Improving together: a new quality framework for GP clusters in Scotland

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Improving Together: A National Framework for Quality and GP Clusters in Scotland

Improving together will complement the development of the Scottish national GP contract that sets out the role of GPs and their important contribution as clinical leaders and expert medical generalists working in a community setting. This framework will be reviewed by the Scottish Government and the Scottish General Practitioners Committee of the BMA on a periodic basis, attentive to feedback from those involved in delivering its intent. As such, it is a framework that will develop to its full potential over time, as elements of the transformation of primary care in Scotland create the capacity to do so

Incorporating a Rapid-Impact Package for Neglected Tropical Diseases with Programs for HIV/AIDS, Tuberculosis, and Malaria: A comprehensive pro-poor health policy and strategy for the developing world

Hotez et al. argue that achieving success in the global fight against HIV/AIDS, tuberculosis, and malaria may well require a concurrent attack on the neglected tropical diseases

Erythroid-Specific Transcriptional Changes in PBMCs from Pulmonary Hypertension Patients

Gene expression profiling of peripheral blood mononuclear cells (PBMCs) is a powerful tool for the identification of surrogate markers involved in disease processes. The hypothesis tested in this study was that chronic exposure of PBMCs to a hypertensive environment in remodeled pulmonary vessels would be reflected by specific transcriptional changes in these cells.The transcript profiles of PBMCs from 30 idiopathic pulmonary arterial hypertension patients (IPAH), 19 patients with systemic sclerosis without pulmonary hypertension (SSc), 42 scleroderma-associated pulmonary arterial hypertensio patients (SSc-PAH), and 8 patients with SSc complicated by interstitial lung disease and pulmonary hypertension (SSc-PH-ILD) were compared to the gene expression profiles of PBMCs from 41 healthy individuals. Multiple gene expression signatures were identified which could distinguish various disease groups from controls. One of these signatures, specific for erythrocyte maturation, is enriched specifically in patients with PH. This association was validated in multiple published datasets. The erythropoiesis signature was strongly correlated with hemodynamic measures of increasing disease severity in IPAH patients. No significant correlation of the same type was noted for SSc-PAH patients, this despite a clear signature enrichment within this group overall. These findings suggest an association of the erythropoiesis signature in PBMCs from patients with PH with a variable presentation among different subtypes of disease.In PH, the expansion of immature red blood cell precursors may constitute a response to the increasingly hypoxic conditions prevalent in this syndrome. A correlation of this erythrocyte signature with more severe hypertension cases may provide an important biomarker of disease progression

Role of Estrogen Response Element in the Human Prolactin Gene:Transcriptional Response and Timing

The use of bacterial artificial chromosome (BAC) reporter constructs in molecular physiology enables the inclusion of large sections of flanking DNA, likely to contain regulatory elements and enhancers regions that contribute to the transcriptional output of a gene. Using BAC recombineering, we have manipulated a 160-kb human prolactin luciferase (hPRL-Luc) BAC construct and mutated the previously defined proximal estrogen response element (ERE) located −1189 bp relative to the transcription start site, to assess its involvement in the estrogen responsiveness of the entire hPRL locus. We found that GH3 cell lines stably expressing Luc under control of the ERE-mutated hPRL promoter (ERE-Mut) displayed a dramatically reduced transcriptional response to 17β-estradiol (E2) treatment compared with cells expressing Luc from the wild-type (WT) ERE hPRL-Luc promoter (ERE-WT). The −1189 ERE controls not only the response to E2 treatment but also the acute transcriptional response to TNFα, which was abolished in ERE-Mut cells. ERE-WT cells displayed a biphasic transcriptional response after TNFα treatment, the acute phase of which was blocked after treatment with the estrogen receptor antagonist 4-hydroxy-tamoxifen. Unexpectedly, we show the oscillatory characteristics of hPRL promoter activity in individual living cells were unaffected by disruption of this crucial response element, real-time bioluminescence imaging showed that transcription cycles were maintained, with similar cycle lengths, in ERE-WT and ERE-Mut cells. These data suggest the −1189 ERE is the dominant response element involved in the hPRL transcriptional response to both E2 and TNFα and, crucially, that cycles of hPRL promoter activity are independent of estrogen receptor binding

Environmental DNA (eDNA) metabarcoding of pond water as a tool to survey conservation and management priority mammals

Environmental DNA (eDNA) metabarcoding can identify terrestrial taxa utilising aquatic habitats alongside aquatic communities, but terrestrial species' eDNA dynamics are understudied. We evaluated eDNA metabarcoding for monitoring semi-aquatic and terrestrial mammals, specifically nine species of conservation or management concern, and examined spatiotemporal variation in mammal eDNA signals. We hypothesised eDNA signals would be stronger for semi-aquatic than terrestrial mammals, and at sites where individuals exhibited behaviours. In captivity, we sampled waterbodies at points where behaviours were observed (‘directed’ sampling) and at equidistant intervals along the shoreline (‘stratified’ sampling). We surveyed natural ponds (N = 6) where focal species were present using stratified water sampling, camera traps, and field signs. eDNA samples were metabarcoded using vertebrate-specific primers. All focal species were detected in captivity. eDNA signal strength did not differ between directed and stratified samples across or within species, between semi-aquatic or terrestrial species, or according to behaviours. eDNA was evenly distributed in artificial waterbodies, but unevenly distributed in natural ponds. Survey methods deployed at natural ponds shared three species detections. Metabarcoding missed badger and red fox recorded by cameras and field signs, but detected small mammals these tools overlooked, e.g. water vole. Terrestrial mammal eDNA signals were weaker and detected less frequently than semi-aquatic mammal eDNA signals. eDNA metabarcoding could enhance mammal monitoring through large-scale, multi-species distribution assessment for priority and difficult to survey species, and provide early indication of range expansions or contractions. However, eDNA surveys need high spatiotemporal resolution and metabarcoding biases require further investigation before routine implementation

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

XML views of relational databases

Our goal was to create a program to link two existing algorithms to query relational databases in an XML format. The first algorithm, CoT, takes a relational schema and generates a corresponding XML schema represented in a proprietary grammar format, called XGrammar. The second algorithm, X2S, handles XPath queries over this XML schema. We wrote a program, G2D, that converts the schema in XGrammar into XML DTDs, annotated with key-foreign key information present in the relational schema. X2S was also modified to now work against these XML DTDs. To further the project, we recommend providing additional functionality allowing updates to occur in the relational databases using our software package