101 research outputs found
Improving Prognostication amongst Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma: An International, 16-Center Study to Validate and Recalibrate HALTHCC
Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus
Reoperative Complications after Primary Orthotopic Liver Transplantation: A Contemporary Single-Center Experience in the PostâModel for End-Stage Liver Disease Era
BackgroundData on complications requiring reoperation after orthotopic liver transplantation (OLT) are limited. We sought to describe the spectrum of reoperative complications after OLT, evaluate the associations with graft and patient survival, and identify predictors of need for reoperation.Study designWe retrospectively studied adult patients who underwent primary OLT at our institution from February 2002 to July 2012. The primary outcomes included occurrence of a reoperative complication. Secondary outcomes were graft and patient survival. Multivariable logistic regression analysis was used to model the associations of recipient, donor, and operative variables with reoperation.ResultsOf 1,620 patients, 470 (29%) had complications requiring reoperation. The most common reoperative complication was bleeding (17.3%). Compared with patients not requiring reoperation, patients with reoperative complications had greater Model for End-Stage Liver Disease scores and need for pretransplantation hospitalization, mechanical ventilation, vasopressors, and renal replacement therapy; considerably longer cold and warm ischemia times and greater intraoperative blood transfusion requirements; and substantially worse 1-, 3-, and 5-year graft and patient survival rates. In multivariable analysis, predictors of reoperative complications included intraoperative transfusion of packed RBCs (odds ratio [OR] = 2.21; 95% CI, 1.91-2.56), donor length of hospitalization >8 days (OR = 1.87; 95% CI, 1.28-2.73), recipient pretransplantation mechanical ventilation (OR = 1.65; 95% CI, 1.21-2.24), cold ischemia time >9 hours (OR = 1.63; 95% CI, 1.23-2.17), warm ischemia time >55 minutes (OR = 1.58; 95% CI, 1.02-2.44), earlier major abdominal surgery (OR = 1.41; 95% CI, 1.03-1.92), and elevated donor serum sodium (OR = 1.17; 95% CI, 1.03-1.31).ConclusionsPatients who require reoperation for complications after OLT have high pretransplantation acuity and inferior post-transplantation survival. We identified factors associated with reoperative complications to guide perioperative donor-recipient matching and improve outcomes
Interactions between HIV-1 Reverse Transcriptase and the Downstream Template Strand in Stable Complexes with Primer-Template
Background: Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) forms stable ternary complexes in which RT is bound tightly at fixed positions on the primer-template (P/T). We have probed downstream interactions between RT and the template strand in the complex containing the incoming dNTP (+1 dNTPNRTNP/T complex) and in the complex containing the pyrophosphate analog, foscarnet (foscarnetNRTNP/T complex). Methods and Results: UV-induced cross-linking between RT and the DNA template strand was most efficient when a bromodeoxyuridine residue was placed in the +2 position (the first template position downstream from the incoming dNTP). Furthermore, formation of the +1 dNTPNRTNP/T complex on a biotin-containing template inhibited binding of streptavidin when biotin was in the +2 position on the template but not when the biotin was in the +3 position. Streptavidin pre-bound to a biotin residue in the template caused RT to stall two to three nucleotides upstream from the biotin residue. The downstream border of the complex formed by the stalled RT was mapped by digestion with exonuclease RecJF. UV-induced cross-linking of the complex formed by the pyrophosphate analog, foscarnet, with RT and P/T occurred preferentially with bromodeoxyuridine in the +1 position on the template in keeping with the location of RT one base upstream in the foscarnetNRTNP/T complex (i.e., in the pre-translocation position). Conclusions: For +1 dNTPNRTNP/T and foscarnetNRTNP/T stable complexes, tight interactions were observed between RT an
Mast Cell Diseases in Practice and Research: Issues and Perspectives Raised by Patients and Their Recommendations to the Scientific Community and Beyond
Background: Since 2010, patients and physicians have collaborated to understand unmet needs of patients with mast cell diseases, incorporating mastocytosis and mast cell activation disorders, which include mast cell activation syndromes. Objective: This Open Innovation in Science project aims to expand understanding of the needs of patients affected by mast cell diseases, and encourage global communication among patient advocacy groups, physicians, researchers, industry, and government. A major aim is to support the scientific community's efforts to improve diagnosis, management, therapy, and patientsâ quality of life by addressing unmet needs. Methods: In collaboration with mast cell disease specialists, 13 patient advocacy groups from 12 countries and regions developed lists of top patient needs. A core team of leaders from patient advocacy groups collected and analyzed the data and proposed possible actions to address patient needs. Results: Findings identified similarities and differences among participating countries in unmet needs between patients with mastocytosis and those with mast cell activation syndromes. Issues emphasized struggles relating to the nature and rarity of mast cell diseases, their impact on quality of life, the diagnostic process, access to appropriate care, more effective treatment, and the need for research. Conclusions: Solutions vary across countries because situations differ, in particular regarding the existence of and access to centers of excellence and reference centers. Multifaceted mast cell activation syndrome barriers necessitate innovative approaches to improve access to appropriate care. The outcomes of this project should greatly support scientists and clinicians in their efforts to improve diagnosis, management, and treatment of patients with mastocytosis and mast cell activation disorders.The authors thank Tania Bray, Jan Hempstead, Heather
Mayne, Joanne Mulder-Brambleby, and Irene Wilson for their
supporting contributions, and all patients and families affected
by MCDs, who shared their needs and concerns for development
of this project. Authors involved in study conception and design
were P. Valent, S.V. Jennings, C.C. Finnerty, J.S. Hobart, M.
MartĂn-MartĂnez, K.A. Sinclair, V.M. Slee, J. Agopian, C. Akin,
I. Ălvarez-Twose, P. Bonadonna, A.A. Bowman, K. Brockow, H.
Bumbea, C. de Haro, J.S. Fok, K. Hartmann, N. Hegmann, O.
Hermine, M. Kalisiak, C.H. Katelaris, J. Kurz, P. Marcis, D.
Mayne, D. Mendoza, A. Moussy, G. Mudretzkyj, N. Nidelea
Vaia, M. Niedoszytko, H. Oude Elberink, A. Orfao, D.H.
Radia, S. Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F.
Siebenhaar, M. Triggiani, G. Tripodo, R. Velazquez, Y. Wielink,
F. Wimazal, T. Yigit, and C. Zubrinich. Authors involved in acquisition and review of data were S.V. Jennings, C.C. Finnerty,
J.S. Hobart, M. MartĂn-MartĂnez, K.A. Sinclair, V.M. Slee, J.
Agopian, C. Akin, I. Ălvarez-Twose, P. Bonadonna, A.A.
Bowman, K. Brockow, H. Bumbea, C. de Haro, J.S. Fok, K.
Hartmann, N. Hegmann, O. Hermine, M. Kalisiak, C.H.
Katelaris, J. Kurz, P. Marcis, D. Mayne, D. Mendoza, A.
Moussy, G. Mudretzkyj, N. Nidelea Vaia, M. Niedoszytko, H.
Oude Elberink, A. Orfao, D.H. Radia, S. Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F. Siebenhaar, M. Triggiani, G.
Tripodo, R. Velazquez, Y. Wielink, F. Wimazal, T. Yigit, C.
Zubrinich, and P. Valent. The Core Group (analysis and interpretation of data and drafting of the manuscript) include S.V.
Jennings, C.C. Finnerty, J.S. Hobart, M. MartĂn-MartĂnez, K.A.
Sinclair, and V.M. Slee. Critical revision was performed by S.V.
Jennings, C.C. Finnerty, J.S. Hobart, M. MartĂn-MartĂnez, K.A.
Sinclair, V.M. Slee, J. Agopian, C. Akin, I. Ălvarez-Twose, P.
Bonadonna, A.A. Bowman, K. Brockow, H. Bumbea, C. de
Haro, J.S. Fok, K. Hartmann, N. Hegmann, O. Hermine, M.
Kalisiak, C.H. Katelaris, J. Kurz, P. Marcis, D. Mayne, D.
Mendoza, A. Moussy, G. Mudretzkyj, N. Nidelea Vaia, M.
Niedoszytko, H. Oude Elberink, A. Orfao, D.H. Radia, S.
Rosenmeier, E. Ribada, W. Schinhofen, J. Schwaab, F. Siebenhaar, M. Triggiani, G. Tripodo, R. Velazquez, Y. Wielink, F Wimazal, T. Yigit, C. Zubrinich, and P. Valent
Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries
RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10-10, OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10-5). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus
A rapid, reproducible, noninvasive predictor of liver graft survival
BACKGROUND: Clinical and laboratory criteria are not reliable predictors of deceased donor liver graft quality. Intraoperative assessment of experienced surgeons is the gold standard. Standardizing and quantifying this assessment is especially needed now that regional sharing is the rule. We prospectively evaluated a novel, simple, rapid, noninvasive, quantitative measure of liver function performed before graft procurement. MATERIALS AND METHODS: Using a portable, finger-probeâbased device, indocyanine green plasma disappearance rates (ICG-PDR) were measured in adult brain-dead donors in the local donor service area before organ procurement. Results were compared with graft function and outcomes. Both donor and recipient teams were blinded to ICG-PDR measurements. RESULTS: Measurements were performed on 53 consecutive donors. Eleven liver grafts were declined by all centers because of quality; the other 42 grafts were transplanted. Logistic regression analysis showed ICG-PDR to be the only donor variable to be significantly associated with 7-d graft survival. Donor risk index, donor age, and transaminase levels at peak or procurement were not significantly associated with 7-d graft survival. CONCLUSIONS: We report the successful use of a portable quantitative means of measuring liver function and its association with graft survival. These data warrant further exploration in a variety of settings to evaluate acceptable values for donated liver grafts
Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries.
RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.
OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.
METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10
CONCLUSIONS: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 nea
Interaction of the amyloid β peptide with sodium dodecyl sulfate as a membrane-mimicking detergent
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