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  • 1
    In: Open Forum Infectious Diseases, Oxford University Press (OUP), Vol. 5, No. 11 ( 2018-11-01)
    Abstract: The aims of this study were to identify common patterns of comorbidities observed in people living with HIV (PLWH), using a data-driven approach, and evaluate associations between patterns identified. Methods A wide range of comorbidities were assessed in PLWH participating in 2 independent cohorts (POPPY: UK/Ireland; AGEhIV: Netherlands). The presence/absence of each comorbidity was determined using a mix of self-reported medical history, concomitant medications, health care resource use, and laboratory parameters. Principal component analysis (PCA) based on Somers’ D statistic was applied to identify patterns of comorbidities. Results PCA identified 6 patterns among the 1073 POPPY PLWH (85.2% male; median age [interquartile range {IQR}], 52 [47–59] years): cardiovascular diseases (CVDs), sexually transmitted diseases (STDs), mental health problems, cancers, metabolic disorders, chest/other infections. The CVDs pattern was positively associated with cancer (r = .32), metabolic disorder (r = .38), mental health (r = .16), and chest/other infection (r = .17) patterns (all P & lt; .001). The mental health pattern was correlated with all the other patterns (in particular cancers: r = .20; chest/other infections: r = .27; both P & lt; .001). In the 598 AGEhIV PLWH (87.6% male; median age [IQR], 53 [48–59] years), 6 patterns were identified: CVDs, chest/liver, HIV/AIDS events, mental health/neurological problems, STDs, and general health. The general health pattern was correlated with all the other patterns (in particular CVDs: r = .14; chest/liver: r = .15; HIV/AIDS events: r = .31; all P & lt; .001), except STDs (r = –.02; P = .64). Conclusions Comorbidities in PLWH tend to occur in nonrandom patterns, reflecting known pathological mechanisms and shared risk factors, but also suggesting potential previously unknown mechanisms. Their identification may assist in adequately addressing the pathophysiology of increasingly prevalent multimorbidity in PLWH.
    Type of Medium: Online Resource
    ISSN: 2328-8957
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
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  • 2
    In: JAMA Cardiology, American Medical Association (AMA), Vol. 7, No. 10 ( 2022-10-01), p. 1000-
    Abstract: In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P  =   .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P   & amp;lt; .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P   & amp;lt; .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%] ; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P  = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%] ; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P   & amp;lt; .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%] ; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P  = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.
    Type of Medium: Online Resource
    ISSN: 2380-6583
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
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  • 3
    In: Pancreatology, Elsevier BV, Vol. 23, No. 6 ( 2023-09), p. 615-621
    Type of Medium: Online Resource
    ISSN: 1424-3903
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2043694-4
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  • 4
    In: Neoplasia, Elsevier BV, Vol. 28 ( 2022-06), p. 100789-
    Type of Medium: Online Resource
    ISSN: 1476-5586
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2008231-9
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  • 5
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 54, No. 11 ( 2022-11), p. 1630-1639
    Abstract: The canonical paradigm for converting genetic association to mechanism involves iteratively mapping individual associations to the proximal genes through which they act. In contrast, in the present study we demonstrate the feasibility of extracting biological insights from a very large region of the genome and leverage this strategy to study the genetic influences on autism. Using a new statistical approach, we identified the 33-Mb p-arm of chromosome 16 (16p) as harboring the greatest excess of autism’s common polygenic influences. The region also includes the mechanistically cryptic and autism-associated 16p11.2 copy number variant. Analysis of RNA-sequencing data revealed that both the common polygenic influences within 16p and the 16p11.2 deletion were associated with decreased average gene expression across 16p. The transcriptional effects of the rare deletion and diffuse common variation were correlated at the level of individual genes and analysis of Hi-C data revealed patterns of chromatin contact that may explain this transcriptional convergence. These results reflect a new approach for extracting biological insight from genetic association data and suggest convergence of common and rare genetic influences on autism at 16p.
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
    RVK:
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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    SSG: 12
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  • 6
    In: Frontiers in Oncology, Frontiers Media SA, Vol. 11 ( 2021-7-15)
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a median survival time of 10-12 months. Clinically, these poor outcomes are attributed to several factors, including late stage at the time of diagnosis impeding resectability, as well as multi-drug resistance. Despite the high prevalence of drug-resistant phenotypes, nearly all patients are offered chemotherapy leading to modest improvements in postoperative survival. However, chemotherapy is all too often associated with toxicity, and many patients elect for palliative care. In cases of inoperable disease, cytotoxic therapies are less efficacious but still carry the same risk of serious adverse effects, and clinical outcomes remain particularly poor. Here we discuss the current state of pancreatic cancer therapy, both surgical and medical, and emerging factors limiting the efficacy of both. Combined, this review highlights an unmet clinical need to improve our understanding of the mechanisms underlying the poor therapeutic responses seen in patients with PDAC, in hopes of increasing drug efficacy, extending patient survival, and improving quality of life.
    Type of Medium: Online Resource
    ISSN: 2234-943X
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
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  • 7
    In: PLOS ONE, Public Library of Science (PLoS), Vol. 18, No. 2 ( 2023-2-22), p. e0281182-
    Abstract: In pancreatic cancer clinical trials, Black patients are under-represented while having higher morbidity and mortality rates as compared to other racial groups. Multiple factors, including socioeconomic and lifestyle factors may contribute to this disparity, but genomic contributions remain unclear. In an exploratory project to identify genes that may contribute to differences in survival between Black (n = 8) and White (n = 20) patients with pancreatic cancer, transcriptomic sequencing of over 24,900 genes was performed in human pancreatic tumor and non-tumor tissue obtained from Black and White patients. Over 4,400 genes were differentially expressed in tumor and non-tumor tissue, irrespective of race. To validate these results, the expression of four genes (AGR2, POSTN, TFF1, and CP) reported to be up-regulated in pancreatic tumor tissue as compared to non-tumor tissue were confirmed using quantitative PCR. Transcriptomic analysis that compared pancreatic tumor tissue from Black and White patients revealed differential expression in 1,200 genes, while a comparison of the non-tumor and tumor gene expression differences within each race revealed over 1,500 tumor-specific differentially expressed genes in pancreatic tumor and non-tumor tissue from Black patients. We identified TSPAN8 as a potential tumor-specific gene significantly overexpressed in pancreatic tumor tissue in Black patients as compared to White patients. Using Ingenuity Pathway Analysis software to compare the race-associated gene expression profiles, over 40 canonical pathways were identified to be potentially impacted by the gene expression differences between the races. Heightened expression of TSPAN8 was associated with poor overall survival, suggesting TSPAN8 as one potential genetic factor contributing to the differential outcomes in Black patients with pancreatic cancer, supporting the potential utility of larger genomic studies to further explore the role of TSPAN8 in pancreatic cancer.
    Type of Medium: Online Resource
    ISSN: 1932-6203
    Language: English
    Publisher: Public Library of Science (PLoS)
    Publication Date: 2023
    detail.hit.zdb_id: 2267670-3
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  • 8
    In: World Journal of Emergency Surgery, Springer Science and Business Media LLC, Vol. 18, No. 1 ( 2023-02-06)
    Abstract: Common bile duct exploration (CBDE) is safe and effective for managing choledocholithiasis, but most US general surgeons have limited experience with CBDE and are uncomfortable performing this procedure in practice. Surgical trainee exposure to CBDE is limited, and their learning curve for achieving autonomous, practice-ready performance has not been previously described. This study tests the hypothesis that receipt of one or more prior CBDE operative performance assessments, combined with formative feedback, is associated with greater resident operative performance and autonomy. Methods Resident and attending assessments of resident operative performance and autonomy were obtained for 189 laparoscopic or open CBDEs performed at 28 institutions. Performance and autonomy were graded along validated ordinal scales. Cases in which the resident had one or more prior CBDE case evaluations ( n  = 48) were compared with cases in which the resident had no prior evaluations ( n  = 141). Results Compared with cases in which the resident had no prior CBDE case evaluations, cases with a prior evaluation had greater proportions of practice-ready or exceptional performance ratings according to both residents (27% vs. 11%, p  = .009) and attendings (58% vs. 19%, p   〈  .001) and had greater proportions of passive help or supervision only autonomy ratings according to both residents (17% vs. 4%, p  = .009) and attendings (69% vs. 32%, p   〈  .01). Conclusions Residents with at least one prior CBDE evaluation and formative feedback demonstrated better operative performance and received greater autonomy than residents without prior evaluations, underscoring the propensity of feedback to help residents achieve autonomous, practice-ready performance for rare operations.
    Type of Medium: Online Resource
    ISSN: 1749-7922
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 9
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 6_Supplement_1 ( 2020-06-01), p. A106-A106
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 6_Supplement_1 ( 2020-06-01), p. A106-A106
    Abstract: Introduction: The racial disparities in pancreatic cancer (PC), while not fully appreciated, are recognized amongst PC experts. African Americans are diagnosed more frequently, present with more advanced disease, and suffer from higher mortality rates than White patients. Overall, cancer cachexia, or cancer-associated muscle wasting, greatly contributes to both morbidity and mortality. While cachexia is experienced by more than 80% of patients with PC, PC-induced cachexia and how it contributes to a disparity amongst African Americans is under investigation. African Americans with PC present with increased muscle wasting (-29%) than their White counterparts with PC (-14%). Therefore, we hypothesize that an established radiographically obtained muscular index (a psoas index) uniquely corresponds to increased disease burden in African Americans with early-stage disease. Methods: African American and White patients with pancreatic ductal adenocarcinoma who underwent surgery at our institution between 2010 and 2017 were included in this retrospective study. A muscular index for each patient was measured from preoperative CT scans by dividing the average area of the psoas muscles at L3 by the L3 vertebral body area to normalize the measurement for patient size. Supplementary relevant clinical, pathologic, and laboratory values were used for comparison. Results: 15 African American and 15 White surgical patients with PC were matched by gender and history of neoadjuvant therapy; age was similar in both groups (65.7 vs. 64.3, p=0.6566). Gross tumor size was similar in African Americans and Whites (2.553 vs. 3.093, p=0.3097). Tumor size, however, inversely correlated to psoas index in African Americans (r=0.4330, p=0.0077), but not in Whites (r=0.002525, p=0.8588). African Americans with lower psoas indices generally had larger tumors. Similar to tumor size, the positive lymph node ratio (LNR) inversely correlated to psoas index in African Americans (r=0.3930, p=0.0124), but not in Whites (r=0.08673, p=0.2867). LNR was significantly greater in Whites than African Americans (0.0627 vs. 0.2253, p=0.0020). Overall survival was, however, similar in both groups (15.8 vs. 14.3, p=0.7117). Conclusion: A decreased psoas index in African American patients is associated with greater tumor size and an increased positive LNR. Notably, the most powerful outcome variable (LNR) did not correlate with psoas index in White patients even in the presence of increased nodal metastases. Most surprisingly, overall survival was similar in both patient groups. This suggests that a limited tumor burden does not provide a survival benefit for African Americans. We conclude that recognizing biologic variance among patients with ethnic diversity will allow better strategies to characterize metabolism, tumor microenvironment, and muscle architecture in PC. Together this will lead to improved overall survival. Citation Format: Miles E. Cameron, Patrick W. Underwood, Michael H. Gerber, Steven J. Hughes, Andrew R. Judge, Jennifer B. Permuth, Jose G. Trevino. Key differences in muscular index and tumor burden reveal unique biology in ethnically diverse patients with pancreatic cancer [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr A106.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 1153420-5
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  • 10
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 6_Supplement_2 ( 2020-06-01), p. D106-D106
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 6_Supplement_2 ( 2020-06-01), p. D106-D106
    Abstract: Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a devastating diagnosis with a five-year survival rate below 9%. Among various ethnic groups there are differing incidence and mortality rates that underpin a patient’s overall prognosis. Blacks have higher incidence and mortality rates and a worse prognosis compared to Whites. Conversely, Hispanic/Latino patients have the lowest recorded incidence and mortality rates. Though well recognized by experts, these discrepancies are poorly understood and unaccounted for by socioeconomic means. Therefore, we hypothesize that divergent biology drives the observed disparities in PDAC. Methods: Patients with PDAC that underwent surgery at our institution between 2010 and 2017 were included in this retrospective study. Surgical pathology reports were reviewed, and cases were matched by age, gender, and tumor grade. Psoas muscle indices (PMI) were measured from pre-operative CT scans. Baseline indices for respective ethnic groups were determined from healthy patients with non-oncologic pathology. Whole-exome sequencing was then performed on DNA from tumor and adjacent benign parenchyma. Results: Healthy Blacks have a significantly greater PMI than case-matched Whites (0.90 vs. 0.70, p & lt; 0.005). Blacks and Whites with PDAC have a similar average pre-operative PMI (0.67 vs. 0.61, p = 0.3). However, when comparing pre-operative PMI to the baseline control PMI for the two racial groups, Blacks have a significantly greater percent decrease than Whites (29% vs. 14%, p & lt; 0.05). By whole-exome sequencing, 22 new somatic mutations were identified in Black tumor samples compared to 7 new mutations in Whites. Among mutations exclusively present Blacks, ABCF1 and ANAPC1 were reported to be associated with chemoresponse and survival in colorectal and lung adenocarcinomas, respectively. Cytochrome p450 family member CYP2A7 mutations were associated with peritoneal metastasis. PHACTR4 mutations were associated with Stat3 signaling activation and IL-6 mediated phosphorylation in hepatocellular carcinoma. Lastly, Hispanic/Latino patients, while not part of our tumor molecular sequencing, more frequently sought surgical intervention for pre-malignant cystic pancreatic neoplasms when compared to Whites (28% vs. 7%, p & lt; 0.05). Conclusion: Novel mutations and a strongly cachectic phenotype characterize Blacks with PDAC and may drive a particularly poor prognosis. While more research might define a molecular rationale for the better clinical outcomes in Latinos, Hispanic/Latino patients most frequently seek care for pre-malignant lesions. We conclude that recognizing the biological basis of cancer health disparities is essential for forming appropriate clinical decisions and defining specific therapeutic targets in ethnically diverse patients with PDAC. Citation Format: Miles E Cameron, Patrick W Underwood, Michael U Maduka, Steven J Hughes, Andrea N Riner, Jennifer B Permuth, Andrew R Judge, Jose G Trevino. Divergent biology in ethnically diverse populations is central to health disparities in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr D106.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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