An appraisal of emergency medicine clinical practice guidelines: Do we agree?

BACKGROUND: Clinical practice guidelines (CPGs) have been published by the American College of Emergency Physicians (ACEP) since 1990 to advance evidence-based emergency care. ACEP clinical policies have drawn anecdotal criticism for bias, yet the overall quality of these guidelines has not previously been quantified. We sought to examine ACEP clinical policies using a recognised, validated appraisal instrument: Appraisal of Guidelines for Research & Evaluation (AGREE II). METHODS: Systematic assessment of current ACEP clinical policies was conducted using the AGREE II instrument, which contains 23 appraisal items (scored on a 1-7 scale) in six domains and two overall assessments. Each policy was independently appraised by five trained appraisers. Primary outcomes were AGREE II ratings for each item, domain and "Overall Assessment," and scores were reported as standardised percentages from all five appraisers. Secondary analyses examined associations between AGREE II ratings and policy publication date, strength of underlying evidence and strength of recommendations. Additional analysis examined relationships between domain and "Overall Assessment" ratings. RESULTS: Twenty guidelines published from April 2007 to November 2017 were included. Of the six domains, "Scope and Purpose" scored highest (mean 90%) and "Applicability" scored lowest (mean 35%). The four remaining domains ("Stakeholder Involvement," "Rigor of Development," "Clarity of Presentation" and "Editorial Independence") had mean scores of 53%-78%. The mean "Overall Assessment" rating was 69% and was not associated with policy publication date, strength of underlying evidence or strength of recommendations. We found positive associations between "Overall Assessment" ratings and two domains: "Rigor of Development" (r = 0.70) and "Clarity of Presentation" (r = 0.70). CONCLUSIONS: Based on validated AGREE II criteria, ACEP clinical policies can be most improved by addressing their application in practice. ACEP clinical policies' overall quality did not improve over the assessed time period and is not explained by the quality of underlying evidence.

The Psychology of Gay Men's Cuckolding Fantasies.

Cuckolding (also known as troilism) is a sexual interest in which one obtains sexual arousal from the experience of a romantic partner engaging in sexual activity with someone else. The present study investigated fantasies about and experiences with cuckolding in a large and diverse sample of predominately gay-identified men (N = 580). Compared to previous research focusing on heterosexual men's cuckolding fantasies, our results indicate that gay men's cuckolding fantasies share many common elements; however, they differ in some important ways. Most notably, interracial and BDSM themes do not appear to be as common in gay men's cuckolding fantasies as they are among heterosexual men. Our findings also indicate that frequent fantasies about cuckolding are linked to several overlapping sexual interests (e.g., voyeurism, group sex) and, further, the content of these fantasies is associated with a number of individual differences (e.g., agreeableness, sensation seeking, sociosexuality). Finally, this study also suggests that gay men who act on their cuckolding fantasies tend to report positive experiences; however, the likelihood of reporting positive outcomes appears to depend upon one's personality and attachment style.

Systematic review of emergency medicine clinical practice guidelines: Implications for research and policy.

INTRODUCTION: Over 25 years, emergency medicine in the United States has amassed a large evidence base that has been systematically assessed and interpreted through ACEP Clinical Policies. While not previously studied in emergency medicine, prior work has shown that nearly half of all recommendations in medical specialty practice guidelines may be based on limited or inconclusive evidence. We sought to describe the proportion of clinical practice guideline recommendations in Emergency Medicine that are based upon expert opinion and low level evidence. METHODS: Systematic review of clinical practice guidelines (Clinical Policies) published by the American College of Emergency Physicians from January 1990 to January 2016. Standardized data were abstracted from each Clinical Policy including the number and level of recommendations as well as the reported class of evidence. Primary outcomes were the proportion of Level C equivalent recommendations and Class III equivalent evidence. The primary analysis was limited to current Clinical Policies, while secondary analysis included all Clinical Policies. RESULTS: A total of 54 Clinical Policies including 421 recommendations and 2801 cited references, with an average of 7.8 recommendations and 52 references per guideline were included. Of 19 current Clinical Policies, 13 of 141 (9.2%) recommendations were Level A, 57 (40.4%) Level B, and 71 (50.4%) Level C. Of 845 references in current Clinical Policies, 67 (7.9%) were Class I, 272 (32.3%) Class II, and 506 (59.9%) Class III equivalent. Among all Clinical Policies, 200 (47.5%) recommendations were Level C equivalent, and 1371 (48.9%) of references were Class III equivalent. CONCLUSIONS: Emergency medicine clinical practice guidelines are largely based on lower classes of evidence and a majority of recommendations are expert opinion based. Emergency medicine appears to suffer from an evidence gap that should be prioritized in the national research agenda and considered by policymakers prior to developing future quality standards.

Presentation of continuous outcomes in randomised trials: an observational study.

OBJECTIVE: To characterise the percentage of available outcome data being presented in reports of randomised clinical trials with continuous outcome measures, thereby determining the potential for incomplete reporting bias. DESIGN: Descriptive cross sectional study. DATA SOURCES: A random sample of 200 randomised trials from issues of 20 medical journals in a variety of specialties during 2007-09. MAIN OUTCOME MEASURES: For each paper's best reported primary outcome, we calculated the fraction of data reported using explicit scoring rules. For example, a two arm trial with 100 patients per limb that reported 2 sample sizes, 2 means, and 2 standard deviations reported 6/200 data elements (1.5%), but if that paper included a scatterplot with 200 points it would score 200/200 (100%). We also assessed compliance with 2001 CONSORT items about the reporting of results. RESULTS: The median percentage of data reported for the best reported continuous outcome was 9% (interquartile range 3-26%) but only 3.5% (3-7%) when we adjusted studies to 100 patients per arm to control for varying study size; 17% of articles showed 100% of the data. Tables were the predominant means of presenting the most data (59% of articles), but papers that used figures reported a higher proportion of data. There was substantial heterogeneity among journals with respect to our primary outcome and CONSORT compliance. LIMITATIONS: We studied continuous outcomes of randomised trials in higher impact journals. Results may not apply to categorical outcomes, other study designs, or other journals. CONCLUSIONS: Trialists present only a small fraction of available data. This paucity of data may increase the potential for incomplete reporting bias, a failure to present all relevant information about a study's findings.

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors.

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of ß-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of ß-amyloid peptides; one of which, Aß42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aß42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aß42 production in mice.

Triazoles as γ-secretase modulators.

Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aß42 in Sprague-Dawley rats.

Molecular determinants of dihydrouridine synthase activity.

Dihydrouridine is one of the most abundant modified bases in tRNA. However, little is known concerning the biochemistry of dihydrouridine synthase (DUS) enzymes. To identify molecular determinants that are necessary for DUS activity, we have developed a DUS-complementation assay in Escherichia coli. Using this assay, we have identified amino-acid residues that are critical for the activity of YjbN, an E. coli DUS. We also show that the aq1598 gene product, a putative DUS from Aquifex aeolicus, catalyzes dihydrouridine formation, providing the first biochemical demonstration that A. aeolicus encodes an active DUS.