A phase I dose-escalation study of MEDI-575, a PDGFRα monoclonal antibody, in adults with advanced solid tumors

PURPOSE: The purpose of the study was to evaluate safety and determine the maximum tolerated dose (MTD) of MEDI-575, a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor-α (PDGFRα), in patients with advanced solid tumors. METHODS: This phase I multicenter, open-label, single-arm study enrolled adults in a 3 + 3 dose escalation design to receive MEDI-575 (3, 6, 9, 12, or 15 mg/kg) once weekly (QW) until toxicity or disease progression occurred. One 0.5-mg/kg dose was given before the first dose in the 3-mg/kg cohort to determine pharmacokinetics (PK) and pharmacodynamics under unsaturated conditions. After completion of dose escalation in the QW cohorts, patients were enrolled in two additional cohorts and received MEDI-575 25 or 35 mg/kg every 3 weeks (Q3W). Secondary measures included assessments of PK, immunogenicity, and antitumor activity. RESULTS: A total of 35 patients received MEDI-575 QW (n = 23) or Q3W (n = 12). Most treatment-related adverse events were grade 1 or 2 in severity across all dose levels, with fatigue (n = 12) and nausea (n = 8) being reported most frequently. With no reports of dose-limiting toxicities (DLTs), the MTD was not reached. MEDI-575 exhibited a nonlinear PK profile and increased plasma platelet-derived growth factor-AA levels in a dose-dependent manner with limited immunogenicity. Stable disease was reported as the best tumor response in 9 of 29 evaluable patients; however, no objective responses were reported. CONCLUSION: Administration of MEDI-575 QW or Q3W resulted in a favorable safety profile, including a lack of DLTs, but without evidence of antitumor activity in patients with refractory solid tumors

Lignocellulosic biomass feedstock: A benchmarking green resource for sustainable production of bioplastics

Presence of plastics in the surroundings is ubiquitous, as generation of plastics is booming globally and it gets accumulated in oceans leading to deleterious impacts on marine life, public health and the surrounding environment. Owing to its non-degradable nature, plastic particles remain in surroundings for extended periods which automatically facilitate its out spreading. Therefore, there is a need to shift to bio-based plastics, as bio-based green economy hinges on sustainable employment of bioresources for generating a broad spectrum of products, biofuels, chemicals and bioplastics. Typically bioplastics are synthesized from bio-based resources considered to contribute more to sustainable production of plastic as a part of the circular economy. Bioplastics are luring attention and growing as counterfeit material for petroleum-derived plastics owing to their biodegradability. Recently an engrossed interest has been burgeoning in producing drop-in polymers and new-fangled bioplastics by utilizing lignocellulosic feedstock. This paper reviews the enormous potential of lignocellulosic feedstock as a significant inedible substrate for bioplastic synthesis. Polyhydroxyalkanoates, polyurethanes, polylactic acid and starch-bioplastic are prevailing bio-based plastic comparably derived from lignocellulosic biomass. In forthcoming years bioplastic derived years’ bioplastic derived from lignocellulose will loom as valuable material in numerous fields for an extensive range of cutting-edge applications

Has the Rate of Reduction in Infant Mortality Increased in India Since the Launch of National Rural Health Mission? Analysis of Time Trends 2000-2009 with Projection to 2015

Objectives: National Rural Health Mission (NRHM) – India was launched in 2005 to tackle urban-rural health inequalities, especially in maternal and child health. We examined national and state level trends in Infant Mortality Rates (IMR) from 2000 through 2009 to: 1) assess whether the NRHM had increased the average annual reduction rate (AARR) of IMR 2) evaluate state-wise progress towards Millennium Development Goals (MDG4) and estimate required AARRs for ‘off track’ states. Methods: Log-linear regression models were applied to national and state IMR data collated from the Sample Registration System (SRS)-India to estimate average annual reduction rates and compare AAARs before and after introduction of NRHM. The log-linear trend of infant mortality rates was also projected forward to 2015. Results: The infant mortality rate in rural India declined from 74 to 55/1000 live births between 2000 and 2009, with AARR of 3.0% (95% CI=2.6%-3.4%) and the urban-rural gap in infant mortality narrowed (p =0.036). However there was no evidence (p=0.49) that AARR in rural India increased post NRHM (3.4%, 95% CI 2.0-4.7%) compared to pre NRHM (2.8%, 95% CI 2.1%-3.5%). States varied widely in rates of infant mortality reduction. Projections of infant mortality rates suggested that only eight states might be on track to help India achieve MDG4 by 2015. Conclusions and Public Health Implications: Despite a narrowing urban-rural gap and high AARRs in some states, there was no evidence that the rate of reduction in infant mortality has increased in rural India post NRHM introduction. India appears unlikely to achieve child survival-related NRHM and millennium development goals. Government should revisit the child survival related NRHM strategies and ensure equitable access to health services. More robust monitoring and evaluation mechanisms must be inbuilt for following years. Key Words: India • National Rural Health Mission • Infant Mortality Rate • Millennium Development Goals • Health Systems Copyright © 2013 Narwal et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Has the Rate of Reduction in Infant Mortality Increased in India Since the Launch of National Rural Health Mission? Analysis of Time Trends 2000-2009 with Projection to 2015

Objectives: National Rural Health Mission (NRHM) – India was launched in 2005 to tackle urban-rural health inequalities, especially in maternal and child health. We examined national and state level trends in Infant Mortality Rates (IMR) from 2000 through 2009 to: 1) assess whether the NRHM had increased the average annual reduction rate (AARR) of IMR 2) evaluate state-wise progress towards Millennium Development Goals (MDG4) and estimate required AARRs for ‘off track’ states. Methods: Log-linear regression models were applied to national and state IMR data collated from the Sample Registration System (SRS)-India to estimate average annual reduction rates and compare AAARs before and after introduction of NRHM. The log-linear trend of infant mortality rates was also projected forward to 2015. Results: The infant mortality rate in rural India declined from 74 to 55/1000 live births between 2000 and 2009, with AARR of 3.0% (95% CI=2.6%-3.4%) and the urban-rural gap in infant mortality narrowed (p =0.036). However there was no evidence (p=0.49) that AARR in rural India increased post NRHM (3.4%, 95% CI 2.0-4.7%) compared to pre NRHM (2.8%, 95% CI 2.1%-3.5%). States varied widely in rates of infant mortality reduction. Projections of infant mortality rates suggested that only eight states might be on track to help India achieve MDG4 by 2015. Conclusions and Public Health Implications: Despite a narrowing urban-rural gap and high AARRs in some states, there was no evidence that the rate of reduction in infant mortality has increased in rural India post NRHM introduction. India appears unlikely to achieve child survival-related NRHM and millennium development goals. Government should revisit the child survival related NRHM strategies and ensure equitable access to health services. More robust monitoring and evaluation mechanisms must be inbuilt for following years

Screening of Pearl Millet F1 Hybrids for Heat Tolerance at Early Seedling Stage

Ten pearl millet genotypes selected on the basis of response to supra-optimal temperature tolerance were crossed in a half-diallel mating system. The 45 F1 hybrids produced were tested along with parents for heat tolerance and related traits at seedling stage. Field screening and laboratory screening techniques were simultaneously used for the evaluation of F1 hybrids and their parents. Heat tolerance was measured as seedling thermotolerance index (STI) and seed to seedling thermotolerance index (SSTI) under field conditions, but membrane thermostability (MTS) in the laboratory. The hybrid H77/29-2 × CVJ-2-5-3-1-3 showed highest STI value followed by H77/833-2 × 96AC-93. The genotype H77/833-2 × 96AC-93 had the highest worth for SSTI. These three indices were highly correlated among themselves. STI values were invariably high, whereas SSTI has lower values, as it also covers the effect of under soil mortality (USM). It was seen that the heat tolerance indices STI and SSTI were not showing any perceptible pooled correlation with developmental traits except germination and emergence rate. Based on our results, it could be suggested that membrane thermostability (MTS) may be used for screening large number of genotypes. Field based indices STI and SSTI may be used for evaluation of hybrids and varieties before they are released

Development of a population pharmacokinetic model for atorvastatin acid and its lactone metabolite

Background and Objectives: Atorvastatin lactone, a metabolite of theHMG-CoAreductase inhibitor (statin) atorvastatin acid, is believed to be myotoxic. Our objectives were to develop a population pharmacokinetic model for atorvastatin acid and its lactone metabolite and to identify patient characteristics that are predictive of variability in the pharmacokinetic parameters of the parent drug and its lactone metabolite. Subjects and Methods: Twenty-six subjects, 13 of whom had experienced atorvastatin-induced myopathy, received atorvastatin 10mg once daily for 7 days. Plasma samples taken on day 7 at 0 hours (predose) and 0.5, 1, 1.5, 2, 3, 5, 7, 9, 12, 22 and 24 hours post-dose were analysed for both atorvastatin acid and atorvastatin lactone, using a validated liquid chromatography assay with tandem mass spectrometry, and the data were modelled using nonlinear mixed-effects modelling software (NONMEM®). The influence of the patients\u27 demographic characteristics, biochemical indices and pharmacogenomics was evaluated. Final model validation was carried out using a visual predictive check. Results: The pharmacokinetics of atorvastatin acid and atorvastatin lactone were best described by two-and one-compartment models, respectively. The main pharmacokinetic parameters of atorvastatin acid (mean [relative standard error {RSE}]) for a subject with mean covariate values were the first-order absorption rate constant (3.5 h-1 fixed); oral clearance (504 L/h [29%]); apparent volume of the central compartment (3250L [16.5%]); and apparent volume of the peripheral compartment (2170L [9.3%]). The main pharmacokinetic parameters of atorvastatin lactone (mean [RSE]) were the apparent clearance to atorvastatin acid (24L/h [154%]); apparent total body clearance (116 L/h [9.5%]); and apparent volume of distribution (137 L [33.7%]). The value of aspartate transaminase was identified as a significant covariate for the apparent volume of the central compartment for atorvastatin acid and for the apparent total body clearance of atorvastatin lactone, signifying the importance of liver function in atorvastatin pharmacokinetics. The visual predictive plots demonstrated that the model adequately described the pharmacokinetics of both species. Conclusion: A population pharmacokinetics model was developed and validated to describe atorvastatin acid and its lactone metabolite concentration-time data. This model may be useful for atorvastatin dose individualization or analysis of sparse data. © 2010 Adis Data Information BV. All rights reserved

National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications.

BACKGROUND: Preterm birth is the second largest direct cause of child deaths in children younger than 5 years. Yet, data regarding preterm birth (<37 completed weeks of gestation) are not routinely collected by UN agencies, and no systematic country estimates nor time trend analyses have been done. We report worldwide, regional, and national estimates of preterm birth rates for 184 countries in 2010 with time trends for selected countries, and provide a quantitative assessment of the uncertainty surrounding these estimates. METHODS: We assessed various data sources according to prespecified inclusion criteria. National Registries (563 datapoints, 51 countries), Reproductive Health Surveys (13 datapoints, eight countries), and studies identified through systematic searches and unpublished data (162 datapoints, 40 countries) were included. 55 countries submitted additional data during WHO's country consultation process. For 13 countries with adequate quality and quantity of data, we estimated preterm birth rates using country-level loess regression for 2010. For 171 countries, two regional multilevel statistical models were developed to estimate preterm birth rates for 2010. We estimated time trends from 1990 to 2010 for 65 countries with reliable time trend data and more than 10,000 livebirths per year. We calculated uncertainty ranges for all countries. FINDINGS: In 2010, an estimated 14·9 million babies (uncertainty range 12·3-18·1 million) were born preterm, 11·1% of all livebirths worldwide, ranging from about 5% in several European countries to 18% in some African countries. More than 60% of preterm babies were born in south Asia and sub-Saharan Africa, where 52% of the global livebirths occur. Preterm birth also affects rich countries, for example, USA has high rates and is one of the ten countries with the highest numbers of preterm births. Of the 65 countries with estimated time trends, only three (Croatia, Ecuador, and Estonia), had reduced preterm birth rates 1990-2010. INTERPRETATION: The burden of preterm birth is substantial and is increasing in those regions with reliable data. Improved recording of all pregnancy outcomes and standard application of preterm definitions is important. We recommend the addition of a data-quality indicator of the per cent of all live preterm births that are under 28 weeks' gestation. Distinguishing preterm births that are spontaneous from those that are provider-initiated is important to monitor trends associated with increased caesarean sections. Rapid scale up of basic interventions could accelerate progress towards Millennium Development Goal 4 for child survival and beyond. FUNDING: Bill & Melinda Gates Foundation through grants to Child Health Epidemiology Reference Group (CHERG) and Save the Children's Saving Newborn Lives programme; March of Dimes; the Partnership for Maternal Newborn and Childe Health; and WHO, Department of Reproductive Health and Research