The Enantioselective Construction of Tetracyclic Diterpene Skeletons with Friedel-Crafts Alkylation and Palladium-catalyzed Cycloalkenylation Reactions

Due to the profound extent to which natural products inspire medicinal chemists in drug discovery, there is demand for innovative syntheses of these often complex materials. This article describes the synthesis of tricarbocyclic natural product architectures through an extension of the enantioselective Birch-Cope sequence with intramolecular Friedel-Crafts alkylation reactions. Additionally, palladium-catalyzed enol silane cycloalkenylation of the tricarbocyclic structures afforded the challenging bicyclo[3.2.1]octane C/D ring system found in the gibberellins and the ent-kauranes, two natural products with diverse medicinal value. In the case of the ent-kaurane derivative, an unprecedented alkene rearrangement converted four alkene isomers to one final product

A systematic review and quality analysis of pediatric traumatic brain injury clinical practice guidelines

<div><p>Background</p><p>Traumatic brain injuries (TBI) are a significant cause of mortality and morbidity for children globally. Adherence to evidence-based treatment guidelines have been shown to improve TBI outcomes. To inform the creation of a pediatric TBI management guideline for a low and middle income country context, we assessed the quality of available clinical practice guidelines (CPGs) for the acute management pediatric TBI.</p><p>Methods</p><p>Articles were identified and retrieved from MEDLINE, EMBASE, Cochrane Library, LILACS, Africa-Wide Information and Global Index Medicus. These articles were screened by four reviewers independently. Based on the eligibility criteria, with the exception of literature reviews, opinion papers and editor’s letters, articles published from 1995 to November 11, 2016 which covered clinical recommendations, clinical practice or treatment guidelines for the acute management of pediatric TBI (within 24 hours) were included for review. A reference and citation analysis was performed. Seven independent reviewers from low, middle and high income clinical settings with knowledge of pediatric TBI management appraised the guidelines using the AGREE II instrument. Scores for the CPGs were aggregated by domain and overall assessment was determined.</p><p>Results</p><p>We screened 2372 articles of which 17 were retained for data extraction and guideline appraisal. Except for one CPG from a middle income country, the majority (16/17) of the guidelines were developed in high income countries. Seven guidelines were developed specifically for the pediatric population, while the remaining CPGs addressed the acute management of TBI in both adult and pediatric populations. The New Zealand Guideline Group (NZGG, 2006) received the highest overall assessment score of 46/49 (93.88%) followed by the Scandinavian Neurotrauma Committee (SNC, 2016) with a score of 45/49 (91.84%) followed by the Scottish Intercollegiate Guideline Network (SIGN, 2009) and Brain Trauma Foundation (BTF 2012) both with scores of 44/49 (89.80%). CPGs from Cincinnati Children’s Hospital (CCH 2006) and Sao Paulo Medical School Hospital/Brazilian Society of Neurosurgery (USP/BSN, 2001) received the lowest score of 27/49 (55.10%) subsequently followed by the Appropriateness Criteria (ACR, 2015) with 29/49 (59.18%). The domains for scope and purpose and clarity of presentation received the highest scores across the CPGs, while applicability and editorial independence domains had the lowest scores with a wider variability in score range for rigor of development and stakeholder involvement.</p><p>Conclusions</p><p>To our knowledge, this is the first systematic review and guideline appraisal for pediatric CPGs concerning the acute management of TBI. Targeted guideline creation specific to the pediatric population has the potential to improve the quality of acute TBI CPGs. Furthermore, it is crucial to address the applicability of a guideline to translate the CPG from a published manuscript into clinically relevant local practice tools and for resource limited practice settings.</p></div

Characteristics of clinical practice guidelines.

<p>Characteristics of clinical practice guidelines.</p

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram.

<p>Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram.</p

AGREE II overall guideline assessment.

<p>AGREE II overall guideline assessment.</p

Inter-rater reliability for the AGREE II domains.

<p>Inter-rater reliability for the AGREE II domains.</p

AGREE II aggregated scores by domain.

<p>AGREE II aggregated scores by domain.</p