Showing papers by "University of Washington published in 2014"

Review of Particle Physics

Abstract: The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,283 new measurements from 899 Japers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as heavy neutrinos, supersymmetric and technicolor particles, axions, dark photons, etc. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as Supersymmetry, Extra Dimensions, Particle Detectors, Probability, and Statistics. Among the 112 reviews are many that are new or heavily revised including those on: Dark Energy, Higgs Boson Physics, Electroweak Model, Neutrino Cross Section Measurements, Monte Carlo Neutrino Generators, Top Quark, Dark Matter, Dynamical Electroweak Symmetry Breaking, Accelerator Physics of Colliders, High-Energy Collider Parameters, Big Bang Nucleosynthesis, Astrophysical Constants and Cosmological Parameters.

Active learning increases student performance in science, engineering, and mathematics

Abstract: creased by 0.47 SDs under active learning (n = 158 studies), and that the odds ratio for failing was 1.95 under traditional lecturing (n = 67 studies). These results indicate that average examination scores improved by about 6% in active learning sections, and that students in classes with traditional lecturing were 1.5 times more likely to fail than were students in classes with active learning. Heterogeneity analyses indicated that both results hold across the STEM disciplines, that active learning increases scores on concept inventories more than on course examinations, and that active learning appears effective across all class sizes—although the greatest effects are in small (n ≤ 50) classes. Trim and fill analyses and fail-safe n calculations suggest that the results are not due to publication bias. The results also appear robust to variation in the methodological rigor of the included studies, based on the quality of controls over student quality and instructor identity. This is the largest and most comprehensive metaanalysis of undergraduate STEM education published to date. The results raise questions about the continued use of traditional lecturing as a control in research studies, and support active learning as the preferred, empirically validated teaching practice in regular classrooms.

A general framework for estimating the relative pathogenicity of human genetic variants

Abstract: Our capacity to sequence human genomes has exceeded our ability to interpret genetic variation. Current genomic annotations tend to exploit a single information type (e.g. conservation) and/or are restricted in scope (e.g. to missense changes). Here, we describe Combined Annotation Dependent Depletion (CADD), a framework that objectively integrates many diverse annotations into a single, quantitative score. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human derived alleles from 14.7 million simulated variants. We pre-compute “C-scores” for all 8.6 billion possible human single nucleotide variants and enable scoring of short insertions/deletions. C-scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects, and complex trait associations, and highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious, and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current annotation.

Comprehensive molecular characterization of gastric adenocarcinoma

Abstract: Gastric cancer was the world’s third leading cause of cancer mortality in 2012, responsible for 723,000 deaths1. The vast majority of gastric cancers are adenocarcinomas, which can be further subdivided into intestinal and diffuse types according to the Lauren classification2. An alternative system, proposed by the World Health Organization, divides gastric cancer into papillary, tubular, mucinous (colloid) and poorly cohesive carcinomas3. These classification systems have little clinical utility, making the development of robust classifiers that can guide patient therapy an urgent priority. The majority of gastric cancers are associated with infectious agents, including the bacterium Helicobacter pylori4 and Epstein–Barr virus (EBV). The distribution of histological subtypes of gastric cancer and the frequencies of H. pylori and EBV associated gastric cancer vary across the globe5. A small minority of gastric cancer cases are associated with germline mutation in E-cadherin (CDH1)6 or mismatch repair genes7 (Lynch syndrome), whereas sporadic mismatch repair-deficient gastric cancers have epigenetic silencing of MLH1 in the context of a CpG island methylator phenotype (CIMP)8. Molecular profiling of gastric cancer has been performed using gene expression or DNA sequencing9–12, but has not led to a clear biologic classification scheme. The goals of this study by The Cancer Genome Atlas (TCGA) were to develop a robust molecular classification of gastric cancer and to identify dysregulated pathways and candidate drivers of distinct classes of gastric cancer.

Worldwide Epidemiology of Atrial Fibrillation: A Global Burden of Disease 2010 Study

Abstract: Background— The global burden of atrial fibrillation (AF) is unknown. Methods and Results— We systematically reviewed population-based studies of AF published from 1980 to 2010 from the 21 Global Burden of Disease regions to estimate global/regional prevalence, incidence, and morbidity and mortality related to AF (DisModMR software). Of 377 potential studies identified, 184 met prespecified eligibility criteria. The estimated number of individuals with AF globally in 2010 was 33.5 million (20.9 million men [95% uncertainty interval (UI), 19.5–22.2 million] and 12.6 million women [95% UI, 12.0–13.7 million]). Burden associated with AF, measured as disability-adjusted life-years, increased by 18.8% (95% UI, 15.8–19.3) in men and 18.9% (95% UI, 15.8–23.5) in women from 1990 to 2010. In 1990, the estimated age-adjusted prevalence rates of AF (per 100 000 population) were 569.5 in men (95% UI, 532.8–612.7) and 359.9 in women (95% UI, 334.7–392.6); the estimated age-adjusted incidence rates were 60.7 per 100 000 person-years in men (95% UI, 49.2–78.5) and 43.8 in women (95% UI, 35.9–55.0). In 2010, the prevalence rates increased to 596.2 (95% UI, 558.4–636.7) in men and 373.1 (95% UI, 347.9–402.2) in women; the incidence rates increased to 77.5 (95% UI, 65.2–95.4) in men and 59.5 (95% UI, 49.9–74.9) in women. Mortality associated with AF was higher in women and increased by 2-fold (95% UI, 2.0–2.2) and 1.9-fold (95% UI, 1.8–2.0) in men and women, respectively, from 1990 to 2010. There was evidence of significant regional heterogeneity in AF estimations and availability of population-based data. Conclusions— These findings provide evidence of progressive increases in overall burden, incidence, prevalence, and AF-associated mortality between 1990 and 2010, with significant public health implications. Systematic, regional surveillance of AF is required to better direct prevention and treatment strategies.

TaintDroid: An Information-Flow Tracking System for Realtime Privacy Monitoring on Smartphones

Abstract: Today’s smartphone operating systems frequently fail to provide users with visibility into how third-party applications collect and share their private data. We address these shortcomings with TaintDroid, an efficient, system-wide dynamic taint tracking and analysis system capable of simultaneously tracking multiple sources of sensitive data. TaintDroid enables realtime analysis by leveraging Android’s virtualized execution environment. TaintDroid incurs only 32p performance overhead on a CPU-bound microbenchmark and imposes negligible overhead on interactive third-party applications. Using TaintDroid to monitor the behavior of 30 popular third-party Android applications, in our 2010 study we found 20 applications potentially misused users’ private information; so did a similar fraction of the tested applications in our 2012 study. Monitoring the flow of privacy-sensitive data with TaintDroid provides valuable input for smartphone users and security service firms seeking to identify misbehaving applications.

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis

Abstract: Background Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. Methods We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George’s Respiratory Questionnaire, both assessed over a 52-week period. Results A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was −114.7 ml with nintedanib versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P = 0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P = 0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. Conclusions In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Abstract: Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults. A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations. When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided. Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

Status and ecological effects of the world's largest carnivores.

Abstract: Large carnivores face serious threats and are experiencing massive declines in their populations and geographic ranges around the world. We highlight how these threats have affected the conservation status and ecological functioning of the 31 largest mammalian carnivores on Earth. Consistent with theory, empirical studies increasingly show that large carnivores have substantial effects on the structure and function of diverse ecosystems. Significant cascading trophic interactions, mediated by their prey or sympatric mesopredators, arise when some of these carnivores are extirpated from or repatriated to ecosystems. Unexpected effects of trophic cascades on various taxa and processes include changes to bird, mammal, invertebrate, and herpetofauna abundance or richness; subsidies to scavengers; altered disease dynamics; carbon sequestration; modified stream morphology; and crop damage. Promoting tolerance and coexistence with large carnivores is a crucial societal challenge that will ultimately determine the fate of Earth's largest carnivores and all that depends upon them, including humans.

Enzalutamide in Metastatic Prostate Cancer before Chemotherapy

Abstract: BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

Spin and pseudospins in layered transition metal dichalcogenides

Abstract: The recent emergence of two-dimensional layered materials — in particular the transition metal dichalcogenides — provides a new laboratory for exploring the internal quantum degrees of freedom of electrons and their potential for new electronics. These degrees of freedom are the real electron spin, the layer pseudospin, and the valley pseudospin. New methods for the quantum control of the spin and these pseudospins arise from the existence of Berry phase-related physical properties and strong spin–orbit coupling. The former leads to the versatile control of the valley pseudospin, whereas the latter gives rise to an interplay between the spin and the pseudospins. Here, we provide a brief review of both theoretical and experimental advances in this field. Understanding the physics of two-dimensional materials beyond graphene is of both fundamental and practical interest. Recent theoretical and experimental advances uncover the interplay between real spin and pseudospins in layered transition metal dichalcogenides.

Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Group†

Abstract: Temporomandibular disorders (TMD) are a significant public health problem affecting approximately 5% to 12% of the population.1 TMD is the second most common musculoskeletal condition (after chronic low back pain) resulting in pain and disability.1 Pain-related TMD can impact the individual's daily activities, psychosocial functioning, and quality of life. Overall, the annual TMD management cost in the USA, not including imaging, has doubled in the last decade to $4 billion.1 Patients often seek consultation with dentists for their TMD, especially for pain-related TMD. Diagnostic criteria for TMD with simple, clear, reliable, and valid operational definitions for the history, examination, and imaging procedures are needed to render physical diagnoses in both clinical and research settings. In addition, biobehavioral assessment of pain-related behavior and psychosocial functioning—an essential part of the diagnostic process—is required and provides the minimal information whereby one can determine whether the patient's pain disorder, especially when chronic, warrants further multidisciplinary assessment. Taken together, a new dual-axis Diagnostic Criteria for TMD (DC/TMD) will provide evidence-based criteria for the clinician to use when assessing patients, and will facilitate communication regarding consultations, referrals, and prognosis.2 The research community benefits from the ability to use well-defined and clinically relevant characteristics associated with the phenotype in order to facilitate more generalizable research. When clinicians and researchers use the same criteria, taxonomy, and nomenclature, then clinical questions and experience can be more easily transferred into relevant research questions, and research findings are more accessible to clinicians to better diagnose and manage their patients. The Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) have been the most widely employed diagnostic protocol for TMD research since its publication in 1992.3 This classification system was based on the biopsychosocial model of pain4 that included an Axis I physical assessment, using reliable and well-operationalized diagnostic criteria, and an Axis II assessment of psychosocial status and pain-related disability. The intent was to simultaneously provide a physical diagnosis and identify other relevant characteristics of the patient that could influence the expression and thus management of their TMD. Indeed, the longer the pain persists, the greater the potential for emergence and amplification of cognitive, psychosocial, and behavioral risk factors, with resultant enhanced pain sensitivity, greater likelihood of additional pain persistence, and reduced probability of success from standard treatments.5 The RDC/TMD (1992) was intended to be only a first step toward improved TMD classification, and the authors stated the need for future investigation of the accuracy of the Axis I diagnostic algorithms in terms of reliability and criterion validity—the latter involving the use of credible reference standard diagnoses. Also recommended was further assessment of the clinical utility of the Axis II instruments. The original RDC/TMD Axis I physical diagnoses have content validity based on the critical review by experts of the published diagnostic approach in use at that time and were tested using population-based epidemiologic data.6 Subsequently, a multicenter study showed that, for the most common TMD, the original RDC/TMD diagnoses exhibited sufficient reliability for clinical use.7 While the validity of the individual RDC/TMD diagnoses has been extensively investigated, assessment of the criterion validity for the complete spectrum of RDC/TMD diagnoses had been absent until recently.8 For the original RDC/TMD Axis II instruments, good evidence for their reliability and validity for measuring psychosocial status and pain-related disability already existed when the classification system was published.9–13 Subsequently, a variety of studies have demonstrated the significance and utility of the original RDC/TMD biobehavioral measures in such areas as predicting outcomes of clinical trials, escalation from acute to chronic pain, and experimental laboratory settings.14–20 Other studies have shown that the original RDC/TMD biobehavioral measures are incomplete in terms of prediction of disease course.21–23 The overall utility of the biobehavioral measures in routine clinical settings has, however, yet to be demonstrated, in part because most studies have to date focused on Axis I diagnoses rather than Axis II biobehavioral factors.24 The aims of this article are to present the evidence-based new Axis I and Axis II DC/TMD to be used in both clinical and research settings, as well as present the processes related to their development.

The contribution of de novo coding mutations to autism spectrum disorder

Abstract: Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively. Including copy number variants, coding de novo mutations contribute to about 30% of all simplex and 45% of female diagnoses. Almost all LGD mutations occur opposite wild-type alleles. LGD targets in affected females significantly overlap the targets in males of lower intelligence quotient (IQ), but neither overlaps significantly with targets in males of higher IQ. We estimate that LGD mutation in about 400 genes can contribute to the joint class of affected females and males of lower IQ, with an overlapping and similar number of genes vulnerable to contributory missense mutation. LGD targets in the joint class overlap with published targets for intellectual disability and schizophrenia, and are enriched for chromatin modifiers, FMRP-associated genes and embryonically expressed genes. Most of the significance for the latter comes from affected females.

The global burden of low back pain: estimates from the Global Burden of Disease 2010 study

Abstract: Supported by the Bill and Melinda Gates Foundation (to Dr Hoy and Prof Vos), the Australian Commonwealth Department of Health and Ageing (to Dr Smith (University of Sydney, Institute of Bone and Joint Research) and Prof March), the Australian National Health and Medical Research Council (Postgraduate Scholarship 569772 to Dr Hoy and Practitioner Fellowships 334010 (2005–2009) and 606429 (2010–2014) to Prof Buchbinder, and the Ageing and Alzheimers Research Foundation (Asst Prof Blyth).

Nature and Health

Abstract: Urbanization, resource exploitation, and lifestyle changes have diminished possibilities for human contact with nature in many societies. Concern about the loss has helped motivate research on the health benefits of contact with nature. Reviewing that research here, we focus on nature as represented by aspects of the physical environment relevant to planning, design, and policy measures that serve broad segments of urbanized societies. We discuss difficulties in defining “nature” and reasons for the current expansion of the research field, and we assess available reviews. We then consider research on pathways between nature and health involving air quality, physical activity, social cohesion, and stress reduction. Finally, we discuss methodological issues and priorities for future research. The extant research does describe an array of benefits of contact with nature, and evidence regarding some benefits is strong; however, some findings indicate caution is needed in applying beliefs about those benefits,...

Spironolactone for Heart Failure with Preserved Ejection Fraction

Abstract: Background Mineralocorticoid-receptor antagonists improve the prognosis for patients with heart failure and a reduced left ventricular ejection fraction. We evaluated the effects of spironolactone in patients with heart failure and a preserved left ventricular ejection fraction. Methods In this randomized, double-blind trial, we assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction of 45% or more to receive either spironolactone (15 to 45 mg daily) or placebo. The primary outcome was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. Results With a mean follow-up of 3.3 years, the primary outcome occurred in 320 of 1722 patients in the spironolactone group (18.6%) and 351 of 1723 patients in the placebo group (20.4%) (hazard ratio, 0.89; 95% confidence interval [CI], 0.77 to 1.04; P = 0.14). Of the components of the primary outcome, only hospitalization for heart failure had a significantly lower incidence in the spironolactone group than in the placebo group (206 patients [12.0%] vs. 245 patients [14.2%]; hazard ratio, 0.83; 95% CI, 0.69 to 0.99, P = 0.04). Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. Treatment with spiron olactone was associated with increased serum creatinine levels and a doubling of the rate of hyperkalemia (18.7%, vs. 9.1% in the placebo group) but reduced hypokalemia. With frequent monitoring, there were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 mg per deciliter (265 μmol per liter) or higher, or dialysis. Conclusions In patients with heart failure and a preserved ejection fraction, treatment with spironolactone did not significantly reduce the incidence of the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. (Funded by the National Heart, Lung, and Blood Institute; TOPCAT ClinicalTrials.gov number, NCT00094302.)

Defining the role of common variation in the genomic and biological architecture of adult human height

Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America

Abstract: A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.

The complete genome sequence of a Neanderthal from the Altai Mountains

Abstract: We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Abstract: We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55–4.30; P = 2 × 10−16). We also show six risk loci associated with proximal gene expression or DNA methylation.

Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.

Abstract: BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).

Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

Abstract: Background: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This s ...

Electrically tunable excitonic light-emitting diodes based on monolayer WSe2 p-n junctions.

Abstract: Bright and electrostatically tunable electroluminescence from monolayer WSe2 p–n junctions is reported.

An Integrated Risk Function for Estimating the Global Burden of Disease Attributable to Ambient Fine Particulate Matter Exposure

Abstract: Background: Estimating the burden of disease attributable to long-term exposure to fine particulate matter (PM2.5) in ambient air requires knowledge of both the shape and magnitude of the relative ...