Reproductive health services in KwaZulu Natal, South Africa: A situation analysis study focusing on HIV/AIDS services

This Horizons report examines the readiness of reproductive health services in South Africa, which are primarily geared to women, to deliver HIV and AIDS treatment, care, and prevention services. The goal of the study was to obtain information from a representative sample of provincial health care facilities offering reproductive health services in KwaZulu Natal to meet the growing demand for HIV/AIDS-related services. Ninety-eight hospitals, community health centers, and clinics participated in the situation analysis that identified gaps in service delivery and determined priorities for service integration. Results of the study were presented to a large audience of Department of Health, NGO, and donor agency staff with the hope that this workshop would set a trend for feedback and the use of research for service improvement

Ethanol Consumption Induces Nonspecific Inflammation and Functional Defects in Alveolar Macrophages.

Chronic alcohol drinking is associated with increased susceptibility to viral and bacterial respiratory pathogens. In this study, we use a rhesus macaque model of voluntary ethanol self-administration to study the effects of long-term alcohol drinking on the immunological landscape of the lung. We report a heightened inflammatory state in alveolar macrophages (AMs) obtained from ethanol (EtOH)-drinking animals that is accompanied by increased chromatin accessibility in intergenic regions that regulate inflammatory genes and contain binding motifs for transcription factors AP-1, IRF8, and NFKB p-65. In line with these transcriptional and epigenetic changes at the basal state, AMs from EtOH-drinking animals generate elevated inflammatory mediator responses to lipopolysaccharides and respiratory syncytial virus. However, the transcriptional analysis revealed an inefficient induction of interferon-stimulated genes with EtOH in response to the respiratory syncytial virus, suggesting disruption of antimicrobial defenses. Correspondingly, AMs from EtOH-drinking animals exhibited transcriptional shifts indicative of increased oxidative stress and oxidative phosphorylation, which was coupled with higher cytosolic reactive oxygen species and mitochondrial potential. This heightened oxidative stress state was accompanied by decreased ability to phagocytose bacteria. Bulk RNA and assay for transposase-accessible chromatin sequencing data further revealed reduced expression and chromatin accessibility of loci associated with tissue repair and maintenance with chronic EtOH drinking. Similarly, analysis of single-cell RNA sequencing data revealed shifts in cell states from tissue maintenance to inflammatory responses with EtOH. Collectively, these data provide novel insight into mechanisms by which chronic EtOH drinking increases susceptibility to infection in patients with alcohol use disorders

Profiling of extracellular vesicle‐bound miRNA to identify candidate biomarkers of chronic alcohol drinking in nonhuman primates

BackgroundLong-term alcohol drinking is associated with numerous health complications including susceptibility to infection, cancer, and organ damage. However, due to the complex nature of human drinking behavior, it has been challenging to identify reliable biomarkers of alcohol drinking behavior prior to signs of overt organ damage. Recently, extracellular vesicle-bound microRNAs (EV-miRNAs) have been found to be consistent biomarkers of conditions that include cancer and liver disease.MethodsIn this study, we profiled the plasma EV-miRNA content by miRNA-Seq from 80 nonhuman primates after 12 months of voluntary alcohol drinking.ResultsWe identified a list of up- and downregulated EV-miRNA candidate biomarkers of heavy drinking and those positively correlated with ethanol dose. We overexpressed these candidate miRNAs in control primary peripheral immune cells to assess their potential functional mechanisms. We found that overexpression of miR-155, miR-154, miR-34c, miR-450a, and miR-204 led to increased production of the inflammatory cytokines TNFα or IL-6 in peripheral blood mononuclear cells after stimulation.ConclusionThis exploratory study identified several EV-miRNAs that could serve as biomarkers of long-term alcohol drinking and provide a mechanism to explain alcohol-induced peripheral inflammation

Sea quark effects in B Spectroscopy and Decay Constants

We present comprehensive results for the spectrum and decay constants of hadrons containing a single b quark. The heavy quark is simulated using an $O(1/M)$ NRQCD action and the light quark using the $O(a)$ tadpole-improved clover action on gauge configurations containing two degenerate flavours of sea quarks at $\beta^{n_f=2}=5.6$ provided by the HEMCGC collaboration. We present detailed results for the lower lying $S$ and $P$ wave $B$ meson states and the $\Lambda_b$ baryon. We find broad agreement with experiment. In addition, we present results for the pseudoscalar and, for the first time, the vector decay constants fully consistent to $O(\alpha/M): f_B = 186(5)(stat)(19)(pert)(9)(disc)(13)(NRQCD)(+50)(a^{-1})MeV, f_B^* = 181(6) (stat)(18)(pert)(9)(disc)(13)(NRQCD)(+55)(a^{-1})MeV$ and $f_{B_s}/f_B = 1.14(2)(stat)(-2)(\kappa_s)$. We present an investigation of sea quark effects in the $B$ spectrum and decay constants. We compare our results with those from similar quenched simulations at $\beta^{n_f=0}=6.0$. For the spectrum, the quenched results reproduce the experimental spectrum well and there is no significant difference between the quenched and $n_f=2$ results. For the decay constants, our results suggest that sea quark effects may be large. We find that $f_B$ increases by approximately 25% between $n_f=0$ and $n_f=2$.Comment: 49 pages, 16 figures, revtex, the discussion of systematic errors and the comparison of the pseudoscalar decay constant at nf=0 and nf=2 has been expande

The ABCD of usability testing

We introduce a methodology for tracking and auditing feedback, errors and suggestions for software packages. This short paper describes how we innovate on the evaluation mechanism, introducing an (Antecedent, Barrier, Consequence and Development) ABCD form, embedded within an eParticipation platform to enable end users to easily report on any usability issues. This methodology will be utilised to improve the STEP cloud eParticipation platform (part of the current STEP Horizon2020 project http://step4youth.eu. The platform is currently being piloted in real life contexts, with the participation of public authorities that are integrating the eParticipation platform into their regular decision-making practices. The project is involving young people, through engagement and motivation strategies and giving them a voice in Environmental decision making at the local level. The pilot evaluation aims to demonstrate how open engagement needs to be embedded within public sector processes and the usability methodology reported here will help to identify the key barriers for wide scale deployment of the platform

Heavy-light Mesons and Baryons with b quarks

We present lattice results for the spectrum of mesons containing one heavy quark and of baryons containing one or two heavy quarks. The calculation is done in the quenched approximation using the NRQCD formalism for the heavy quark. We analyze the dependence of the mass splittings on both the heavy and the light quark masses. Meson P-state fine structure and baryon hyperfine splittings are resolved for the first time. We fix the b quark mass using both M_B and M_{\Lambda_b}, and our best estimate is m_b^\MSbar(m_b^\MSbar) = 4.35(10)({}^{-3}_{+2})(10) GeV. The spectrum, obtained by interpolation to m_b, is compared with the experimental data.Comment: 34 pages, LaTeX, 13 postscript figures, version as publish in Phys. Rev.

Scaling of the B and D meson spectrum in lattice QCD

We give results for the $B$ and the $D$ meson spectrum using NRQCD on the lattice in the quenched approximation. The masses of radially and orbitally excited states are calculated as well as $S$-wave hyperfine and $P$-wave fine structure. Radially excited $P$-states are observed for the first time. Radial and orbital excitation energies match well to experiment, as does the strange-non-strange $S$-wave splitting. We compare the light and heavy quark mass dependence of various splittings to experiment. Our $B$-results cover a range in lattice spacings of more than a factor of two. Our $D$-results are from a single lattice spacing and we compare them to numbers in the literature from finer lattices using other methods. We see no significant dependence of physical results on the lattice spacing. PACS: 11.15.Ha 12.38.Gc 14.40.Lb 14.40.NdComment: 78 pages, 29 tables, 30 figures Revised version. Minor corrections to spelling and wordin

A Prospective Longitudinal Study of the Clinical Outcomes from Cryptococcal Meningitis following Treatment Induction with 800 mg Oral Fluconazole in Blantyre, Malawi

Introduction: Cryptococcal meningitis is the most common neurological infection in HIV infected patients in Sub Saharan Africa, where gold standard treatment with intravenous amphotericin B and 5 flucytosine is often unavailable or difficult to administer. Fluconazole monotherapy is frequently recommended in national guidelines but is a fungistatic drug compromised by uncertainty over optimal dosing and a paucity of clinical end-point outcome data. Methods: From July 2010 until March 2011, HIV infected adults with a first episode of cryptococcal meningitis were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients were treated with oral fluconazole monotherapy 800 mg daily, as per national guidelines. ART was started at 4 weeks. Outcomes and factors associated with treatment failure were assessed 4, 10 and 52 weeks after fluconazole initiation. Results: Sixty patients were recruited. 26/60 (43%) died by 4 weeks. 35/60 (58.0%) and 43/56 (77%) died or failed treatment by 10 or 52 weeks respectively. Reduced consciousness (Glasgow Coma Score ,14 of 15), moderate/severe neurological disability (modified Rankin Score .3 of 5) and confusion (Abbreviated Mental Test Score ,8 of 10) were all common at baseline and associated with death or treatment failure. ART prior to recruitment was not associated with better outcomes. Conclusions: Mortality and treatment failure from cryptococcal meningitis following initiation of treatment with 800 mg oral fluconazole is unacceptably high. To improve outcomes, there is an urgent need for better therapeutic strategies and point-of-care diagnostics, allowing earlier diagnosis before development of neurological deficit

The Toxoplasma gondii mitochondrial transporter ABCB7L is essential for the biogenesis of cytosolic and nuclear iron-sulfur cluster proteins and cytosolic translation

Iron-sulfur (Fe-S) clusters are ubiquitous inorganic cofactors required for numerous essential cellular pathways. Since they cannot be scavenged from the environment, Fe-S clusters are synthesized de novo in cellular compartments such as the apicoplast, mitochondrion, and cytosol. The cytosolic Fe-S cluster biosynthesis pathway relies on the transport of an intermediate from the mitochondrial pathway. An ATP-binding cassette (ABC) transporter called ABCB7 is responsible for this role in numerous commonly studied organisms, but its role in the medically important apicomplexan parasites has not yet been studied. Here we identify and characterize a Toxoplasma gondii ABCB7 homolog, which we name ABCB7-like (ABCB7L). Genetic depletion shows that it is essential for parasite growth and that its disruption triggers partial stage conversion. Characterization of the knock-down line highlights a defect in the biogenesis of cytosolic and nuclear Fe-S proteins leading to defects in protein translation and other pathways including DNA and RNA replication and metabolism. Our work provides support for a broad conservation of the connection between mitochondrial and cytosolic pathways in Fe-S cluster biosynthesis and reveals its importance for parasite survival

Quantification of macrophage-driven inflammation during myocardial infarction with 18F-LW223, a novel TSPO radiotracer with binding independent of the rs6971 human polymorphism

Myocardial infarction (MI) is one of the leading causes of death worldwide, and inflammation is central to tissue response and patient outcomes. The 18-kDa translocator protein (TSPO) has been used in PET as an inflammatory biomarker. The aims of this study were to screen novel, fluorinated, TSPO radiotracers for susceptibility to the rs6971 genetic polymorphism using in vitro competition binding assays in human brain and heart; assess whether the in vivo characteristics of our lead radiotracer, 18F-LW223, are suitable for clinical translation; and validate whether 18F-LW223 can detect macrophage-driven inflammation in a rat MI model. Methods: Fifty-one human brain and 29 human heart tissue samples were screened for the rs6971 polymorphism. Competition binding assays were conducted with 3H-PK11195 and the following ligands: PK11195, PBR28, and our novel compounds (AB5186 and LW223). Naïve rats and mice were used for in vivo PET kinetic studies, radiometabolite studies, and dosimetry experiments. Rats underwent permanent coronary artery ligation and were scanned using PET/CT with an invasive input function at 7 d after MI. For quantification of PET signal in the hypoperfused myocardium, K1 (rate constant for transfer from arterial plasma to tissues) was used as a surrogate marker of perfusion to correct the binding potential for impaired radiotracer transfer from plasma to tissue (BPTC). Results: LW223 binding to TSPO was not susceptible to the rs6971 genetic polymorphism in human brain and heart samples. In rodents, 18F-LW223 displayed a specific uptake consistent with TSPO expression, a slow metabolism in blood (69% of parent at 120 min), a high plasma free fraction of 38.5%, and a suitable dosimetry profile (effective dose of 20.5–24.5 μSv/MBq). 18F-LW223 BPTC was significantly higher in the MI cohort within the infarct territory of the anterior wall relative to the anterior wall of naïve animals (32.7 ± 5.0 vs. 10.0 ± 2.4 cm3/mL/min, P ≤ 0.001). Ex vivo immunofluorescent staining for TSPO and CD68 (macrophage marker) resulted in the same pattern seen with in vivo BPTC analysis. Conclusion: 18F-LW223 is not susceptible to the rs6971 genetic polymorphism in in vitro assays, has favorable in vivo characteristics, and is able to accurately map macrophage-driven inflammation after MI