DOM Recent Discoveries

Subscribe to DOM Recent Discoveries feed NCBI pubmed

URL: https://eutils.ncbi.nlm.nih.gov/entrez/eutils/erss.cgi?rss_guid=1ZSp7ZOQTWbaf7UNhc_yGLkNMqadiJYLoEpLqIZGIwVtkz5EuX

Updated: 16 hours 9 min ago

Items Per Page:             

Complications of Proton Pump Inhibitor Therapy.

Related Articles

Complications of Proton Pump Inhibitor Therapy.

Gastroenterology. 2017 May 18;:

Authors: Vaezi MF, Yang YX, Howden CW

Abstract
Safety issues associated with proton pump inhibitors (PPIs) have recently attracted widespread media and lay attention. Gastroenterologists are frequently asked about the appropriateness of PPI therapy for specific patients. Furthermore, some patients may have had PPI therapy discontinued abruptly or inappropriately due to safety concerns. Faced with such a wide variety of potentially serious adverse consequences, prescribers need to evaluate the evidence objectively to discern the likelihood that any reported association might actually be causal. Here, we review many of the proposed adverse consequences of PPI therapy and apply established criteria for the determination of causation. We also consider the potential contribution of residual confounding in many of the reported studies. Evidence is inadequate to establish causal relationships between PPI therapy and many of the proposed associations. Residual confounding related to study design and the over-extrapolation of quantitatively small estimates of effect size have probably led to much of the current controversy about PPI safety. In turn, this has caused unnecessary concern among patients and prescribers. The benefits of PPI therapy for appropriate indications need to be considered along with the likelihood of the proposed risks. Patients with a proven indication for a PPI should continue to receive it in the lowest effective dose. PPI dose escalation and continued chronic therapy in those unresponsive to initial empiric therapy is discouraged.

PMID: 28528705 [PubMed - as supplied by publisher]

An endpoint associated with clinical benefit after initial treatment for chronic graft-versus-host disease.

Related Articles

An endpoint associated with clinical benefit after initial treatment for chronic graft-versus-host disease.

Blood. 2017 May 11;:

Authors: Martin PJ, Storer BE, Inamoto Y, Flowers MED, Carpenter PA, Pidala J, Palmer J, Arora M, Jagasia M, Arai S, Cutler C, Lee SJ

Abstract
No gold standard has been established as a primary endpoint in trials of initial treatment for chronic graft-versus-host disease (GVHD), and evidence showing the association of any proposed primary endpoint with clinical benefit has not been conclusively demonstrated. To address this gap, we analyzed outcomes in a cohort of 328 patients enrolled in a prospective, multicenter, observational study within 3 months after diagnosis of chronic GVHD. Complete and partial response, stable disease and progressive disease were defined according to the 2014 NIH Consensus Development Conference on Criteria for Clinical Trials in Chronic Graft-versus-host Disease. Success was defined as complete or partial response with no secondary systemic treatment or recurrent malignancy at 1 year after enrollment. Success was observed in less than 20% of the patients. The burden of disease manifestations at 1 year was lower for patients in this category than for those with stable or progressive disease. Systemic treatment ended earlier and subsequent mortality was lower among patients with complete or partial response than among those with stable or progressive disease and those who had received secondary systemic treatment. We conclude that survival with a complete or partial response and no previous secondary systemic treatment or recurrent malignancy at 1 year after initial systemic therapy is associated with clinical benefit, a critical characteristic for consideration as a primary endpoint in a pivotal clinical trial. This prospective observational study was registered at www.clinicaltrials.gov as #NCT00637689.

PMID: 28495794 [PubMed - as supplied by publisher]

A review of metabolomics approaches and their application in identifying causal pathways of childhood asthma.

Related Articles

A review of metabolomics approaches and their application in identifying causal pathways of childhood asthma.

J Allergy Clin Immunol. 2017 May 04;:

Authors: Turi KN, Romick-Rosendale L, Ryckman KK, Hartert TV

Abstract
As asthma is a disease that results from host x environment interactions, an approach which allows assessment of the impact of the environment on the host is needed to understand disease. Metabolomics has appealing potential as an application to study pathways to childhood asthma development. The objective of this review is to provide an overview of metabolomics methods, and their application to understanding host x environment pathways in asthma development. We reviewed recent literature on advances in metabolomics and their application to study pathways to childhood asthma development. We highlighted 1) the potential of metabolomics in understanding the pathogenesis of disease and the discovery of biomarkers, 2) choice of metabolomics techniques, biospecimen handling, and data analysis, 3) the application to studying the role of environment on asthma development, 4) review of metabolomics applied to the outcome of asthma, 5) recommendations for application of metabolomics based -omics data integration in understanding disease pathogenesis, and 6) limitations. In conclusion metabolomics allows use of biospecimens to identify useful biomarkers and pathways involved in disease development, and subsequently to inform a greater understanding of the disease pathogenesis and endotypes, and predicting the clinical course of childhood asthma phenotypes.

PMID: 28479327 [PubMed - as supplied by publisher]

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission.

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission.

J Clin Oncol. 2017 May 05;:JCO2017722157

Authors: Landsburg DJ, Falkiewicz MK, Maly J, Blum KA, Howlett C, Feldman T, Mato AR, Hill BT, Li S, Medeiros LJ, Torka P, Hernandez-Ilizaliturri F, Reddy NM, Singavi A, Fenske TS, Chavez JC, Kaplan JB, Behdad A, Petrich AM, Bast MA, Vose JM, Olszewski AJ, Costa C, Lansigan F, Gerson JN, Barta SK, Calzada O, Cohen JB, Lue JK, Amengual JE, Rivera X, Persky DO, Peace DJ, Nathan S, Cassaday RD

Abstract
Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

PMID: 28475457 [PubMed - as supplied by publisher]

PD-1 blockade for relapsed lymphoma post allogeneic hematopoietic cell transplant: high response rate but frequent GVHD.

Related Articles

PD-1 blockade for relapsed lymphoma post allogeneic hematopoietic cell transplant: high response rate but frequent GVHD.

Blood. 2017 May 03;:

Authors: Haverkos BM, Abbott D, Hamadani M, Armand P, Flowers ME, Merryman R, Kamdar M, Kanate AS, Saad A, Mehta A, Ganguly S, Fenske TS, Hari P, Lowsky R, Andritsos L, Jagasia M, Bashey A, Brown S, Bachanova V, Stephens D, Mineishi S, Nakamura R, Chen YB, Blazar BR, Gutman J, Devine SM

Abstract
Given the limited treatment options for relapsed lymphoma post allogeneic hematopoietic cell transplantation (allo-HCT) and the success of PD-1 blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label following allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post allo-HCT and prior to anti-PD-1. Median follow up was 428 days (range 133-833) after the first dose of anti-PD-1. Overall response rate (ORR) was 77% (15 complete response (CR) and 8 partial responses) in 30 evaluable patients. At last follow up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive with 8 (26%) deaths related to new onset GVHD after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment refractory GVHD. PD-1 blockade post allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.

PMID: 28468799 [PubMed - as supplied by publisher]

Loss of Cardio-Protective Effects at the ADAMTS7 Locus Due to Gene-Smoking Interactions.

Related Articles

Loss of Cardio-Protective Effects at the ADAMTS7 Locus Due to Gene-Smoking Interactions.

Circulation. 2017 May 01;:

Authors: Saleheen D, Zhao W, Young R, Nelson CP, Ho WK, Ferguson JF, Rasheed A, Ou K, Nurnberg ST, Bauer RC, Goel A, Do R, Stewart AFR, Hartiala J, Zhang W, Thorleifsson G, Strawbridge RJ, Sinisalo J, Kanoni S, Sedaghat S, Marouli E, Kristiansson K, Zhao JH, Scott R, Gauguier D, Shah SH, Smith AV, Van Zuydam N, Cox AJ, Willenborg C, Kessler T, Zeng L, Province MA, Ganna A, Lind L, Pedersen NL, White CC, Joensuu A, Kleber ME, Hall AS, März W, Salomaa V, O'Donnell C, Ingelsson E, Feitosa MF, Erdmann J, Bowden DW, Palmer CNA, Gudnason V, de Faire U, Zalloua P, Wareham N, Thompson JR, Kuulasmaa K, Dedoussis G, Perola M, Dehghan A, Chambers JC, Kooner J, Allayee H, Deloukas P, McPherson R, Stefansson K, Schunkert H, Kathiresan S, Farrall M, Frossard PM, Rader DJ, Samani N, Reilly MP, EPIC-CVD, PROMIS, CARDIoGRAMplusC4D

Abstract
Background -Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-environment interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. Methods -We analyzed data on 60,919 CHD cases and 80,243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to associate with CHD risk. We also studied 5 loci associated with smoking behavior. Study specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P-value< 1.0x10(-3) (Bonferroni correction for 50 tests). Results -We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P-value: 1.3x10(-16)) compared to 5% in ever-smokers (P-value: 2.5x10(-4)) translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (Interaction P-value: 8.7x10(-5)). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7Conclusions -Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in "never-smokers" compared to "ever-smokers". Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

PMID: 28461624 [PubMed - as supplied by publisher]

Genetic Risk Prediction of Atrial Fibrillation.

Related Articles

Genetic Risk Prediction of Atrial Fibrillation.

Circulation. 2017 Apr 04;135(14):1311-1320

Authors: Lubitz SA, Yin X, Lin HJ, Kolek M, Smith JG, Trompet S, Rienstra M, Rost NS, Teixeira PL, Almgren P, Anderson CD, Chen LY, Engström G, Ford I, Furie KL, Guo X, Larson MG, Lunetta KL, Macfarlane PW, Psaty BM, Soliman EZ, Sotoodehnia N, Stott DJ, Taylor KD, Weng LC, Yao J, Geelhoed B, Verweij N, Siland JE, Kathiresan S, Roselli C, Roden DM, van der Harst P, Darbar D, Jukema JW, Melander O, Rosand J, Rotter JI, Heckbert SR, Ellinor PT, Alonso A, Benjamin EJ, AFGen Consortium

Abstract
BACKGROUND: Atrial fibrillation (AF) has a substantial genetic basis. Identification of individuals at greatest AF risk could minimize the incidence of cardioembolic stroke.
METHODS: To determine whether genetic data can stratify risk for development of AF, we examined associations between AF genetic risk scores and incident AF in 5 prospective studies comprising 18 919 individuals of European ancestry. We examined associations between AF genetic risk scores and ischemic stroke in a separate study of 509 ischemic stroke cases (202 cardioembolic [40%]) and 3028 referents. Scores were based on 11 to 719 common variants (≥5%) associated with AF at P values ranging from <1×10(-3) to <1×10(-8) in a prior independent genetic association study.
RESULTS: Incident AF occurred in 1032 individuals (5.5%). AF genetic risk scores were associated with new-onset AF after adjustment for clinical risk factors. The pooled hazard ratio for incident AF for the highest versus lowest quartile of genetic risk scores ranged from 1.28 (719 variants; 95% confidence interval, 1.13-1.46; P=1.5×10(-4)) to 1.67 (25 variants; 95% confidence interval, 1.47-1.90; P=9.3×10(-15)). Discrimination of combined clinical and genetic risk scores varied across studies and scores (maximum C statistic, 0.629-0.811; maximum ΔC statistic from clinical score alone, 0.009-0.017). AF genetic risk was associated with stroke in age- and sex-adjusted models. For example, individuals in the highest versus lowest quartile of a 127-variant score had a 2.49-fold increased odds of cardioembolic stroke (95% confidence interval, 1.39-4.58; P=2.7×10(-3)). The effect persisted after the exclusion of individuals (n=70) with known AF (odds ratio, 2.25; 95% confidence interval, 1.20-4.40; P=0.01).
CONCLUSIONS: Comprehensive AF genetic risk scores were associated with incident AF beyond associations for clinical AF risk factors but offered small improvements in discrimination. AF genetic risk was also associated with cardioembolic stroke in age- and sex-adjusted analyses. Efforts are warranted to determine whether AF genetic risk may improve identification of subclinical AF or help distinguish between stroke mechanisms.

PMID: 27793994 [PubMed - indexed for MEDLINE]

Innate and adaptive immunity shape circulating HCV strains.

Related Articles

Innate and adaptive immunity shape circulating HCV strains.

Nat Genet. 2017 Apr 26;49(5):657-658

Authors: Gaudieri S, Lucas M

Abstract
An unbiased genome-to-genome analysis in chronic hepatitis C virus (HCV) infection confirms the innate and adaptive arms of the immune system as drivers of viral evolution. Viral adaptation has a critical role in the interaction between host and pathogen and has important clinical implications for infection outcome.

PMID: 28442794 [PubMed - in process]

Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis.

Related Articles

Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis.

Proc Natl Acad Sci U S A. 2017 Apr 18;:

Authors: Kulkarni S, Micci MA, Leser J, Shin C, Tang SC, Fu YY, Liu L, Li Q, Saha M, Li C, Enikolopov G, Becker L, Rakhilin N, Anderson M, Shen X, Dong X, Butte MJ, Song H, Southard-Smith EM, Kapur RP, Bogunovic M, Pasricha PJ

Abstract
According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.

PMID: 28420791 [PubMed - as supplied by publisher]

Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.

Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.

N Engl J Med. 2017 Apr 05;:

Authors: Beigneux AP, Miyashita K, Ploug M, Blom DJ, Ai M, Linton MF, Khovidhunkit W, Dufour R, Garg A, McMahon MA, Pullinger CR, Sandoval NP, Hu X, Allan CM, Larsson M, Machida T, Murakami M, Reue K, Tontonoz P, Goldberg IJ, Moulin P, Charrière S, Fong LG, Nakajima K, Young SG

Abstract
Background A protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies. Methods Using a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1. Results We identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents. Conclusions In six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).

PMID: 28402248 [PubMed - as supplied by publisher]

Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial.

Related Articles

Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial.

Blood. 2017 Apr 07;:

Authors: Taub JW, Berman JN, Hitzler JK, Sorrell AD, Lacayo NJ, Mast K, Head D, Raimondi S, Hirsch B, Ge Y, Gerbing RB, Wang YC, Alonzo TA, Campana D, Coustan-Smith E, Mathew P, Gamis AS

Abstract
Patients with myeloid leukemia of Down syndrome (ML-DS) have a favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of Induction and 2 cycles of Intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second Induction cycle instead of the Intensification cycle and one of four daunorubicin containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of Induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n=125) was 92.7% versus 76.2% for MRD-positive patients (n=21) (log-rank P =0.011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. The trial was registered at https://clinicaltrials.gov/ as NCT00369317.

PMID: 28389462 [PubMed - as supplied by publisher]

A Multimodality Strategy for Cardiovascular Risk Assessment: Performance in Two Population-Based Cohorts.

Related Articles

A Multimodality Strategy for Cardiovascular Risk Assessment: Performance in Two Population-Based Cohorts.

Circulation. 2017 Mar 30;:

Authors: de Lemos JA, Ayers CR, Levine BD, deFilippi CR, Wang TJ, Hundley WG, Berry JD, Seliger SL, McGuire DK, Ouyang P, Drazner MH, Budoff MJ, Greenland P, Ballantyne CM, Khera A

Abstract
Background -Current strategies for cardiovascular disease (CVD) risk assessment among adults without known CVD are limited by suboptimal performance and a narrow focus on only atherosclerotic CVD (ASCVD). We hypothesized that a strategy combining promising biomarkers across multiple different testing modalities would improve global and atherosclerotic CVD risk assessment among individuals without known CVD. Methods -We included participants from the Multi-Ethnic Study of Atherosclerosis (MESA, n=6621) and Dallas Heart Study (DHS, n=2202) who were free from CVD and underwent measurement of left ventricular hypertrophy by electrocardiogram (ECG-LVH), coronary artery calcium (CAC), N-terminal pro B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity C-reactive protein (hs-CRP). Associations of test results with the global composite CVD outcome (CVD death, myocardial infarction [MI], stroke, coronary or peripheral revascularization, incident heart failure or atrial fibrillation) and ASCVD (fatal or nonfatal MI or stroke) were assessed over > 10 years of follow-up. Multivariable analyses for the primary global CVD endpoint adjusted for traditional risk factors plus statin use and creatinine (base model). Results -Each test result was independently associated with global composite CVD events in MESA after adjustment for the components of the base model and the other test results (p< 0.05 for each). When the five tests were added to the base model, the c-statistic improved from 0.74 to 0.79 (p=0.001), significant integrated discrimination improvement (0.07, 95% CI 0.06-0.08, p<0.001) and net reclassification improvement (0.47, 95% CI 0.38-0.56, p=0.003) were observed, and the model was well calibrated (χ2=12.2, p=0.20). Using a simple integer score counting the number of abnormal tests, compared with those with a score of 0, global CVD risk was increased among participants with a score of 1 (adjusted HR 1.9, 95% CI 1.4-2.6), 2 (HR 3.2, 95% CI 2.3-4.4), 3 (HR 4.7, 95% CI 3.4, 6.5) and ≥4 (HR 7.5, 95% CI 5.2-10.6). Findings replicated in DHS and were similar for the ASCVD outcome. Conclusions -Among adults without known CVD, a novel multimodality testing strategy using ECG-LVH, CAC, NT-proBNP, hs-cTnT and hs-CRP significantly improved global CVD and ASCVD risk assessment.

PMID: 28360032 [PubMed - as supplied by publisher]

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

Nat Genet. 2017 Mar 27;:

Authors: Phelan CM, Kuchenbaecker KB, Tyrer JP, Kar SP, Lawrenson K, Winham SJ, Dennis J, Pirie A, Riggan MJ, Chornokur G, Earp MA, Lyra PC, Lee JM, Coetzee S, Beesley J, McGuffog L, Soucy P, Dicks E, Lee A, Barrowdale D, Lecarpentier J, Leslie G, Aalfs CM, Aben KK, Adams M, Adlard J, Andrulis IL, Anton-Culver H, Antonenkova N, AOCS study group, Aravantinos G, Arnold N, Arun BK, Arver B, Azzollini J, Balmaña J, Banerjee SN, Barjhoux L, Barkardottir RB, Bean Y, Beckmann MW, Beeghly-Fadiel A, Benitez J, Bermisheva M, Bernardini MQ, Birrer MJ, Bjorge L, Black A, Blankstein K, Blok MJ, Bodelon C, Bogdanova N, Bojesen A, Bonanni B, Borg Å, Bradbury AR, Brenton JD, Brewer C, Brinton L, Broberg P, Brooks-Wilson A, Bruinsma F, Brunet J, Buecher B, Butzow R, Buys SS, Caldes T, Caligo MA, Campbell I, Cannioto R, Carney ME, Cescon T, Chan SB, Chang-Claude J, Chanock S, Chen XQ, Chiew YE, Chiquette J, Chung WK, Claes KB, Conner T, Cook LS, Cook J, Cramer DW, Cunningham JM, D'Aloisio AA, Daly MB, Damiola F, Damirovna SD, Dansonka-Mieszkowska A, Dao F, Davidson R, DeFazio A, Delnatte C, Doheny KF, Diez O, Ding YC, Doherty JA, Domchek SM, Dorfling CM, Dörk T, Dossus L, Duran M, Dürst M, Dworniczak B, Eccles D, Edwards T, Eeles R, Eilber U, Ejlertsen B, Ekici AB, Ellis S, Elvira M, EMBRACE Study, Eng KH, Engel C, Evans DG, Fasching PA, Ferguson S, Ferrer SF, Flanagan JM, Fogarty ZC, Fortner RT, Fostira F, Foulkes WD, Fountzilas G, Fridley BL, Friebel TM, Friedman E, Frost D, Ganz PA, Garber J, García MJ, Garcia-Barberan V, Gehrig A, GEMO Study Collaborators, Gentry-Maharaj A, Gerdes AM, Giles GG, Glasspool R, Glendon G, Godwin AK, Goldgar DE, Goranova T, Gore M, Greene MH, Gronwald J, Gruber S, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hansen TV, Harrington PA, Harris HR, Hauke J, HEBON Study, Hein A, Henderson A, Hildebrandt MA, Hillemanns P, Hodgson S, Høgdall CK, Høgdall E, Hogervorst FB, Holland H, Hooning MJ, Hosking K, Huang RY, Hulick PJ, Hung J, Hunter DJ, Huntsman DG, Huzarski T, Imyanitov EN, Isaacs C, Iversen ES, Izatt L, Izquierdo A, Jakubowska A, James P, Janavicius R, Jernetz M, Jensen A, Jensen UB, John EM, Johnatty S, Jones ME, Kannisto P, Karlan BY, Karnezis A, Kast K, KConFab Investigators, Kennedy CJ, Khusnutdinova E, Kiemeney LA, Kiiski JI, Kim SW, Kjaer SK, Köbel M, Kopperud RK, Kruse TA, Kupryjanczyk J, Kwong A, Laitman Y, Lambrechts D, Larrañaga N, Larson MC, Lazaro C, Le ND, Le Marchand L, Lee JW, Lele SB, Leminen A, Leroux D, Lester J, Lesueur F, Levine DA, Liang D, Liebrich C, Lilyquist J, Lipworth L, Lissowska J, Lu KH, Lubinński J, Luccarini C, Lundvall L, Mai PL, Mendoza-Fandiño G, Manoukian S, Massuger LF, May T, Mazoyer S, McAlpine JN, McGuire V, McLaughlin JR, McNeish I, Meijers-Heijboer H, Meindl A, Menon U, Mensenkamp AR, Merritt MA, Milne RL, Mitchell G, Modugno F, Moes-Sosnowska J, Moffitt M, Montagna M, Moysich KB, Mulligan AM, Musinsky J, Nathanson KL, Nedergaard L, Ness RB, Neuhausen SL, Nevanlinna H, Niederacher D, Nussbaum RL, Odunsi K, Olah E, Olopade OI, Olsson H, Olswold C, O'Malley DM, Ong KR, Onland-Moret NC, OPAL study group, Orr N, Orsulic S, Osorio A, Palli D, Papi L, Park-Simon TW, Paul J, Pearce CL, Pedersen IS, Peeters PH, Peissel B, Peixoto A, Pejovic T, Pelttari LM, Permuth JB, Peterlongo P, Pezzani L, Pfeiler G, Phillips KA, Piedmonte M, Pike MC, Piskorz AM, Poblete SR, Pocza T, Poole EM, Poppe B, Porteous ME, Prieur F, Prokofyeva D, Pugh E, Pujana MA, Pujol P, Radice P, Rantala J, Rappaport-Fuerhauser C, Rennert G, Rhiem K, Rice P, Richardson A, Robson M, Rodriguez GC, Rodríguez-Antona C, Romm J, Rookus MA, Rossing MA, Rothstein JH, Rudolph A, Runnebaum IB, Salvesen HB, Sandler DP, Schoemaker MJ, Senter L, Setiawan VW, Severi G, Sharma P, Shelford T, Siddiqui N, Side LE, Sieh W, Singer CF, Sobol H, Song H, Southey MC, Spurdle AB, Stadler Z, Steinemann D, Stoppa-Lyonnet D, Sucheston-Campbell LE, Sukiennicki G, Sutphen R, Sutter C, Swerdlow AJ, Szabo CI, Szafron L, Tan YY, Taylor JA, Tea MK, Teixeira MR, Teo SH, Terry KL, Thompson PJ, Thomsen LC, Thull DL, Tihomirova L, Tinker AV, Tischkowitz M, Tognazzo S, Toland AE, Tone A, Trabert B, Travis RC, Trichopoulou A, Tung N, Tworoger SS, van Altena AM, Van Den Berg D, van der Hout AH, van der Luijt RB, Van Heetvelde M, Van Nieuwenhuysen E, van Rensburg EJ, Vanderstichele A, Varon-Mateeva R, Vega A, Edwards DV, Vergote I, Vierkant RA, Vijai J, Vratimos A, Walker L, Walsh C, Wand D, Wang-Gohrke S, Wappenschmidt B, Webb PM, Weinberg CR, Weitzel JN, Wentzensen N, Whittemore AS, Wijnen JT, Wilkens LR, Wolk A, Woo M, Wu X, Wu AH, Yang H, Yannoukakos D, Ziogas A, Zorn KK, Narod SA, Easton DF, Amos CI, Schildkraut JM, Ramus SJ, Ottini L, Goodman MT, Park SK, Kelemen LE, Risch HA, Thomassen M, Offit K, Simard J, Schmutzler RK, Hazelett D, Monteiro AN, Couch FJ, Berchuck A, Chenevix-Trench G, Goode EL, Sellers TA, Gayther SA, Antoniou AC, Pharoah PD

Abstract
To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC.

PMID: 28346442 [PubMed - as supplied by publisher]

Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.

Related Articles

Bedside Back to Bench: Building Bridges between Basic and Clinical Genomic Research.

Cell. 2017 Mar 23;169(1):6-12

Authors: Manolio TA, Fowler DM, Starita LM, Haendel MA, MacArthur DG, Biesecker LG, Worthey E, Chisholm RL, Green ED, Jacob HJ, McLeod HL, Roden D, Rodriguez LL, Williams MS, Cooper GM, Cox NJ, Herman GE, Kingsmore S, Lo C, Lutz C, MacRae CA, Nussbaum RL, Ordovas JM, Ramos EM, Robinson PN, Rubinstein WS, Seidman C, Stranger BE, Wang H, Westerfield M, Bult C

Abstract
Genome sequencing has revolutionized the diagnosis of genetic diseases. Close collaborations between basic scientists and clinical genomicists are now needed to link genetic variants with disease causation. To facilitate such collaborations, we recommend prioritizing clinically relevant genes for functional studies, developing reference variant-phenotype databases, adopting phenotype description standards, and promoting data sharing.

PMID: 28340351 [PubMed - in process]

Cardiovascular Outcomes With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure: The CAT-HF Trial.

Related Articles

Cardiovascular Outcomes With Minute Ventilation-Targeted Adaptive Servo-Ventilation Therapy in Heart Failure: The CAT-HF Trial.

J Am Coll Cardiol. 2017 Mar 28;69(12):1577-1587

Authors: O'Connor CM, Whellan DJ, Fiuzat M, Punjabi NM, Tasissa G, Anstrom KJ, Benjafield AV, Woehrle H, Blase AB, Lindenfeld J, Oldenberg O

Abstract
BACKGROUND: Sleep apnea is common in hospitalized heart failure (HF) patients and is associated with increased morbidity and mortality.
OBJECTIVES: The CAT-HF (Cardiovascular Improvements With MV-ASV Therapy in Heart Failure) trial investigated whether minute ventilation (MV) adaptive servo-ventilation (ASV) improved cardiovascular outcomes in hospitalized HF patients with moderate-to-severe sleep apnea.
METHODS: Eligible patients hospitalized with HF and moderate-to-severe sleep apnea were randomized to ASV plus optimized medical therapy (OMT) or OMT alone (control). The primary endpoint was a composite global rank score (hierarchy of death, cardiovascular hospitalizations, and percent changes in 6-min walk distance) at 6 months.
RESULTS: 126 of 215 planned patients were randomized; enrollment was stopped early following release of the SERVE-HF (Adaptive Servo-Ventilation for Central Sleep Apnea in Systolic Heart Failure) trial results. Average device usage was 2.7 h/night. Mean number of events measured by the apnea-hypopnea index decreased from 35.7/h to 2.1/h at 6 months in the ASV group versus 35.1/h to 19.0/h in the control group (p < 0.0001). The primary endpoint did not differ significantly between the ASV and control groups (p = 0.92 Wilcoxon). Changes in composite endpoint components were not significantly different between ASV and control. There was no significant interaction between treatment and ejection fraction (p = 0.10 Cox model); however, pre-specified subgroup analysis suggested a positive effect of ASV in patients with HF with preserved ejection fraction (p = 0.036).
CONCLUSIONS: In hospitalized HF patients with moderate-to-severe sleep apnea, adding ASV to OMT did not improve 6-month cardiovascular outcomes. Study power was limited for detection of safety signals and identifying differential effects of ASV in patients with HF with preserved ejection fraction, but additional studies are warranted in this population. (Cardiovascular Improvements With MV ASV Therapy in Heart Failure [CAT-HF]; NCT01953874).

PMID: 28335841 [PubMed - in process]

Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans.

Related Articles

Apolipoprotein L1 Variants and Blood Pressure Traits in African Americans.

J Am Coll Cardiol. 2017 Mar 28;69(12):1564-1574

Authors: Nadkarni GN, Galarneau G, Ellis SB, Nadukuru R, Zhang J, Scott SA, Schurmann C, Li R, Rasmussen-Torvik LJ, Kho AN, Hayes MG, Pacheco JA, Manolio TA, Chisholm RL, Roden DM, Denny JC, Kenny EE, Bottinger EP

Abstract
BACKGROUND: African Americans (AA) are disproportionately affected by hypertension-related health disparities. Apolipoprotein L1 (APOL1) risk variants are associated with kidney disease in hypertensive AAs.
OBJECTIVES: This study assessed the APOL1 risk alleles' association with blood pressure traits in AAs.
METHODS: The discovery cohort included 5,204 AA participants from Mount Sinai's BioMe biobank. Replication cohorts included additional BioMe (n = 1,623), Vanderbilt BioVU (n = 1,809), and Northwestern NUgene (n = 567) AA biobank participants. Single nucleotide polymorphisms determining APOL1 G1 and G2 risk alleles were genotyped in BioMe and imputed in BioVU/NUgene participants. APOL1 risk alleles' association with blood pressure-related traits was tested in the discovery cohort, a meta-analysis of replication cohorts, and a combined meta-analysis under recessive and additive models after adjusting for age, sex, body mass index, and estimated glomerular filtration rate.
RESULTS: There were 14% to 16% of APOL1 variant allele homozygotes (2 copies of G1/G2) across cohorts. APOL1 risk alleles were associated under an additive model with systolic blood pressure (SBP) and age at diagnosis of hypertension, which was 2 to 5 years younger in the APOL1 variant allele homozygotes (Cox proportional hazards analysis, p value for combined meta-analysis [pcom] = 1.9 × 10(-5)). APOL1 risk alleles were associated with overall SBP (pcom = 7.0 × 10(-8)) and diastolic blood pressure (pcom = 2.8 × 10(-4)). After adjustment for all covariates, those in the 20- to 29-year age range showed an increase in SBP of 0.94 ± 0.44 mm Hg (pcom = 0.01) per risk variant copy. APOL1-associated estimated glomerular filtration rate decline was observed starting a decade later in life in the 30- to 39-year age range.
CONCLUSIONS: APOL1 risk alleles are associated with higher SBP and earlier hypertension diagnoses in young AAs; this relationship appears to follow an additive model.

PMID: 28335839 [PubMed - in process]