Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Varicella Viruses Inhibit Interferon-Stimulated JAK-STAT Signaling through Multiple Mechanisms

Varicella zoster virus (VZV) causes chickenpox in humans and, subsequently, establishes latency in the sensory ganglia from where it reactivates to cause herpes zoster. Infection of rhesus macaques with simian varicella virus (SVV) recapitulates VZV pathogenesis in humans thus representing a suitable animal model for VZV infection. While the type I interferon (IFN) response has been shown to affect VZV replication, the virus employs counter mechanisms to prevent the induction of anti-viral IFN stimulated genes (ISG). Here, we demonstrate that SVV inhibits type I IFN-activated signal transduction via the JAK-STAT pathway. SVV-infected rhesus fibroblasts were refractory to IFN stimulation displaying reduced protein levels of IRF9 and lacking STAT2 phosphorylation. Since previous work implicated involvement of the VZV immediate early gene product ORF63 in preventing ISG-induction we studied the role of SVV ORF63 in generating resistance to IFN treatment. Interestingly, SVV ORF63 did not affect STAT2 phosphorylation but caused IRF9 degradation in a proteasome-dependent manner, suggesting that SVV employs multiple mechanisms to counteract the effect of IFN. Control of SVV ORF63 protein levels via fusion to a dihydrofolate reductase (DHFR)-degradation domain additionally confirmed its requirement for viral replication. Our results also show a prominent reduction of IRF9 and inhibition of STAT2 phosphorylation in VZV-infected cells. In addition, cells expressing VZV ORF63 blocked IFN-stimulation and displayed reduced levels of the IRF9 protein. Taken together, our data suggest that varicella ORF63 prevents ISG-induction both directly via IRF9 degradation and indirectly via transcriptional control of viral proteins that interfere with STAT2 phosphorylation. SVV and VZV thus encode multiple viral gene products that tightly control IFN-induced anti-viral responses

ATLAS Run 1 searches for direct pair production of third-generation squarks at the Large Hadron Collider

This paper reviews and extends searches for the direct pair production of the scalar supersymmetric partners of the top and bottom quarks in proton-proton collisions collected by the ATLAS collaboration during the LHC Run 1. Most of the analyses use 20 fb$^{-1}$ of collisions at a centre-of-mass energy of $\sqrt{s}$ = 8 TeV, although in some case an additional 4.7 fb$^{-1}$ of collision data at $\sqrt{s}$ = 7 TeV are used. New analyses are introduced to improve the sensitivity to specific regions of the model parameter space. Since no evidence of third-generation squarks is found, exclusion limits are derived by combining several analyses and are presented in both a simplified model framework, assuming simple decay chains, as well as within the context of more elaborate phenomenological supersymmetric models

Tomography patterns of lung disease in systemic sclerosis

Currently, lung impairment is the leading factor responsible for the morbidity and mortality associated with systemic sclerosis. Therefore, the recognition of the various tomography patterns becomes decisive in the clinical management of these patients. In high-resolution computed tomography studies, the most common pattern is that of nonspecific interstitial pneumonia. However, there are other forms of lung involvement that must also be recognized. The aim of this study was to review the literature on the main changes resulting from pulmonary involvement in systemic sclerosis and the corresponding radiological findings, considering the current classification of interstitial diseases. We searched the Medline (PubMed), Lilacs, and SciELO databases in order to select articles related to pulmonary changes in systemic sclerosis and published in English between 2000 and 2015. The pulmonary changes seen on computed tomography in systemic sclerosis are varied and are divided into three main categories: interstitial, alveolar, and vascular. Interstitial changes constitute the most common type of pulmonary involvement in systemic sclerosis. However, alveolar and vascular manifestations must also be recognized and considered in the presence of atypical clinical presentations and inadequate treatment responses

The WPA-Lancet Psychiatry Commission on the Future of Psychiatry

We are partnered by the World Psychiatric Association, and would like to thank them for financial help with initial research and funding for accommodation. TW acknowledges the support of the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King's College London and her NIHR Senior Investigator Award.Background This Commission addresses several priority areas for psychiatry over the next decade, and into the 21st century. These represent challenges and opportunities for the profession to sustain and develop itself to secure the best possible future for the millions of people worldwide who will face life with mental illness. Part 1: The patient and treatment Who will psychiatrists help? The patient population of the future will reflect general demographic shifts towards older, more urban, and migrant populations. While technical advances such as the development of biomarkers will potentially alter diagnosis and treatment, and digital technology will facilitate assessment of remote populations, the human elements of practice such as cultural sensitivity and the ability to form a strong therapeutic alliance with the patient will remain central. Part 2: Psychiatry and health-care systems Delivering mental health services to those who need them will require reform of the traditional structure of services. Few existing models have evidence of clinical effectiveness and acceptability to service users. Services of the future should consider stepped care, increased use of multidisciplinary teamwork, more of a public health approach, and the integration of mental and physical health care. These services will need to fit into the cultural and economic framework of a diverse range of settings in high-income, low-income, and middle-income countries. Part 3: Psychiatry and society Increased emphasis on social interventions and engagement with societal expectations might be an important area for psychiatry's development. This could encompass advocacy for the rights of individuals living with mental illnesses, political involvement concerning the social risk factors for mental illness, and, on a smaller scale, work with families and local social networks and communities. Psychiatrists should therefore possess communication skills and knowledge of the social sciences as well as the basic biological sciences. Part 4: The future of mental health law Mental health law worldwide tends to be based on concerns about risk rather than the protection of the rights of individuals experiencing mental illness. The United Nations Convention on the Rights of Persons with Disabilities, which states that compulsion based in whole or in part on mental disability is discriminatory, is a landmark document that should inform the future formulation and reform of mental health laws. An evidence-based approach needs to be taken: mental health legislation should mandate mental health training for all health professionals; ensure access to good-quality care; and cover wider societal issues, particularly access to housing, resources, and employment. All governments should include a mental health impact assessment when drafting relevant legislation. Part 5: Digital psychiatry—enhancing the future of mental health Digital technology might offer psychiatry the potential for radical change in terms of service delivery and the development of new treatments. However, it also carries the risk of commercialised, unproven treatments entering the medical marketplace with detrimental effect. Novel research methods, transparency standards, clinical evidence, and care delivery models must be created in collaboration with a wide range of stakeholders. Psychiatrists need to remain up to date and educated in the evolving digital world. Part 6: Training the psychiatrist of the future Rapid scientific advance and evolving models of health-care delivery have broad implications for future psychiatry training. The psychiatrist of the future must not only be armed with the latest medical knowledge and clinical skills but also be prepared to adapt to a changing landscape. Training programmes in an age in which knowledge of facts is less important than how new knowledge is accessed and deployed must refocus from the simple delivery of information towards acquisition of skills in lifelong learning and quality improvement. Conclusion Psychiatry faces major challenges. The therapeutic relationship remains paramount, and psychiatrists will need to acquire the necessary communication skills and cultural awareness to work optimally as patient demographics change. Psychiatrists must work with key stakeholders, including policy makers and patients, to help to plan and deliver the best services possible. The contract between psychiatry and society needs to be reviewed and renegotiated on a regular basis. Mental health law should be reformed on the basis of evidence and the rights of the individual. Psychiatry should embrace the possibilities offered by digital technology, and take an active role in ensuring research and care delivery in this area is ethically sound and evidence based. Psychiatry training must reflect these multiple pressures and demands by focusing on lifelong learning rather than simply knowledge delivery. IntroductionWe are partnered by the World Psychiatric Association, and would like to thank them for financial help with initial research and funding for accommodation. TW acknowledges the support of the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King's College London and her NIHR Senior Investigator Award