Enhancement of Aqueous Solubility and Oral Bioavailability of Nelfinavir by Complexation with β- Cyclodextrin

Purpose: To determine if complexation with β- cyclodextrin (β-CD) increases water solubility and subsequent bioavailability of nelfinavir mesylate (NM).Methods: Complexation of NM with β-CD in 1:1.5 molar ratio was carried out by solvent evaporation, freeze-drying and kneading methods. The complexes were characterized by Fourier transform infrared spectroscopy (FTIR). The in vitro solubility of the pure drug as well as that of the complexes was evaluated using USP type 2 apparatus. One of the drug complexes was also evaluated in vivo using Wistar rats to determine its pharmacokinetic profile.Results: Freeze-dried NM-βCD complex was selected for in vivo studies based on its free flowing property and superior texture. The complexes prepared by the three methods all showed largely similar dissolution rate. The in vivo pharmacokinetic study of the freeze-dried complex in male Wistar rats showed significant increase in Cmax, tmax and AUC (p ≤ 0.05) compared to those of the plain drug.Conclusion: These findings suggest that complexation of NM with β-CD is an effective and promising approach to increasing the oral bioavailability of NM

The non-Abelian gauge theory of matrix big bangs

We study at the classical and quantum mechanical level the time-dependent Yang-Mills theory that one obtains via the generalisation of discrete light-cone quantisation to singular homogeneous plane waves. The non-Abelian nature of this theory is known to be important for physics near the singularity, at least as far as the number of degrees of freedom is concerned. We will show that the quartic interaction is always subleading as one approaches the singularity and that close enough to t=0 the evolution is driven by the diverging tachyonic mass term. The evolution towards asymptotically flat space-time also reveals some surprising features.Comment: 29 pages, 8 eps figures, v2: minor changes, references added: v3 small typographical changes

Implementing stratified primary care management for low back pain: cost utility analysis alongside a prospective, population-based, sequential comparison study

STUDY DESIGN: Within-study cost-utility analysis. OBJECTIVE:To explore the cost-utility of implementing stratified care for low back pain (LBP) in general practice, compared with usual care, within risk-defined patient subgroups (that is, patients at low, medium, and high risk of persistent disabling pain). SUMMARY OF BACKGROUND DATA: Individual-level data collected alongside a prospective, sequential comparison of separate patient cohorts with 6-month follow-up. METHODS: Adopting a cost-utility framework, the base case analysis estimated the incremental LBP-related health care cost per additional quality-adjusted life year (QALY) by risk subgroup. QALYs were constructed from responses to the 3-level EQ-5D, a preference-based health-related quality of life instrument. Uncertainty was explored with cost-utility planes and acceptability curves. Sensitivity analyses examined alternative methodological approaches, including a complete case analysis, the incorporation of non-back pain-related health care use and estimation of societal costs relating to work absence. RESULTS: Stratified care was a dominant treatment strategy compared with usual care for patients at high risk, with mean health care cost savings of £124 and an incremental QALY estimate of 0.023. The likelihood that stratified care provides a cost-effective use of resources for patients at low and medium risk is no greater than 60% irrespective of a decision makers' willingness-to-pay for additional QALYs. Patients at medium and high risk of persistent disability in paid employment at 6-month follow-up reported, on average, 6 fewer days of LBP-related work absence in the stratified care cohort compared with usual care (associated societal cost savings per employed patient of £736 and £652, respectively). CONCLUSION: At the observed level of adherence to screening tool recommendations for matched treatments, stratified care for LBP is cost-effective for patients at high risk of persistent disabling LBP only. LEVEL OF EVIDENCE: 2.The IMPaCT Back study was funded by the Health Foundation (grant code: 346/4540) with support from the National Institutes for Health Research (NIHR) Primary Care Research Network-North West, the Keele Academic General Practice Partnership and the Primary Care Musculoskeletal Research Consortium. NEF was supported, in part, by a National Coordinating Centre for Research Capacity Development (NCCRCD) Primary Care Career Scientist Award and is currently supported by an NIHR Research Professorship (NIHR-RP-011-015). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.This is the final published version. It first appeared at http://journals.lww.com/spinejournal/Fulltext/2015/03150/Implementing_Stratified_Primary_Care_Management.14.aspx

Accurate and Fast Retrieval for Complex Non-metric Data via Neighborhood Graphs

We demonstrate that a graph-based search algorithm-relying on the construction of an approximate neighborhood graph-can directly work with challenging non-metric and/or non-symmetric distances without resorting to metric-space mapping and/or distance symmetrization, which, in turn, lead to substantial performance degradation. Although the straightforward metrization and symmetrization is usually ineffective, we find that constructing an index using a modified, e.g., symmetrized, distance can improve performance. This observation paves a way to a new line of research of designing index-specific graph-construction distance functions

Discursive positioning and planned change in organizations

This study uses discursive positioning theory to explore how planned change messages influence organizational members’ identity and the way they experienced organizational change. Based on an in-depth case study of a home healthcare and hospice organization that engaged in a multiyear planned change process, our analysis suggests that workers experienced salient change messages as constituting unfavorable identities, which were associated with the experiences of violation, recitation, habituation, or reservation. Our study also explores the way discursive and material contexts enabled and constrained the governing board’s change messages as they responded to external and internal audiences. We highlight the importance of viewing messaging as a process of information transfer as well as discursive construction, which has important implications for the way change agents approach issues of sense making, emotionality, resistance, and materiality during planned change processes.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

The use of phylogeny to interpret cross-cultural patterns in plant use and guide medicinal plant discovery: an example from Pterocarpus (Leguminosae)

The study of traditional knowledge of medicinal plants has led to discoveries that have helped combat diseases and improve healthcare. However, the development of quantitative measures that can assist our quest for new medicinal plants has not greatly advanced in recent years. Phylogenetic tools have entered many scientific fields in the last two decades to provide explanatory power, but have been overlooked in ethnomedicinal studies. Several studies show that medicinal properties are not randomly distributed in plant phylogenies, suggesting that phylogeny shapes ethnobotanical use. Nevertheless, empirical studies that explicitly combine ethnobotanical and phylogenetic information are scarce.In this study, we borrowed tools from community ecology phylogenetics to quantify significance of phylogenetic signal in medicinal properties in plants and identify nodes on phylogenies with high bioscreening potential. To do this, we produced an ethnomedicinal review from extensive literature research and a multi-locus phylogenetic hypothesis for the pantropical genus Pterocarpus (Leguminosae: Papilionoideae). We demonstrate that species used to treat a certain conditions, such as malaria, are significantly phylogenetically clumped and we highlight nodes in the phylogeny that are significantly overabundant in species used to treat certain conditions. These cross-cultural patterns in ethnomedicinal usage in Pterocarpus are interpreted in the light of phylogenetic relationships.This study provides techniques that enable the application of phylogenies in bioscreening, but also sheds light on the processes that shape cross-cultural ethnomedicinal patterns. This community phylogenetic approach demonstrates that similar ethnobotanical uses can arise in parallel in different areas where related plants are available. With a vast amount of ethnomedicinal and phylogenetic information available, we predict that this field, after further refinement of the techniques, will expand into similar research areas, such as pest management or the search for bioactive plant-based compounds

Reference values for methacholine reactivity (SAPALDIA study)

BACKGROUND: The distribution of airway responsiveness in a general population of non-smokers without respiratory symptoms has not been established, limiting its use in clinical and epidemiological practice. We derived reference equations depending on individual characteristics (i.e., sex, age, baseline lung function) for relevant percentiles of the methacholine two-point dose-response slope. METHODS: In a reference sample of 1567 adults of the SAPALDIA cross-sectional survey (1991), defined by excluding subjects with respiratory conditions, responsiveness during methacholine challenge was quantified by calculating the two-point dose-response slope (O'Connor). Weighted L1-regression was used to estimate reference equations for the 95(th ), 90(th ), 75(th )and 50(th )percentiles of the two-point slope. RESULTS: Reference equations for the 95(th ), 90(th ), 75(th )and 50(th )percentiles of the two-point slope were estimated using a model of the form a + b* Age + c* FEV(1 )+ d* (FEV(1))(2 ), where FEV(1 )corresponds to the pre-test (or baseline) level of FEV(1). For the central half of the FEV(1 )distribution, we used a quadratic model to describe the dependence of methacholine slope on baseline FEV(1). For the first and last quartiles of FEV(1), a linear relation with FEV(1 )was assumed (i.e., d was set to 0). Sex was not a predictor term in this model. A negative linear association with slope was found for age. We provide an Excel file allowing calculation of the percentile of methacholine slope of a subject after introducing age – pre-test FEV(1 )– and results of methacholine challenge of the subject. CONCLUSION: The present study provides equations for four relevant percentiles of methacholine two-point slope depending on age and baseline FEV(1 )as basic predictors in an adult reference population of non-obstructive and non-atopic persons. These equations may help clinicians and epidemiologists to better characterize individual or population airway responsiveness

Effect of Smoke-Free Legislation on Adult Smoking Behaviour in England in the 18 Months following Implementation

Comprehensive smoke-free legislation covering all enclosed public places and workplaces was implemented in England on 1 July 2007. This study examines the impact of this legislation on smoking prevalence, number of cigarettes smoked and location of smoking, controlling for secular trends through the end of 2008.Repeat cross sectional survey using nationally representative data from the Health Survey for England (HSE). In total there are 54,333 respondents from 2003-2008. Logit and linear regression models were used to examine the effect of the legislation on smoking prevalence and the number of cigarettes smoked daily among continuing smokers which took the underlying trend into account. Our finding suggest that smoking prevalence (current smoker) decreased from 25% in 2003 to 21% in 2008 (AOR = 0.96 per year, 95% CI = 0.95-0.98, P<0.01) and the mean number of cigarettes consumed daily by smokers decreased from 14.1 in 2003 to 13.1 in 2008 (coefficient for time trend = -0.28±0.06 SE cig/day per year, P<0.01). After adjusting for these trends the introduction of smoke-free legislation was not associated with additional reductions in smoking prevalence (AOR = 1.02, 95% CI = 0.94-1.11, P = 0.596) or daily cigarette use in smokers (0.42±0.28 SE; P = 0.142). The percentage of respondents reporting smoking 'at work' and 'inside pubs or bars' decreased significantly from 14% to 2% (p<0.001) and from 34% to 2% (p<0.001), respectively, after the legislation. The percentage reporting smoking 'inside restaurants, cafes, or canteens' decreased significantly from 9% to 1% (p<0.001) and 'inside their home' decreased significantly from 65% to 55% (p<0.01).There is widespread compliance with the smoke-free legislation in England, which has led to large drops in indoor smoking in all venues, including at home. Declines in smoking prevalence and consumption continued along existing trends; they did not accelerate during the 18 months immediately following implementation

Benefits and barriers among volunteer teaching faculty: comparison between those who precept and those who do not in the core pediatrics clerkship

Background: Community-based outpatient experiences are a core component of the clinical years in medical school. Central to the success of this experience is the recruitment and retention of volunteer faculty from the community. Prior studies have identified reasons why some preceptors volunteer their time however, there is a paucity of data comparing those who volunteer from those who do not. Methods: A survey was developed following a review of previous studies addressing perceptions of community-based preceptors. A non-parametric, Mann&#x2013;Whitney U test was used to compare active preceptors (APs) and inactive preceptors (IPs) and all data were analyzed in SPSS 20.0. Results: There was a 28% response rate. Preceptors showed similar demographic characteristics, valued intrinsic over extrinsic benefits, and appreciated Continuing Medical Education (CME)/Maintenance of Certification (MOC) opportunities as the highest extrinsic reward. APs were more likely to also precept at the M1/M2 level and value recognition and faculty development opportunities (p&#x3C;0.05). IPs denoted time as the most significant barrier and, in comparison to APs, rated financial compensation as more important (p&#x3C;0.05). Conclusions: Community preceptors are motivated by intrinsic benefits of teaching. Efforts to recruit should initially focus on promoting awareness of teaching opportunities and offering CME/MOC opportunities. Increasing the pool of preceptors may require financial compensation

A Controlled Investigation of Optimal Internal Medicine Ward Team Structure at a Teaching Hospital

BACKGROUND: The optimal structure of an internal medicine ward team at a teaching hospital is unknown. We hypothesized that increasing the ratio of attendings to housestaff would result in an enhanced perceived educational experience for residents. METHODS: Harbor-UCLA Medical Center (HUMC) is a tertiary care, public hospital in Los Angeles County. Standard ward teams at HUMC, with a housestaff∶attending ratio of 5:1, were split by adding one attending and then dividing the teams into two experimental teams containing ratios of 3:1 and 2:1. Web-based Likert satisfaction surveys were completed by housestaff and attending physicians on the experimental and control teams at the end of their rotations, and objective healthcare outcomes (e.g., length of stay, hospital readmission, mortality) were compared. RESULTS: Nine hundred and ninety patients were admitted to the standard control teams and 184 were admitted to the experimental teams (81 to the one-intern team and 103 to the two-intern team). Patients admitted to the experimental and control teams had similar age and disease severity. Residents and attending physicians consistently indicated that the quality of the educational experience, time spent teaching, time devoted to patient care, and quality of life were superior on the experimental teams. Objective healthcare outcomes did not differ between experimental and control teams. CONCLUSIONS: Altering internal medicine ward team structure to reduce the ratio of housestaff to attending physicians improved the perceived educational experience without altering objective healthcare outcomes