Histopathological studies in Alzheimer's disease (AD) suggest severe and region-specific neurodegeneration of the basal forebrain cholinergic system (BFCS). Here, we studied the between-center reliability and diagnostic accuracy of MRI-based BFCS volumetry in a large multicenter data set, including participants with prodromal (n = 41) or clinically manifest AD (n = 134) and 148 cognitively healthy controls. Atrophy was determined using voxel-based and region-of-interest based analyses of high-dimensionally normalized MRI scans using a newly created map of the BFCS based on postmortem in cranio MRI and histology. The AD group showed significant volume reductions of all subregions of the BFCS, which were most pronounced in the posterior nucleus basalis Meynert (NbM). The mild cognitive impairment-AD group showed pronounced volume reductions in the posterior NbM, but preserved volumes of anterior-medial regions. Diagnostic accuracy of posterior NbM volume was superior to hippocampus volume in both groups, despite higher multicenter variability of the BFCS measurements. The data of our study suggest that BFCS morphometry may provide an emerging biomarker in AD.
Atrophy; biomarker; cholinergic system; dementia; European DTI Study on Dementia
We aimed to discover whether metabolic complications of schizophrenia (SZ) are present in first episode (FE) and unmedicated (UM) patients, in comparison with patients established on antipsychotic medication (AP).
A systematic search, critical appraisal, and meta-analysis were conducted of studies to December 2011 using Medline, PsycINFO, Embase and experts. Twenty-six studies examined FE SZ patients (n = 2548) and 19 included UM SZ patients (n = 1325). For comparison we identified 78 publications involving 24 892 medicated patients who had chronic SZ already established on AP.
In UM, the overall rate of metabolic syndrome (MetS) was 9.8% using any standardized criteria. Diabetes was found in only 2.1% and hyperglycaemia (>100mg/dl) in 6.4%. In FE, the overall MetS rate was 9.9%, diabetes was found in only 1.2%, and hyperglycaemia in 8.7%. In UM and FE, the rates of overweight were 26.6%, 22%; hypertriglyceridemia 16.9%, 19.6%; low HDL 20.4%, 21.9%; high blood pressure 24.3%, 30.4%; smoking 40.2%, 46.8%, respectively. In both groups all metabolic components and risk factors were significantly less common in early SZ than in those already established on AP. Waist size, blood pressure and smoking were significantly lower in UM compared with FE.
There is a significantly lower cardiovascular risk in early SZ than in chronic SZ. Both diabetes and pre-diabetes appear uncommon in the early stages, especially in UM. However, smoking does appear to be elevated early after diagnosis. Clinicians should focus on preventing initial cardiometabolic risk because subsequent reduction in this risk is more difficult to achieve, either through behavioral or pharmacologic interventions.
cardiovascular risk; diabetes; lipids; glucose; waist; obesity
Individuals with schizophrenia have high levels of medical comorbidity and cardiovascular risk factors. The presence of 3 or more specific factors is indicative of metabolic syndrome, which is a significant influence upon future morbidity and mortality. We aimed to clarify the prevalence and predictors of metabolic syndrome (MetS) in adults with schizophrenia and related disorders, accounting for subgroup differences. A PRISMA systematic search, appraisal, and meta-analysis were conducted of 126 analyses in 77 publications (n = 25 692). The overall rate of MetS was 32.5% (95% CI = 30.1%–35.0%), and there were only minor differences according to the different definitions of MetS, treatment setting (inpatient vs outpatient), by country of origin and no appreciable difference between males and females. Older age had a modest influence on the rate of MetS (adjusted R
2 = .20; P < .0001), but the strongest influence was of illness duration (adjusted R
2 = .35; P < .0001). At a study level, waist size was most useful in predicting high rate of MetS with a sensitivity of 79.4% and a specificity of 78.8%. Sensitivity and specificity of high blood pressure, high triglycerides, high glucose and low high-density lipoprotein, and age (>38 y) are shown in supplementary appendix 2 online. Regarding prescribed antipsychotic medication, highest rates were seen in those prescribed clozapine (51.9%) and lowest rates of MetS in those who were unmedicated (20.2%). Present findings strongly support the notion that patients with schizophrenia should be considered a high-risk group. Patients with schizophrenia should receive regular monitoring and adequate treatment of cardio-metabolic risk factors.
metabolic syndrome; cardiovascular risk; diabetes; lipids; glucose; schizophrenia; waist; obesity; smoking
Aims and method To examine research productivity of staff working across 57 National Health Service (NHS) mental health trusts in England. We examined research productivity between 2010 and 2012, including funded portfolio studies and all research (funded and unfunded).
Results Across 57 trusts there were 1297 National Institute for Health Research (NIHR) studies in 2011/2012, involving 46 140 participants and in the same year staff in these trusts published 1334 articles (an average of only 23.4 per trust per annum). After correcting for trust size and budget, the South London and Maudsley NHS Foundation Trust was the most productive. In terms of funded portfolio studies, Manchester Mental Health and Social Care Trust as well as South London and Maudsley NHS Foundation Trust, Oxford Health NHS Foundation Trust and Cambridgeshire and Peterborough NHS Foundation Trust had the strongest performance in 2011/2012.
Clinical implications Trusts should aim to capitalise on valuable staff resources and expertise and better support and encourage research in the NHS to help improve clinical services.
Motivation: Robust large-scale sequence analysis is a major challenge in modern genomic science, where biologists are frequently trying to characterize many millions of sequences. Here, we describe a new Java-based architecture for the widely used protein function prediction software package InterProScan. Developments include improvements and additions to the outputs of the software and the complete reimplementation of the software framework, resulting in a flexible and stable system that is able to use both multiprocessor machines and/or conventional clusters to achieve scalable distributed data analysis. InterProScan is freely available for download from the EMBl-EBI FTP site and the open source code is hosted at Google Code.
Availability and implementation: InterProScan is distributed via FTP at ftp://ftp.ebi.ac.uk/pub/software/unix/iprscan/5/ and the source code is available from http://code.google.com/p/interproscan/.
http://www.ebi.ac.uk/support or email@example.com or firstname.lastname@example.org
An association between multiple sclerosis (MS) prevalence as well as MS mortality and vitamin D nutrition has led to the hypothesis that high levels of vitamin D could be beneficial for MS. The purpose of this systematic review is to establish whether there is evidence for or against vitamin D in the treatment of MS.
Systematic literature searches were performed to locate randomized, placebo-controlled, double-blind trials measuring the clinical effect of vitamin D on MS in human participants. Data were extracted in a standardized manner and methodological quality was assessed by the Jadad score.
Five trials were located meeting the selection criteria. Of the five trials, four showed no effect of vitamin D on any outcome, and one showed a significant effect, namely upon reduction in the number of T1 enhancing lesions on brain magnetic resonance imaging. Three studies commented on adverse effects of vitamin D, with gastrointestinal adverse effects being the most frequently reported. The literature is limited by small study sizes (studies size ranged from 23 to 68 patients) and heterogeneity of dosing, form of vitamin D tested (vitamin D3 in four trials, and vitamin D2 in one), and outcome clinical measures. Therefore, a meta-analysis was not performed.
The evidence for vitamin D as a treatment for MS is inconclusive. Larger studies are warranted to assess the effect of vitamin D on clinical outcomes in patients with MS. We further encourage researchers to also test the effect of vitamin D on the health-related quality of life experienced by patients and their families.
Multiple sclerosis; treatment; systematic review; vitamin D
Metagenomics is a relatively recently established but rapidly expanding field that uses high-throughput next-generation sequencing technologies to characterize the microbial communities inhabiting different ecosystems (including oceans, lakes, soil, tundra, plants and body sites). Metagenomics brings with it a number of challenges, including the management, analysis, storage and sharing of data. In response to these challenges, we have developed a new metagenomics resource (http://www.ebi.ac.uk/metagenomics/) that allows users to easily submit raw nucleotide reads for functional and taxonomic analysis by a state-of-the-art pipeline, and have them automatically stored (together with descriptive, standards-compliant metadata) in the European Nucleotide Archive.
This cross-sectional survey investigated whether there were ethnic differences in depressive symptoms among British South Asian (BSA) patients with cancer compared with British White (BW) patients during 9 months following presentation at a UK Cancer Centre. We examined associations between depressed mood, coping strategies and the burden of symptoms.
Questionnaires were administered to 94 BSA and 185 BW recently diagnosed patients with cancer at baseline and at 3 and 9 months. In total, 53.8% of the BSA samples were born in the Indian subcontinent, 33% in Africa and 12.9% in the UK. Three screening tools for depression were used to counter concerns about ethnic bias and validity in linguistic translation. The Hospital Anxiety and Depression Scale (HADS-D), Patient Health Questionnaire-9 (both validated in Gujarati), Emotion Thermometers (including the Distress Thermometer (DT), Mini-MAC and the newly developed Cancer Insight and Denial questionnaire (CIDQ) were completed.
Leicestershire Cancer Centre, UK.
94 BSA and 185 BW recently diagnosed patients with cancer.
BSA self-reported significantly higher rates of depressive symptoms compared with BW patients longitudinally (HADS-D ≥8: baseline: BSA 35.1% vs BW 16.8%, p=0.001; 3 months BSA 45.6% vs BW 20.8%, p=0.001; 9 months BSA 40.6% vs BW 15.3%, p=0.004). BSA patients used potentially maladaptive coping strategies more frequently than BW patients at baseline (hopelessness/helplessness p=0.005, fatalism p=0.0005, avoidance p=0.005; the CIDQ denial statement ‘I do not really believe I have cancer’ p=0.0005). BSA patients experienced more physical symptoms (DT checklist), which correlated with ethnic differences in depressive symptoms especially at 3 months.
Health professionals need to be aware of a greater probability of depressive symptomatology (including somatic symptoms) and how this may present clinically in the first 9 months after diagnosis if this ethnic disparity in mental well-being is to be addressed.
Mental Health; Ethnicity; Depression
Determine whether adults with hepatitis C, regardless of substance use disorder, are more likely to discount delayed rewards than adults without hepatitis C, and explore the relationship between delay discounting and neuropsychological functioning.
Procedures included clinical interviews, neuropsychological testing, and a delay discounting task.
Regardless of substance abuse history, adults with hepatitis C were significantly more likely to choose smaller immediate rewards over larger delayed rewards. Delay discounting correlated with performance on executive functioning tasks.
Increased discounting is associated with broad executive dysfunction, suggesting that HCV associated executive dysfunction may lead to altered decision making style.
hepatitis C; neuropsychology; impulsive behavior; substance-related disorders; delay discounting
Systems for efficient case finding of women with major depression during pregnancy and postpartum are needed. Here we assess the diagnostic accuracy of a modified 2-item patient health questionnaire (PHQ-2) as a pre-screen in assessing depression.
Cross-sectional assessments at 15 weeks’ gestation (n = 414), 30 weeks’ gestation (n = 334), and 6 to 16 weeks postpartum (n = 193) among women from a diverse set of races/ethnicities, participating in the IMPLICIT maternal care quality improvement network. The Edinburgh Postnatal Depression Scale score (≥13) was used as the criterion measure for the PHQ-2.
A positive 2-item screen had sensitivity of 93%, 82%, and 80% and specificity of 75%, 80%, and 86% for Edinburgh Postnatal Depression Scale score of ≥13 for assessment at 15 and 30 weeks gestational age and postpartum, respectively. The positive/negative predictive values for the PHQ-2 were 44/98, 24/91, and 30/98 for each time point, respectively. Areas under the receiver operating characteristic curve analysis suggested that 2-item assessments at each time point had approximately equal diagnostic validity.
Two questions were efficient to rule out depression and reduced the need for further screening of approximately 60% to 80% of women, depending on the point in pregnancy or postpartum. A diagnostic interview follow-up of women screening positive is still required.
Alzheimer’s disease is one of the most prevalent neurodegenerative disorders. However, there is no current treatment, which definitively influences disease progression over a sustained period. Numerous studies linking an increase in serum cholesterol, mainly during midlife, with the pathogenic process of Alzheimer’s disease have been published. Therefore, the role of statins as a therapy in this disorder may be of great interest. The aim of the present review is to summarize of the role of statins in the treatment of Alzheimer’s disease.
animal models; epidemiology; HMGCoA-inhibitors; clinical trials; prevention; cognitive function
Depression is more likely in patients with chronic physical illness, and is associated with increased rates of disability and mortality. Effective treatment of depression may reduce morbidity and mortality. The use of two stem questions for case finding in diabetes and coronary heart disease is advocated in the Quality and Outcomes Framework, and has become normalised into primary care.
To define the most effective tool for use in consultations to detect depression in people with chronic physical illness.
The following data sources were searched: CENTRAL, CINAHL, Embase, HMIC, MEDLINE, PsycINFO, Web of Knowledge, from inception to July 2009. Three authors selected studies that examined identification tools and used an interview-based ICD (International Classification of Diseases) or DSM (Diagnostic and statistical Manual of Mental Disorders) diagnosis of depression as reference standard. At least two authors independently extracted study characteristics and outcome data and assessed methodological quality.
A total of 113 studies met the eligibility criteria, providing data on 20 826 participants. It was found that two stem questions, PHQ-9 (Patient Health Questionnaire), the Zung, and GHQ-28 (General Health Questionnaire) were the optimal measures for case identification, but no method was sufficiently accurate to recommend as a definitive case-finding tool. Limitations were the moderate-to-high heterogeneity for most scales and the facts that few studies used ICD diagnoses as the reference standard, and that a variety of methods were used to determine DSM diagnoses.
Assessing both validity and ease of use, the two stem questions are the preferred method. However, clinicians should not rely on the two-questions approach alone, but should be confident to engage in a more detailed clinical assessment of patients who score positively.
depression; diagnosis; meta-analysis; primary care
Genome3D, available at http://www.genome3d.eu, is a new collaborative project that integrates UK-based structural resources to provide a unique perspective on sequence–structure–function relationships. Leading structure prediction resources (DomSerf, FUGUE, Gene3D, pDomTHREADER, Phyre and SUPERFAMILY) provide annotations for UniProt sequences to indicate the locations of structural domains (structural annotations) and their 3D structures (structural models). Structural annotations and 3D model predictions are currently available for three model genomes (Homo sapiens, E. coli and baker’s yeast), and the project will extend to other genomes in the near future. As these resources exploit different strategies for predicting structures, the main aim of Genome3D is to enable comparisons between all the resources so that biologists can see where predictions agree and are therefore more trusted. Furthermore, as these methods differ in whether they build their predictions using CATH or SCOP, Genome3D also contains the first official mapping between these two databases. This has identified pairs of similar superfamilies from the two resources at various degrees of consensus (532 bronze pairs, 527 silver pairs and 370 gold pairs).
Methamphetamine (MA) is associated with behavioral and cognitive deficits that may be related to macrostructural abnormalities. Quantitative anatomical comparisons between controls and methamphetamine-dependent individuals have produced conflicting results. We examined local and global differences in brain structure in 61 abstinent methamphetamine-dependent individuals and 44 controls with voxel-based morphometry and tissue segmentation. We related regional differences in gray matter density and whole brain segmentation volumes to performance on a behavioral measure of impulsivity and group membership using multiple linear regression. Within the MA group, we related cortical and subcortical gray matter density to MA use history, length of abstinence and age of first use. Controls had greater density relative to MA in bilateral insula and left middle frontal gyrus. Impulsivity was higher in the MA group and, within all subjects, impulsivity was positively correlated with gray matter density in posterior cingulate cortex and ventral striatum and negatively correlated in left superior frontal gyrus. Length of abstinence from MA was associated with greater amygdalar density. Earlier age of first use of MA (in subjects who initiated use before age 21) was associated with smaller intracranial volume. The findings are consistent with multiple possible mechanisms including neuroadaptations due to addictive behavior, neuroinflammation as well as dopaminergic and serotonergic neurotoxicity.
Several thousand metagenomes have already been sequenced, and this number is set to grow rapidly in the forthcoming years as the uptake of high-throughput sequencing technologies continues. Hand-in-hand with this data bonanza comes the computationally overwhelming task of analysis. Herein, we describe some of the bioinformatic approaches currently used by metagenomics researchers to analyze their data, the issues they face and the steps that could be taken to help overcome these challenges.
metagenomics; next-generation sequencing (NGS); high-throughput sequencing (HTS); functional analysis; environmental bioinformatics
The PRINTS database, now in its 21st year, houses a collection of diagnostic protein family ‘fingerprints’. Fingerprints are groups of conserved motifs, evident in multiple sequence alignments, whose unique inter-relationships provide distinctive signatures for particular protein families and structural/functional domains. As such, they may be used to assign uncharacterized sequences to known families, and hence to infer tentative functional, structural and/or evolutionary relationships. The February 2012 release (version 42.0) includes 2156 fingerprints, encoding 12 444 individual motifs, covering a range of globular and membrane proteins, modular polypeptides and so on. Here, we report the current status of the database, and introduce a number of recent developments that help both to render a variety of our annotation and analysis tools easier to use and to make them more widely available.
There are international differences in the epidemiology of depression and the performance of primary care physicians but the factors underlying these national differences are uncertain.
To examine the international variability in diagnostic performance of primary care physicians when diagnosing depression in primary care.
Design of study
A meta-analysis of unassisted clinical diagnoses against semi-structured interviews.
A systematic literature search, critical appraisal, and pooled analysis were conducted and 25 international studies were identified involving 8917 individuals. A minimum of three independent studies per country were required to aid extrapolation.
Clinicians in the Netherlands performed best at case finding (the ability to rule in cases of depression with minimal false positives) (AUC+ 0.735) and this was statistically significantly better than the ability of clinicians in Australia (AUC+ 0.622) and the US (AUC+ 0.653), who were the worst performers. Clinicians from Italy had intermediate case-finding abilities. Regarding screening (the ability to rule out cases of no depression with minimal false negatives) there were no strong differences. Looking at overall accuracy, primary care physicians in Italy and the Netherlands were most successful in their diagnoses and physicians from the US and Australia least successful (83.5%, 81.9%, 74.3%, and 67.0%, respectively). GPs in the UK appeared to have the lowest ability to detect depression, as a proportion of all cases of depression (45.6%; 95% CI = 27.7% to 64.2%). Several factors influenced detection accuracy including: collecting data on clinical outcomes; routinely comparing the clinical performance of staff; working in small practices; and having long waits to see a specialist.
Assuming these differences are representative, there appear to be international variations in the ability of primary care physicians to diagnose depression, but little differences in screening success. These might be explained by organisational factors.
depression; diagnostic accuracy; international; screening; sensitivity
InterPro amalgamates predictive protein signatures from a number of well-known partner databases into a single resource. To aid with interpretation of results, InterPro entries are manually annotated with terms from the Gene Ontology (GO). The InterPro2GO mappings are comprised of the cross-references between these two resources and are the largest source of GO annotation predictions for proteins. Here, we describe the protocol by which InterPro curators integrate GO terms into the InterPro database. We discuss the unique challenges involved in integrating specific GO terms with entries that may describe a diverse set of proteins, and we illustrate, with examples, how InterPro hierarchies reflect GO terms of increasing specificity. We describe a revised protocol for GO mapping that enables us to assign GO terms to domains based on the function of the individual domain, rather than the function of the families in which the domain is found. We also discuss how taxonomic constraints are dealt with and those cases where we are unable to add any appropriate GO terms. Expert manual annotation of InterPro entries with GO terms enables users to infer function, process or subcellular information for uncharacterized sequences based on sequence matches to predictive models.
http://www.ebi.ac.uk/interpro. The complete InterPro2GO mappings are available at: ftp://ftp.ebi.ac.uk/pub/databases/GO/goa/external2go/interpro2go
InterPro (http://www.ebi.ac.uk/interpro/) is a database that integrates diverse information about protein families, domains and functional sites, and makes it freely available to the public via Web-based interfaces and services. Central to the database are diagnostic models, known as signatures, against which protein sequences can be searched to determine their potential function. InterPro has utility in the large-scale analysis of whole genomes and meta-genomes, as well as in characterizing individual protein sequences. Herein we give an overview of new developments in the database and its associated software since 2009, including updates to database content, curation processes and Web and programmatic interfaces.
Given the uncertainty about factors that influence receipt of Clinical Excellence Awards (CEA) and recent availability of advanced research metrics, we examined the factors that predict CEA success using a convenience sample of English psychiatrists.
Observational study examining region, subspecialty, H-index, M-index, number of publications, years since registration and years in specialty.
ACCEA Nominal Roll, cross-referenced with data from the GMC's list of registered medical practitioners and Thompson's Web of Science database.
A total of 494 psychiatrists including 245 with national levels awards and a random sample with local level awards.
Main outcome measures
Receipt of local or national CEA awards in 2008 and 2009.
Of those with national awards, 126 had university contracts and 119 NHS contracts. Across all staff, years since qualification in medicine and H-index were the dominant influences. For local awards we found that years worked in the specialty was the main predictor of a CEA award with a smaller contribution from H-index. For national awards to university staff (academics) years on the medical register and publication rate were significant predictors. For national awards to NHS staff (non-academics) H-index and total cites were predictive, but these were themselves related to age.
Progression in CEAs among psychiatrists is strongly influenced by age (years spent in specialty and years on the medical register) with an additional contribution from research productivity. Currently, research impact is crudely assessed in the CEA process. We suggest that CEA committees formally assess the impact of NHS-related research using standardized research metrics which are openly available. We also suggest that supporting organizations and local trusts adhere to the rules mandated by the ACCEA.
Background: Despite disproportionately high rates of hepatitis C (HCV) among patients with severe mental illness, to date, there is scant empirical data available regarding antiviral therapy outcomes within this population. Objective: To compare antiviral therapy completion and response rates between HCV patients with vs those without schizophrenia (SCHZ). Methods: A regional Veterans Healthcare Administration database was used to identify veterans meeting criteria for this retrospective chart review. All patients confirmed to have SCHZ and to have received antiviral therapy between 1998 and 2006 (n = 30) were compared with a control group of demographically matched (HCV genotype, age, race, gender) patients with no history of SCHZ (n = 30). Results: For HCV patients with genotype 1, antiviral completion, end of treatment response (ETR), and sustained viral response (SVR) rates did not significantly differ between groups. For those with genotypes 2 and 3 combined, antiviral therapy completion rates did not significantly differ between groups; however, the SCHZ group was significantly (P < 0.050) more likely to achieve an ETR and an SVR. For all genotypes combined, the SCHZ patients were no more likely than controls to discontinue therapy early for psychiatric symptoms, medical complications, or other adverse events, and groups did not significantly differ in terms of hospitalization rates during antiviral therapy. Conclusion: Our retrospective chart review suggests that patients with SCHZ complete and respond to antiviral therapy for HCV at rates comparable with those without SCHZ. Based on these data, SCHZ should not be considered a contraindication to antiviral therapy for HCV.
interferon; mental disorders; psychotic disorders; adverse effects
Antiviral therapy for chronic infection with HCV is associated with significant neuropsychiatric side effects. Research indicates that patients with mental illness are less likely to receive antiviral therapy, despite limited data regarding the influence of antiviral therapy on psychiatric symptoms in patients with specific psychiatric disorders. The aim of this study was to determine whether antiviral therapy is associated with higher rates of psychiatric symptoms in patients with schizophrenia (SCHZ).
A regional Veterans Healthcare Administration database was used to identify veterans meeting criteria for this retrospective chart review. Patients confirmed to have SCHZ and to have received antiviral therapy for HCV between 1998 and 2006 (n=30) were compared with a control group of demographically matched (age, race and gender) patients with SCHZ who did not receive antiviral therapy (n=30). Clinicians blinded to antiviral therapy status used chart notes to evaluate whether patients exhibited prominent symptoms of SCHZ, depression or mania during a 6 month pre-treatment period, the treatment period and a 6 month post-treatment period (or during equivalent periods for the control group).
Groups did not significantly differ in rates of symptoms of SCHZ, depression or mania during any study period. During the treatment period, groups did not significantly differ in rates of emergency room visits or inpatient hospitalizations.
Our retrospective chart review suggests that patients with SCHZ experience similar rates of psychiatric symptoms on and off antiviral therapy. Despite limitations and constraints of the methods, our data suggest that SCHZ is not a contraindication to antiviral therapy for HCV.