL49.5, or rhesus cytomegalovirus Rh185. Each TAP inhibitor reduced surface expression of MHC-Ia molecules but did not reduce surface MHC-E expression. In agreement with modulation of surface MHC-Ia levels, TAP inhibition diminished presentation of MHC-Ia-restricted CD8+ T cell epitopes without impacting presentation of peptide antigen bound by MHC-E. Vaccination of macaques with vectors dually expressing SIVmac239 Gag with ICP47, UL49.5, or Rh185 generated Gag-specific CD8+ T cells classically restricted by MHC-Ia but not MHC-E. These data demonstrate that, in contrast to results in mice, TAP inhibition alone is insufficient for priming of MHC-E-restricted T cell responses in primates and suggest that additional unknown mechanisms govern the induction of CD8+ T cells recognizing MHC-E-bound antigen.IMPORTANCE Due to the near monomorphic nature of MHC-E in the human population and inability of many pathogens to inhibit MHC-E-mediated peptide presentation, MHC-E-restricted T cells have become an attractive vaccine target. However, little is known concerning how these cells are induced. Understanding the underlying mechanisms that induce these T cells would provide a powerful new vaccine strategy to an array of neoplasms and viral and bacterial pathogens. Recent studies have indicated a link between TAP inhibition and induction of MHC-E-restricted T cells. The significance of our research is in demonstrating that TAP inhibition alone does not prime MHC-E-restricted T cell generation and suggests that other, currently unknown mechanisms regulate their induction.

Adherence to Point-of-Use Water Treatment over Short-Term Implementation: Parallel Crossover Trials of Flocculation-Disinfection Sachets in Pakistan and Zambia.

The health benefits of point-of-use (POU) water treatment can only be realized through high adherence: correct, consistent, and sustained use. We conducted parallel randomized, longitudinal crossover trials measuring short-term adherence to two single-use flocculant-disinfectant sachets in Pakistan and Zambia. In both trials, adherence declined sharply for both products over the eight week surveillance periods, with overall lower adherence to both products in Zambia. There was no significant difference in adherence between the two products. Estimated median daily production of treated water dropped over the crossover period from 2.5 to 1.4 L person-1 day-1 (46% decline) in Pakistan and from 1.4 to 1.1 L person-1 day-1 (21% decline) in Zambia. The percentage of surveillance points with detectable total chlorine in household drinking water declined from 70% to 49% in Pakistan and rose marginally from 28% to 30% in Zambia. The relatively low and decreasing adherence observed in this study suggests that these products would have provided little protection from waterborne disease risk in these settings. Our findings underscore the challenge of achieving high adherence to POU water treatment, even under conditions of short-term adoption with intensive follow-up.

The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques.

MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds pathogen-derived peptide Ags for presentation to CD8+ T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology. In this study, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently upregulated by viral pathogens, and bound and presented identical peptides to CD8+ T cells. Indeed, SIV-specific, Mamu-E-restricted CD8+ T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4+ T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E-restricted T cell immunobiology.

Laboratory evaluation of a new coagulant/disinfectant point-of-use water treatment product for emergencies.

AIMS: There is emerging evidence that point-of-use (POU) water treatment can be effective in the improvement of microbial water quality and the decrease in diarrhoeal disease incidence in humanitarian emergencies. Coagulant/disinfection products (CDPs) have the distinct advantage of providing microbial quality improvement, turbidity reductions and a free chlorine residual (FCR). The laboratory treatment performance of a novel CDP, the 'Pureit(®) ' sachet, has been evaluated under different water quality conditions. METHODS AND RESULTS: The CDP performance was evaluated with regard to bacteriological humanitarian water quality objectives as well as the recent World Health Organization recommendations for evaluating POU water treatment options. At least 4 log10 reductions of tested bacterial indicators for a 'highly protective' status were attained in the tested conditions. Treated waters were consistently below 10 MPN per 100 ml with regard to final Escherichia coli concentrations (i.e. 'low risk') with majority of samples with no detectable E. coli (i.e. 'very low risk'). Attainment of the target FCR levels (at least 0·5 and 0·2 mg l(-1) after 0·5 and 24 h respectively) was dependant on the test water matrix. FCRs are thought to have been affected by the product's formulation, which contains a quenching agent intended to reduce chlorinous tastes. Treated water turbidity levels were marginally above the nonhealth-based target of five nephelometric turbidity units, partially due to the filtration cloth employed. CONCLUSIONS: This study has served to identify the performance envelopes of the CDP under challenging conditions. In particular, initial alkaline pHs negatively affected this product's performance with regard to bacterial log10 reductions. SIGNIFICANCE AND IMPACT OF THE STUDY: This CDP has the potential to attain humanitarian drinking water quality objectives when not operating under extreme conditions; consistently achieving E. coli log10 reductions between 4·5 and 5·2 resulting in treated water with E. coli concentrations mostly below the <1 MPN per 100 ml target level.

Water quality risks of 'improved' water sources: evidence from Cambodia.

OBJECTIVES: The objective of this study was to investigate the quality of on-plot piped water and rainwater at the point of consumption in an area with rapidly expanding coverage of 'improved' water sources. METHODS: Cross-sectional study of 914 peri-urban households in Kandal Province, Cambodia, between July-August 2011. We collected data from all households on water management, drinking water quality and factors potentially related to post-collection water contamination. Drinking water samples were taken directly from a subsample of household taps (n = 143), stored tap water (n = 124), other stored water (n = 92) and treated stored water (n = 79) for basic water quality analysis for Escherichia coli and other parameters. RESULTS: Household drinking water management was complex, with different sources used at any given time and across seasons. Rainwater was the most commonly used drinking water source. Households mixed different water sources in storage containers, including 'improved' with 'unimproved' sources. Piped water from taps deteriorated during storage (P < 0.0005), from 520 cfu/100 ml (coefficient of variation, CV: 5.7) E. coli to 1100 cfu/100 ml (CV: 3.4). Stored non-piped water (primarily rainwater) had a mean E. coli count of 1500 cfu/100 ml (CV: 4.1), not significantly different from stored piped water (P = 0.20). Microbial contamination of stored water was significantly associated with observed storage and handling practices, including dipping hands or receptacles in water (P < 0.005), and having an uncovered storage container (P = 0.052). CONCLUSIONS: The microbial quality of 'improved' water sources in our study area was not maintained at the point of consumption, possibly due to a combination of mixing water sources at the household level, unsafe storage and handling practices, and inadequately treated piped-to-plot water. These results have implications for refining international targets for safe drinking water access as well as the assumptions underlying global burden of disease estimates, which posit that 'improved' sources pose minimal risks of diarrhoeal diseases.

Serial cervicovaginal exposures with replication-deficient SIVsm induce higher dendritic cell (pDC) and CD4+ T-cell infiltrates not associated with prevention but a more severe SIVmac251 infection of rhesus macaques.

OBJECTIVE: Intravaginal exposure to simian immunodeficiency virus (SIV) acutely recruits interferon-alpha (IFN-α) producing plasmacytoid dendritic cells (pDC) and CD4 T-lymphocyte targets to the endocervix of nonhuman primates. We tested the impact of repeated cervicovaginal exposures to noninfectious, defective SIV particles over 72 hours on a subsequent cervicovaginal challenge with replication competent SIV. METHODS: Thirty-four female Indian Rhesus macaques were given a 3-day twice-daily vaginal exposures to either SIVsmB7, a replication-deficient derivative of SIVsmH3 produced by a T lymphoblast CEMx174 cell clone (n = 16), or to CEM supernatant controls (n = 18). On the fourth day, animals were either euthanized to assess cervicovaginal immune cell infiltration or intravaginally challenged with SIVmac251. Challenged animals were tracked for plasma viral load and CD4 counts and euthanized at 42 days after infection. RESULTS: At the time of challenge, macaques exposed to SIVsmB7, had higher levels of cervical CD123 pDCs (P = 0.032) and CD4 T cells (P = 0.036) than those exposed to CEM control. Vaginal tissues showed a significant increase in CD4 T-cell infiltrates (P = 0.048) and a trend toward increased CD68 cellular infiltrates. After challenge, 12 SIVsmB7-treated macaques showed 2.5-fold greater daily rate of CD4 decline (P = 0.0408), and viral load rise (P = 0.0036) as compared with 12 control animals. CONCLUSIONS: Repeated nonproductive exposure to viral particles within a short daily time frame did not protect against infection despite pDC recruitment, resulting instead in an accelerated CD4 T-cell loss with an increased rate of viral replication.

Antioxidant status and lipid peroxidation activity in evaluating hepatocellular damage in children.

Serum levels of glutathione reductase (GR), glutathione S-transferase-alpha (GST-alpha) and malondialdehyde (MDA) were determined to evaluate their use in diagnosing hepatocellular damage in 75 children with liver disease. Except for level of GR in patients with HBV, GR, GST-alpha and MDA were raised significantly in patients compared with controls. At 100% specificity, the sensitivity of the 3 markers for detecting hepatitis B virus, hepatitis C virus and schistosomiasis infection respectively were: 16.7%, 100.0% and 17.7% for GR; 33.3%, 62.1% and 38.2% for GST-alpha; and 25.0%, 10.3% and 29.4% for MDA. GR was more sensitive in hepatitis C infection, while MDA reflected changes in liver ultrasound and GST-alpha was the best indicator for histopathological changes.

Antioxidant status and lipid peroxidation activity in evaluating hepatocellular damage in children

Serum levels of glutathione reductase [GR], glutathione S-transferase-alpha [GST-alpha] and malondialdehyde [MDA] were determined to evaluate their use in diagnosing hepatocellular damage in 75 children with liver disease. Except for level of GR in patients with HBV, GR, GST-alpha and MDA were raised significantly in patients compared with controls. At 100% specificity, the sensitivity of the 3 markers for detecting hepatitis B virus, hepatitis C virus and schistosomiasis infection respectively were: 16.7%, 100.0% and 17.7% for GR; 33.3%, 62.1% and 38.2% for GST-alpha; and 25.0%, 10.3% and 29.4% for MDA. GR was more sensitive in hepatitis C infection, while MDA reflected changes in liver ultrasound and GST-alpha was the best indicator for histopathological changes

DNA vaccines: developing new strategies to enhance immune responses.

We have focused our research on understanding the basic biology of and developing novel therapeutic and prophylactic DNA vaccines. We have among others three distinct primary areas of interest which include: 1. Enhancing in vivo delivery and transfection of DNA vaccine vectors 2. Improving DNA vaccine construct immunogenicity 3. Using molecular adjuvants to modulate and skew immune responses. Key to the immunogenicity of DNA vaccines is the presentation of expressed antigen to antigen-presenting cells. To improve expression and presentation of antigen, we have investigated various immunization methods with current focus on a combination of intramuscular injection and electroporation. To improve our vaccine constructs, we also employed methods such as RNA/codon optimization and antigen consensus to enhance expression and cellular/humoral cross-reactivity, respectively. Our lab also researches the potential of various molecular adjuvants to skew Th1/Th2 responses, enhance cellular/humoral responses, and improve protection in various animal models. Through improving our understanding of basic immunology as it is related to DNA vaccine technology, our goal is to develop the technology to the point of utility for human and animal health.

Bifunctional yttrium(III) and titanium(IV) NHC catalysts for lactide polymerisation.

Lewis acidic yttrium(III) and titanium(IV) derivatives of anionic, metal-tethered carbenes apparently act as bifunctional catalysts for the polymerisation of D,L-lactide, using a combination of Lewis acid and base functionalities to initiate ring opening of the cyclic monomer; the alcohol- and amino-functionalised carbenes from which they derive provide models for the first insertion step, and also display metal-free polymerisation catalysis to generate polylactic acid.

Bent metal carbene geometries in amido N-heterocyclic carbene complexes.

Lithium(I) and uranium(VI) amido-tethered Bu(t)-substituted N-heterocyclic carbene (NHC) complexes exhibit very distorted metal-carbene bonds; the corresponding magnesium(II) and mesityl-substituted NHC uranium(VI) complexes are undistorted; the distortion does not affect the ligand binding strength, suggesting a dominance of electrostatic character in closed-shell electropositive metal-carbene bonds.