Showing papers by "University of North Carolina at Chapel Hill published in 2015"
07 Jun 2015
TL;DR: Inception as mentioned in this paper is a deep convolutional neural network architecture that achieves the new state of the art for classification and detection in the ImageNet Large-Scale Visual Recognition Challenge 2014 (ILSVRC14).
Abstract: We propose a deep convolutional neural network architecture codenamed Inception that achieves the new state of the art for classification and detection in the ImageNet Large-Scale Visual Recognition Challenge 2014 (ILSVRC14). The main hallmark of this architecture is the improved utilization of the computing resources inside the network. By a carefully crafted design, we increased the depth and width of the network while keeping the computational budget constant. To optimize quality, the architectural decisions were based on the Hebbian principle and the intuition of multi-scale processing. One particular incarnation used in our submission for ILSVRC14 is called GoogLeNet, a 22 layers deep network, the quality of which is assessed in the context of classification and detection.
40,257 citations
TL;DR: The ImageNet Large Scale Visual Recognition Challenge (ILSVRC) as mentioned in this paper is a benchmark in object category classification and detection on hundreds of object categories and millions of images, which has been run annually from 2010 to present, attracting participation from more than fifty institutions.
Abstract: The ImageNet Large Scale Visual Recognition Challenge is a benchmark in object category classification and detection on hundreds of object categories and millions of images. The challenge has been run annually from 2010 to present, attracting participation from more than fifty institutions. This paper describes the creation of this benchmark dataset and the advances in object recognition that have been possible as a result. We discuss the challenges of collecting large-scale ground truth annotation, highlight key breakthroughs in categorical object recognition, provide a detailed analysis of the current state of the field of large-scale image classification and object detection, and compare the state-of-the-art computer vision accuracy with human accuracy. We conclude with lessons learned in the 5 years of the challenge, and propose future directions and improvements.
30,811 citations
TL;DR: SSD as mentioned in this paper discretizes the output space of bounding boxes into a set of default boxes over different aspect ratios and scales per feature map location, and combines predictions from multiple feature maps with different resolutions to naturally handle objects of various sizes.
Abstract: We present a method for detecting objects in images using a single deep neural network. Our approach, named SSD, discretizes the output space of bounding boxes into a set of default boxes over different aspect ratios and scales per feature map location. At prediction time, the network generates scores for the presence of each object category in each default box and produces adjustments to the box to better match the object shape. Additionally, the network combines predictions from multiple feature maps with different resolutions to naturally handle objects of various sizes. Our SSD model is simple relative to methods that require object proposals because it completely eliminates proposal generation and subsequent pixel or feature resampling stage and encapsulates all computation in a single network. This makes SSD easy to train and straightforward to integrate into systems that require a detection component. Experimental results on the PASCAL VOC, MS COCO, and ILSVRC datasets confirm that SSD has comparable accuracy to methods that utilize an additional object proposal step and is much faster, while providing a unified framework for both training and inference. Compared to other single stage methods, SSD has much better accuracy, even with a smaller input image size. For $300\times 300$ input, SSD achieves 72.1% mAP on VOC2007 test at 58 FPS on a Nvidia Titan X and for $500\times 500$ input, SSD achieves 75.1% mAP, outperforming a comparable state of the art Faster R-CNN model. Code is available at this https URL .
12,678 citations
TL;DR: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations, and has reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-generation sequencing, deep exome sequencing, and dense microarray genotyping.
Abstract: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.
12,661 citations
TL;DR: In the Global Burden of Disease Study 2013 (GBD 2013) as discussed by the authors, the authors used the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data.
5,792 citations
Michael S. Lawrence1, Carrie Sougnez1, Lee Lichtenstein1, Kristian Cibulskis1 +306 more•Institutions (26)
TL;DR: It is shown that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1.
Abstract: The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1 Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22 A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53 Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours Therapeutic candidate alterations were identified in most HNSCCs
2,997 citations
TL;DR: This briefer article should be read as an addendum to the previous full account on the management of hyperglycemia, which described the need to individualize both treatment targets and treatment strategies with an emphasis on patient-centered care and shared decision making.
Abstract: In 2012, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) published a position statement on the management of hyperglycemia in patients with type 2 diabetes (1,2). This was needed because of an increasing array of antihyperglycemic drugs and growing uncertainty regarding their proper selection and sequence. Because of a paucity of comparative effectiveness research on long-term treatment outcomes with many of these medications, the 2012 publication was less prescriptive than prior consensus reports. We previously described the need to individualize both treatment targets and treatment strategies, with an emphasis on patient-centered care and shared decision making, and this continues to be our position, although there are now more head-to-head trials that show slight variance between agents with regard to glucose-lowering effects. Nevertheless, these differences are often small and would be unlikely to reflect any definite differential effect in an individual patient.
The ADA and EASD have requested an update to the position statement incorporating new data from recent clinical trials. Between June and September of 2014, the Writing Group reconvened, including one face-to-face meeting, to discuss the changes. An entirely new statement was felt to be unnecessary. Instead, the group focused on those areas where revisions were suggested by a changing evidence base. This briefer article should therefore be read as an addendum to the previous full account (1,2).
Glucose control remains a major focus in the management of patients with type 2 diabetes. However, this should always be in the context of a comprehensive cardiovascular risk factor reduction program, to include smoking cessation and the adoption of other healthy lifestyle habits, blood pressure control, lipid management with priority to statin medications, and, in some circumstances, antiplatelet therapy. Studies have conclusively determined that reducing hyperglycemia decreases the onset and progression of …
2,553 citations
TL;DR: Increasing evidence in mouse models strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases.
Abstract: The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. They have been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research.
2,291 citations
TL;DR: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events.
Abstract: Background Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. Methods In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Results During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P Conclusions Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).
2,062 citations
TL;DR: This article conducted a meta-analysis of coronary artery disease (CAD) cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 millions low-frequency (0.005 < MAF < 0.5) variants.
Abstract: Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
1,839 citations
Huntsman Cancer Institute1, Rutgers University2, University of North Carolina at Chapel Hill3, University of Texas MD Anderson Cancer Center4, University of Louisville5, Emory University6, Lynn University7, University of California, San Diego8, Amgen9, Vanderbilt University10, Temple University11, University of Iowa Hospitals and Clinics12, University of Arizona13, University of Colorado Boulder14, Washington University in St. Louis15, The Royal Marsden NHS Foundation Trust16, National Institute for Health Research17, McGill University18
TL;DR: T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial and represents a novel potential therapy for patients with metastatic melanoma.
Abstract: Purpose Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1‐derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. Patients and Methods Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. Results Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in 2% of T-VEC‐treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred.
TL;DR: The continuous generation of monolithic polymeric parts up to tens of centimeters in size with feature resolution below 100 micrometers is demonstrated and critical control parameters are delineated and shown that complex solid parts can be drawn out of the resin at rates of hundreds of millimeters per hour.
Abstract: Additive manufacturing processes such as 3D printing use time-consuming, stepwise layer-by-layer approaches to object fabrication. We demonstrate the continuous generation of monolithic polymeric parts up to tens of centimeters in size with feature resolution below 100 micrometers. Continuous liquid interface production is achieved with an oxygen-permeable window below the ultraviolet image projection plane, which creates a "dead zone" (persistent liquid interface) where photopolymerization is inhibited between the window and the polymerizing part. We delineate critical control parameters and show that complex solid parts can be drawn out of the resin at rates of hundreds of millimeters per hour. These print speeds allow parts to be produced in minutes instead of hours.
TL;DR: This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts.
Abstract: Despite a century of research on complex traits in humans, the relative importance and specific nature of the influences of genes and environment on human traits remain controversial. We report a meta-analysis of twin correlations and reported variance components for 17,804 traits from 2,748 publications including 14,558,903 partly dependent twin pairs, virtually all published twin studies of complex traits. Estimates of heritability cluster strongly within functional domains, and across all traits the reported heritability is 49%. For a majority (69%) of traits, the observed twin correlations are consistent with a simple and parsimonious model where twin resemblance is solely due to additive genetic variation. The data are inconsistent with substantial influences from shared environment or non-additive genetic variation. This study provides the most comprehensive analysis of the causes of individual differences in human traits thus far and will guide future gene-mapping efforts. All the results can be visualized using the MaTCH webtool.
Harvard University1, Broad Institute2, Cardiff University3, Icahn School of Medicine at Mount Sinai4, University of Michigan5, University of Cambridge6, Karolinska Institutet7, University of Eastern Finland8, University of Oxford9, Cedars-Sinai Medical Center10, University of Ottawa11, University of Helsinki12, University of Pennsylvania13, University of North Carolina at Chapel Hill14, University of Mississippi Medical Center15
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
Abstract: Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) sequence data for 60,706 individuals of diverse ethnicities. The resulting catalogue of human genetic diversity has unprecedented resolution, with an average of one variant every eight bases of coding sequence and the presence of widespread mutational recurrence. The deep catalogue of variation provided by the Exome Aggregation Consortium (ExAC) can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 79% of which have no currently established human disease phenotype. Finally, we show that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human knockout variants in protein-coding genes.
University of Cologne1, Stanford University2, University of Ulsan3, Hanyang University4, Vancouver General Hospital5, University of Bonn6, University of North Carolina at Chapel Hill7, University of Rostock8, Epigenomics AG9, University of Tsukuba10, University Hospital Heidelberg11, Heidelberg University12, Schiller International University13, University of Zurich14, Vanderbilt University15, University of Belgrade16, Peter MacCallum Cancer Centre17, Casa Sollievo della Sofferenza18, University of Liverpool19, University of Zagreb20, Charité21, Oslo University Hospital22, VU University Medical Center23, Uppsala University24, Haukeland University Hospital25, Max Planck Society26, Memorial Sloan Kettering Cancer Center27, French Institute of Health and Medical Research28
TL;DR: This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
Abstract: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Δex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.
University of Lausanne1, Memorial Sloan Kettering Cancer Center2, University of North Carolina at Chapel Hill3, Rutgers University4, Harvard University5, University of Southern California6, Broad Institute7, Washington University in St. Louis8, Buck Institute for Research on Aging9, University of British Columbia10, Van Andel Institute11, The Chinese University of Hong Kong12, University of Utah13, Stanford University14, University of California, San Francisco15, United States Department of Veterans Affairs16, University of Pittsburgh17, University of Texas MD Anderson Cancer Center18, BC Cancer Agency19
TL;DR: This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options, suggesting differential modulation of ER activity in I LC and IDC.
TL;DR: By digitally separating tumor, stromal and normal gene expression, two tumor subtypes are identified and validated, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers.
Abstract: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal disease with a 5-year survival rate of 4%. A key hallmark of PDAC is extensive stromal involvement, which makes capturing precise tumor-specific molecular information difficult. Here we have overcome this problem by applying blind source separation to a diverse collection of PDAC gene expression microarray data, including data from primary tumor, metastatic and normal samples. By digitally separating tumor, stromal and normal gene expression, we have identified and validated two tumor subtypes, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers. Furthermore, we define 'normal' and 'activated' stromal subtypes, which are independently prognostic. Our results provide new insights into the molecular composition of PDAC, which may be used to tailor therapies or provide decision support in a clinical setting where the choice and timing of therapies are critical.
University of California, Los Angeles1, Vanderbilt University2, University of Zurich3, University of Duisburg-Essen4, University of Paris-Sud5, Harvard University6, Sheba Medical Center7, New York University8, University of Colorado Denver9, University of Arizona10, Netherlands Cancer Institute11, Durham University12, Seattle Cancer Care Alliance13, University of Tübingen14, University of Pennsylvania15, Temple University16, University of North Carolina at Chapel Hill17, University of Pittsburgh18, Memorial Sloan Kettering Cancer Center19, Merck & Co.20, University of California, San Francisco21
TL;DR: In this article, the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma were compared.
Abstract: Summary Background Patients with melanoma that progresses on ipilimumab and, if BRAF V600 mutant-positive, a BRAF or MEK inhibitor or both, have few treatment options. We assessed the efficacy and safety of two pembrolizumab doses versus investigator-choice chemotherapy in patients with ipilimumab-refractory melanoma. Methods We carried out a randomised phase 2 trial of patients aged 18 years or older from 73 hospitals, clinics, and academic medical centres in 12 countries who had confirmed progressive disease within 24 weeks after two or more ipilimumab doses and, if BRAF V600 mutant-positive, previous treatment with a BRAF or MEK inhibitor or both. Patients had to have resolution of all ipilimumab-related adverse events to grade 0–1 and prednisone 10 mg/day or less for at least 2 weeks, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and at least one measurable lesion to be eligible. Using a centralised interactive voice response system, we randomly assigned (1:1:1) patients in a block size of six to receive intravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide). Randomisation was stratified by ECOG performance status, lactate dehydrogenase concentration, and BRAF V600 mutation status. Individual treatment assignment between pembrolizumab and chemotherapy was open label, but investigators and patients were masked to assignment of the dose of pembrolizumab. We present the primary endpoint at the prespecified second interim analysis of progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01704287. The study is closed to enrolment but continues to follow up and treat patients. Findings Between Nov 30, 2012, and Nov 13, 2013, we enrolled 540 patients: 180 patients were randomly assigned to receive pembrolizumab 2 mg/kg, 181 to receive pembrolizumab 10 mg/kg, and 179 to receive chemotherapy. Based on 410 progression-free survival events, progression-free survival was improved in patients assigned to pembrolizumab 2 mg/kg (HR 0·57, 95% CI 0·45–0·73; p Interpretation These findings establish pembrolizumab as a new standard of care for the treatment of ipilimumab-refractory melanoma. Funding Merck Sharp & Dohme.
TL;DR: Although some associations between implicit bias and health care outcomes were nonsignificant, results showed that implicit bias was significantly related to patient-provider interactions, treatment decisions, treatment adherence, and patient health outcomes.
Abstract: Background. In the United States, people of color face disparities in access to health care, the quality of care received, and health outcomes. The attitudes and behaviors of health care providers have been identified as one of many factors that contribute to health disparities. Implicit attitudes are thoughts and feelings that often exist outside of conscious awareness, and thus are difficult to consciously acknowledge and control. These attitudes are often automatically activated and can influence human behavior without conscious volition.Objectives. We investigated the extent to which implicit racial/ethnic bias exists among health care professionals and examined the relationships between health care professionals’ implicit attitudes about racial/ethnic groups and health care outcomes.Search Methods. To identify relevant studies, we searched 10 computerized bibliographic databases and used a reference harvesting technique.Selection Criteria. We assessed eligibility using double independent screening ba...
TL;DR: A genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Abstract: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
Memorial Sloan Kettering Cancer Center1, Institut Gustave Roussy2, University of North Carolina at Chapel Hill3, Roswell Park Cancer Institute4, Vanderbilt University5, University of Rennes6, Ohio State University7, University of California, Davis8, Beth Israel Medical Center9, Lehigh Valley Hospital10, University Hospitals of Cleveland11, Providence Portland Medical Center12, University of Miami13, Ludwig Maximilian University of Munich14, Bristol-Myers Squibb15, Emory University16
TL;DR: Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer and these data support the assessment of nivolumsab in randomised, controlled, phase 3 studies of first-line and second-line treatment.
Abstract: Summary Background Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Methods We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Findings Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Interpretation Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Funding Bristol-Myers Squibb.
TL;DR: Six new EBPs were identified in this review, and one EBP from the previous review was removed, and the authors discuss implications for current practices and future research.
Abstract: The purpose of this study was to identify evidenced-based, focused intervention practices for children and youth with autism spectrum disorder. This study was an extension and elaboration of a previous evidence-based practice review reported by Odom et al. (Prev Sch Fail 54:275–282, 2010b, doi:
10.1080/10459881003785506
). In the current study, a computer search initially yielded 29,105 articles, and the subsequent screening and evaluation process found 456 studies to meet inclusion and methodological criteria. From this set of research studies, the authors found 27 focused intervention practices that met the criteria for evidence-based practice (EBP). Six new EBPs were identified in this review, and one EBP from the previous review was removed. The authors discuss implications for current practices and future research.
Fred Hutchinson Cancer Research Center1, University of Washington2, American Society of Clinical Oncology3, Cleveland Clinic4, University of British Columbia5, Pennsylvania State University6, Duke University7, Emory University8, University of Rochester9, University of North Carolina at Chapel Hill10, McMaster University11, University of Southern California12, University of California, San Francisco13, University of Michigan14
TL;DR: Current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer and oncology professionals should educate patients about the signs and symptoms of VTE.
Abstract: Purpose To provide current recommendations about the prophylaxis and treatment of venous thromboembolism (VTE) in patients with cancer.
TL;DR: ExoCAT provided significant neuroprotective effects in in vitro and in vivo models of PD and has a potential to be a versatile strategy to treat inflammatory and neurodegenerative disorders.
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TL;DR: This work presents a technique for adding global context to deep convolutional networks for semantic segmentation, and achieves state-of-the-art performance on SiftFlow and PASCAL-Context with small additional computational cost over baselines.
Abstract: We present a technique for adding global context to deep convolutional networks for semantic segmentation. The approach is simple, using the average feature for a layer to augment the features at each location. In addition, we study several idiosyncrasies of training, significantly increasing the performance of baseline networks (e.g. from FCN). When we add our proposed global feature, and a technique for learning normalization parameters, accuracy increases consistently even over our improved versions of the baselines. Our proposed approach, ParseNet, achieves state-of-the-art performance on SiftFlow and PASCAL-Context with small additional computational cost over baselines, and near current state-of-the-art performance on PASCAL VOC 2012 semantic segmentation with a simple approach. Code is available at this https URL .
TL;DR: A high prevalence of periodontitis in US adults aged ≥30 years is confirmed, with almost fifty-percent affected, and the prevalence was greater in non-Hispanic Asians than non- Hispanic whites, although lower than other minorities.
Abstract: Background: This report describes prevalence, severity, and extent of periodontitis in the US adult population using combined data from the 2009 to 2010 and 2011 to 2012 cycles of the National Health and Nutrition Examination Survey (NHANES).Methods: Estimates were derived for dentate adults, aged ≥30 years, from the US civilian non-institutionalized population. Periodontitis was defined by combinations of clinical attachment loss (AL) and periodontal probing depth (PD) from six sites per tooth on all teeth, except third molars, using standard surveillance case definitions. For the first time in NHANES history, sufficient numbers of non-Hispanic Asians were sampled in 2011 to 2012 to provide reliable estimates of their periodontitis prevalence.Results: In 2009 to 2012, 46% of US adults, representing 64.7 million people, had periodontitis, with 8.9% having severe periodontitis. Overall, 3.8% of all periodontal sites (10.6% of all teeth) had PD ≥4 mm, and 19.3% of sites (37.4% teeth) had AL ≥3 mm. Periodont...
Yeshiva University1, Harvard University2, Hamilton Health Sciences3, Sunnybrook Research Institute4, Loyola University Chicago5, University of Michigan6, Virginia Commonwealth University7, University of North Carolina at Chapel Hill8, Mayo Clinic9, University of Maryland, Baltimore10, Duke University11, National Institutes of Health12, Wake Forest University13, Indiana University14, Northwestern University15, Washington University in St. Louis16, Baylor College of Medicine17, Yonsei University18, Allegheny General Hospital19, Emory University20, University of Texas at San Antonio21, Vanderbilt University22, University of Pittsburgh23, Rutgers University24, Stanford University25, Indiana University – Purdue University Indianapolis26
TL;DR: In this article, a prospective trial involving women with hormone-receptor-positive, human epidermal growth factor receptor type 2 (HER2)-negative, axillary node-negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0cm in the intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features.
Abstract: BackgroundPrior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. MethodsWe performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-...
TL;DR: An overview of the miRNA pathway, including biogenesis routes, biological roles, and clinical approaches is presented, including clinical diagnostics and therapeutic targets.
TL;DR: The evidence reviewed indicated high interdevice reliability for steps, distance, energy expenditure, and sleep for certain Fitbit models, and consistency between the devices was high.
Abstract: Consumer-wearable activity trackers are electronic devices used for monitoring fitness- and other health-related metrics. The purpose of this systematic review was to summarize the evidence for validity and reliability of popular consumer-wearable activity trackers (Fitbit and Jawbone) and their ability to estimate steps, distance, physical activity, energy expenditure, and sleep. Searches included only full-length English language studies published in PubMed, Embase, SPORTDiscus, and Google Scholar through July 31, 2015. Two people reviewed and abstracted each included study. In total, 22 studies were included in the review (20 on adults, 2 on youth). For laboratory-based studies using step counting or accelerometer steps, the correlation with tracker-assessed steps was high for both Fitbit and Jawbone (Pearson or intraclass correlation coefficients (CC) > =0.80). Only one study assessed distance for the Fitbit, finding an over-estimate at slower speeds and under-estimate at faster speeds. Two field-based studies compared accelerometry-assessed physical activity to the trackers, with one study finding higher correlation (Spearman CC 0.86, Fitbit) while another study found a wide range in correlation (intraclass CC 0.36–0.70, Fitbit and Jawbone). Using several different comparison measures (indirect and direct calorimetry, accelerometry, self-report), energy expenditure was more often under-estimated by either tracker. Total sleep time and sleep efficiency were over-estimated and wake after sleep onset was under-estimated comparing metrics from polysomnography to either tracker using a normal mode setting. No studies of intradevice reliability were found. Interdevice reliability was reported on seven studies using the Fitbit, but none for the Jawbone. Walking- and running-based Fitbit trials indicated consistently high interdevice reliability for steps (Pearson and intraclass CC 0.76–1.00), distance (intraclass CC 0.90–0.99), and energy expenditure (Pearson and intraclass CC 0.71–0.97). When wearing two Fitbits while sleeping, consistency between the devices was high. This systematic review indicated higher validity of steps, few studies on distance and physical activity, and lower validity for energy expenditure and sleep. The evidence reviewed indicated high interdevice reliability for steps, distance, energy expenditure, and sleep for certain Fitbit models. As new activity trackers and features are introduced to the market, documentation of the measurement properties can guide their use in research settings.
TL;DR: A patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication, and a different variant is found that is determined to be pathogenic.
Abstract: On autopsy, a patient is found to have hypertrophic cardiomyopathy The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy on echocardiography Five years later, during a routine clinic visit of one of the genotype-positive family members, the cardiologist queries a database for current knowledge on the genetic variant and discovers that the variant is now interpreted as “likely benign” by another laboratory that uses more recently derived population-frequency data A newly available testing panel for additional genes that are implicated in hypertrophic cardiomyopathy is initiated on an affected family member, and a different variant is found that is determined to be pathogenic Family members are retested, and one member who previously tested negative is now found to be positive for this new variant An immediate clinical workup detects evidence of cardiomyopathy, and an intracardiac defibrillator is implanted to reduce the risk of sudden cardiac death