tbuckley/cabot-search huggingface dataset:
Abstract P371: Short-term Repeatability of the Peguero Electrocardiographic Index of Left Ventricular Hypertrophy
Authors: Dominique N Drager, Michelle L Meyer, Elsayed Z Soliman, Gerardo Heiss
Journal: Circulation (2019)

Background: Electrocardiographic left ventricular hypertrophy (ECG-LVH) represents preclinical cardiovascular disease and predicts cardiovascular disease and mortality. Current criteria include the Cornell voltage, Sokolow-Lyon, and the newly developed Peguero index (S D + SV 4 ). While the Peguero index has been shown to have better prognostic prediction compared with current criteria, its short term repeatability remains uncertain. Objectives: Characterize the repeatability and minimal detectable change of the Peguero ECG-LVH index. Methods: Participants (n=63; mean age 50 years; 31 females) underwent two standardized visits one week apart. At each visit, trained and certified technicians obtained two ECGs following a standardized protocol. The Epidemiological Cardiology Research Center automatically processed the ECGs using GE Marquette GE 12-SL software (GE, Milwaukee, WI) to obtain the Peguero (S D + SV 4 ) LHV index, defined as the deepest S wave in any single lead S D + SV 4 . We created a dichotomous using the following cut points: &gt;2.3 mV for women and &gt;2.8 mV for men. Random effects, mixed models were used to parse the variance of the index into the between-participant, between-visit, and within-visit components. We then calculated the intra-class correlation coefficient (ICC), Kappa coefficients, and minimal detectable change (95% confidence) between repeat measures. Results: Between-participant variation accounted for 93.58% (262,958 out of 280,985 SD points) of the total variation of the Peguero LVH index, while between-visit variation and within-visit variation were 5.51% (15,480 out of 280,985 SD points) and 0.91% (2,547 out of 280,985 SD points), respectively. The index had an ICC (95% confidence interval) of 0.94 (0.91-0.97) and a minimum detectable change value of 372.16 mV. Within visit Kappas were 0.79 (0.40-1.00) for the first visit and 1.00 (1.00-1.00) for the second visit. Between visit Kappas were 0.77 (0.70-0.84) for the first measurements of each visit and 0.79 (0.72-0.86) for the second measurements of each visit. Conclusion: The Peguero LVH index shows excellent repeatability for both within and between visits. The ICC and resulting confidence interval of the continuous index suggests near perfect agreement between groups. The Kappa values also suggest concurrence between groups of the dichotomous index, although the measures are not as precise as the ICC measure. The repeatability of this measure can be used to inform clinical and epidemiological studies and expand research of this novel index of ECG-LVH.
Intensity modulated radiation therapy concurrent chemotherapy for esophageal cancer with postoperative recurrence.
Authors: Hua Tao, Jincheng Lu, Dayong Gu
Journal: Journal of Clinical Oncology (2015)

e15099 Background: Esophageal cancer squamous cell carcinoma is the dominant pathological type in Asia, with the 5-year overall survival rate of 20.9% in China. The median overall survival time of postoperative recurrent esophageal cancer patients has been revealed to be no more than 1 year. The optimal salvage treatment is in suspense. The purpose of this prospective study is to assess the efficacy and toxicity of intensity modulated radiation therapy concurrent chemotherapy for esophageal cancer with postoperative recurrence. Methods: Between October 2009 and October 2011, 44 patients were recruited. When recurrence was diagnosed, they received intensity modulated radiotherapy delivered by 5-7 field technique with 6MV photon-beam energy. Gross tumor volume comprised of enlarged recurrent lymph node. Clinical target volume (CTV) included GTV with a margin of 0.5-1 cm prescribed dose 60Gy/30f, 2.0Gy per fraction per day, five days a week. Planning target volume (PTV) consisted of CTV and bilateral supraclavicular LN areas and Upper-middle mediastinal LN areas administered dose 45-50.4Gy/25-28f, 1.8Gy per fraction per day. Chemotherapy was given using 5-fluorouracil (5-FU) 500mg/m2/d ,d1-5/ and nedaplatin (CDGP) 75mg/ m2,d1 for 2 cycles during radiation therapy and 2 cycles consolidation chemotherapy. The chemotherapy interval was no less than 28 days. Results: All the patients completed the treatment without modification. Eight of the 44 patients were still alive. The1-, 2-year and 3-year overall survival rates were 77%, 36% and 18%, respectively, with a median survival period of 22.0 months (95% CI = 20.2-23.8). The 1-, 2-year and 3-year progression-free survival rates were 70%, 23% and 9%, respectively. No severe toxicities related to treatment were observed in this study. Most of acute toxicities were represented as in-field sore throat caused by radiotherapy. Conclusions: Intensity modulated radiation therapy concurrent chemotherapy is safe and valuable for esophageal cancer with postoperative recurrence.
Alterations in DNA damage repair (DDR) genes and outcomes to systemic therapy in 225 immune-oncology (IO) versus tyrosine kinase inhibitor (TKI) treated metastatic clear cell renal cell carcinoma (mccRCC) patients (pts).
Authors: Yasser Ged, Joshua Chaim, Andrea Knezevic, Maria Isabel Carlo, Ashley Foster, Darren R. Feldman, Min Yuen Teo, Nadeem Riaz, Chung-Han Lee, Sujata Patil, Timothy An-thy Chan, A. Ari Hakimi, Robert J. Motzer, Martin Henner Voss
Journal: Journal of Clinical Oncology (2019)

551 Background: Loss of function alterations in DDR genes including core components of mismatch repair and homologous recombination deficiency pathways are associated with tumorigenesis and may determine benefit from IO therapies as shown in colon cancer. The significance for standard IO and TKI treatments in mccRCC is unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for two large cohorts of mccRCC: pts treated with pure IO therapy (cohort 1); and pts receiving first-line TKI (cohort 2). Tumor and germline DNA was subject to targeted panel testing across &gt;400 genes of interest, including 34 DDR machinery genes. Presence of truncating mutations, deletions and functionally validated missense mutations identified individual patient as ‘DDR altered’ (DDRa). Tumor mutational burden (TMB) was inferred for all pts. Non-parametric tests were applied to determine association between DDR status, TMB and treatment outcomes. Results: 225 pts were included (cohort 1=107, cohort 2=118), 37 (16%) were DDRa. Most commonly altered genes were ATM (n=8, 4%) and CHEK2 (n=8, 4%). DDR germline alterations were seen in 12 pts (5%). Median TMB was 4.1 per megabase (range: 0-21.7), and higher TMB (≥ median) was associated with being DDRa (Fisher’s exact, p=0.03). DDRa status correlated significantly with longer overall survival (OS) in the IO cohort (HR 0.29, logrank p=0.04) but not in the TKI cohort (HR 0.74, logrank p=0.44). We found no interaction between objective response and DDR status in either cohort. Conclusions: Loss of function in DDR genes was associated with superior OS in IO-treated but not in TKI-treated RCC pts. Possible underlying mechanisms beyond increase in TMB observed here deserve further study. [Table: see text]
Randomised controlled trial of WISENSE, a real-time quality improving system for monitoring blind spots during esophagogastroduodenoscopy
Authors: Lianlian Wu, Jun Zhang, Wei Zhou, Ping An, Lei Shen, Jun Liu, Xiaoda Jiang, Xu Huang, Ganggang Mu, Xinyue Wan, Xiaoguang Lv, Juan Gao, Ning Cui, Shan Hu, Yiyun Chen, Xiao Hu, Jiangjie Li, Di Chen, Dexin Gong, Xinqi He, Qianshan Ding, Xiaoyun Zhu, Suqin Li, Xiao Wei, Xia Li, Xuemei Wang, Jie Zhou, Mengjiao Zhang, Hong Gang Yu
Journal: Gut (2019)

Objective Esophagogastroduodenoscopy (EGD) is the pivotal procedure in the diagnosis of upper gastrointestinal lesions. However, there are significant variations in EGD performance among endoscopists, impairing the discovery rate of gastric cancers and precursor lesions. The aim of this study was to construct a real-time quality improving system, WISENSE, to monitor blind spots, time the procedure and automatically generate photodocumentation during EGD and thus raise the quality of everyday endoscopy. Design WISENSE system was developed using the methods of deep convolutional neural networks and deep reinforcement learning. Patients referred because of health examination, symptoms, surveillance were recruited from Renmin hospital of Wuhan University. Enrolled patients were randomly assigned to groups that underwent EGD with or without the assistance of WISENSE. The primary end point was to ascertain if there was a difference in the rate of blind spots between WISENSE-assisted group and the control group. Results WISENSE monitored blind spots with an accuracy of 90.40% in real EGD videos. A total of 324 patients were recruited and randomised. 153 and 150 patients were analysed in the WISENSE and control group, respectively. Blind spot rate was lower in WISENSE group compared with the control (5.86% vs 22.46%, p&lt;0.001), and the mean difference was −15.39% (95% CI −19.23 to −11.54). There was no significant adverse event. Conclusions WISENSE significantly reduced blind spot rate of EGD procedure and could be used to improve the quality of everyday endoscopy. Trial registration number ChiCTR1800014809; Results.
Machine learning identifies an immunological pattern associated with multiple juvenile idiopathic arthritis subtypes
Authors: Erika Van Nieuwenhove, Vasiliki Lagou, Lien Van Eyck, James Dooley, Ulrich Bodenhofer, Carlos Roca, Marijne Vandebergh, An Goris, Stéphanie Humblet-Baron, Carine Wouters, Adrian Liston
Journal: Annals of the Rheumatic Diseases (2019)

Juvenile idiopathic arthritis (JIA) is the most common class of childhood rheumatic diseases, with distinct disease subsets that may have diverging pathophysiological origins. Both adaptive and innate immune processes have been proposed as primary drivers, which may account for the observed clinical heterogeneity, but few high-depth studies have been performed.Here we profiled the adaptive immune system of 85 patients with JIA and 43 age-matched controls with indepth flow cytometry and machine learning approaches.Immune profiling identified immunological changes in patients with JIA. This immune signature was shared across a broad spectrum of childhood inflammatory diseases. The immune signature was identified in clinically distinct subsets of JIA, but was accentuated in patients with systemic JIA and those patients with active disease. Despite the extensive overlap in the immunological spectrum exhibited by healthy children and patients with JIA, machine learning analysis of the data set proved capable of discriminating patients with JIA from healthy controls with ~90% accuracy.These results pave the way for large-scale immune phenotyping longitudinal studies of JIA. The ability to discriminate between patients with JIA and healthy individuals provides proof of principle for the use of machine learning to identify immune signatures that are predictive to treatment response group.
Long-Term Outcomes after Prolonged Mechanical Ventilation: What of Those Cast Away?
Authors: Anica C. Law, Allan J. Walkey
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

We appreciate Mahler's correspondence related to our research statement (1), the goal of which was to identify knowledge gaps that future research studies can address to efficiently translate biomarkers into clinical practice.To reach this goal, we chose to focus on example biomarkers for select lung diseases rather than create a comprehensive list of all biomarkers for all pulmonary diseases.As stated in the article, "the biomarkers discussed in this research statement are not intended to be comprehensive."Thus, we did not state or intend to imply that fibrinogen is the "sole" biomarker in chronic obstructive pulmonary disease (COPD).We agree with Mahler that the peak inspiratory flow rate is a promising COPD biomarker, and encourage studies of this and other promising biomarkers for COPD and other lung diseases.
Gab2 is Essential for Transformation by FLT3‐ITD in Acute Myeloid Leukemia
Authors: Katharina Sies, Corinna Spohr, Albert Gründer, Rumyana Todorova, Franziska Maria Uhl, Julia Huber, Robert Zeiser, Heike Luise Pahl, Heiko Becker, Konrad Aumann, Tilman Brummer, Sebastian Halbach
Journal: HemaSphere (2019)

Supplemental Digital Content is available in the text
TALAPRO-1: An open-label, response rate phase II study of talazoparib (TALA) in men with DNA damage repair (DDR) defects and metastatic castration-resistant prostate cancer (mCRPC) who previously received taxane-based chemotherapy (CT) and progressed on greater than or equal to one novel hormonal therapy (NHT).
Authors: Johann S. De Bono, Celestia S. Higano, Fred Saad, Kurt Miller, Hsiang-Chun Chen, Akos Czibere, Cynthia Healy, Karim Fizazi
Journal: Journal of Clinical Oncology (2019)

TPS342 Background: There are no approved therapies for mCRPC that has progressed on taxane and NHT. Preclinical studies showed that DDR-positive prostate tumors may be sensitized to PARP inhibition. TALA inhibits PARP, causing cell death in BRCA1/2-mutated cells. Methods: This study (NCT03148795) is enrolling patients (pts) (N ≈ 100) with measurable soft tissue disease per RECIST v1.1, progressive mCRPC, DDR likely to sensitize to PARP inhibition, ECOG performance status ≤ 2, and no brain metastases, who received 1-2 CT regimens (including ≥ 1 taxane-based CT) and progressed on ≥ 1 NHT (enzalutamide/abiraterone acetate). Prior use of PARP inhibitors, cyclophosphamide, mitoxantrone, or platinum-based CT ≤ 6 mos before study or progression on a platinum-based CT at any time are excluded. Pts will receive TALA 1 mg/d orally (pts with moderate renal impairment, 0.75 mg/d) until radiographic progression, unacceptable toxicity, or withdrawal of consent. TALA should not be discontinued based on increased prostate specific antigen (PSA) or circulating tumor cell (CTC) count alone. Primary endpoint is best objective response (OR) rate (complete/partial soft tissue response; exact 2-sided 95% confidence interval). Responses must be confirmed ≥ 4 wks later by computed tomography/magnetic resonance imaging with no evidence of bone progression ≥ 6 wks later per PCWG3 criteria. Secondary endpoints include time to OR, duration of response, PSA decrease ≥ 50%, CTC count conversion (to CTC = 0 and &lt; 5 per 7.5 mL of blood), time to PSA progression, radiographic progression-free survival, overall survival, safety, pt-reported outcomes, and pharmacokinetics of TALA. Efficacy will be assessed every 8 wks for the first 24 wks, then every 12 wks thereafter. An initial safety and efficacy analysis will be performed on 20 pts after ≥ 8 wks of treatment. An interim efficacy analysis is planned when 60 pts have completed ≥ 6 mos of treatment. This study was sponsored by Pfizer Inc. Previously presented at ESMO 2018, FPN 859TiP, De Bono JS et al. Reused with permission. Clinical trial information: NCT03148795.
ctDNA and copy-number variant quantification in mCRPC at the time of progression.
Authors: Patrick Cotogno, Marcus Marie Moses, Lahiru Ranasinghe, Bryce Raymon Christensen, Peter Steinwald, Lynne Chapman, Charlotte Manogue, Brian E. Lewis, Jodi Lyn Layton, A. Oliver Sartor, Elisa Ledet
Journal: Journal of Clinical Oncology (2019)

265 Background: Tumor burden is a prognostic biomarker in cancer; however, in metastatic castration resistant prostate cancer (mCRPC), quantification of tumor burden markers is difficult. Circulating ctDNA is an accessible biomarker which can be used to characterize somatic DNA. The goal of this study was to evaluate the utility of ctDNA quantification and characterization at time of disease progression in mCRPC. Methods: From 2015 to 2018, 221 mCRPC patients underwent ctDNA screening with Guardant 360 (Guardant Health, Inc. Redwood City, CA) at times of disease progression. This analysis consisted of exonic coverage of 70 genes as well as amplifications in 18 genes, with pathogenic mutations categorized by effect and mutant fraction ctDNA. Clinical annotation including lines of life-extending therapies (LET) before and after testing were collected. Statistical analyses included repeated measure ANOVA, logistic regression, and parameter estimations. Results: An increasing number of LETs resulted in a clinically significant increase in mutant ctDNA fraction (P &lt; 0.001). Subjects that received ≥ 5 or 3-4 LETs had significantly higher total mutant ctDNA fraction compared to subjects exposed with either 0 (p = 0.0007 and 0.0196, respectively) or 1-2 LETs (p = 0.0013 and 0.0432, respectively). 1-2 LETs did not demonstrate a significantly different total mutant ctDNA compared to subjects with 0 LETs (p = 0.4578). The estimated mean total mutant ctDNA fraction demonstrated a positive trend with an increasing number of LETs, including 2.08% (95% CI 1.24-3.49) without a LET, 2.62% (95% CI 1.71–4.01%) with 1-2 LETs, 4.58% (95% CI 2.92–7.17) with 3–4 LETs, and 7.79% (95% CI 4.51-13.48) for subjects with ≥5 LETs. The presence of copy number gain variations (CNVs) demonstrated an increased frequency with exposure to more LETs (p = 0.0005). Subjects with ≥5 or 3-4 LETs were 5.192 (p = 0. 0.0011, 95% CI 1.934-13.942) and 4.808 (p = 0.0019, 1.780-12.983) times more likely to have CNVs present compared to those without LETs. Conclusions: As mCRPC patients progress through lines of therapy, both the mutant ctDNA fraction and frequency of copy number gain variations increase.
Abstract P048: Early Cardiometabolic Risk: The Prevalence of Compensatory Hyperinsulinemia in U.S. Populations
Authors: David P Cistola, Liliana Bonilla, Erin B Campbell
Journal: Circulation (2019)

Introduction: Metabolic syndrome (MetS) and prediabetes (PreD) identify individuals at increased cardiometabolic risk. However, by the time those conditions develop, a significant decline in beta-cell insulin secretion has already occurred. The earliest stage in the pathogenesis of type 2 diabetes includes compensatory hyperinsulinemia, the robust response of intact beta cells to peripheral insulin resistance. This state of early metabolic dysregulation is not detected by conventional glucose and lipid screening. Hypothesis: The U.S. prevalence of compensatory hyperinsulinemia is high. Methods: Population-weighted data from the 2013-2014 cohort of the U.S. National Health and Nutrition Examination Survey (NHANES) were analyzed. The inclusion criteria were ages 12 and up, and the exclusion criteria were type 2 diabetes (fasting glucose ≥ 125 mg/dL, HbA1c ≥ 6.5 or 2-Hr glucose from OGTT ≥ 200 mg/dL), fasting triglycerides ≥ 885 mg/dL (familial hypertriglyceridemia), pregnancy or missing lab values. After population weighting, the 2,128 subjects sampled represented 198,424,653 non-diabetic individuals, approximately 62% of the U.S. population. Results: The subjects were categorized into four groups: NN: no MetS or PreD, no hyperinsulinemia; NY: no MetS or PreD with hyperinsulinemia; YN: MetS and/or PreD, no hyperinsulinemia; and YY: MetS and/or PreD with hyperinsulinemia. Hyperinsulinemia was defined as fasting insulin ≥ 12.2 μIU/ml based on prior calibration against the euglycemic clamp. The NY group represented compensatory hyperinsulinemia (CH). The 2013-2014 prevalence of CH was 11.2% of the non-diabetic U.S. population (95% CI: 11.17, 11.18). This group represented ~20% of the total at-risk subjects, defined as the sum of the NY, YN and YY groups. The prevalence of CH was highest in the youngest age groups and declined with age: 21.1% (21.08, 21.12) for ages 12-19, 13.2% (13.22,13.24) for ages 20-39, 7.7% (7.74, 7.75) for ages 40-59, 6.4% (6.34, 6.36) for ages 60-79, and 2.6% (2.63, 2.66) for ages 80 and up. The CH prevalence was higher in females vs. males: 12.7% (12.72, 12.73) vs. 9.6% (9.60, 9.61). In addition, CH prevalence was highest among Mexican Americans (17.0%; 16.98, 17.01) and other Hispanics (18.2%; 18.22, 18.27), followed by non-Hispanic blacks (12.3%; 12.29, 12.31), Native American/mixed race/other (10.8%; 10.79, 18.84), non-Hispanic whites (9.8%; 9.79, 9.80) and Asians (6.3%; 6.26, 6.29). Conclusion: The prevalence of compensatory hyperinsulinemia is high, especially in adolescents and young adults. These findings highlight a target population for early screening and intervention strategies to improve diabetes prevention outcomes.
Abstract 17735: Neddylation is Essential for Early Embryonic Heart Development via Regulation of Notch Signaling
Authors: Rodney Littlejohn, Jianqiu Zou, Wenxia Ma, Jie Li, Neal Weintraub, Jiliang Zhou, Huabo Su
Journal: Circulation (2017)

Congenital heart disease originates at least in part from genetic defects altering the development and maturation of the heart, and the role of protein modifiers in this process is not understood. The ubiquitin-like protein NEDD8 modifies proteins in a way similar to ubiquitin, termed neddylation, and requires NEDD8-specific E1 (NAE), E2 (Ubc12), and E3 ligases. Through regulating the function of protein targets, neddylation participates in diverse cellular processes and pathophysiological events. At the moment, it is not known whether or not neddylation plays a role in heart development. Here we report a previously unrecognized role of neddylation in early cardiogenesis and embryonic viability. Neddylation is activated in embryonic mouse hearts, but downregulated in adult hearts. Germline knockout (KO) of NAE1, a regulatory subunit of NAE, leads to embryonic lethality prior to E10.5, suggesting a critical role in early embryonic development. Mice with cardiac progenitor cell-specific (Nkx2.5Cre/+::NAE1fl...
Abstract MP22: Ideal Cardiovascular Health and Lifetime Risk of Cardiovascular Disease: the Cardiovascular Disease Lifetime Risk Pooling Project
Authors: Joshua D Bundy, Hongyan Ning, Amanda E Paluch, Victor W Zhong, Donald M Lloyd-Jones, John T Wilkins, Norrina B Allen
Journal: Circulation (2019)

Introduction: Ideal cardiovascular health (CVH) is associated with lower risk of cardiovascular disease (CVD) compared with intermediate and poor CVH. Quantifying the associations of ideal, intermediate, and poor CVH with lifetime risk of CVD can improve estimation of future population disease burden. Hypothesis: Individuals with ideal CVH have lower lifetime risk of CVD compared with individuals with intermediate and poor CVH. Methods: We pooled individual-level data from 7 US cohort studies (n=34027) that are included in the Lifetime Risk Pooling Project. We defined CVH based on levels of 7 health factors: smoking status, body mass index, physical activity, dietary pattern, total cholesterol, blood pressure, and diabetes mellitus. Each factor is scored as ideal (2 points), intermediate (1 point), or poor (0 points). The total CVH score was used to define overall CVH according to categories of ideal (12-14 points), intermediate (9-11 points), or poor (0-8 points). We used a modified Kaplan-Meier analysis, accounting for the competing risk of death, to assess the lifetime risk of CVD (CVD deaths, myocardial infarction, stroke, heart failure) separately in men and women free of CVD at index age categories of &lt;40, 40-59, and ≥60 years. Results: Over 553379 person-years of follow-up, we observed 6858 CVD events (103 events in ideal, 1514 in intermediate, and 5241 in poor CVH categories). Men had higher lifetime risk of CVD than women across all CVH categories. In the 40-59 years index age group (Figure), participants with ideal CVH had lower lifetime risk of CVD (men, 14.3%; women, 12.0%) compared with intermediate (men, 21.9%; women, 16.9%) and poor (men, 42.7%; women, 33.8%) CVH. Patterns were similar for the &lt;40 and ≥60 years index age groups. Conclusions: Ideal CVH is associated with substantially lower lifetime risk of CVD in US men and women. Further research is warranted to investigate strategies for maintaining and restoring ideal CVH throughout the life course to prevent associated risk of CVD.