Peripheral positions encode transport specificity in the small multidrug resistance exporters.

In secondary active transporters, a relatively limited set of protein folds have evolved diverse solute transport functions. Because of the conformational changes inherent to transport, altering substrate specificity typically involves remodeling the entire structural landscape, limiting our understanding of how novel substrate specificities evolve. In the current work, we examine a structurally minimalist family of model transport proteins, the small multidrug resistance (SMR) transporters, to understand the molecular basis for the emergence of a novel substrate specificity.

Structure-Activity Relationships of Natural and Semisynthetic Plecomacrolides Suggest Distinct Pathways for HIV-1 Immune Evasion and Vacuolar ATPase-Dependent Lysosomal Acidification.

The human immunodeficiency virus (HIV)-encoded accessory protein Nef enhances pathogenicity by reducing major histocompatibility complex I (MHC-I) cell surface expression, protecting HIV-infected cells from immune recognition. Nef-dependent downmodulation of MHC-I can be reversed by subnanomolar concentrations of concanamycin A (), a well-known inhibitor of vacuolar ATPase, at concentrations below those that interfere with lysosomal acidification or degradation. We conducted a structure-activity relationship study that assessed 76 compounds for Nef inhibition, 24 and 72 h viability, and lysosomal neutralization in Nef-expressing primary T cells.

A Core Outcome Set for Inflammatory Bowel Diseases: Development and Recommendations for Implementation in Clinical Practice Through an International Multi-stakeholder Consensus Process.

Background And Aims: Standardising health outcome measurements supports delivery of care and enables data-driven learning systems and secondary data use for research. As part of the Health Outcomes Observatory [H2O] initiative, and building on existing knowledge, a core outcome set [COS] for inflammatory bowel diseases [IBD] was defined through an international modified Delphi method.

Methods: Stakeholders rated 90 variables on a 9-point importance scale twice, allowing score modification based on feedback displayed per stakeholder group.

Development of α-Selective Glycosylation with l-Oleandral and Its Application to the Total Synthesis of Oleandrin.

This letter describes the development of an α-selective glycosylation using l-oleandrose, a 2-deoxysugar that is frequently found in natural products, and its application to the total synthesis of the natural cardiotonic steroids oleandrin and beaumontoside. To improve the reaction diastereoselectivity and to minimize side-product formation, an extensive evaluation and optimization of the conditions leading to α-selective glycosylation of digitoxigenin with l-oleandrose-based donors was conducted. These studies led to the exploration of 8 different phosphine·acid complexes or salts and yielded HBr·PPh as the optimal catalyst, which provided in the cleanest α-glycosylation and produced protected beaumontoside in 67% yield.

International development of a patient-centered core outcome set for assessing health-related quality of life in metastatic breast cancer patients.

Purpose: For patients living with metastatic breast cancer (MBC), achieving best possible health-related quality of life, along with maximizing survival, is vital. Yet, we have no systemic way to determine if we achieve these goals. A Core Outcome Set (COS) that allows standardized measurement of outcomes important to patients, but also promotes discussing these outcomes during clinical encounters, is long overdue.

Development, implementation and validation of resource-stratified guidelines in low-income and middle-income countries: a scoping review protocol.

Introduction: Nearly every field of medicine has some form of clinical practice guidelines. However, only within the past 5-10 years has the medical community acknowledged the need for well-developed guidelines tailored to the local healthcare needs and the resources available. In most low-income and middle-income countries (LMICs), healthcare workers depend on guidelines developed in high-income countries (HICs), yet many interventions validated in a HIC are ineffective when implemented in an LMIC.

System dynamics modeling for traumatic brain injury: Mini-review of applications.

Traumatic brain injury (TBI) is a highly complex phenomenon involving a cascade of disruptions across biomechanical, neurochemical, neurological, cognitive, emotional, and social systems. Researchers and clinicians urgently need a rigorous conceptualization of brain injury that encompasses nonlinear and mutually causal relations among the factors involved, as well as sources of individual variation in recovery trajectories. System dynamics, an approach from systems science, has been used for decades in fields such as management and ecology to model nonlinear feedback dynamics in complex systems.

Protocol for a Multicenter, Prospective, Observational Pilot Study on the Implementation of Resource-Stratified Algorithms for the Treatment of Severe Traumatic Brain Injury Across Four Treatment Phases: Prehospital, Emergency Department, Neurosurgery, and Intensive Care Unit.

Background: Severe traumatic brain injury (sTBI) is a public health issue with great disparity among low- and middle-income countries where the implementation of evidence-based guidelines is challenging because resources are often unavailable. A consensus process including experts in the prehospital, emergency department, neurosurgery, and intensive care unit took place in Colombia to develop a set of stratified protocols called BOOTStraP, targeting resource-poor environments, but it has not been systematically implemented and tested.

Objective: To identify the facilitators of, and barriers to, collecting data about patients with sTBI and to implement a stratified protocol across the treatment phases of prehospital, emergency department, neurosurgery, and intensive care unit in low-resource settings.

Synthesis of Cardiotonic Steroids Oleandrigenin and Rhodexin B.

This article describes a concise synthesis of cardiotonic steroids oleandrigenin () and its subsequent elaboration into the natural product rhodexin B () from the readily available intermediate () that could be derived from the commercially available steroids testosterone or DHEA three-step sequences. These studies feature an expedient installation of the β16-oxidation based on β14-hydroxyl-directed epoxidation and subsequent epoxide rearrangement. The following singlet oxygen oxidation of the C17 furan moiety provides access to oleandrigenin () in 12 steps (LLS) and a 3.

Prehospital Airway Management: A Systematic Review.

To assess comparative benefits and harms across three airway management approaches (bag valve mask [BVM], supraglottic airway [SGA], and endotracheal intubation [ETI]) used by prehospital emergency medical services (EMS) to treat patients with trauma, cardiac arrest, or medical emergencies, and how they differ based on techniques and devices, EMS personnel and patient characteristics. We searched electronic citation databases (Ovid® MEDLINE, CINAHL, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus) from 1990 to September 2020. We followed Agency for Healthcare Research and Quality Effective Health Care Program Methods guidance.

Fungal-derived brevianamide assembly by a stereoselective semipinacolase.

Fungal bicyclo[2.2.2]diazaoctane indole alkaloids represent an important family of natural products with a wide-spectrum of biological activities.

Recent Progress in Steroid Synthesis Triggered by the Emergence of New Catalytic Methods.

The rich biology associated with steroids dictates a growing demand for the new synthetic strategies that would improve the access to natural and unnatural representatives of this family. The recent advances in the field of catalysis have greatly impacted the field of natural product synthesis including the synthesis of steroids. This article provides a short overview of the recent progress in the synthesis of steroids that was enabled by the advances in catalysis.

Recommendations of the Colombian Consensus Committee for the Management of Traumatic Brain Injury in Prehospital, Emergency Department, Surgery, and Intensive Care (Beyond One Option for Treatment of Traumatic Brain Injury: A Stratified Protocol [BOOTStraP]).

 Traumatic brain injury (TBI) is a global public health problem. In Colombia, it is estimated that 70% of deaths from violence and 90% of deaths from road traffic accidents are TBI related. In the year 2014, the Ministry of Health of Colombia funded the development of a clinical practice guideline (CPG) for the diagnosis and treatment of adult patients with severe TBI.

The Role of Decompressive Craniectomy in the Context of Severe Traumatic Brain Injury: Summary of Results and Analysis of the Confidence Level of Conclusions From Systematic Reviews and Meta-Analyses.

Traumatic brain injury (TBI) is a global epidemic. The incidence of TBI in low and middle-income countries (LMICs) is three times greater than in high-income countries (HICs). Decompressive craniectomy (DC) is a surgical procedure to reduce intracranial pressure (ICP) and prevent secondary injury.

Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary.

Objectives: The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients.

Methods And Main Results: This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence.

Management of Pediatric Severe Traumatic Brain Injury: 2019 Consensus and Guidelines-Based Algorithm for First and Second Tier Therapies.

Objectives: To produce a treatment algorithm for the ICU management of infants, children, and adolescents with severe traumatic brain injury.

Data Sources: Studies included in the 2019 Guidelines for the Management of Pediatric Severe Traumatic Brain Injury (Glasgow Coma Scale score ≤ 8), consensus when evidence was insufficient to formulate a fully evidence-based approach, and selected protocols from included studies.

Data Synthesis: Baseline care germane to all pediatric patients with severe traumatic brain injury along with two tiers of therapy were formulated.

Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary.

The purpose of this work is to identify and synthesize research produced since the second edition of these Guidelines was published and incorporate new results into revised evidence-based recommendations for the treatment of severe traumatic brain injury in pediatric patients. This document provides an overview of our process, lists the new research added, and includes the revised recommendations. Recommendations are only provided when there is supporting evidence.

Geographical Disparity and Traumatic Brain Injury in America: Rural Areas Suffer Poorer Outcomes.

Introduction: Significant heterogeneity exists in traumatic brain injury (TBI) outcomes. In the United States, TBI remains a primary driver of injury-related mortality and morbidity. Prior work has suggested that disparity exists in rural areas; our objective was to evaluate potential differences in TBI mortality across urban and rural areas on a national scale.

Predictive Utility of the Total Glasgow Coma Scale Versus the Motor Component of the Glasgow Coma Scale for Identification of Patients With Serious Traumatic Injuries.

Study Objective: The motor component of the Glasgow Coma Scale (mGCS) has been proposed as an easier-to-use alternative to the total GCS (tGCS) for field assessment of trauma patients by emergency medical services. We perform a systematic review and meta-analysis to compare the predictive utility of the tGCS versus the mGCS or Simplified Motor Scale in field triage of trauma for identifying patients with adverse outcomes (inhospital mortality or severe brain injury) or who underwent procedures (neurosurgical intervention or emergency intubation) indicating need for high-level trauma care.

Methods: Ovid MEDLINE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Health and Psychosocial Instruments, and the Cochrane databases were searched through June 2016 for English-language cohort studies.

Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition.

The scope and purpose of this work is 2-fold: to synthesize the available evidence and to translate it into recommendations. This document provides recommendations only when there is evidence to support them. As such, they do not constitute a complete protocol for clinical use.