Clinical characteristics associated with the prescribing of SSRI medication in adolescents with major unipolar depression.

Unipolar major depressions (MD) emerge markedly during adolescence. National Institute for Health and Care Excellence (NICE) UK recommends psychological therapies, with accompanying selective serotonin reuptake inhibitors (SSRIs) prescribed in severe cases only. Here, we seek to determine the extent and rationale of SSRI prescribing in adolescent MD before entering a randomised clinical trial. SSRI prescribing, together with their clinical characteristics was determined in 465 adolescent patients with MD prior to receiving a standardised psychological therapy as part of the Improving mood with psychoanalytic and cognitive therapies (IMPACT) clinical trial. Overall, 88 (19 %) had been prescribed antidepressants prior to psychological treatment. The clinical correlates varied by gender: respectively, depression severity in boys and self-harming behaviours in girls. Prescribing also differed between clinical research centres. Medical practitioners consider severity of depression in boys as an indicator for antidepressant prescribing. Self-injury in girls appears to be utilised as a prescribing aid which is inconsistent with past and current revised UK NICE guidelines.RCT Study supported by a grant to IMG (Chief Investigator) from the NIHR-HTA (trial number ISRCTN83033550, grant number 06/05/01).This is the author accepted manuscript. It is currently under an indefinite embargo pending publication by Springer

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

Identification of Novel Antimalarial Chemotypes via Chemoinformatic Compound Selection Methods for a High-Throughput Screening Program against the Novel Malarial Target, PfNDH2: Increasing Hit Rate via Virtual Screening Methods

Malaria is responsible for approximately 1 million deaths annually; thus, continued efforts to discover new antimalarials are required. A HTS screen was established to identify novel inhibitors of the parasite's mitochondrial enzyme NADH:quinone oxidoreductase (PfNDH2). On the basis of only one known inhibitor of this enzyme, the challenge was to discover novel inhibitors of PfNDH2 with diverse chemical scaffolds. To this end, using a range of ligand-based chemoinformatics methods, ~17000 compounds were selected from a commercial library of ~750000 compounds. Forty-eight compounds were identified with PfNDH2 enzyme inhibition IC(50) values ranging from 100 nM to 40 μM and also displayed exciting whole cell antimalarial activity. These novel inhibitors were identified through sampling 16% of the available chemical space, while only screening 2% of the library. This study confirms the added value of using multiple ligand-based chemoinformatic approaches and has successfully identified novel distinct chemotypes primed for development as new agents against malaria

Effects of controlled diesel exhaust exposure on apoptosis and proliferation markers in bronchial epithelium – an in vivo bronchoscopy study on asthmatics, rhinitics and healthy subjects

BackgroundEpidemiological evidence demonstrates that exposure to traffic-derived pollution worsens respiratory symptoms in asthmatics, but controlled human exposure studies have failed to provide a mechanism for this effect. Here we investigated whether diesel exhaust (DE) would induce apoptosis or proliferation in the bronchial epithelium in vivo and thus contribute to respiratory symptoms.MethodsModerate (n?=?16) and mild (n?=?16) asthmatics, atopic non-asthmatic controls (rhinitics) (n?=?13) and healthy controls (n?=?21) were exposed to filtered air or DE (100 ?g/m 3 ) for 2 h, on two separate occasions. Bronchial biopsies were taken 18 h post-exposure and immunohistochemically analysed for pro-apoptotic and anti-apoptotic proteins (Bad, Bak, p85 PARP, Fas, Bcl-2) and a marker of proliferation (Ki67). Positive staining was assessed within the epithelium using computerized image analysis.ResultsNo evidence of epithelial apoptosis or proliferation was observed in healthy, allergic or asthmatic airways following DE challenge.ConclusionIn the present study, we investigated whether DE exposure would affect markers of proliferation and apoptosis in the bronchial epithelium of asthmatics, rhinitics and healthy controls, providing a mechanistic basis for the reported increased airway sensitivity in asthmatics to air pollutants. In this first in vivo exposure investigation, we found no evidence of diesel exhaust-induced effects on these processes in the subject groups investigated

Ensuring FAIR-Compliant Molecular Analysis Software with MDAKits

Scientific progress relies on the reproducibility and transparency of scientific findings. Scientific codes, for both data generation and analysis, are often not required to be released and are thus not held to these critical standards, making replication of previous results needlessly difficult. Researchers are rarely given incentives to overcome the substantial barriers to ensuring their software is properly tested and available to the community. The MDAnalysis (https://www.mdanalysis.org) Python library is used for the analysis of molecular simulation and structural data and is used by thousands of researchers across the world. To address these concerns regarding software based on MDAnalysis, the "MDAKits" framework was developed. The MDAKits framework addresses these barriers and encourages the development of FAIR-compliant MDAnalysis toolkits. MDAKits are standalone packages using MDAnalysis to solve scientific problems. The framework provides a template for producing an MDAKit base code, best practices documentation, and a kit validation registry which also provides an overview of the available kits using only metadata for the registered kits. Thus, MDAKits facilitate sharing and publicizing researchers' code while they still maintain full control of the codebase

Cognition and multiple sclerosis: a historical analysis of medical perceptions

The earliest descriptions of multiple sclerosis (MS) rarely distinguished cognitive impairment from the general category of "mental symptoms", which also encompassed a broad range of affective disorders. Case-study methods led to disputes about the extent and nature of these symptoms, exacerbated by different national medical traditions. Appropriate scientific methods were only used to investigate cognitive performance in a modest number of studies up to the 1960s, and it was being argued as late as the mid 1970s that affective processes rather than cognitive processes were the key to understanding the psychological aspects of MS. However, the early 1980s, saw major developments in test procedures for the detection of subtle and selective cognitive changes, in the use of brain imaging techniques, and in collaboration between neurologists and neuropsychologists. Pressure to use research findings to improve patients' daily lives suggests a need to reconsider the connection between affective and cognitive processes in MS

mHTT-induced neuronal toxicity: 7,8-dihydroxyflavone and LM22A-4 pharmacology.

<p>Using our primary rat cortico-striatal co-culture system we stimulated with 7,8-dihydroxyflavone, LM22A-4 or BDNF over the indicated concentration range according to the mHTT-induced co-culture protocol (A), as described in Methods. % Rescue (Normalized to in-plate controls; 1 nM BDNF (100% Rescue) and vehicle (0% Rescue)) values were plotted for striatal neurons over the indicated concentrations of each ligand (n = 6 ± SD for each data point). Rat primary cortico-striatal cells (non-transfected) were stimulated with 7,8-dihydroxyflavone (B) or LM22A-4 (C) using the indicated concentrations for 15 minutes and profiled by western blot. BDNF- (10 nM) mediated TrkB phosphorylation validated the experimental system.</p