The Sleep Or Mood Novel Adjunctive therapy (SOMNA) trial: a study protocol for a randomised controlled trial evaluating an internet-delivered cognitive behavioural therapy program for insomnia on outcomes of standard treatment for depression in men

BACKGROUND: Insomnia is a significant risk factor for depression onset, can result in more disabling depressive illness, and is a common residual symptom following treatment cessation that can increase the risk of relapse. Internet-based cognitive behavioural therapy for insomnia has demonstrated efficacy and acceptability to men who are less likely than women to seek help in standard care. We aim to evaluate whether internet delivered cognitive behavioural therapy for insomnia as an adjunct to a standard depression therapeutic plan can lead to improved mood outcomes.METHODS/DESIGN: Male participants aged 50 years or more, meeting Diagnostic and Statistical Manual of Mental Disorders criteria for current Major Depressive Episode and/or Dysthymia and self-reported insomnia symptoms, will be screened to participate in a single-centre double-blind randomised controlled trial with two parallel groups involving adjunctive internet-delivered cognitive behavioural therapy for insomnia and an internet-based control program. The trial will consist of a nine-week insomnia intervention period with a six-month follow-up period. During the insomnia intervention period participants will have their depression management coordinated by a psychiatrist using standard guideline-based depression treatments. The study will be conducted in urban New South Wales, Australia, where 80 participants from primary and secondary care and direct from the local community will be recruited. The primary outcome is change in the severity of depressive symptoms from baseline to week 12. DISCUSSION: This study will provide evidence on whether a widely accessible, evidence-based, internet-delivered cognitive behavioural therapy for insomnia intervention can lead to greater improvements than standard treatment for depression alone, in a group who traditionally do not readily access psychotherapy. The study is designed to establish effect size, feasibility and processes associated with implementing e-health solutions alongside standard clinical care, to warrant undertaking a larger more definitive clinical trial.Trial registration: Australian and New Zealand Clinical Trials Registry ACTRN12612000985886.The study is supported by beyondblue: the national depression and anxiety initiative National Priority Driven Research Program and funded through a donation from the Movember Foundation

TarO : a target optimisation system for structural biology

This work was funded by the UK Biotechnology and Biological Sciences Research Council (BBSRC) Structural Proteomics of Rational Targets (SPoRT) initiative, (Grant BBS/B/14434). Funding to pay the Open Access publication charges for this article was provided by BBSRC.TarO (http://www.compbio.dundee.ac.uk/taro) offers a single point of reference for key bioinformatics analyses relevant to selecting proteins or domains for study by structural biology techniques. The protein sequence is analysed by 17 algorithms and compared to 8 databases. TarO gathers putative homologues, including orthologues, and then obtains predictions of properties for these sequences including crystallisation propensity, protein disorder and post-translational modifications. Analyses are run on a high-performance computing cluster, the results integrated, stored in a database and accessed through a web-based user interface. Output is in tabulated format and in the form of an annotated multiple sequence alignment (MSA) that may be edited interactively in the program Jalview. TarO also simplifies the gathering of additional annotations via the Distributed Annotation System, both from the MSA in Jalview and through links to Dasty2. Routes to other information gateways are included, for example to relevant pages from UniProt, COG and the Conserved Domains Database. Open access to TarO is available from a guest account with private accounts for academic use available on request. Future development of TarO will include further analysis steps and integration with the Protein Information Management System (PIMS), a sister project in the BBSRC Structural Proteomics of Rational Targets initiative.Publisher PDFPeer reviewe

What is the prevalence, and what are the clinical correlates, of insulin resistance in young people presenting for mental health care? A cross-sectional study

Objectives: To report the distribution and predictors of insulin resistance (IR) in young people presenting to primary care-based mental health services. Design: Cross-sectional. Setting: Headspace-linked clinics operated by the Brain and Mind Centre of the University of Sydney. Participants: 768 young people (66% female, mean age 19.7±3.5, range 12–30 years). Main outcome measures: IR was estimated using the updated homeostatic model assessment (HOMA2-IR). Height and weight were collected from direct measurement or self-report for body mass index (BMI). Results: For BMI, 20.6% of the cohort were overweight and 10.2% were obese. However,6.9 mmol/L). By contrast, 9.9% had a HOMA2-IR score \u3e2.0 (suggesting development of IR) and 11.7% (n=90) had a score between 1.5 and 2. Further, there was a positive correlation between BMI and HOMA2-IR (r=0.44, p Conclusions: Emerging IR is evident in a significant subgroup of young people presenting to primary care based mental health services. While the major modifiable risk factor is BMI, a large proportion of the variance is not accounted for by other demographic, clinical or treatment factors. Given the early emergence of IR, secondary prevention interventions may need to commence prior to the development of full-threshold or major mood or psychotic disorders

Subjective memory complaints, vascular risk factors and psychological distress in the middle-aged: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Subjective memory complaints (SMC) are common but their significance is still unclear. It has been suggested they are a precursor of mild cognitive impairment (MCI) or dementia and an early indicator of cognitive decline. Vascular risk factors have an important role in the development of dementia and possibly MCI. We therefore aimed to test the hypothesis that vascular risk factors were associated with SMC, independent of psychological distress, in a middle-aged community-dwelling population.</p> <p>Methods</p> <p>A cross-sectional analysis of baseline data from the 45 and Up Study was performed. This is a cohort study of people living in New South Wales (Australia), and we explored the sample of 45, 532 participants aged between 45 and 64 years. SMC were defined as 'fair' or 'poor' on a self-reported five-point Likert scale of memory function. Vascular risk factors of obesity, diabetes, hypertension, hypercholesterolemia and smoking were identified by self-report. Psychological distress was measured by the Kessler Psychological Distress Scale. We tested the model generated from a randomly selected exploratory sample (n = 22, 766) with a confirmatory sample of equal size.</p> <p>Results</p> <p>5, 479/45, 532 (12%) of respondents reported SMC. Using multivariate logistic regression, only two vascular risk factors: smoking (OR 1.18; 95% CI = 1.03 - 1.35) and hypercholesterolaemia (OR 1.19; 95% CI = 1.04 - 1.36) showed a small independent association with SMC. In contrast psychological distress was strongly associated with SMC. Those with the highest levels of psychological distress were 7.00 (95% CI = 5.41 - 9.07) times more likely to have SMC than the non-distressed. The confirmatory sample also demonstrated the strong association of SMC with psychological distress rather than vascular risk factors.</p> <p>Conclusions</p> <p>In a large sample of middle-aged people without any history of major affective illness or stroke, psychological distress was strongly, and vascular risk factors only weakly, associated with SMC, although we cannot discount psychological distress acting as a mediator in any association between vascular risk factors and SMC. Given this, clinicians should be vigilant regarding the presence of an affective illness when assessing middle-aged patients presenting with memory problems.</p

The rhizoferrin biosynthetic gene in the fungal pathogen Rhizopus delemar is a novel member of the NIS gene family

This work was supported by the Natural Sciences and Engineering Research Council of Canada award to MM (grant number 611181). C. Carroll thanks Simon Fraser University for a travel and research award.Iron is essential for growth and in low iron environments such as serum many bacteria and fungi secrete ferric iron-chelating molecules called siderophores. All fungi produce hydroxamate siderophores with the exception of Mucorales fungi, which secrete rhizoferrin, a polycarboxylate siderophore. Here we investigated the biosynthesis of rhizoferrin by the opportunistic human pathogen, Rhizopus delemar. We searched the genome of R. delemar 99–880 for a homologue of the bacterial NRPS-independent siderophore (NIS) protein, SfnaD that is involved in biosynthesis of staphyloferrin A in Staphylococcus aureus. A protein was identified in R. delemar with 22% identity and 37% similarity with SfnaD, containing an N-terminal IucA/IucC family domain, and a C-terminal conserved ferric iron reductase FhuF-like transporter domain. Expression of the putative fungal rhizoferrin synthetase (rfs) gene was repressed by iron. The rfs gene was cloned and expressed in E.coli and siderophore biosynthesis from citrate and diaminobutane was confirmed using high resolution LC–MS. Substrate specificity was investigated showing that Rfs produced AMP when oxaloacetic acid, tricarballylic acid, ornithine, hydroxylamine, diaminopentane and diaminopropane were employed as substrates. Based on the production of AMP and the presence of a mono-substituted rhizoferrin, we suggest that Rfs is a member of the superfamily of adenylating enzymes. We used site-directed mutagenesis to mutate selected conserved residues predicted to be in the Rfs active site. These studies revealed that H484 is essential for Rfs activity and L544 may play a role in amine recognition by the enzyme. This study on Rfs is the first characterization of a fungal NIS enzyme. Future work will determine if rhizoferrin biosynthesis is required for virulence in Mucorales fungi.PostprintPeer reviewe

Quantitative signal properties from standardized MRIs correlate with multiple sclerosis disability

OBJECTIVE: To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS-related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice. METHODS: We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1-weighted and 3D-FLAIR (T2-weighted) images from 5010 participants enrolled in a multinational database of MS patients which collected imaging, neuroperformance and disability measures. RESULTS: Intensity distribution metrics distinguished MS patients from control participants based on normalized non-lesional signal differences. This analysis revealed non-lesional differences between relapsing MS versus progressive MS subtypes. Further, the correlation between our non-lesional measures and disability was approximately three times greater than that between total lesion volume and disability, measured using the patient derived disease steps. Multivariate modeling revealed that measures of extra-lesional tissue integrity and atrophy contribute uniquely, and approximately equally, to the prediction of MS-related disability. INTERPRETATION: These results support the notion that non-lesional abnormalities correlate more strongly with MS-related disability than lesion burden and provide new insight into the basis of abnormalities in NA WM. Non-lesional abnormalities distinguish relapsing from progressive MS but do not distinguish between progressive subtypes suggesting a common progressive pathophysiology. Image intensity parameters and existing biomarkers each independently correlate with MS-related disability

Isolated rapid eye movement sleep behaviour disorder (iRBD) in the Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study: protocol and baseline characteristics

Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α-synuclein-related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video-polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home-based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results

Porins and small-molecule translocation across the outer membrane of Gram-negative bacteria

Gram-negative bacteria and their complex cell envelope, which comprises an outer membrane and an inner membrane, are an important and attractive system for studying the translocation of small molecules across biological membranes. In the outer membrane of Enterobacteriaceae, trimeric porins control the cellular uptake of small molecules, including nutrients and antibacterial agents. The relatively slow porin-mediated passive uptake across the outer membrane and active efflux via efflux pumps in the inner membrane creates a permeability barrier. The synergistic action of outer membrane permeability, efflux pump activities and enzymatic degradation efficiently reduces the intracellular concentrations of small molecules and contributes to the emergence of antibiotic resistance. In this Review, we discuss recent advances in our understanding of the molecular and functional roles of general porins in small-molecule translocation in Enterobacteriaceae and consider the crucial contribution of porins in antibiotic resistance