Synthesis and Antiobesity Properties of 6-(4-Chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (BMS-814580): A Highly Efficacious Melanin Concentrating Hormone Receptor 1 (MCHR1) Inhibitor.

The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.

Non-basic azolotriazinone MCHR1 antagonists for the treatment of obesity: An empirical brain-exposures-driven candidate selection for in vivo efficacy studies.

Non-basic azolotriazinones were explored using an empirical free brain exposures-driven approach to identify potent MCHR1 antagonists for evaluation in in vivo efficacy studies. An optimized lead from this series, 1j (rMCHR1 Ki=1.8 nM), demonstrated a 6.9% reduction in weight gain relative to vehicle in a rat model at 30 mg/kg after 4 days of once-daily oral treatment as a glycine prodrug. Despite a promising efficacy profile, an assessment of the biliary toxicity risk of this compound rendered this compound non-progressible.

Dihydropyrrolopyrazol-6-one MCHR1 antagonists for the treatment of obesity: Insights on in vivo efficacy from a novel FLIPR assay setup.

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.

Agency for Healthcare Research and Quality Evidence-based Practice Center methods for systematically reviewing complex multicomponent health care interventions.

OBJECTIVES: The purpose of this Agency for Healthcare Research and Quality Evidence-based Practice Center methods white paper was to outline approaches to conducting systematic reviews of complex multicomponent health care interventions. STUDY DESIGN AND SETTING: We performed a literature scan and conducted semistructured interviews with international experts who conduct research or systematic reviews of complex multicomponent interventions (CMCIs) or organizational leaders who implement CMCIs in health care. RESULTS: Challenges identified include lack of consistent terminology for such interventions (eg, complex, multicomponent, multidimensional, multifactorial); a wide range of approaches used to frame the review, from grouping interventions by common features to using more theoretical approaches; decisions regarding whether and how to quantitatively analyze the interventions, from holistic to individual component analytic approaches; and incomplete and inconsistent reporting of elements critical to understanding the success and impact of multicomponent interventions, such as methods used for implementation the context in which interventions are implemented. CONCLUSION: We provide a framework for the spectrum of conceptual and analytic approaches to synthesizing studies of multicomponent interventions and an initial list of critical reporting elements for such studies. This information is intended to help systematic reviewers understand the options and tradeoffs available for such reviews.

Identification of a nonbasic melanin hormone receptor 1 antagonist as an antiobesity clinical candidate.

Identification of MCHR1 antagonists with a preclinical safety profile to support clinical evaluation as antiobesity agents has been a challenge. Our finding that a basic moiety is not required for MCHR1 antagonists to achieve high affinity allowed us to explore structures less prone to off-target activities such as hERG inhibition. We report the SAR evolution of hydroxylated thienopyrimidinone ethers culminating in the identification of 27 (BMS-819881), which entered obesity clinical trials as the phosphate ester prodrug 35 (BMS-830216).

Screening for methicillin-resistant Staphylococcus aureus: a comparative effectiveness review.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of health care-associated infections. Although the evidence in support of MRSA screening has been promising, a number of questions remain about the effectiveness of active surveillance. METHODS: We searched the literature for studies that examined MRSA acquisition, MRSA infection, morbidity, mortality, harms of screening, and resource utilization when screening for MRSA carriage was compared with no screening or with targeted screening. Because of heterogeneity of the data and weaknesses in study design, meta-analysis was not performed. Strength of evidence (SOE) was determined using the system developed by the Grading of Recommendations Assessment, Development and Evaluation Working Group. RESULTS: One randomized controlled trial and 47 quasi-experimental studies met our inclusion criteria. We focused on the 14 studies that addressed health care-associated outcomes and that attempted to control for confounding and/or secular trends, because those studies had the potential to support causal inferences. With universal screening for MRSA carriage compared with no screening, 2 large quasi-experimental studies found reductions in health care-associated MRSA infection. The SOE for this finding is low. For each of the other screening strategies evaluated, this review found insufficient evidence to determine the comparative effectiveness of screening. CONCLUSIONS: Although there is low SOE that universal screening of hospital patients decreases MRSA infection, there is insufficient evidence to determine the consequences of universal screening or the effectiveness of other screening strategies.

Cervical cancer screening, diagnosis and treatment interventions for racial and ethnic minorities: a systematic review.

OBJECTIVES: To systematically review the literature to determine which interventions improve the screening, diagnosis or treatment of cervical cancer for racial and/or ethnic minorities. DATA SOURCES: Medline on OVID, Cochrane Register of Controlled Trials, CINAHL, PsycINFO and Cochrane Systematic Reviews. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: We searched the above databases for original articles published in English with at least one intervention designed to improve cervical cancer prevention, screening, diagnosis or treatment that linked participants to the healthcare system; that focused on US racial and/or ethnic minority populations; and that measured health outcomes. Articles were reviewed to determine the population, intervention(s), and outcomes. Articles published through August 2010 were included. STUDY APPRAISAL AND SYNTHESIS METHODS: One author rated the methodological quality of each of the included articles. The strength of evidence was assessed using the criteria developed by the GRADE Working Group. RESULTS: Thirty-one studies were included. The strength of evidence is moderate that telephone support with navigation increases the rate of screening for cervical cancer in Spanish- and English-speaking populations; low that education delivered by lay health educators with navigation increases the rate of screening for cervical cancer for Latinas, Chinese Americans and Vietnamese Americans; low that a single visit for screening for cervical cancer and follow up of an abnormal result improves the diagnosis and treatment of premalignant disease of the cervix for Latinas; and low that telephone counseling increases the diagnosis and treatment of premalignant lesions of the cervix for African Americans. LIMITATIONS: Studies that did not focus on racial and/or ethnic minority populations may have been excluded. In addition, this review excluded interventions that did not link racial and ethnic minorities to the health care system. While inclusion of these studies may have altered our findings, they were outside the scope of our review. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Patient navigation with telephone support or education may be effective at improving screening, diagnosis, and treatment among racial and ethnic minorities. Research is needed to determine the applicability of the findings beyond the populations studied.

Teaching about health care disparities in the clinical setting.

Clinical teachers often observe interactions that may contribute to health care disparities, yet may hesitate to teach about them. A pedagogical model could help faculty structure teaching about health care disparities in the clinical setting, but to our knowledge, none have been adapted for this purpose. In this paper, we adapt an established model, Time-Effective Strategies for Teaching (TEST), to the teaching of health care disparities. We use several case scenarios to illustrate the core components of the model: diagnose the learner, teach rapidly to the learner's need, and provide feedback. The TEST model is straightforward, easy to use, and enables the incorporation of teaching about health care disparities into routine clinical teaching.

A strategy for improving health disparities education in medicine.

INTRODUCTION: A health disparities curriculum that uses evidence-based knowledge rooted in pedagogic theory is needed to educate health care providers to meet the needs of an increasingly diverse U.S. population. DESCRIPTION: The Health Disparities Education: Beyond Cultural Competency Precourse, along with its accompanying Train the Trainer Guide: Health Disparities Education (2008), developed by the Society of General Internal Medicine (SGIM) Disparities Task Force (DTF), is a comprehensive tool to facilitate developing, implementing and evaluating health disparities education. The curriculum includes five modules highlighting several fundamental concepts in health disparities, suggestions for teaching about health disparities in a wide range of settings and strategies for curriculum evaluation. The modules are Disparities Foundations, Teaching Disparities in the Clinical Setting, Disparities Beyond the Clinical Setting, Teaching about Disparities Through Community Involvement, and Curriculum Evaluation. EVALUATION: All five modules were delivered as a precourse at the 31st Annual SGIM Annual Meeting in Pittsburgh, PA and received the "Best Precourse Award". This award is given to the most highly rated precourse based on participant evaluations. The modules have also been adapted into a web-based guide that has been downloaded at least 59 times. CONCLUSION: Ultimately, the modules are designed to develop a professional commitment to eliminating racial and ethnic disparities in health care quality, promote an understanding of the role of health care providers in reducing health care disparities through comprehensive education and training, and provide a framework with which providers can address the causes of disparities in various educational settings.

Changing attitudes toward homeless people.

We assessed the impact of a 2-week required rotation in homeless health care on primary care residents' attitudes toward homeless people. Attitudes were assessed before and after the course using the Attitudes Toward Homelessness Inventory (ATHI), an instrument previously validated among undergraduate students. Attitude scores on the ATHI improved from 46 to 52 (range of possible scores 11 to 66; P =.001). The ATHI subscales showed, after the course, that residents had a greater belief that homelessness had societal causes and felt more comfortable affiliating with homeless people. After the course, residents also reported an increased interest in volunteering with homeless populations on an anonymous survey.