Evaluating the Impact of Zimbabwe’s Prevention of Mother-to-Child HIV Transmission Program: Population-Level Estimates of HIV-Free Infant Survival Pre-Option A

Objective

We estimated HIV-free infant survival and mother-to-child HIV transmission (MTCT) rates in Zimbabwe, some of the first community-based estimates from a UNAIDS priority country.

Methods

In 2012 we surveyed mother-infant pairs residing in the catchment areas of 157 health facilities randomly selected from 5 of 10 provinces in Zimbabwe. Enrolled infants were born 9–18 months before the survey. We collected questionnaires, blood samples for HIV testing, and verbal autopsies for deceased mothers/infants. Estimates were assessed among i) all HIV-exposed infants, as part of an impact evaluation of Option A of the 2010 WHO guidelines (rolled out in Zimbabwe in 2011), and ii) the subgroup of infants unexposed to Option A. We compared province-level MTCT rates measured among women in the community with MTCT rates measured using program monitoring data from facilities serving those communities.

Findings

Among 8568 women with known HIV serostatus, 1107 (12.9%) were HIV-infected. Among all HIV-exposed infants, HIV-free infant survival was 90.9% (95% confidence interval (CI): 88.7–92.7) and MTCT was 8.8% (95% CI: 6.9–11.1). Sixty-six percent of HIV-exposed infants were still breastfeeding. Among the 762 infants born before Option A was implemented, 90.5% (95% CI: 88.1–92.5) were alive and HIV-uninfected at 9–18 months of age, and 9.1% (95%CI: 7.1–11.7) were HIV-infected. In four provinces, the community-based MTCT rate was higher than the facility-based MTCT rate. In Harare, the community and facility-based rates were 6.0% and 9.1%, respectively.

Conclusion

By 2012 Zimbabwe had made substantial progress towards the elimination of MTCT. Our HIV-free infant survival and MTCT estimates capture HIV transmissions during pregnancy, delivery and breastfeeding regardless of whether or not mothers accessed health services. These estimates also provide a baseline against which to measure the impact of Option A guidelines (and subsequently Option B+).     

Structure-activity relationships of precursors and analogs of natural 3-enoyl-tetramic acids

Fragments and synthetic precursors prepared en route to the macrocyclic 3-acyltetramic acids (=3-acyl-1,5-dihydro-4-hydroxy-2H-pyrrol-2-ones) aburatubolactam and macrocidin A, as well as other analogs with variance in the ring heteroatom (N, O, S), and the residues at N(1), C(3), and C(5) were tested for cytotoxic and antimicrobial effects. Anticancer activity against various tumor cell lines in vitro did not necessarily require an intact pyrrolidin-2,4-dione ring. An acyclic β-hydroxy-octatrienoyl amide precursor to aburatubolactam also exhibited distinct activity with an IC?? (120?h) value of <2.5?μM. The length of 3-oligoenoyl residues had little influence on the anticancer activity, but 3-alka-oligoenoyl tetramic acids were far more efficacious than their 3-(4-methoxycinnamoyl) congeners. N-H-3-acyltetramic acids were generally more active than their N-Me or N-Boc analogs, unless further polar groups necessitated an increased lipophilicity for sufficient uptake. Tetronic and thiotetronic acids were far less antiproliferative in cancer cells when compared with identically substituted tetramic acids.     

Hematology and serum chemistry in stranded and wild-caught harbor seals in central California: reference intervals, predictors of survival, and parameters affecting blood variables

Blood was collected from stranded harbor seal (Phoca vitulina) pups at admission (n=64) and release (n=45) from rehabilitation in 2007 and 2008 and from wild-caught harbor seal pups, subadults, and adults (n=110) in 2004, 2007, and 2008. Blood values measured at the time of admission were not predictive of survival during rehabilitation. Mass was associated with survival until release, and all pups that died weighed less than 10 kg at the time of admission. D?hle bodies were observed in leukocytes from 15% to 22% of the pups in rehabilitation, but not in the wild pups. Thresholds (95% confidence intervals) among wild pups were less than those in the released pups for leukocytes, neutrophils, total cholesterol, alanine aminotransferase (ALT), glucose, phosphorus, sodium, potassium, total protein, albumin, and globulin; thresholds were greater in wild pups than in released pups for hemoglobin (HGB), hematocrit (HCT), and glucose. Thresholds among released pups were less than those in wild pups for HGB, HCT, mean cell volume, chloride, and creatine kinase; thresholds among released pups were greater than those in wild pups for neutrophils, platelets, total cholesterol, triglycerides, ALT, aspartate aminotransferase, sorbitol dehydrogenase, bilirubin, phosphorus, potassium, total protein, and albumin. Age, girth, and geographic location affected the blood variables from wild-caught pups; age class, geographic location, sex, and body condition affected the blood variables of wild-caught, subadult and adult harbor seals.     

The C-terminal regulatory domain is required for catalysis by Neisseria meningitidis α-isopropylmalate synthase

α-Isopropylmalate synthase (α-IPMS) catalyses the first committed step in leucine biosynthesis in many pathogenic bacteria, including Neisseria meningitidis. This enzyme (NmeIPMS) has been purified, characterised, and compared to α-IPMS proteins from other bacteria. NmeIPMS is a homodimer which catalyses the condensation of α-ketoisovalerate (α-KIV) and acetyl coenzyme A (AcCoA), and is inhibited by leucine. NmeIPMS can use alternate α-ketoacids as substrates and, in contrast to α-IPMS from other sources, is activated by a range of metal ions including Cd²⁺ and Zn²⁺ that have previously been reported as inhibitory, since they suppress the dithiodipyridone assay system rather than the enzyme itself. Previous studies indicate that α-IPMS is a TIM barrel enzyme with an allosteric leucine-binding domain. To assess the importance of this domain, a truncated form of NmeIPMS was generated and characterised. Loss of the regulatory domain resulted in a loss of the ability to catalyse the aldol reaction, although the enzyme was still able to slowly hydrolyse AcCoA independently of α-KIV at a rate similar to that of the WT enzyme. This implies that the regulatory domain is not only required for control of enzymatic activity but may assist in the positioning of key residues in the catalytic TIM barrel. The importance of this domain to catalytic function may offer new strategies for inhibitor design.     

Quantification of the oxidative damage biomarker 2,3-dinor-8-isoprostaglandin-F2α in human urine using liquid chromatography-tandem mass spectrometry

F₂-isoprostanes are useful biomarkers of oxidative status in humans. We developed an ultraperformance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify 2,3-dinor-8-iso prostaglandin F_2α, a urinary metabolite of 8-iso-prostaglandin F_2α. Urine was purified by solid-phase extraction and analyzed by UPLC-MS/MS with negative-ion electrospray ionization. The method was robust with a mean inaccuracy of 9%, interday and intraday imprecision of 7.5% or lower, and a lower limit of quantification of 0.5 μg/L, equivalent to 0.04 pmol injected onto the column. An analysis time of 6 min was shorter than previously published methods and amenable to large studies.     

Developmental regulation of group I metabotropic glutamate receptors in the premature brain and their protective role in a rodent model of periventricular leukomalacia

Cerebral white matter injury in premature infants, known as periventricular leukomalacia (PVL), is common after hypoxia-ischemia (HI). While ionotropic glutamate receptors (iGluRs) can mediate immature white matter injury, we have previously shown that excitotoxic injury to premyelinating oligodendrocytes (preOLs) in vitro can be attenuated by group I metabotropic glutamate receptor (mGluR) agonists. Thus, we evaluated mGluR expression in developing white matter in rat and human brain, and tested the protective efficacy of a central nervous system (CNS)-penetrating mGluR agonist on injury to developing oligodendrocytes (OLs) in vivo. Group I mGluRs (mGluR1 and mGluR5) were strongly expressed on OLs in neonatal rodent cerebral white matter throughout normal development, with highest expression early in development on preOLs. Specifically at P6, mGluR1 and mGLuR5 were most highly expressed on GalC-positive OLs compared to neurons, axons, astrocytes and microglia. Systemic administration of (1S,3R) 1-aminocyclopentane-trans-1,3,-dicarboxylic acid (ACPD) significantly attenuated the loss of myelin basic protein in the white matter following HI in P6 rats. Assessment of postmortem human tissue showed both mGluR1 and mGluR5 localized on immature OLs in white matter throughout development, with mGluR5 highest in the preterm period. These data indicate group I mGluRs are highly expressed on OLs during the peak period of vulnerability to HI and modulation of mGluRs is protective in a rodent model of PVL. Group I mGluRs may represent important therapeutic targets for protection from HI-mediated white matter injury.     

Rabies in vaccinated raccoons from Ontario, Canada

From 1999 to 2006, 132 cases of raccoon rabies, caused by the raccoon variant of rabies virus, were confirmed in eastern Ontario, Canada. Trap-vaccinate-release (TVR) and point infection control (PIC) programs were implemented to control the disease; 43,014 raccoons (Procyon lotor) were vaccinated against rabies by injection (Imrab3) during that period. Two vaccinated raccoons were diagnosed with rabies at 6 mo and at 2 wk postvaccination. One may have been due to a vaccination failure. The other was likely due to the animal being in the late stages of incubation for rabies at the time of vaccination. This information will be useful to wildlife rehabilitators and agencies that hold raccoons in captivity in that a vaccinated raccoon is not necessarily immune to rabies.