Quality by design-steered development and validation of analytical and bioanalytical methods for raloxifene: Application of Monte Carlo simulations and variance inflation factor.

A sensitive, rapid, reproducible, and economical HPLC method is reported for the quantification of raloxifene hydrochloride employing Quality by Design (QbD) principles. Factor screening studies, employing Taguchi design, indicated buffer volume percentage and isocratic flow rate as the critical method parameters (CMPs), which significantly influence the chosen critical analytical attributes, that is, tailing factor and theoretical plate number. Method conditions were subsequently optimized using face-centered cubic design with magnitude of variance inflation factor for assessing multicollinearity among CMPs. Method operable design region (MODR) was earmarked and liquid chromatographic separation optimized using 0.05 M citrate buffer, acetonitrile, and methanol (57:40:3 v/v/v) as ggmobile phase at 0.9 mL min-1 flow rate, λmax of 280 nm, and column temperature of 40°C. Validation of the developed analytical method was accomplished as per International Council on Harmonization (ICH) guidelines confirming high levels of linearity, precision, accuracy, robustness, and sensitivity. Application of Monte Carlo simulations enabled the attainment of best plausible chromatographic resolution and corroboration of the demarcated MODR. Establishment and validation of the bioanalytical method using rat plasma samples, along with forced degradation and stability studies, corroborated the aptness of developed HPLC methods for drug quantification in the biological fluids, as well as in bulk and marketed dosage forms.

Assessing Patient-Reported Financial Hardship in Patients With Cancer in Routine Clinical Care.

PURPOSE: Financial hardship (FH) in cancer care is a growing challenge for patients, their caregivers, and health care providers with impact on morbidity and mortality. In this study, we report on a standardized approach to describe the prevalence and predictors for FH as part of routine clinical workflow. We also report on the association of FH with survival in our cancer patient population. METHODS: This study includes patients who completed a FH screen at least once between 2018 and 2020. Demographics, disease state, and mortality data were extracted from the medical records. Multivariable logistic regression models were used to examine association of sociodemographic and disease variables with FH. By using propensity score weighting to account for differences in demographic and clinical factors between patients with and without FH, we then fit Cox proportional hazards models to examine the relationship between FH and survival. RESULTS: The study cohort included 31,154 patients. FH was reported by 14% (n = 4,250) of the patients. A significantly higher likelihood of having FH (P < .001 for all) was reported by racial/ethnic minority patients; those who were unemployed/disabled, single, or divorced; patients from disadvantaged neighborhoods; and those who were self-pay or had government insurance. Older age, being retired, and living farther from the cancer center were associated with significantly less likelihood of endorsing FH. Patients who endorsed FH had a lower survival (hazard ratio for mortality 1.46). CONCLUSION: Our study identified key groups more likely to report FH in a relatively affluent population at a large cancer center and showed an adverse association between FH and survival. Further research is needed to develop clinical care pathways for patients at high risk for worse financial and clinical outcomes.

State of the science in reconciling top-down and bottom-up approaches for terrestrial CO2 budget.

Robust estimates of CO2 budget, CO2 exchanged between the atmosphere and terrestrial biosphere, are necessary to better understand the role of the terrestrial biosphere in mitigating anthropogenic CO2 emissions. Over the past decade, this field of research has advanced through understanding of the differences and similarities of two fundamentally different approaches: "top-down" atmospheric inversions and "bottom-up" biosphere models. Since the first studies were undertaken, these approaches have shown an increasing level of agreement, but disagreements in some regions still persist, in part because they do not estimate the same quantity of atmosphere-biosphere CO2 exchange. Here, we conducted a thorough comparison of CO2 budgets at multiple scales and from multiple methods to assess the current state of the science in estimating CO2 budgets. Our set of atmospheric inversions and biosphere models, which were adjusted for a consistent flux definition, showed a high level of agreement for global and hemispheric CO2 budgets in the 2000s. Regionally, improved agreement in CO2 budgets was notable for North America and Southeast Asia. However, large gaps between the two methods remained in East Asia and South America. In other regions, Europe, boreal Asia, Africa, South Asia, and Oceania, it was difficult to determine whether those regions act as a net sink or source because of the large spread in estimates from atmospheric inversions. These results highlight two research directions to improve the robustness of CO2 budgets: (a) to increase representation of processes in biosphere models that could contribute to fill the budget gaps, such as forest regrowth and forest degradation; and (b) to reduce sink-source compensation between regions (dipoles) in atmospheric inversion so that their estimates become more comparable. Advancements on both research areas will increase the level of agreement between the top-down and bottom-up approaches and yield more robust knowledge of regional CO2 budgets.

Quantifying the biophysical and socioeconomic drivers of changes in forest and agricultural land in South and Southeast Asia.

South and Southeast Asia (SSEA) has been a hotspot for land use and land cover change (LULCC) in the past few decades. The identification and quantification of the drivers of LULCC are crucial for improving our understanding of LULCC trends. So far, the biophysical and socioeconomic drivers of forest change have not been quantified at the regional scale, particularly for SSEA. In this study, we quantify the biophysical and socioeconomic drivers of forest change on a country-by-country basis in SSEA using an integrated quantitative methodology, which systematically accounts for previously published driver information and regional datasets. We synthesize more than 200 publications to identify the drivers of the forest change at different spatial scales in SSEA. Subsequently, we collect spatially explicit proxy data to represent the identified drivers. We quantify the dynamics of forest and agricultural land from 1992 to 2015 using the Climate Change Initiative (CCI) land cover data developed by the European Space Agency (ESA). A geographically weighted regression method is employed to quantify the spatially heterogeneous drivers of forest change. Our results show that socioeconomic drivers are more important than biophysical drivers for the conversion of forest to agricultural land in South Asia and maritime Southeast Asia. In contrast, biophysical drivers are more important than socioeconomic drivers for the conversion of agricultural land to forest in maritime Southeast Asia and less important in South Asia. Both biophysical and socioeconomic drivers contribute approximately equally to both changes in the mainland Southeast Asia region. By quantifying the dynamics of forest and agricultural land and the spatially explicit drivers of their changes in SSEA, this study provides a solid foundation for LULCC modeling and projection.

An Analysis of Medicare Reimbursement to Ophthalmologists: Years 2012 to 2013.

PURPOSE: To analyze trends in utilization and payment of ophthalmic services in the Medicare population for years 2012 and 2013. DESIGN: Retrospective, cross-sectional study. METHODS: A retrospective cross-sectional observational analysis was performed using publicly available Medicare Physician and Other Supplier aggregate file and the Physician and Other Supplier Public Use File. Variables analyzed included aggregate beneficiary demographics, Medicare payments to ophthalmologists, ophthalmic medical services provided, and the most common Medicare-reimbursed ophthalmic services. RESULTS: In 2013, total Medicare Part B reimbursement for ophthalmology was $5.8 billion, an increase of 3.6% from the previous year. From 2012 to 2013, the total number of ophthalmology services rendered increased by 2.2%, while average dollar amount reimbursed per ophthalmic service decreased by 5.4%. The top 5 highest reimbursed services accounted for 85% of total ophthalmic Medicare payments in 2013, an 11% increase from 2012. During 2013, drug reimbursement represented 32.8% of the total Medicare payments to ophthalmologists. Ranibizumab and aflibercept alone accounted for 95% of the entire $1.9 billion in drug reimbursements ophthalmologists in 2013. CONCLUSION: Medicare Part B reimbursement for ophthalmologists was primarily driven by use of anti-vascular endothelial growth factor (anti-VEGF) injections from 2012 to 2013. Of the total drug payments to ophthalmologists, biologic anti-VEGF agents ranibizumab and aflibercept accounted for 95% of all drug reimbursement. This is in contrast to other specialties, in which drug reimbursement represented only a small portion of Medicare reimbursement.

Influence of Television Advertising on Behavior of Children across Socioeconomic Backgrounds.

INTRODUCTION: This research analyzed the influence of television on the behavior of children belonging to urban and rural socioeconomic backgrounds of Bhopal city and its vicinity. MATERIALS AND METHODS: About 400 parents with children between 1 and 18 years of age were subjected to a self-designed questionnaire, which sought information regarding the television viewing habits of children. Differences in responses were noted between the subjects of urban and rural areas. Obtained data were subjected to statistical analysis using Pearson's chi-square test to determine the level of significance. RESULTS: The urban class showed a dominating pattern in the positive aspects of television viewing, such as significantly better awareness of oral health, more emphasis shown toward oral care adverts, and a higher knowledge of the cause of dental caries. However, the urban class also possessed a poor attitude; the appearance of a dentist on television did not remind them about oral needs, products with gifts pleased their children to a greater extent, they had more demanding children, parents fulfilled their children's demand more, and they relied on the self for selection of toothpaste. Overall, in all aspects, the rural class lacked significantly. CONCLUSION: Television exerts a positive as well as negative influence on children's behavior among urban and rural communities, with the influence being more obvious in the urban class. CLINICAL SIGNIFICANCE: The results of this study can be utilized in bringing about better and effective advertising oriented toward attaining optimum oral health of children; overall general health through adverts that discourage obesogenic diet and promote a diet rich in protein and fiber can also be focused on.

A clinical rating scale for the assessment of facial aging in Indian population.

BACKGROUND: Estimation of facial aging has assumed growing importance due to the advent of several antiaging therapies. Evidence-based estimation of global facial aging is often necessary, especially for validation of these treatment modalities. Most available methods are expensive and have been used in fair skinned individuals. AIM: We attempted to develop a clinical rating scale for the estimation of global facial aging applied on an Indian population which has brown to black skin. We have also measured the association of this rating scale score with the chronological age. METHODS: Initially, a 14- item summated rating scale was developed with inputs from five dermatologists and a clinical pharmacologist. The rating scale was applied to 105 consenting subjects with healthy facial skin between 30 to 90 years of age. Intra- and inter-rater reliability was assessed. RESULTS: The summated rating score showed a significant positive correlation with the chronological age (Pearson's correlation coefficient 0.834, P < 0.001). We omitted one item from the scale due to a low inter-rater agreement. The resulting 13-item rating scale was internally consistent (Cronbach's alpha: 0.905), with substantial inter- and intra-rater reliability (intraclass correlation coefficient: 0.973 and 0.788, respectively). Principal components and predictive equation for perceptible age were identified on further computation. LIMITATIONS: Participants of this study were limited to a particular ethnic group from West Bengal and other neighboring states of Eastern India. CONCLUSIONS: We have developed and validated a 13-item rating scale for the quantification of global facial aging suitable for Indian (brown to black) skin type. This scale can be utilized effectively for clinical estimation of global facial aging.

The Interplay Between Bioenergy Grass Production and Water Resources in the United States of America.

We apply a land surface model to evaluate the interplay between potential bioenergy grass (Miscanthus, Cave-in-Rock, and Alamo) production, water quantity, and nitrogen leaching (NL) in the Central and Eastern U.S. Water use intensity tends to be lower where grass yields are modeled to be high, for example in the Midwest for Miscanthus and Cave-in-Rock and the upper southeastern U.S. for Alamo. However, most of these regions are already occupied by crops and forests and substitution of these biome types for ethanol production implies trade-offs. In general, growing Miscanthus consumes more water, Alamo consumes less water, and Cave-in-Rock consumes approximately the same amount of water as existing vegetation. Bioenergy grasses can maintain high productivity over time, even in water limited regions, because their roots can grow deeper and extract the water from the deep, moist soil layers. However, this may not hold where there are frequent and intense drought events, particularly in regions with shallow soil depths. One advantage of bioenergy grasses is that they mitigate nitrogen leaching relative to row crops and herbaceous plants when grown without applying N fertilizer; and bioenergy grasses, especially Miscanthus, generally require less N fertilizer application than row crops and herbaceous plants.

Advanced technology paths to global climate stability: energy for a greenhouse planet.

Stabilizing the carbon dioxide-induced component of climate change is an energy problem. Establishment of a course toward such stabilization will require the development within the coming decades of primary energy sources that do not emit carbon dioxide to the atmosphere, in addition to efforts to reduce end-use energy demand. Mid-century primary power requirements that are free of carbon dioxide emissions could be several times what we now derive from fossil fuels (approximately 10(13) watts), even with improvements in energy efficiency. Here we survey possible future energy sources, evaluated for their capability to supply massive amounts of carbon emission-free energy and for their potential for large-scale commercialization. Possible candidates for primary energy sources include terrestrial solar and wind energy, solar power satellites, biomass, nuclear fission, nuclear fusion, fission-fusion hybrids, and fossil fuels from which carbon has been sequestered. Non-primary power technologies that could contribute to climate stabilization include efficiency improvements, hydrogen production, storage and transport, superconducting global electric grids, and geoengineering. All of these approaches currently have severe deficiencies that limit their ability to stabilize global climate. We conclude that a broad range of intensive research and development is urgently needed to produce technological options that can allow both climate stabilization and economic development.