tbuckley/cabot-search huggingface dataset:
Abstract P260: Large-scale Meta-analysis of Diverse Ancestry Genome-wide Association Studies to Identify Pharmacogenomic Interactions of Sulfonylureas and ECG Phenotypes
Authors: James S Floyd, Colleen Sitlani, Christy L Avery, Eric A Whitsel, Leslie Lange, Albert V Smith, Daniel S Evans, Xiahui Li, Stella Trompet, Raymond Noordam, Bruno Stricker
Journal: Circulation (2016)

Introduction: Sulfonylureas are a commonly-used class of diabetes medication that can prolong the QT-interval, which is a leading cause of drug withdrawals from the market given the possible risk of life-threatening arrhythmias. Previously, we conducted a meta-analysis of genome-wide association studies of sulfonylurea-genetic interactions on QT interval among 9 European-ancestry (EA) cohorts using cross-sectional data, with null results. To improve our power to identify novel drug-gene interactions, we have included repeated measures of medication use and QT interval and expanded our study to include several additional cohorts, including African-American (AA) and Hispanic-ancestry (HA) cohorts with a high prevalence of sulfonylurea use. To identify potentially differential effects on cardiac depolarization and repolarization, we have also added two phenotypes - the JT and QRS intervals, which together comprise the QT interval. Hypothesis: The use of repeated measures and expansion of our meta-analysis to include diverse ancestry populations will allow us to identify novel pharmacogenomic interactions for sulfonylureas on the ECG phenotypes QT, JT, and QRS. Methods: Cohorts with unrelated individuals used generalized estimating equations to estimate interactions; cohorts with related individuals used mixed effect models clustered on family. For each ECG phenotype (QT, JT, QRS), we conducted ancestry-specific (EA, AA, HA) inverse variance weighted meta-analyses using standard errors based on the t-distribution to correct for small sample inflation in the test statistic. Ancestry-specific summary estimates were combined using MANTRA, an analytic method that accounts for differences in local linkage disequilibrium between ethnic groups. Results: Our study included 65,997 participants from 21 cohorts, including 4,020 (6%) sulfonylurea users, a substantial increase from the 26,986 participants and 846 sulfonylureas users in the previous meta-analysis. Preliminary ancestry-specific meta-analyses have identified genome-wide significant associations (P &lt; 5х10–8) for each ECG phenotype, and analyses with MANTRA are in progress. Conclusions: In the setting of the largest collection of pharmacogenomic studies to date, we used repeated measurements and leveraged diverse ancestry populations to identify new pharmacogenomic loci for ECG traits associated with cardiovascular risk.
c-CSN: Single-Cell RNA Sequencing Data Analysis by Conditional Cell-Specific Network
Authors: Lin Li, Hao Dai, Zhaoyuan Fang, Luonan Chen
Journal: Genomics Proteomics & Bioinformatics (2021)

The rapid advancement of single-cell technologies has shed new light on the complex mechanisms of cellular heterogeneity. However, compared to bulk RNA sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq) suffers from higher noise and lower coverage, which brings new computational difficulties. Based on statistical independence, cell-specific network (CSN) is able to quantify the overall associations between genes for each cell, yet suffering from a problem of overestimation related to indirect effects. To overcome this problem, we propose the c-CSN method, which can construct the conditional cell-specific network (CCSN) for each cell. c-CSN method can measure the direct associations between genes by eliminating the indirect associations. c-CSN can be used for cell clustering and dimension reduction on a network basis of single cells. Intuitively, each CCSN can be viewed as the transformation from less "reliable" gene expression to more "reliable" gene-gene associations in a cell. Based on CCSN, we further design network flow entropy (NFE) to estimate the differentiation potency of a single cell. A number of scRNA-seq datasets were used to demonstrate the advantages of our approach. 1) One direct association network is generated for one cell. 2) Most existing scRNA-seq methods designed for gene expression matrices are also applicable to c-CSN-transformed degree matrices. 3) CCSN-based NFE helps resolving the direction of differentiation trajectories by quantifying the potency of each cell. c-CSN is publicly available at https://github.com/LinLi-0909/c-CSN.
The cellular immunotherapy of integrated photothermal anti-oxidation Pd–Se nanoparticles in inhibition of the macrophage inflammatory response in rheumatoid arthritis
Authors: Chuping Zheng, Aiping Wu, Xinyun Zhai, Hong Ji, Zhikang Chen, Xu Chen, Xiyong Yu
Journal: Acta Pharmaceutica Sinica B (2021)

Reducing the inflammatory response is a major goal in the therapy of rheumatoid arthritis (RA). Herein, we integrated palladium nanoparticles (Pd NPs) with selenium nanoparticles (Se NPs) and obtained a multiple nanosystem ([email protected] NPs) that could simultaneously scavenge hydroxyl radicals (⋅OH) and provide a photothermal effect. The [email protected] NPs were constructed by a simple self-assembly method in which Se NPs were electrostatically bonded to Pd NPs; hyaluronic acid (HA) was linked to the NPs by ester bonding to provide macrophage targeting ability. The experiments show that the combined therapy of eliminating ⋅OH with Se NPs and utilizing PTT with Pd NPs could effectively reduce the inflammatory response in macrophages more effectively than either individual NP treatment. In addition, the outer layer of HA could specifically target the CD44 receptor to enhance the accumulation of [email protected] NPs at the lesion, further enhancing the therapeutic effect. After treatment for 15 days, the [email protected] NPs nearly eliminated the inflammatory response in the joints of mice in an induced RA model, and prevented joint damage and degradation.
Unusual stomach and duodenum mucosal changes in a kidney transplant patient after long-term peritoneal dialysis
Authors: Jin Roh, Choong-Kyun Noh
Journal: Gut (2021)

A 33-year-old man presented with a 2-month history of dyspepsia and nausea. He had undergone kidney transplantation (KT) 22 years ago due to renal failure of unknown aetiology. He underwent peritoneal dialysis for 14 years due to recurrent renal failure. Fourteen months ago, he underwent a second KT from a living donor. After transplantation, he had been taking prednisolone and tacrolimus. Laboratory studies showed the following results: blood urea nitrogen, 11.0 mg/dL (normal range, 8.0–23.0 mg/dL); creatinine, 0.92 mg/dL (normal range, 0.7–1.2 mg/dL); total calcium, 11.1 mg/dL (normal range, 8.6–10.2 mg/dL); corrected calcium, 11.3 mg/dL; phosphate, 2.6 mg/dL (normal range, 2.5–4.5 mg/dL) and alkaline phosphatase, 156 U/L (normal range, 40–129 U/L).

Upper endoscopy was performed to evaluate the patient’s …
Neutrophil Phospholipase Cγ2 Drives Autoantibody‐Induced Arthritis Through the Generation of the Inflammatory Microenvironment
Authors: Krisztina Futosi, Orsolya Kása, Kata P. Szilveszter, Attila Mócsai
Journal: Arthritis & Rheumatology (2021)

Gain-of-function mutations and genome-wide association studies have linked phospholipase Cγ2 (PLCγ2) to various inflammatory diseases, including arthritis in humans and mice. PLCγ2-deficient (Plcg2-/- ) mice are also protected against experimental arthritis. This study was undertaken to test how PLCγ2 triggers autoantibody-induced arthritis in mice.PLCγ2 was deleted from various mouse cellular lineages. Deletion efficacy and specificity were tested by immunoblotting and intracellular flow cytometry. Autoantibody-induced arthritis was triggered by K/BxN serum transfer. The role of neutrophil PLCγ2 was further investigated by analysis of the inflammatory exudate, competitive in vivo migration assays, and in vitro functional studies.PLCγ2 deficiency in the entire hematopoietic compartment completely blocked autoantibody-induced arthritis. Arthritis development was abrogated by deletion of PLCγ2 from myeloid cells or neutrophils but not from mast cells or platelets. Neutrophil infiltration was reduced in neutrophil-specific PLCγ2-deficient (Plcg2ΔPMN ) mice. However, this was not due to an intrinsic migration defect since Plcg2ΔPMN neutrophils accumulated normally when wild-type cells were also present in mixed bone marrow chimeras. Instead, the Plcg2ΔPMN mutation blocked the accumulation of interleukin-1β, macrophage inflammatory protein 2 (MIP-2), and leukotriene B4 (LTB4 ) in synovial tissues and reduced the secondary infiltration of macrophages. These findings were supported by in vitro studies showing normal chemotactic migration but defective immune complex-induced respiratory burst and MIP-2 or LTB4 release in PLCγ2-deficient neutrophils.Neutrophil PLCγ2 is critical for arthritis development, supposedly through the generation of the inflammatory microenvironment. PLCγ2-expressing neutrophils exert complex indirect effects on other inflammatory cells. PLCγ2-targeted therapies may provide particular benefit in inflammatory diseases with a major neutrophil component.
68Ga-DOTATOC PET/CT in Pleural Solitary Fibrous Tumors
Authors: Filippo Lococo, Vittoria Rufini, Angelina Filice, Massimiliano Paci, Guido Rindi
Journal: Clinical Nuclear Medicine (2021)

Solitary fibrous tumor of the pleura (SFTP) is a rare mesenchymal neoplasm. Preoperative diagnosis is usually difficult and based on radiological findings only. We report the imaging results observed in 5 patients with SFTP (2 malignant) obtained by 68Ga-DOTATOC PET/CT. At qualitative analysis, all tumors showed uptake of 68Ga-DOTATOC. Mean tumor SUVmax was 9.9 ± 5.7. The expression of SST2 (somatostatin receptors subtype 2) was confirmed by immunohistochemistry in 2 tumor samples, and by gene amplification of SST2 mRNA in all cases. These data suggest a diagnostic role of radioreceptor PET/CT in SFTP, and open novel potential treatment options in unresectable/metastatic disease.
Association of Acute Care Surgeon Experience With Emergency Surgery Patient Outcomes and Mortality
Authors: Kevin M. Schuster, Joshua P. Hazelton, Deviney Rattigan, Javier Martin Perez, Bishwajit Bhattacharya
Journal: JAMA Surgery (2021)

Previous studies comparing emergency surgery outcomes with surgeon experience have been small or used administrative databases without controlling for patient physiology or operative complexity.To evaluate the association of acute care surgeon experience with patient morbidity and mortality after emergency surgical procedures.This cohort study evaluated the association of surgeon experience with emergency surgery outcomes at 5 US academic level 1 trauma centers where the same surgeons provided emergency general surgical care. A total of 772 patients who presented with a traumatic injury and required an emergency surgical procedure or who presented with or developed a condition requiring an emergency general surgical intervention were operated on by 1 of 56 acute care surgeons. Surgeon groups were divided by experience of less than 6 years (early career), 6 to 10 years (early midcareer), 11 to 30 years (late midcareer), and 30 years or more (late career) from the end of training. Surgeons with less than 3 years of experience were also compared with the entire cohort. Hierarchical logistic regression models were constructed controlling for Emergency Surgery Score, case complexity, preoperative transfusion, and trauma or emergency general surgery. Data were collected from May 2015 to July 2017 and analyzed from February to May 2020.Mortality, complications, length of stay, blood loss, and unplanned return to the operating room.Of 772 included patients, 469 (60.8%) were male, and the mean (SD) age was 50.1 (20.0) years. Of 772 operations, 618 were by surgeons with less than 10 years of experience. Early- and late-midcareer surgeons generally operated on older patients and patients with more septic shock, acute kidney failure, and higher Emergency Surgery Scores. Patient mortality, complications, postoperative transfusion, organ-space surgical site infection, and length of stay were similar between surgeon groups. Patients operated on by early-career surgeons had higher rates of unplanned return to the operating room compared with those operated on by early-midcareer surgeons (odds ratio [OR], 0.66; 95% CI, 0.40-1.09), late-midcareer surgeons (OR, 0.34; 95% CI, 0.13-0.90), and late-career surgeons (OR, 1.11; 95% CI, 0.45-2.75). Patients operated on by surgeons with less than 3 years of experience had similar mortality compared with the rest of the cohort (OR, 1.97; 95% CI, 0.85-4.57) but higher rates of complications (OR, 2.07; 95% CI, 1.05-4.07).In this study, experienced surgeons generally operated on older patients with more septic shock and kidney failure without affecting risk-adjusted mortality. Increased complications and unplanned return to the operating room may improve with experience. Early-career surgeons' outcomes may be improved if they are supported while experience is garnered.
At the Heart of Immune Checkpoint Inhibitor–Induced Immune Toxicity
Authors: Arabella Young, Jeffrey A. Bluestone
Journal: Cancer Discovery (2021)

Abstract Summary: Wei and colleagues showcase a genetic mouse model of immune-mediated myocarditis that shares homology with immune checkpoint inhibitor (CPI)–induced myocarditis in patients with cancer. They demonstrate that abatacept (CTLA4–Ig) limits cardiac toxicity in the mouse model and, thus, may ameliorate the CPI-induced myocarditis in patients with cancer while potentially maintaining antitumor activity. See related article by Wei et al., p. 614.
Pulmonary Alveolar Microlithiasis Complicated by Tuberculosis
Authors: Gunar Günther, Chalese Einbeck
Journal: New England Journal of Medicine (2021)

A 36-year-old woman presented with cough and shortness of breath. A chest radiograph showed fine micronodular opacities. A transbronchial biopsy revealed microliths, and a diagnosis of pulmonary alveolar microlithiasis was made.
233P Intensiveneoadjuvantchemotherapyfollowedby chemoradiation and intraluminal HDR brachytherapyin esophageal cancer
Authors: F. Samiei, S. Sarbaz, N. Samiei, N. Farzi, M. Forootan, S. Babak, E. Karimzadeh
Journal: Annals of Oncology (2016)
Global Harmonization of Morphological Definitions in Hidradenitis Suppurativa for a Proposed Glossary
Authors: John W. Frew, Michelle Anne Lowes, Noah Goldfarb, Melissa Butt, Vincent Piguet, Elizabeth O’Brien, John Ingram, Gregor B. E. Jemec, Jerry Tan, Christos Zouboulis, Afsaneh Alavi, Joslyn S. Kirby
Journal: JAMA Dermatology (2021)

Standard morphological terminology and definitions are vital for identification of lesion types in the clinical trial setting and communication about the condition. For hidradenitis suppurativa (HS), morphological definitions have been proposed by different groups, representing various regions of the world, but no international consensus has been reached regarding such definitions. A lack of globally harmonized terminology and definitions may contribute to poor-quality data collection in clinical trials as well as poor communication among clinicians, investigators, and patients.To establish and validate consensus definitions for typical morphological findings for HS lesions.This study was conducted from August 2019 to August 2020. A Delphi study technique was used to assess agreement and then resolve disagreement on HS terminology among international experts. After an initial preparation phase, the process consisted of 3 rounds. In each round, participants reviewed preliminary definitions and rated them as "keep, with no changes," "keep, with changes," or "remove." Eight HS primary lesions, including papule, pustule, nodule, plaque, ulcer, abscess, comedo, and tunnel, were selected because they are most frequently used in HS clinician-reported outcome measures. The initial definitions were based on extant literature, and modifications were made between rounds based on qualitative thematic analysis of open-ended responses or discussion. Consensus was defined as greater than 70% to accept a definition. Consensus stability across rounds was defined as less than 15% change in agreement. Reliability was evaluated using the Gwet agreement coefficient. Validation was based on assessment of face validity and stability across rounds.A total of 31 experts participated. All 8 HS primary lesion definitions achieved greater than 70% consensus by Delphi round 3. Stability was achieved for papule, pustule, and abscess. The Gwet agreement coefficient increased from 0.49 (95% CI, 0.26-0.71) in round 1 to 0.78 (95% CI, 0.64-0.92) in round 3. Face validity was supported by expert endorsement to keep terms in survey responses. Previously unmeasured variation among clinicians' definition of tunnels was identified, and consensus was achieved.An international group of experts agreed on definitions for morphological features of HS lesions frequently included in HS clinical trials. These international consensus terms and definitions are needed to support consistency of lesion identification and quantification in clinical trials.
Care homes: reversing decades of policy neglect
Authors: Clive Bowman
Journal: BMJ (2021)

Manthorpe and Iliffe go some way to identifying the risk of failure in the care home market, but their suggestion of an NHS franchise model (like that which underpins general practice) is a reflex solution based on their frustration with the current impasse around funding and access.1 Starting with a clear understanding of the role of care homes now and in the future might be …
Early sedation with dexmedetomidine in ventilated critically ill patients and heterogeneity of treatment effect in the SPICE III randomised controlled trial
Authors: Yahya Shehabi, Ary Serpa Neto, Belinda D. Howe, Rinaldo Bellomo, Yaseen M. Arabi, Michael Bailey, Frances E. Bass, Suhaini Bin Kadiman, Colin J. McArthur, Michael C. Reade, Ian M. Seppelt, Jukka Takala, Matt P. Wise, Steve A. Webb
Journal: Intensive Care Medicine (2021)
Supportive care in the acute phase of Stevens–Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi‐based consensus
Authors: M.‐C. Brüggen, S.T. Le, S. Walsh, A. Toussi, N. Prost, A. Ranki, B. Didona, A. Colin, B. Horváth, E. Brezinova, B. Milpied, C. Moss, C. Bodemer, D. Meyersburg, C. Salavastru, G.‐S. Tiplica, E. Howard, E. Bequignon, J.N. Bouwes Bavinck, J. Newman, J. Gueudry, M. Nägeli, K. Zaghbib, K. Pallesen, A. Bygum, P. Joly, P. Wolkenstein, S.‐L. Chua, R. Le Floch, N.H. Shear, C.‐Y. Chu, N. Hama, R. Abe, W.‐H. Chung, T. Shiohara, M. Ardern‐Jones, P. Romanelli, E.J. Phillips, R.S. Stern, J. Cotliar, R.G. Micheletti, A. Brassard, J.T. Schulz, R.P. Dodiuk‐Gad, A.R. Dominguez, A.S. Paller, L. Seminario‐Vidal, A. Mostaghimi, M.H. Noe, S. Worswick, D. Tartar, R. Sheridan, B.H. Kaffenberger, K. Shinkai, E. Maverakis, L.E. French, S. Ingen‐Housz‐Oro
Journal: British Journal of Dermatology (2021)

Background Supportive care is the cornerstone of management of adult and paediatric Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. Objectives Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. Methods Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. Results Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. Conclusions We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.
Abstract 16951: Feasibility of IVUS-Derived FFR as a Novel Technique to Estimate Functional Severity of Coronary Stenosis: Systematic Evaluation of Optimal Major Side Branch Definition to Determine the Reference Site for Automated FFR Calculation
Authors: Kuninobu Kashiyama, Shinjo Sonoda, Kozo Okada, Kensuke Matsushita, Kiyoshi Hibi, M Brooke Hollak, Paul G Yock, Alan Young, Peter Fitzgerald, Yasuhiro Honda
Journal: Circulation (2020)

Background: IVUS-derived FFR (IVUS-FFR) is a novel technique to estimate functional severity of coronary stenosis. Using a fluid dynamics algorithm, pressure loss (ΔP) across a stenosis is calculated as ΔP = FV + SV 2 , where V is the flow velocity; F and S are the coefficients defined based on IVUS-determined minimum lumen area (MLA), stenosis length, and reference lumen area (RLA). While the first 2 variables are well defined by IVUS, the RLA can be affected by the presence of side branches near the target lesion due to blood flow distribution. Methods: To determine the threshold of side branch size that affects the RLA for IVUS-FFR calculation, 73 coronary lesions (41 LAD: 9 LCx: 23 RCA) underwent both IVUS and wire-derived FFR (W-FFR). RLA was defined as the largest lumen area proximal or distal to the target lesion with no intervening major side branches. In determining the reference site, 3 different definitions of the “major” side branch were used: &gt;25%, &gt;50%, and &gt;75% of the main vessel in diameter. The diagnostic accuracy of calculated IVUS-FFR was then evaluated with each definition as referenced to W-FFR. Results: In this patient population, 42% of the lesions were physiologically significant (W-FFR &lt;0.8). MLA and W-FFR were 2.1±0.9 mm 2 and 0.81±0.1, respectively. Overall, IVUS-FFR showed significant linear correlations with W-FFR (p&lt;0.0001 for all definitions). Among the 3 definitions tested, the &gt;50% definition showed the highest diagnostic accuracy (area under the curve [AUC]: 0.95) for physiologic ischemia (Figure). Conclusion: In defining the reference site for IVUS-FFR calculation, the optimal definition of the major side branch was &gt;50% of main vessel in diameter. The current results help to develop objective and automated estimation of FFR using IVUS. Further investigation is warranted to evaluate clinical utility of combined anatomical and physiological information that IVUS may offer through this technology.