Timing the Emergence of Resistance to Anti-HIV Drugs with Large Genetic Barriers

New antiretroviral drugs that offer large genetic barriers to resistance, such as the recently approved inhibitors of HIV-1 protease, tipranavir and darunavir, present promising weapons to avert the failure of current therapies for HIV infection. Optimal treatment strategies with the new drugs, however, are yet to be established. A key limitation is the poor understanding of the process by which HIV surmounts large genetic barriers to resistance. Extant models of HIV dynamics are predicated on the predominance of deterministic forces underlying the emergence of resistant genomes. In contrast, stochastic forces may dominate, especially when the genetic barrier is large, and delay the emergence of resistant genomes. We develop a mathematical model of HIV dynamics under the influence of an antiretroviral drug to predict the waiting time for the emergence of genomes that carry the requisite mutations to overcome the genetic barrier of the drug. We apply our model to describe the development of resistance to tipranavir in in vitro serial passage experiments. Model predictions of the times of emergence of different mutant genomes with increasing resistance to tipranavir are in quantitative agreement with experiments, indicating that our model captures the dynamics of the development of resistance to antiretroviral drugs accurately. Further, model predictions provide insights into the influence of underlying evolutionary processes such as recombination on the development of resistance, and suggest guidelines for drug design: drugs that offer large genetic barriers to resistance with resistance sites tightly localized on the viral genome and exhibiting positive epistatic interactions maximally inhibit the emergence of resistant genomes

Cost-effectiveness of price subsidies on fortified packaged infant cereals in reducing iron deficiency anemia in 6-23-month-old children in urban India

Introduction: Iron deficiency anaemia (IDA) is a major public health problem in India and especially harmful in early childhood due to its impact on cognitive development and increased all-cause mortality. We estimate the cost-effectiveness of price subsidies on fortified packaged infant cereals (F-PICs) in reducing IDA in 6-23-monthold children in urban India. Materials and Methods: Cost-effectiveness is estimated by comparing the net social cost of price subsidies with the disability-adjusted life-years (DALYs) averted with price subsidies. The net social costs correspond to the cost of the subsidy minus the monetary costs saved by reducing IDA. The estimation proceeds in three steps: 1) the current lifetime costs of IDA are assessed with a health economic model combining the prevalence of anemia, derived from a large population survey, with information on the health consequences of IDA and their costs in terms of mortality, morbidity, and DALYs. 2) The effects of price subsidies on the demand for F-PICs are assessed with a market survey among 4801 households in 12 large Indian cities. 3) The cost-effectiveness is calculated by combining the findings of the first two steps with the results of a systematic review on the effectiveness of F-PICs in reducing IDA. We compare the cost-effectiveness of interventions that differ in the level of the subsidy and in the socio-economic strata (SES) eligible for the subsidy. Results: The lifetime social costs of IDA in 6-23-month-old children in large Indian cities amount to production losses of 3222 USD and to 726,000 DALYs. Poor households incur the highest costs, yet even wealthier households suffer substantial losses. The market survey reveals that few households currently buy F-PICs, with the share ranging from 14% to 36%. Wealthier households are generally more likely to buy FPICs. The costs of the subsidies per DALY averted range from 909 to 3649 USD. Interventions targeted at poorer households are most effective. Almost all interventions are cost saving from a societal perspective when taking into account the reduction of future production losses. Return per DALY averted ranges between gains of 1655 USD to a cost of 411 USD. Conclusion: Price subsidies on F-PICs are a cost-effective way to reduce the social costs of IDA in 6-23-month-old children in large Indian cities. Interventions targeting poorer households are especially cost-effective

Cooking practices, air quality, and the acceptability of advanced cookstoves in Haryana, India: an exploratory study to inform large-scale interventions.

BackgroundIn India, approximately 66% of households rely on dung or woody biomass as fuels for cooking. These fuels are burned under inefficient conditions, leading to household air pollution (HAP) and exposure to smoke containing toxic substances. Large-scale intervention efforts need to be informed by careful piloting to address multiple methodological and sociocultural issues. This exploratory study provides preliminary data for such an exercise from Palwal District, Haryana, India.MethodsTraditional cooking practices were assessed through semi-structured interviews in participating households. Philips and Oorja, two brands of commercially available advanced cookstoves with small blowers to improve combustion, were deployed in these households. Concentrations of particulate matter (PM) with a diameter <2.5 μm (PM2.5) and carbon monoxide (CO) related to traditional stove use were measured using real-time and integrated personal, microenvironmental samplers for optimizing protocols to evaluate exposure reduction. Qualitative data on acceptability of advanced stoves and objective measures of stove usage were also collected.ResultsTwenty-eight of the thirty-two participating households had outdoor primary cooking spaces. Twenty households had liquefied petroleum gas (LPG) but preferred traditional stoves as the cost of LPG was higher and because meals cooked on traditional stoves were perceived to taste better. Kitchen area concentrations and kitchen personal concentrations assessed during cooking events were very high, with respective mean PM2.5 concentrations of 468 and 718 µg/m3. Twenty-four hour outdoor concentrations averaged 400 µg/m3. Twenty-four hour personal CO concentrations ranged between 0.82 and 5.27 ppm. The Philips stove was used more often and for more hours than the Oorja.ConclusionsThe high PM and CO concentrations reinforce the need for interventions that reduce HAP exposure in the aforementioned community. Of the two stoves tested, participants expressed satisfaction with the Philips brand as it met the local criteria for usability. Further understanding of how the introduction of an advanced stove influences patterns of household energy use is needed. The preliminary data provided here would be useful for designing feasibility and/or pilot studies aimed at intervention efforts locally and nationally

Social costs of iron deficiency anemia in 6–59-month-old children in India

Introduction: Inadequate nutrition has a severe impact on health in India. According to the WHO, iron deficiency is the single most important nutritional risk factor in India, accounting for more than 3% of all disability-adjusted life years (DALYs) lost. We estimate the social costs of iron deficiency anemia (IDA) in 6-59-month-old children in India in terms of intangible costs and production losses. Materials and Methods: We build a health economic model estimating the life-time costs of a birth cohort suffering from IDA between the ages of 6 and 59 months. The model is stratified by 2 age groups (6-23 and 24-59-months), 2 geographical areas (urban and rural), 10 socio-economic strata and 3 degrees of severity of IDA (mild, moderate and severe). Prevalence of anemia is calculated with the last available National Family Health Survey. Information on the health consequences of IDA is extracted from the literature. Results: IDA prevalence is 49.5% in 6-23-month-old and 39.9% in 24-58-month-old children. Children living in poor households in rural areas are particularly affected but prevalence is high even in wealthy urban households. The estimated yearly costs of IDA in 6–59-month-old children amount to intangible costs of 8.3 m DALYs and production losses of 24,001 m USD, equal to 1.3% of gross domestic product. Previous calculations have considerably underestimated the intangible costs of IDA as the improved WHO methodology leads to a threefold increase of DALYs due to IDA. Conclusion: Despite years of iron supplementation programs and substantial economic growth, IDA remains a crucial public health issue in India and an obstacle to the economic advancement of the poor. Young children are especially vulnerable due to the irreversible effects of IDA on cognitive development. Our research may contribute to the design of new effective interventions aiming to reduce IDA in early childhood

The health burden and economic costs averted by ambient PM 2.5 pollution reductions in Nagpur, India

National estimates of the health and economic burdens of exposure to ambient fine particulate matter (PM2.5) in India reveal substantial impacts. This information, often lacking at the local level, can justify and drive mitigation interventions. Here, we assess the health and economic gains resulting from attainment of WHO guidelines for PM2.5 concentrations – including interim target 2 (IT-2), interim target 3 (IT-3), and theWHO air quality guideline (AQG) – in Nagpur district to inform policy decision making for mitigation. We conducted a detailed assessment of concentrations of PM2.5 in 9 areas, covering urban, peri-urban and rural environments, from February 2013 to June 2014. We used a combination of hazard and survival analyses based on the life table method to calculate attributed annual number of premature deaths and disability-adjusted life years (DALYs) for five health outcomes linked to PM2.5 exposure: acute lower respiratory infection for children b5 years, ischemic heart disease, chronic obstructive pulmonary disease, stroke and lung cancer in adults !25 years. We used GBD 2013 data on deaths and DALYs for these diseases. We calculated averted deaths, DALYs and economic loss resulting from planned reductions in average PM2.5 concentration from current level to IT-2, IT-3 and AQG by the years 2023, 2033 and 2043, respectively. The economic cost for premature mortality was estimated as the product of attributed deaths and value of statistical life for India, while morbidity was assumed to be 10% of the mortality cost. The annual average PM2.5 concentration in Nagpur district is 34± 17 μg m−3 and results in 3.3 (95% confidence interval [CI]: 2.6, 4.2) thousand premature deaths and 91 (95% CI: 68, 116) thousand DALYs in 2013 with economic loss of USD 2.2 (95% CI: 1.7, 2.8) billion in that year. It is estimated that interventions that achieve IT-2, IT-3 and AQG by 2023, 2033 and 2043,would avert, respectively, 15, 30 and 36%, of the attributed health and economic loss in those years, translating into an impressively large health and economic gain. To achieve this, we recommend an exposure-integrated source reduction approach

Effect of post harvest treatments and harvesting stage on vase life and flower quality of cut Oriental lily

An investigation was carried out to study the effect of post harvest treatments and harvesting stage on vase life and flower quality of cut Oriental lily cv. Avocado. The results showed that highest vase life (15.83 days) and vase solution uptake (49.17 ml) was recorded with sucrose (2%) + 5-SSA (200ppm), whereas maximum flower diameter (15.17 cm) was recorded in vase solution containing sucrose (2%) + 5-SSA (100ppm). Earliest opening of florets (4.42 days) reported under sucrose (2%) + 5-SSA (200ppm). Effect of treatments was found non-significant in respect to opening of florets. Harvesting at green bud stage exhibited extended vase life (14.33 days) and higher vase solution uptake (40.43 ml), whereas maximum flower diameter (14.25 cm) recorded at 75% colour development stage. Based on the results it is concluded that 5-SSA could be an inexpensive and potential chemical for delaying senescence and for extending the keeping quality of cut liliums commercially

Razvoj i optimizacija sustava za isporuku metoprolol sukcinata sa zadržavanjem u želucu

Metoprolol succinate (MS) gastroretentive (GR) controlled release system was formulated to increase gastric residence time leading to improved drug bioavailability. Box-Behnken model was followed using novel combinations of sodium alginate (SA), sodium carboxymethylcellulose (NaCMC), magnesium alumino metasilicate (MAS) as independent variables. Floating lag time (Flag), t25, t50, t75, diffusion exponent as dependent variables revealed that the amount of SA, NaCMC and MAS have a significant effect (p < 0.05) on t25, t50, t75 and Flag. MSGR tablets were prepared and evaluated for mass, thickness, hardness, friability, drug content and floating property. Tablets were studied for dissolution for 24 h and exhibited controlled release of MS with floating for 16 h. The release profile of the optimized batch MS01 fitted first-order kinetics (R2 = 0.9868, n = 0.543), indicating non-Fickian diffusion or anomalous transport by diffusion and swelling.U radu je opisan razvoj sustava za isporuku metoprolol sukcinata (MS) s kontroliranim oslobađanjem i produljenim vremenom zadržavanja u želucu (GR), u svrhu poboljšanja bioraspoloživosti. Primijenjen je Box-Behnkenov model, a kao zavisne varijable izabrane su nove kombinacije natrijevog alginata (SA), natrijeve soli karboksimetilceluloze (NaCMC) i magnezijevog aluminometasilikata (MAS). Vrijeme plutanja (Flag), t25, t50, t75 i difuzijski eksponent kao zavisne varijable otkrili su da količina SA, NaCMC i MAS ima značajan učinak (p < 0,05) na t25, t50, t75 i Flag. Pripravljenim tabletama određena je masa, debljina, tvrdoća, lomljivost, sadržaj ljekovite tvari i sposobnost plutanja. Oslobađanje MS praćeno je 24 h. Rezultati pokazuju da je oslobađanje kontrolirano, a vrijeme plutanja 16 h. Oslobađanje iz optimiranog pripravka MS01 slijedi kinetiku prvog reda (R2 = 0,9868, n = 0,543), što ukazuje na difuziju koja ne slijedi Fickov zakon već anomalni transport difuzijom i bubrenjem