The Impact of Monitoring HIV Patients Prior to Treatment in Resource-Poor Settings: Insights from Mathematical Modelling

Using a stochastic model based on data from Africa, Timothy Hallett and colleagues find that starting HIV treatment based on regular CD4 monitoring, rather than on symptoms, would substantially increase survival

Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models.

BACKGROUND: New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly. METHODS: We used multiple independent mathematical models in four settings-South Africa, Zambia, India, and Vietnam-to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered 'very cost-effective' if the$/DALY was less than the country's per capita gross domestic product (GDP; South Africa: $8040, Zambia:$1425, India: $1489, Vietnam:$1407) and 'cost-effective' if $/DALY was less than three times per capita GDP. FINDINGS: In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from$237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to$749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to$241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective. INTERPRETATION: Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets. FUNDING: The Bill and Melinda Gates Foundation and World Health Organization

Optimal Uses of Antiretrovirals for Prevention in HIV-1 Serodiscordant Heterosexual Couples in South Africa: A Modelling Study

Hallett et al use a mathematical model to examine the long-term impact and cost-effectiveness of different pre-exposure prophylaxis (PrEP) strategies for HIV prevention in serodiscordant couples

Luminescent rhenium fac-tricarbonyl-containing complexes of androgenic oxo-steroids

A new route to luminescent derivatives of androgenic steroids containing a ketone group in the 3- or 17-position has been developed. Reaction with the fac-Re(CO)3Cl complex of 3,3’-diamino-2,2’- bipyridine (complex 1) afforded a cyclic aminal product with different steroids. The rate of reaction and yield varies according to the conjugation or steric hindrance around the ketone grou

The yeast magmas ortholog pam16 has an essential function in fermentative growth that involves sphingolipid metabolism.

Magmas is a growth factor responsive gene encoding an essential mitochondrial protein in mammalian cells. Pam16, the Magmas ortholog in Saccharomyces cerevisiae, is a component of the presequence translocase-associated motor. A temperature-sensitive allele (pam16-I61N) was used to query an array of non-essential gene-deletion strains for synthetic genetic interactions. The pam16-I61N mutation at ambient temperature caused synthetic lethal or sick phenotypes with genes involved in lipid metabolism, perixosome synthesis, histone deacetylation and mitochondrial protein import. The gene deletion array was also screened for suppressors of the pam16-I61N growth defect to identify compensatory pathways. Five suppressor genes were identified (SUR4, ISC1, IPT1, SKN1, and FEN1) and all are involved in sphingolipid metabolism. pam16-I61N cells cultured in glucose at non-permissive temperatures resulted in rapid growth inhibition and G1 cell cycle arrest, but cell viability was maintained. Altered mitochondria morphology, reduced peroxisome induction in glycerol/ethanol and oleate, and changes in the levels of several sphingolipids including C18 alpha-hydroxy-phytoceramide, were also observed in the temperature sensitive strain. Deletion of SUR4, the strongest suppressor, reversed the temperature sensitive fermentative growth defect, the morphological changes and the elevated levels of C18 alpha-hydroxy phytoceramide in pam16-I61N. Deletion of the other four suppressor genes had similar effects on C18 alpha-hydroxy-phytoceramide levels and restored proliferation to the pam16-I61N strain. In addition, pam16-I61N inhibited respiratory growth, likely by reducing cardiolipin, which is essential for mitochondrial function. Our results suggest that the pleiotropic effects caused by impaired Pam16/Magmas function are mediated in part by changes in lipid metabolism

U.S. Prison Seminaries: Structural Charity, Religious Establishment, and Neoliberal Corrections

Using archival and site-based research, this article explores operational practices at six U.S. prison seminary programs regarding concepts of religious establishment. Further highlighted is a shift toward faith-based volunteerism as a “structural charity” in correctional budgeting. While religious programs offer powerfully transformative access to social capital for many inmates, the recent insertion of Christian “seminaries” into U.S. prisons arguably fosters religious establishment in four key areas: a lack of state neutrality toward religion, excessive state entanglement with religious service providers, inadequate solicitation of alternative programming, and a de facto measure of coercion in delivery of services

Effects of <i>pam16-I61N</i> and <i>sur4</i>Δ on yeast morphology.

<p>Yeast strains were examined by transmission electron microscopy. <i>pam16-I61N</i> (Panel B) had fewer and smaller mitochondria (horizontal arrows) than wt cells (Panel A). <i>pam16-I61N</i> cells had vesicles with thickened walls and no electron dense material in the center (upward angled arrows). The <i>sur4</i>Δ mutation restores near normal mitochondrial morphology to the <i>pam16-I61N</i> strain and increases peroxisome number (upward vertical arrows in Panels C and D)(12,000× magnification; scale bar  = 500 nm).</p

Synthetic lethal partners of <i>pam16-I61N</i>.

<p>28 of the 46 SSL partners of <i>pam16-I61N</i> were grouped into 4 major biological functions. They are mitochondrial protein import (red), histone modification (green), mitochondrial lipid metabolism (blue), and peroxisome biogenesis and glycolysis (yellow). Genes that are functionally related radiate from a central point.</p

Effects of <i>pam16-I61N</i> and <i>sur4</i>Δ on peroxisome formation in glucose, glycerol/ethanol and oleic acid containing media.

<p>Live-cell fluorescence microscopy (top frames) and the corresponding differential interference contrast (DIC) image (bottom frames) of wt (A), <i>pam16-I61N</i> (B), <i>sur4</i>Δ (C), and <i>pam16-I61N sur4</i>Δ (D) cells containing GFP-tagged Pot1 to identify peroxisomes. Cultures grown in synthetic media at 30°C with glucose were then grown at 32°C for an additional 3 h with glucose, glycerol/ethanol or oleic acid as the carbon source. Quantitation of peroxisomes/cell (E) for each strain grown on the indicated carbon source. Western blot (F) of Pot1-GFP (<i>M</i>_r = 75 kD) and Pgk1 (<i>M</i>_r = 45 kD) in wt, <i>pam16</i>-<i>I61N</i>, <i>sur4</i>Δ and <i>pam16</i>-<i>I61N sur4</i>Δ whole cell lysates (40 µg protein/lane). Pgk1 was used to demonstrate that Pot1 is specifically induced by media with glycerol/ethanol and oleic acid carbon sources. Numbers indicate the quantitation of band volumes for Pot1-GFP (×10⁻⁵) and Pgk1 (×10⁻⁶) in pixels. BD indicates that the band was below the level of detection.</p