Advancing precision medicine for acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high.

Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV): Designing Master Protocols for Evaluation of Candidate COVID-19 Therapeutics.

Working in an unprecedented time frame, the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public-private partnership developed and launched 9 master protocols between 14 April 2020 and 31 May 2021 to allow for the coordinated and efficient evaluation of multiple investigational therapeutic agents for COVID-19. The ACTIV master protocols were designed with a portfolio approach to serve the following patient populations with COVID-19: mild to moderately ill outpatients, moderately ill inpatients, and critically ill inpatients. To facilitate the execution of these studies and minimize start-up time, ACTIV selected several existing networks to launch the master protocols.

Rationale and Design of ORCHID: A Randomized Placebo-controlled Clinical Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including ) widespread, off-label use of the study drug before the availability of safety and efficacy data; ) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; ) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; ) obtaining indistinguishable drug and placebo without delaying enrollment; and ) rapidly obtaining administrative and regulatory approvals.

National Heart, Lung, and Blood Institute and American Association for Thoracic Surgery Workshop Report: Identifying collaborative clinical research priorities in lung transplantation.

This report summarizes the discussion and recommendations from the June 2017 NHLBI-AATS Workshop on Identifying Collaborative Clinical Research Priorities in Lung Transplantation.

Liberal Versus Restrictive Intravenous Fluid Therapy for Early Septic Shock: Rationale for a Randomized Trial.

Prompt intravenous fluid therapy is a fundamental treatment for patients with septic shock. However, the optimal approach for administering intravenous fluid in septic shock resuscitation is unknown. Two competing strategies are emerging: a liberal fluids approach, consisting of a larger volume of initial fluid (50 to 75 mL/kg [4 to 6 L in an 80-kg adult] during the first 6 hours) and later use of vasopressors, versus a restrictive fluids approach, consisting of a smaller volume of initial fluid (≤30 mL/kg [≤2 to 3 L]), with earlier reliance on vasopressor infusions to maintain blood pressure and perfusion.

Effect of public reporting on intensive care unit discharge destination and outcomes.

Rationale: Public reporting of hospital performance is designed to improve healthcare outcomes by promoting quality improvement and informing consumer choice, but these programs may carry unintended consequences.

Objective: To determine whether publicly reporting in-hospital mortality rates for intensive care unit (ICU) patients influenced discharge patterns or mortality.

Methods: We performed a retrospective cohort study taking advantage of a natural experiment in which California, but not other states, publicly reported hospital-specific severity-adjusted ICU mortality rates between 2007 and 2012.

Hospital factors associated with discharge bias in ICU performance measurement.

Objective: Performance assessments based on in-hospital mortality for ICU patients can be affected by discharge practices such that differences in mortality may reflect variation in discharge patterns rather than quality of care. Time-specific mortality rates, such as 30-day mortality, are preferred but are harder to measure. The degree to which the difference between 30-day and in-hospital ICU mortality rates-or "discharge bias"-varies by hospital type is unknown.

Nighttime intensivist staffing and the timing of death among ICU decedents: a retrospective cohort study.

Introduction: Intensive care units (ICUs) are increasingly adopting 24-hour intensivist physician staffing. Although nighttime intensivist staffing does not consistently reduce mortality, it may affect other outcomes such as the quality of end-of-life care.

Methods: We conducted a retrospective cohort study of ICU decedents using the 2009-2010 Acute Physiology and Chronic Health Evaluation clinical information system linked to a survey of ICU staffing practices.

Viral infections of the central nervous system: a case-based review.

Three patients with viral infections of the central nervous system (CNS) were evaluated on an inpatient infectious diseases consultation service within a two-week period. These cases, caused by herpes simplex virus, varicella zoster virus and enterovirus, highlight the importance of viral pathogens in causing debilitating infections of the CNS and provide examples of the utility of molecular diagnostics in evaluating patients with encephalitis and meningitis. The importance of antiviral therapy is particularly underscored by these cases, as is the variability in response of patients to such agents.

"Diffusion-clinical mismatch" is associated with potential for early recovery of aphasia.

Background: Diffusion-perfusion mismatch (perfusion-weighted imaging [PWI] abnormality minus diffusion-weighted imaging [DWI] abnormality) can identify candidates for acute stroke intervention, but PWI is often not obtainable. The authors hypothesized that language tests can predict volume of hypoperfusion, and thus mismatch, in acute left hemisphere stroke, and that the estimated mismatch can predict potential for early recovery of language.

Methods: A consecutive series of 81 patients with acute left hemisphere ischemic stroke underwent language testing within 1 day of MRI scans.

Crystal structure of the Ly49I natural killer cell receptor reveals variability in dimerization mode within the Ly49 family.

Natural killer (NK) cells play a crucial role in the detection and destruction of virally infected and tumor cells during innate immune responses. The cytolytic activity of NK cells is regulated through a balance of inhibitory and stimulatory signals delivered by NK receptors that recognize classical major histocompatabilty complex class I (MHC-I) molecules, or MHC-I homologs such as MICA, on target cells. The Ly49 family of NK receptors (Ly49A through W), which includes both inhibitory and activating receptors, are homodimeric type II transmembrane glycoproteins, with each subunit composed of a C-type lectin-like domain tethered to the membrane by a stalk region.