Transitioning a Large Scale HIV/AIDS Prevention Program to Local Stakeholders: Findings from the Avahan Transition Evaluation

Background

Between 2009–2013 the Bill and Melinda Gates Foundation transitioned its HIV/AIDS prevention initiative in India from being a stand-alone program outside of government, to being fully government funded and implemented. We present an independent prospective evaluation of the transition.

Methods

The evaluation drew upon (1) a structured survey of transition readiness in a sample of 80 targeted HIV prevention programs prior to transition; (2) a structured survey assessing institutionalization of program features in a sample of 70 targeted intervention (TI) programs, one year post-transition; and (3) case studies of 15 TI programs.

Findings

Transition was conducted in 3 rounds. While the 2009 transition round was problematic, subsequent rounds were implemented more smoothly. In the 2011 and 2012 transition rounds, Avahan programs were well prepared for transition with the large majority of TI program staff trained for transition, high alignment with government clinical, financial and managerial norms, and strong government commitment to the program. One year post transition there were significant program changes, but these were largely perceived positively. Notable negative changes were: limited flexibility in program management, delays in funding, commodity stock outs, and community member perceptions of a narrowing in program focus. Service coverage outcomes were sustained at least six months post-transition.

Interpretation

The study suggests that significant investments in transition preparation contributed to a smooth transition and sustained service coverage. Notwithstanding, there were substantive program changes post-transition. Five key lessons for transition design and implementation are identified.     

Snakebite mortality in India: a nationally representative mortality survey

Background

India has long been thought to have more snakebites than any other country. However, inadequate hospital-based reporting has resulted in estimates of total annual snakebite mortality ranging widely from about 1,300 to 50,000. We calculated direct estimates of snakebite mortality from a national mortality survey.

Methods and Findings

We conducted a nationally representative study of 123,000 deaths from 6,671 randomly selected areas in 2001–03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. Discrepancies were resolved by anonymous reconciliation or, failing that, by adjudication.A total of 562 deaths (0.47% of total deaths) were assigned to snakebites. Snakebite deaths occurred mostly in rural areas (97%), were more common in males (59%) than females (41%), and peaked at ages 15–29 years (25%) and during the monsoon months of June to September. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6–4.5), with higher rates in rural areas (5.4/100,000; 99% CI 4.8–6.0), and with the highest state rate in Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500).

Conclusions

Snakebite remains an underestimated cause of accidental death in modern India. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Community education, appropriate training of medical staff and better distribution of antivenom, especially to the 13 states with the highest prevalence, could reduce snakebite deaths in India.     

Intramolecular Conformation of Puromycin in Solution As Studied by Proton Magnetic Resonance

Abstract

The intramolecular conformation of puromycin, a broad spectrum antiobiotic, in solution has been investigated by proton magnetic resonance (PMR) spectroscopy. A comparison of the proton chemical shift and proton-proton coupling constant data of puromycin with puromycin aminonucleoside suggests that puromycin in solution exists as an equilibrium blend of extended and folded conformers. These folded conformers are the result of flexibility around the C^α-C^β bond of the aminoacyl segment of puromycin. One of the folded conformers predicted by PMR is in excellent agreement with the x-ray data.     

Genetic Correction of a LRRK2 Mutation in Human iPSCs Links Parkinsonian Neurodegeneration to ERK-Dependent Changes in Gene Expression

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Highlights? hiPSC-derived neurons with LRRK2 G2019S exhibit Parkinsonian neurodegeneration ? Genetic correction of the LRRK2 mutation rescued neurodegenerative phenotypes ? Comparative analysis links LRRK2 G2019S, gene dysregulation, and ERK activation ? ERK-dependent gene dysregulation by LRRK2 G2019S contributes to neurodegeneration     

Lead optimization of isocytosine-derived xanthine oxidase inhibitors

We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained.     

In vitro cultures and regeneration of Bienertia sinuspersici (Chenopodiaceae) under increasing concentrations of sodium chloride and carbon dioxide

To study the developmental transition of chloroplasts from C₃ to C₄ photosynthesis in the terrestrial single-cell C₄ species Bienertia sinuspersici, a regeneration protocol was developed. Stem explant material developed callus either with or without red nodular structures (RNS) when cultured on Murashige–Skoog (MS) salts and vitamins, supplemented with 5 mM phosphate, plus 1 mg L⁻¹ dichloropenoxy-acetic acid (2,4-D), and 87 mM sucrose (Stage 1 media). Only calli having RNS were able to regenerate plantlets. MS media plus phosphate was used throughout regeneration, with the Stage 2 media containing 2 mg L⁻¹ 6-benzylaminopurine, 43 mM sucrose and 1.5% soluble starch. Stage 3 media had no hormones or organic sources of carbon, and cultures were grown under ambient (~400 ppm) versus CO₂ enrichment (1.2% CO₂). When calli without RNS were cultured under Stage 3 conditions with 1.2% CO₂, there was an increase in growth, protein content, and photosystem II yield, while structural and biochemical analyses indicated the cells in the calli had C₃ type photosynthesis. CO₂ enrichment during growth of RNS during Stage 3 had a large effect on regeneration success, increasing efficiency of shoot and root development, size of plantlets, leaf soluble protein, and chlorophyll concentration. Anatomical analysis of plantlets, which developed under 1.2% CO₂, showed leaves developed C₄ type chlorenchyma cells, including expression of key C₄ biochemical enzymes. Increasing salinity in the media, from 0 to 200 mM NaCl, increased tissue osmolality, average plantlet area and regeneration success, but did not affect protein or chlorophyll content.     

p38 and ERK1/2 MAPKs mediate the interplay of TNF-alpha and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis

It is known that TNF-alpha increases the production of ROS and decreases antioxidant enzymes, resulting in an increase in oxidative stress. IL-10 appears to modulate these effects. The present study investigated the role of p38 and ERK1/2 MAPKs in mediating the interplay of TNF-alpha and IL-10 in regulating oxidative stress and cardiac myocyte apoptosis in Sprague-Dawley male rats. Isolated adult cardiac myocytes were exposed to TNF-alpha (10 ng/ml), IL-10 (10 ng/ml), and IL-10 + TNF-alpha (ratio 1) for 4 h. H(2)O(2) (100 microM) as a positive control and the antioxidant Trolox (20 micromol/l) were used to confirm the involvement of oxidative stress. H(2)O(2) treatment increased oxidative stress and apoptosis; TNF-alpha mimicked these effects. Exposure to TNF-alpha significantly increased ROS production, caused cell injury, and increased the number of apoptotic cells and Bax-to-Bcl-xl ratio. This change was associated with an increase in the phospho-p38 MAPK-to-total p38 MAPK ratio and a decrease in the phospho-ERK1/2-to-total ERK1/2 ratio. IL-10 treatment by itself had no effect on these parameters, but it prevented the above-listed changes caused by TNF-alpha. The antioxidant Trolox modulated TNF-alpha-induced changes in Bax/Bcl-xl, cell injury, and MAPKs. Preexposure of cells to the p38 MAPK inhibitor SB-203580 prevented TNF-alpha-induced changes. Inhibition of the ERK pathway with PD-98059 attenuated the protective role of IL-10 against TNF-alpha-induced apoptosis. This study provides evidence in support of the essential role of p38 and ERK1/2 MAPKs in the interactive role of TNF-alpha and IL-10 in cardiac myocyte apoptosis.     

Multicystic nephroma: a case report

BACKGROUND: Cystic nephroma is an uncommon pediatric renal neoplasm. It needs to be differentiated from cystic partially differentiated nephroblastoma and from other renal neoplasms showing extensive cystic change. It is scantily reported in the cytology literature. CASE: A 7-month-old female with a left-sided abdominal lump was diagnosed as having cystic Wilms' tumor on computed tomography. Fine needle aspiration cytology showed cellular smears composed of monomorphic, round to oval cells, suggestive of a small round cell tumor, possibly rhabdomyosarcoma. However, histopathologic examination showed it to be a multicystic nephroma. On review of the cytologic smears, the blastemal component was absent. CONCLUSION: This case highlights 1 extreme and unexpected cytologic appearance of cystic nephroma; it may result in misdiagnosis.     

Inter-Model Comparison of the Landscape Determinants of Vector-Borne Disease: Implications for Epidemiological and Entomological Risk Modeling

Extrapolating landscape regression models for use in assessing vector-borne disease risk and other applications requires thoughtful evaluation of fundamental model choice issues. To examine implications of such choices, an analysis was conducted to explore the extent to which disparate landscape models agree in their epidemiological and entomological risk predictions when extrapolated to new regions. Agreement between six literature-drawn landscape models was examined by comparing predicted county-level distributions of either Lyme disease or Ixodes scapularis vector using Spearman ranked correlation. AUC analyses and multinomial logistic regression were used to assess the ability of these extrapolated landscape models to predict observed national data. Three models based on measures of vegetation, habitat patch characteristics, and herbaceous landcover emerged as effective predictors of observed disease and vector distribution. An ensemble model containing these three models improved precision and predictive ability over individual models. A priori assessment of qualitative model characteristics effectively identified models that subsequently emerged as better predictors in quantitative analysis. Both a methodology for quantitative model comparison and a checklist for qualitative assessment of candidate models for extrapolation are provided; both tools aim to improve collaboration between those producing models and those interested in applying them to new areas and research questions.