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Recent Discoveries


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Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding.

Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding.

JAMA. 2018 Dec 04;320(21):2221-2230

Authors: Ray WA, Chung CP, Murray KT, Smalley WE, Daugherty JR, Dupont WD, Stein CM

Abstract
Importance: Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment.
Objectives: To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk.
Design, Setting, and Participants: Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015.
Exposures: Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy.
Main Outcomes and Measures: Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10 000 person-years of anticoagulant treatment, incidence rate ratios (IRRs).
Results: There were 1 643 123 patients with 1 713 183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651 427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870 330 person-years [74.9%]). During 754 389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n = 7119) was 115 per 10 000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n = 1278) was 144 per 10 000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n = 279; 73 per 10 000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n = 629; 120 per 10 000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n = 4933; 113 per 10 000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, -47.5 [95% CI,-60.6 to -34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, -40.5 [95% CI, -50.0 to -31.0]). When anticoagulant treatment with PPI cotherapy (264 447 person-years; 76 per 10 000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n = 2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, -24 [95% CI, -38 to -11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, -61.1 [95% CI, -74.8 to -47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, -35.5 [95% CI, -48.6 to -22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, -39.3 [95% CI, -44.5 to -34.2]).
Conclusions and Relevance: Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

PMID: 30512099 [PubMed - in process]

ACC/AHA Versus ESC Guidelines for Diagnosis and Management of Peripheral Artery Disease: JACC Guideline Comparison.

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ACC/AHA Versus ESC Guidelines for Diagnosis and Management of Peripheral Artery Disease: JACC Guideline Comparison.

J Am Coll Cardiol. 2018 Dec 04;72(22):2789-2801

Authors: Kithcart AP, Beckman JA

Abstract
Peripheral artery disease is a common yet underdiagnosed cause of morbidity worldwide. Significant recent advances in management have resulted in new guideline creation for the diagnosis and management of peripheral artery disease in the United States and Europe. Here, we analyze each set of guidelines with special attention to those areas where the 2 groups disagree. Both groups emphasize the importance of risk factor reduction, including smoking cessation, lipid lowering, blood pressure management, and glucose control. The U.S. guidelines place additional attention on lifestyle factors, including regular physical activity and supervised exercise. The European guidelines offer a number of recommendations for revascularization in patients with limb-threatening ischemia. Both agree that more evidence is needed to understand which patients are at highest risk for tissue loss. A consistent charge to each committee fostering a similar approach to available data and more randomized studies would align recommendations across both organizations.

PMID: 30497565 [PubMed - in process]

Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.

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Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.

J Clin Invest. 2018 Dec 03;:

Authors: Haliyur R, Tong X, Sanyoura M, Shrestha S, Lindner J, Saunders DC, Aramandla R, Poffenberger G, Redick SD, Bottino R, Prasad N, Levy SE, Blind RD, Harlan DM, Philipson LH, Stein RW, Brissova M, Powers AC

Abstract
Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.

PMID: 30507613 [PubMed - as supplied by publisher]

Discovery of common and rare genetic risk variants for colorectal cancer.

Discovery of common and rare genetic risk variants for colorectal cancer.

Nat Genet. 2018 Dec 03;:

Authors: Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, Conti DV, Qu C, Jeon J, Edlund CK, Greenside P, Wainberg M, Schumacher FR, Smith JD, Levine DM, Nelson SC, Sinnott-Armstrong NA, Albanes D, Alonso MH, Anderson K, Arnau-Collell C, Arndt V, Bamia C, Banbury BL, Baron JA, Berndt SI, Bézieau S, Bishop DT, Boehm J, Boeing H, Brenner H, Brezina S, Buch S, Buchanan DD, Burnett-Hartman A, Butterbach K, Caan BJ, Campbell PT, Carlson CS, Castellví-Bel S, Chan AT, Chang-Claude J, Chanock SJ, Chirlaque MD, Cho SH, Connolly CM, Cross AJ, Cuk K, Curtis KR, de la Chapelle A, Doheny KF, Duggan D, Easton DF, Elias SG, Elliott F, English DR, Feskens EJM, Figueiredo JC, Fischer R, FitzGerald LM, Forman D, Gala M, Gallinger S, Gauderman WJ, Giles GG, Gillanders E, Gong J, Goodman PJ, Grady WM, Grove JS, Gsur A, Gunter MJ, Haile RW, Hampe J, Hampel H, Harlid S, Hayes RB, Hofer P, Hoffmeister M, Hopper JL, Hsu WL, Huang WY, Hudson TJ, Hunter DJ, Ibañez-Sanz G, Idos GE, Ingersoll R, Jackson RD, Jacobs EJ, Jenkins MA, Joshi AD, Joshu CE, Keku TO, Key TJ, Kim HR, Kobayashi E, Kolonel LN, Kooperberg C, Kühn T, Küry S, Kweon SS, Larsson SC, Laurie CA, Le Marchand L, Leal SM, Lee SC, Lejbkowicz F, Lemire M, Li CI, Li L, Lieb W, Lin Y, Lindblom A, Lindor NM, Ling H, Louie TL, Männistö S, Markowitz SD, Martín V, Masala G, McNeil CE, Melas M, Milne RL, Moreno L, Murphy N, Myte R, Naccarati A, Newcomb PA, Offit K, Ogino S, Onland-Moret NC, Pardini B, Parfrey PS, Pearlman R, Perduca V, Pharoah PDP, Pinchev M, Platz EA, Prentice RL, Pugh E, Raskin L, Rennert G, Rennert HS, Riboli E, Rodríguez-Barranco M, Romm J, Sakoda LC, Schafmayer C, Schoen RE, Seminara D, Shah M, Shelford T, Shin MH, Shulman K, Sieri S, Slattery ML, Southey MC, Stadler ZK, Stegmaier C, Su YR, Tangen CM, Thibodeau SN, Thomas DC, Thomas SS, Toland AE, Trichopoulou A, Ulrich CM, Van Den Berg DJ, van Duijnhoven FJB, Van Guelpen B, van Kranen H, Vijai J, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Weigl K, Weinstein SJ, White E, Win AK, Wolf CR, Wolk A, Woods MO, Wu AH, Zaidi SH, Zanke BW, Zhang Q, Zheng W, Scacheri PC, Potter JD, Bassik MC, Kundaje A, Casey G, Moreno V, Abecasis GR, Nickerson DA, Gruber SB, Hsu L, Peters U

Abstract
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

PMID: 30510241 [PubMed - as supplied by publisher]

Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis.

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Integrated Analysis of Mouse and Human Gastric Neoplasms Identifies Conserved microRNA Networks in Gastric Carcinogenesis.

Gastroenterology. 2018 Nov 28;:

Authors: Chen Z, Li Z, Soutto M, Wang W, Piazuelo MB, Zhu S, Guo Y, Maturana MJ, Corvalan AH, Chen X, Xu Z, El-Rifai WM

Abstract
BACKGROUND & AIMS: microRNAs (miRNAs) are small non-coding RNAs that bind to 3'UTR regions of mRNAs to promote their degradation or block their translation. Mice with disruption of the trefoil factor 1 gene (Tff1) develop gastric neoplasms. We studied these mice to identify conserved miRNA networks involved in gastric carcinogenesis.
METHODS: We performed next-generation miRNA sequencing analysis of normal gastric tissues (based on histology) from subjects without evidence of gastric neoplasm from patients (n=64) and TFF1-knockout mice (n=22). We validated our findings using 270 normal gastric tissues (including 61 samples from patients without evidence of neoplastic lesions) and 234 gastric tumor tissues from 3 separate cohorts of patients and from mice. We performed molecular and functional assays using cell lines (MKN28, MKN45, STKM2, and AGS cells), gastric organoids, and mice with xenograft tumors.
RESULTS: We identified 117 miRNAs that were significantly deregulated in mouse and human gastric tumor tissues, compared with non-tumor tissues. We validated changes in levels of 6 miRNAs by quantitative real-time PCR analyses of neoplastic gastric tissues from mice (n=39) and 3 independent cohorts patients (332 patients total). We found levels of MIR135B-5p, MIR196B-5p, and MIR92A-5p to be increased in tumor tissues whereas levels of MIR143-3p, MIR204-5p, and MIR133-3p were decreased in tumor tissues. Levels of MIR143-3p were reduced not only in gastric cancer tissues, but also in normal tissues adjacent to tumors in humans and low-grade dysplasia in mice. Transgenic expression of MIR143-3p in gastric cancer cell lines reduced their proliferation and restored their sensitivity to cisplatin. AGS cells with stable transgenic expression of MIR143-3p grew more slowly as xenograft tumors in mice than control AGS cells; tumor growth from AGS cells that expressed MIR143-3p, but not control cells, was sensitive to cisplatin. We identified and validated bromodomain containing 2 (BRD2) as a direct target of MIR143-3p; increased levels of BRD2 in gastric tumors associated with shorter survival times of patients.
CONCLUSIONS: In an analysis of miRNA profiles of gastric tumors from mice and human patients, we identified a conserved signature associated with early stages of gastric tumorigenesis. Strategies to restore MIR143-3p or inhibit BRD2 might be developed for treatment of gastric cancer.

PMID: 30502323 [PubMed - as supplied by publisher]

Chronic Rhinosinusitis in Elderly Patients is Associated with an Exaggerated Neutrophilic Pro-Inflammatory Response to Pathogenic Bacteria.

Chronic Rhinosinusitis in Elderly Patients is Associated with an Exaggerated Neutrophilic Pro-Inflammatory Response to Pathogenic Bacteria.

J Allergy Clin Immunol. 2018 Nov 20;:

Authors: Morse JC, Li P, Ely KA, Shilts MH, Wannemuehler TJ, Huang LC, Sheng Q, Chowdhury NI, Chandra RK, Das SR, Turner JH

Abstract
BACKGROUND: Potential effects of aging on chronic rhinosinusitis (CRS) pathophysiology have not been well defined, but may have important ramifications given a rapidly aging U.S. and world population.
OBJECTIVE: The goal of the current study was to determine whether advanced age is associated with specific inflammatory CRS endotypes or immune signatures.
METHODS: Seventeen mucus cytokines and inflammatory mediators were measured in 147 CRS patients. Hierarchical cluster analysis was used to identify and characterize inflammatory CRS endotypes as well as determine whether age was associated with specific immune signatures.
RESULTS: A CRS endotype with a pro-inflammatory, neutrophilic immune signature was enriched with older patients. In the overall cohort, patients 60 years and older had elevated mucus levels of IL-1β, IL-6, IL-8, and TNF-α when compared to their younger counterparts. Increases in pro-inflammatory cytokines were associated with both tissue neutrophilia and symptomatic bacterial infection/colonization in aged patients.
CONCLUSIONS: Aged CRS patients have a unique inflammatory signature that corresponds to a neutrophilic pro-inflammatory response. Neutrophil-driven inflammation in aged CRS patients may be less likely to respond to corticosteroids and may be closely linked with chronic microbial infection or colonization.

PMID: 30468775 [PubMed - as supplied by publisher]

Dust Bath.

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Dust Bath.

Ann Intern Med. 2018 Nov 20;169(10):715

Authors: Christman BW

PMID: 30452574 [PubMed - in process]

Assembly of a pan-genome from deep sequencing of 910 humans of African descent.

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Assembly of a pan-genome from deep sequencing of 910 humans of African descent.

Nat Genet. 2018 Nov 19;:

Authors: Sherman RM, Forman J, Antonescu V, Puiu D, Daya M, Rafaels N, Boorgula MP, Chavan S, Vergara C, Ortega VE, Levin AM, Eng C, Yazdanbakhsh M, Wilson JG, Marrugo J, Lange LA, Williams LK, Watson H, Ware LB, Olopade CO, Olopade O, Oliveira RR, Ober C, Nicolae DL, Meyers DA, Mayorga A, Knight-Madden J, Hartert T, Hansel NN, Foreman MG, Ford JG, Faruque MU, Dunston GM, Caraballo L, Burchard EG, Bleecker ER, Araujo MI, Herrera-Paz EF, Campbell M, Foster C, Taub MA, Beaty TH, Ruczinski I, Mathias RA, Barnes KC, Salzberg SL

Abstract
We used a deeply sequenced dataset of 910 individuals, all of African descent, to construct a set of DNA sequences that is present in these individuals but missing from the reference human genome. We aligned 1.19 trillion reads from the 910 individuals to the reference genome (GRCh38), collected all reads that failed to align, and assembled these reads into contiguous sequences (contigs). We then compared all contigs to one another to identify a set of unique sequences representing regions of the African pan-genome missing from the reference genome. Our analysis revealed 296,485,284 bp in 125,715 distinct contigs present in the populations of African descent, demonstrating that the African pan-genome contains ~10% more DNA than the current human reference genome. Although the functional significance of nearly all of this sequence is unknown, 387 of the novel contigs fall within 315 distinct protein-coding genes, and the rest appear to be intergenic.

PMID: 30455414 [PubMed - as supplied by publisher]

Standardizing return of participant results.

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Standardizing return of participant results.

Science. 2018 Nov 16;362(6416):759-760

Authors: Botkin JR, Appelbaum PS, Bakken S, Brown C, Burke W, Fabsitz R, Gamble VN, Gonsalves G, Kost R, Leonard DGB, McGuire A, Nichols JH, Patrick-Lake B, Wilkins CH, Zikmund-Fisher BJ

PMID: 30442797 [PubMed - in process]

Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

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Publisher Correction: Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.

Nat Genet. 2018 Nov 14;:

Authors: Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, Ntritsos G, Dimou N, Cabrera CP, Karaman I, Ng FL, Evangelou M, Witkowska K, Tzanis E, Hellwege JN, Giri A, Velez Edwards DR, Sun YV, Cho K, Gaziano JM, Wilson PWF, Tsao PS, Kovesdy CP, Esko T, Mägi R, Milani L, Almgren P, Boutin T, Debette S, Ding J, Giulianini F, Holliday EG, Jackson AU, Li-Gao R, Lin WY, Luan J, Mangino M, Oldmeadow C, Prins BP, Qian Y, Sargurupremraj M, Shah N, Surendran P, Thériault S, Verweij N, Willems SM, Zhao JH, Amouyel P, Connell J, de Mutsert R, Doney ASF, Farrall M, Menni C, Morris AD, Noordam R, Paré G, Poulter NR, Shields DC, Stanton A, Thom S, Abecasis G, Amin N, Arking DE, Ayers KL, Barbieri CM, Batini C, Bis JC, Blake T, Bochud M, Boehnke M, Boerwinkle E, Boomsma DI, Bottinger EP, Braund PS, Brumat M, Campbell A, Campbell H, Chakravarti A, Chambers JC, Chauhan G, Ciullo M, Cocca M, Collins F, Cordell HJ, Davies G, de Borst MH, de Geus EJ, Deary IJ, Deelen J, Del Greco M F, Demirkale CY, Dörr M, Ehret GB, Elosua R, Enroth S, Erzurumluoglu AM, Ferreira T, Frånberg M, Franco OH, Gandin I, Gasparini P, Giedraitis V, Gieger C, Girotto G, Goel A, Gow AJ, Gudnason V, Guo X, Gyllensten U, Hamsten A, Harris TB, Harris SE, Hartman CA, Havulinna AS, Hicks AA, Hofer E, Hofman A, Hottenga JJ, Huffman JE, Hwang SJ, Ingelsson E, James A, Jansen R, Jarvelin MR, Joehanes R, Johansson Å, Johnson AD, Joshi PK, Jousilahti P, Jukema JW, Jula A, Kähönen M, Kathiresan S, Keavney BD, Khaw KT, Knekt P, Knight J, Kolcic I, Kooner JS, Koskinen S, Kristiansson K, Kutalik Z, Laan M, Larson M, Launer LJ, Lehne B, Lehtimäki T, Liewald DCM, Lin L, Lind L, Lindgren CM, Liu Y, Loos RJF, Lopez LM, Lu Y, Lyytikäinen LP, Mahajan A, Mamasoula C, Marrugat J, Marten J, Milaneschi Y, Morgan A, Morris AP, Morrison AC, Munson PJ, Nalls MA, Nandakumar P, Nelson CP, Niiranen T, Nolte IM, Nutile T, Oldehinkel AJ, Oostra BA, O'Reilly PF, Org E, Padmanabhan S, Palmas W, Palotie A, Pattie A, Penninx BWJH, Perola M, Peters A, Polasek O, Pramstaller PP, Nguyen QT, Raitakari OT, Ren M, Rettig R, Rice K, Ridker PM, Ried JS, Riese H, Ripatti S, Robino A, Rose LM, Rotter JI, Rudan I, Ruggiero D, Saba Y, Sala CF, Salomaa V, Samani NJ, Sarin AP, Schmidt R, Schmidt H, Shrine N, Siscovick D, Smith AV, Snieder H, Sõber S, Sorice R, Starr JM, Stott DJ, Strachan DP, Strawbridge RJ, Sundström J, Swertz MA, Taylor KD, Teumer A, Tobin MD, Tomaszewski M, Toniolo D, Traglia M, Trompet S, Tuomilehto J, Tzourio C, Uitterlinden AG, Vaez A, van der Most PJ, van Duijn CM, Vergnaud AC, Verwoert GC, Vitart V, Völker U, Vollenweider P, Vuckovic D, Watkins H, Wild SH, Willemsen G, Wilson JF, Wright AF, Yao J, Zemunik T, Zhang W, Attia JR, Butterworth AS, Chasman DI, Conen D, Cucca F, Danesh J, Hayward C, Howson JMM, Laakso M, Lakatta EG, Langenberg C, Melander O, Mook-Kanamori DO, Palmer CNA, Risch L, Scott RA, Scott RJ, Sever P, Spector TD, van der Harst P, Wareham NJ, Zeggini E, Levy D, Munroe PB, Newton-Cheh C, Brown MJ, Metspalu A, Hung AM, O'Donnell CJ, Edwards TL, Million Veteran Program, Psaty BM, Tzoulaki I, Barnes MR, Wain LV, Elliott P, Caulfield MJ

Abstract
In the version of this article originally published, the name of author Martin H. de Borst was coded incorrectly in the XML. The error has now been corrected in the HTML version of the paper.

PMID: 30429575 [PubMed - as supplied by publisher]

Direct-acting Antiviral Therapy for HCV Infection is Associated with a Reduced Risk of Cardiovascular Disease Events.

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Direct-acting Antiviral Therapy for HCV Infection is Associated with a Reduced Risk of Cardiovascular Disease Events.

Gastroenterology. 2018 Nov 13;:

Authors: Butt AA, Yan P, Shuaib A, Abou-Samra AB, Shaikh OS, Freiberg MS

Abstract
BACKGROUND & AIMS: Infection with hepatitis virus C (HCV) is associated with an increased risk of cardiovascular disease (CVD) events. It is not clear whether treatment with direct-acting antiviral (DAA) agents affects risk of CVD.
METHODS: We searched the Electronically Retrieved Cohort of HCV-infected Veterans database for patients with chronic HCV infection (n=242,680), identifying patients who had been treated with a pegylated interferon and ribavirin regimen (n=4436) or a DAA-containing regimen (12,667). Treated patients were matched for age, race, sex, and baseline values with patients who had never received treatment for HCV infection (controls). All subjects were free of any CVD event diagnosis of HCV infection at baseline. The primary outcome was incident CVD events, identified by ICD9/10 code, in the different groups and among patients with vs without a sustained virologic response (SVR) to therapy.
RESULTS: There were 1239 (7.2%) incident CVD events in the treated and 2361 (13.8%) in the control group. The incidence rate was 30.9/1000 patient-years (95% CI, 29.6-32.1) in the control group and 20.3/1000 patient-years (95% CI, 19.2-21.5) in the treated groups (P<.0001). Treatment with pegylated interferon and ribavirin (hazard ratio, 0.78; 95% CI, 0.71-0.85) or a DAA regimen (0.57; 95% CI, 0.51-0.65) was associated with a significantly lower risk of a CVD event, compared with no treatment (controls). Incidence rates for CVD events were 23.5/1000 patient-years (95% CI, 21.8-25.3) in group treated with pegylated interferon and ribavirin regimen, 16.3/1000 patient-years (95% CI, 14.7-18.0) in the group treated with a DAA regimen, and 30.4 (95%, 29.2-31.7) in the control group. An SVR was associated with a lower risk of incident CVD events (hazard ratio, 0.87; 95% CI, 0.77-0.98).
CONCLUSIONS: In an analysis of a cohort of HCV-infected Veterans, we found treatment of HCV infection to be associated with a significant reduction in risk of CVD events. Patients treated with a DAA regimen and patients who achieved SVRs had the lowest risk for CVD events.

PMID: 30445009 [PubMed - as supplied by publisher]

Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis.

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Ectonucleoside Triphosphate Diphosphohydrolase-3 Antibody Targets Adult Human Pancreatic β Cells for In Vitro and In Vivo Analysis.

Cell Metab. 2018 Nov 12;:

Authors: Saunders DC, Brissova M, Phillips N, Shrestha S, Walker JT, Aramandla R, Poffenberger G, Flaherty DK, Weller KP, Pelletier J, Cooper T, Goff MT, Virostko J, Shostak A, Dean ED, Greiner DL, Shultz LD, Prasad N, Levy SE, Carnahan RH, Dai C, Sévigny J, Powers AC

Abstract
Identification of cell-surface markers specific to human pancreatic β cells would allow in vivo analysis and imaging. Here we introduce a biomarker, ectonucleoside triphosphate diphosphohydrolase-3 (NTPDase3), that is expressed on the cell surface of essentially all adult human β cells, including those from individuals with type 1 or type 2 diabetes. NTPDase3 is expressed dynamically during postnatal human pancreas development, appearing first in acinar cells at birth, but several months later its expression declines in acinar cells while concurrently emerging in islet β cells. Given its specificity and membrane localization, we utilized an NTPDase3 antibody for purification of live human β cells as confirmed by transcriptional profiling, and, in addition, for in vivo imaging of transplanted human β cells. Thus, NTPDase3 is a cell-surface biomarker of adult human β cells, and the antibody directed to this protein should be a useful new reagent for β cell sorting, in vivo imaging, and targeting.

PMID: 30449685 [PubMed - as supplied by publisher]

Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice.

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Increased Ripk1-mediated bone marrow necroptosis leads to myelodysplasia and bone marrow failure in mice.

Blood. 2018 Nov 09;:

Authors: Wagner PN, Shi Q, Salisbury-Ruf CT, Zou J, Savona MR, Fedoriw Y, Zinkel SS

Abstract
Hematopoiesis is a dynamic system that requires balanced cell division, differentiation, and death. The two major modes of programmed cell death (PCD), apoptosis and necroptosis, share molecular machinery, but diverge in outcome with important implications for the microenvironment: apoptotic cells are removed in an immune silent process, whereas necroptotic cells leak cellular contents that incite inflammation. Given the importance of cytokine directed cues for hematopoietic cell survival and differentiation, the impact on hematopoietic homeostasis of biasing cell death fate to necroptosis is substantial and poorly understood. Here we present a mouse model with increased bone marrow necroptosis. Deletion of the pro-apoptotic Bcl-2 family members Bax and Bak inhibits bone marrow apoptosis. Further deletion of the BH3-only member Bid, to generate VavCreBaxBakBid TKO mice, leads to unrestrained bone marrow necroptosis driven by increased Rip1 kinase (Ripk1). TKO mice display loss of progenitor cells leading to increased cytokine production and increased stem cell proliferation and exhaustion, culminating in bone marrow failure (BMF). Genetically restoring Ripk1 to wild type levels restores peripheral red cell counts as well as normal cytokine production. TKO bone marrow is hyper cellular with abnormal differentiation, resembling the human disorder Myelodysplastic syndrome (MDS), and we demonstrate increased necroptosis in MDS bone marrow. Finally, we show that Bid impacts necroptotic signaling through modulation of Caspase-8-mediated Ripk1 degradation. Thus we demonstrate that dysregulated necroptosis in hematopoiesis promotes bone marrow progenitor cell death that incites inflammation, impairs hematopoietic stem cells, and recapitulates the salient features of the bone marrow failure disorder, MDS.

PMID: 30413413 [PubMed - as supplied by publisher]

Health Outcome Priorities of Older Adults with Advanced CKD and Concordance with Their Nephrology Providers' Perceptions.

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Health Outcome Priorities of Older Adults with Advanced CKD and Concordance with Their Nephrology Providers' Perceptions.

J Am Soc Nephrol. 2018 Nov 01;:

Authors: Ramer SJ, McCall NN, Robinson-Cohen C, Siew ED, Salat H, Bian A, Stewart TG, El-Sourady MH, Karlekar M, Lipworth L, Ikizler TA, Abdel-Kader K

Abstract
BACKGROUND: Older adults with advanced CKD have significant pain, other symptoms, and disability. To help ensure that care is consistent with patients' values, nephrology providers should understand their patients' priorities when they make clinical recommendations.
METHODS: Patients aged ≥60 years with advanced (stage 4 or 5) non-dialysis-dependent CKD receiving care at a CKD clinic completed a validated health outcome prioritization tool to ascertain their health outcome priorities. For each patient, the nephrology provider completed the same health outcome prioritization tool. Patients also answered questions to self-rate their health and completed an end-of-life scenarios instrument. We examined the associations between priorities and self-reported health status and between priorities and acceptance of common end-of-life scenarios, and also measured concordance between patients' priorities and providers' perceptions of priorities.
RESULTS: Among 271 patients (median age 71 years), the top health outcome priority was maintaining independence (49%), followed by staying alive (35%), reducing pain (9%), and reducing other symptoms (6%). Nearly half of patients ranked staying alive as their third or fourth priority. There was no relationship between patients' self-rated health status and top priority, but acceptance of some end-of-life scenarios differed significantly between groups with different top priorities. Providers' perceptions about patients' top health outcome priorities were correct only 35% of the time. Patient-provider concordance for any individual health outcome ranking was similarly poor.
CONCLUSIONS: Nearly half of older adults with advanced CKD ranked maintaining independence as their top heath outcome priority. Almost as many ranked being alive as their last or second-to-last priority. Nephrology providers demonstrated limited knowledge of their patients' priorities.

PMID: 30385652 [PubMed - as supplied by publisher]

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.

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Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.

Cell. 2018 Oct 30;:

Authors: Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A, Contreras DC, Maseda D, Liberti MV, Paz K, Kishton RJ, Johnson ME, de Cubas AA, Wu P, Li G, Zhang Y, Newcomb DC, Wells AD, Restifo NP, Rathmell WK, Locasale JW, Davila ML, Blazar BR, Rathmell JC

Abstract
Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

PMID: 30392958 [PubMed - as supplied by publisher]

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

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Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness.

N Engl J Med. 2018 Oct 22;:

Authors: Girard TD, Exline MC, Carson SS, Hough CL, Rock P, Gong MN, Douglas IS, Malhotra A, Owens RL, Feinstein DJ, Khan B, Pisani MA, Hyzy RC, Schmidt GA, Schweickert WD, Hite RD, Bowton DL, Masica AL, Thompson JL, Chandrasekhar R, Pun BT, Strength C, Boehm LM, Jackson JC, Pandharipande PP, Brummel NE, Hughes CG, Patel MB, Stollings JL, Bernard GR, Dittus RS, Ely EW, MIND-USA Investigators

Abstract
BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU).
METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation.
RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms.
CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .).

PMID: 30346242 [PubMed - as supplied by publisher]

Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

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Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.

Nat Genet. 2018 Oct 08;:

Authors: Mahajan A, Taliun D, Thurner M, Robertson NR, Torres JM, Rayner NW, Payne AJ, Steinthorsdottir V, Scott RA, Grarup N, Cook JP, Schmidt EM, Wuttke M, Sarnowski C, Mägi R, Nano J, Gieger C, Trompet S, Lecoeur C, Preuss MH, Prins BP, Guo X, Bielak LF, Below JE, Bowden DW, Chambers JC, Kim YJ, Ng MCY, Petty LE, Sim X, Zhang W, Bennett AJ, Bork-Jensen J, Brummett CM, Canouil M, Ec Kardt KU, Fischer K, Kardia SLR, Kronenberg F, Läll K, Liu CT, Locke AE, Luan J, Ntalla I, Nylander V, Schönherr S, Schurmann C, Yengo L, Bottinger EP, Brandslund I, Christensen C, Dedoussis G, Florez JC, Ford I, Franco OH, Frayling TM, Giedraitis V, Hackinger S, Hattersley AT, Herder C, Ikram MA, Ingelsson M, Jørgensen ME, Jørgensen T, Kriebel J, Kuusisto J, Ligthart S, Lindgren CM, Linneberg A, Lyssenko V, Mamakou V, Meitinger T, Mohlke KL, Morris AD, Nadkarni G, Pankow JS, Peters A, Sattar N, Stančáková A, Strauch K, Taylor KD, Thorand B, Thorleifsson G, Thorsteinsdottir U, Tuomilehto J, Witte DR, Dupuis J, Peyser PA, Zeggini E, Loos RJF, Froguel P, Ingelsson E, Lind L, Groop L, Laakso M, Collins FS, Jukema JW, Palmer CNA, Grallert H, Metspalu A, Dehghan A, Köttgen A, Abecasis GR, Meigs JB, Rotter JI, Marchini J, Pedersen O, Hansen T, Langenberg C, Wareham NJ, Stefansson K, Gloyn AL, Morris AP, Boehnke M, McCarthy MI

Abstract
We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).

PMID: 30297969 [PubMed - as supplied by publisher]

Serological response to Helicobacter pylori proteins associate with risk of colorectal cancer among diverse populations in the United States.

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Serological response to Helicobacter pylori proteins associate with risk of colorectal cancer among diverse populations in the United States.

Gastroenterology. 2018 Oct 05;:

Authors: Butt J, Varga MG, Blot WJ, Teras L, Visvanathan K, Le Marchand L, Haiman C, Chen Y, Bao Y, Sesso HD, Wassertheil-Smoller S, Ho GYF, Tinker LE, Peek RM, Potter JD, Cover TL, Hendrix LH, Huang LC, Hyslop T, Um C, Grodstein F, Song M, Zeleniuch-Jacquotte A, Berndt S, Hildesheim A, Waterboer T, Pawlita M, Epplein M

Abstract
BACKGROUND & AIMS: Previous studies reported an association of the bacteria Helicobacter pylori, the primary cause of gastric cancer, and risk of colorectal cancer (CRC). However, these findings have been inconsistent, appear to vary with population characteristics, and may be specific for virulence factor VacA. To more thoroughly evaluate the potential association of H pylori antibodies with CRC risk, we assembled a large consortium of cohorts representing diverse populations in the United States.
METHODS: We used H pylori multiplex serologic assays to analyze serum samples from 4063 incident cases of CRC, collected before diagnosis, and 4063 matched individuals without CRC (controls) from 10 prospective cohorts for antibody responses to 13 H pylori proteins, including virulence factors VacA and CagA. The association of sero-positivity to H pylori proteins, as well as protein-specific antibody level, with odds of CRC was determined by conditional logistic regression.
RESULTS: Overall 40% of controls and 41% of cases were H. pylori sero-positive (odds ratio [OR], 1.09; 95% CI, 0.99-1.20). H pylori VacA-specific sero-positivity was associated with an 11% increased odds of CRC (OR, 1.11; 95% CI, 1.01-1.22), and this association was particularly strong among African Americans (OR, 1.45; 95% CI, 1.08-1.95). Additionally, odds of CRC increased with level of VacA antibody in the overall cohort (P=.008) and specifically among African Americans (P=.007).
CONCLUSION: In an analysis of a large consortium of cohorts representing diverse populations, we found serologic responses to H pylori VacA to associate with increased risk of CRC risk-particularly for African Americans. Future studies should seek to understand whether this marker is related to virulent H pylori strains carried in these populations.

PMID: 30296434 [PubMed - as supplied by publisher]