CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson's Disease Associated Protein.

The CACHE challenges are a series of prospective benchmarking exercises to evaluate progress in the field of computational hit-finding. Here we report the results of the inaugural CACHE challenge in which 23 computational teams each selected up to 100 commercially available compounds that they predicted would bind to the WDR domain of the Parkinson's disease target LRRK2, a domain with no known ligand and only an apo structure in the PDB. The lack of known binding data and presumably low druggability of the target is a challenge to computational hit finding methods.

Computer-aided drug design to generate a unique antibiotic family.

The World Health Organization has identified antibiotic resistance as one of the three greatest threats to human health. The need for antibiotics is a pressing matter that requires immediate attention. Here, computer-aided drug design is used to develop a structurally unique antibiotic family targeting holo-acyl carrier protein synthase (AcpS).

Nebulized Furosemide for Pulmonary Inflammation in Intubated Patients With COVID-19: A Phase 2 Randomized Controlled Double-Blind Study.

Objectives: Respiratory failure secondary to COVID-19 is associated with morbidity and mortality. Current anti-inflammatory therapies are effective but are given systemically and have significant side effects. Furosemide has anti-inflammatory properties, can be administered by inhalation, and is inexpensive.

Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer's Disease.

Background: Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer's disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes.

Methods: To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing.

Results: We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration.

Match injuries in English schoolboy rugby union.

Objective: This study describes the incidence, severity and burden of match injuries in schoolboy rugby union in England, across three age groups: under-13 (U13), under-15 (U15) and under-18 (U18).

Methods: Data regarding 574 24-hour time-loss match injuries and 18 485 player-hours of match exposure were collected from a total of 35 schools (66 teams) in the 2017/18, 2018/19 and 2019/20 seasons. Injury incidence (injuries/1000 hours), severity (mean and median days lost) and burden (days lost/1000 hours) were calculated for each age group, injury region, event, playing position and match period and were compared using Z scores.

National Nurse Work Environments - October 2021: A Status Report.

Background: The health of nurse work environments has been shown to affect both patient and nurse outcomes. In 2005, the American Association of Critical-Care Nurses published the AACN Standards for Establishing and Sustaining Healthy Work Environments: A Journey to Excellence, and a second edition was published in 2016. The American Association of Critical-Care Nurses conducted critical care nurse work environment studies in 2006, 2008, 2013, 2018, and, most recently, October 2021, which was expanded to include registered nurses in all areas of practice.

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites.

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aβ) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses.

Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aβ-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD.

Effectiveness of the injury prevention exercise programme to prevent injury in schoolboy rugby union.

Objective: The efficacious injury prevention exercise programme has been shown to prevent injuries in English schoolboy rugby union. There is now a need to assess the implementation and effectiveness of in the applie setting.

Methods: This quasi-experimental study used a 24-hour time-loss injury definition to calculate incidence (/1000 hours) and burden (days lost/1000 hours) for individuals whose teams adopted (used during season) versus non-adopters.

Canadian High School Rugby Coaches Readiness for an Injury Prevention Strategy Implementation: Evaluating a Train-the-Coach Workshop.

Canadian rugby coach injury prevention beliefs and attitudes have not been studied, yet are key to informing injury prevention strategy implementation. Despite neuromuscular training (NMT) warm-up success in reducing injury, adoption of these programs is variable. Therefore, objectives of this study included (1) describing Canadian youth rugby coach injury prevention beliefs and attitudes and current warm-up practices and (2) evaluating intention to use a rugby-specific NMT warm-up.

Utilising a Behaviour Change Model to Improve Implementation of the Injury Prevention Exercise Programme in Schoolboy Rugby Union.

The Health Action Process Approach (HAPA) is a behaviour change model showing promise in positively changing youth sport coaches' injury prevention behaviours. This study incorporated the HAPA model into coach training workshops for , an efficacious rugby injury prevention programme. Primary aims were to investigate the effect of the workshop on schoolboy rugby union coaches' (1) perceptions towards injury risk and prevention, (2) adoption and adherence.

Implementation of the injury prevention exercise programme in English schoolboy rugby union.

Objectives: The implementation of the injury prevention exercise programme has not been assessed in an applied context. This study aimed to (1) describe the knowledge and perceptions of school rugby coaches and players towards injury risk, prevention and and (2) evaluate implementation in schoolboy rugby using the reach, effectiveness, adoption, implementation and maintenance framework.

Methods: Bespoke electronic surveys were administered to coaches (including support staff) and players at participating English schools (2018-2020).

Furazans in Medicinal Chemistry.

Incorporation of heterocycles into drug molecules can enhance physical properties and biological activity. A variety of heterocyclic groups is available to medicinal chemists, many of which have been reviewed in detail elsewhere. Oxadiazoles are a class of heterocycle containing one oxygen and two nitrogen atoms, available in three isomeric forms.

Employing Standardised Methods to Compare Injury Risk Across Seven Youth Team Sports.

Injury surveillance systems seek to describe injury risk for a given sport, in order to inform preventative strategies. This often leads to comparisons between studies, although these inferences may be inappropriate, considering the range of methods adopted. This study aimed to describe the injury epidemiology of seven youth sports, enabling valid comparisons of injury risk.

Evaluating the Implementation of Injury Prevention Strategies in Rugby Union and League: A Systematic Review using the RE-AIM Framework.

Rugby (union and league) has come under intense scrutiny due to its injury risk. Various interventions have been introduced to protect players from injury, with many deemed efficacious and advocated for use across various worldwide contexts. However, their implementation is less clear.

Small molecule therapeutics for COVID-19: repurposing of inhaled furosemide.

The novel coronavirus SARS-CoV-2 has become a global health concern. The morbidity and mortality of the potentially lethal infection caused by this virus arise from the initial viral infection and the subsequent host inflammatory response. The latter may lead to excessive release of pro-inflammatory cytokines, IL-6 and IL-8, as well as TNF-α ultimately culminating in hypercytokinemia ("cytokine storm").

Is Inhaled Furosemide a Potential Therapeutic for COVID-19?

The potentially lethal infection caused by the novel Severe Acute Respiratory Disease Coronavirus-2 (SARS-CoV-2) has evolved into a global crisis. Following the initial viral infection is the host inflammatory response that frequently results in excessive secretion of inflammatory cytokines (e.g.

The Brain Exposure Efficiency (BEE) Score.

The blood-brain barrier (BBB), composed of microvascular tight junctions and glial cell sheathing, selectively controls drug permeation into the central nervous system (CNS) by either passive diffusion or active transport. Computational techniques capable of predicting molecular brain penetration are important to neurological drug design. A novel prediction algorithm, termed the Brain Exposure Efficiency Score (BEE), is presented.

The Blood-Brain Barrier (BBB) Score.

The blood-brain barrier (BBB) protects the brain from the toxic side effects of drugs and exogenous molecules. However, it is crucial that medications developed for neurological disorders cross into the brain in therapeutic concentrations. Understanding the BBB interaction with drug molecules based on physicochemical property space can guide effective and efficient drug design.

The Novel Small Molecule TRVA242 Stabilizes Neuromuscular Junction Defects in Multiple Animal Models of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder in which the neuromuscular junction progressively degenerates, leading to movement difficulties, paralysis, and eventually death. ALS is currently being treated by only two FDA-approved drugs with modest efficacy in slowing disease progression. Often, the translation of preclinical findings to bedside terminates prematurely as the evaluation of potential therapeutic compounds focuses on a single study or a single animal model.

Cervical Spine Movement in a Cadaveric Model of Severe Spinal Instability: A Study Comparing Tracheal Intubation with 4 Different Laryngoscopes.

Background: This study compared the Macintosh blade direct laryngoscope, Glidescope, C-Mac d-Blade, and McGrath MAC X-blade video laryngoscopes in 2 cadaveric models with severe cervical spinal instability. We hypothesized that the Glidescope video laryngoscope would allow for intubation with the least amount of cervical spine movement. Our secondary endpoints were glottic visualization and intubation success.

Critical Care Nurse Work Environments 2018: Findings and Implications.

Background: The health of critical care nurse work environments affects patient and nurse outcomes. The results of the 2018 Critical Care Nurse Work Environment Study are reported here with comparisons to previous studies and recommendations for continued improvement.

Objective: To evaluate the current state of critical care nurse work environments.

Epidemiology of Injury in Elite English Schoolboy Rugby Union: A 3-Year Study Comparing Different Competitions.

Context:   Injury risks in professional and community rugby union have been extensively described; however, less is known about injury epidemiology at the schoolboy level.

Objective:   To investigate the injury risk in English schoolboy rugby union matches, comparing an elite competition (Achieving Academic and Sporting Excellence [AASE]) with subelite matches (non-AASE).

Design:   Retrospective cohort study.