tbuckley/cabot-search huggingface dataset:
Clare Gerada: Shame and perfectionism among doctors
Authors: Clare Gerada
Journal: BMJ (2020)

I recently had the good fortune to be invited to talk alongside firemen, air ambulance crew, and other emergency personnel about how professionals risk their lives in the service of others. Doctors, in contrast, do not (often) risk their physical wellbeing to keep us safe—indeed, the actual practice of medicine has become less dangerous. Doctors work in safer physical spaces, for shorter hours, and with better technology for more routine tasks. But, as I argued, doctors do risk their psychological lives, increasingly so—owing to shame, perfectionism, and isolation.

Shame is a powerful, primitive, and silent emotion, …
Epigenetic Link Between Statin Therapy and Type 2 Diabetes
Authors: Carolina Ochoa-Rosales, Eliana Portilla-Fernandez, Jana Nano, Rory Wilson, Benjamin Lehne, Pashupati P. Mishra, Xu Gao, Mohsen Ghanbari, Oscar L. Rueda-Ochoa, Diana Juvinao-Quintero, Marie Loh, Weihua Zhang, Jaspal S. Kooner, Hans J. Grabe, Stephan B. Felix, Ben Schöttker, Yan Zhang, Christian Gieger, Martina Müller-Nurasyid, Margit Heier, Annette Peters, Terho Lehtimäki, Alexander Teumer, Hermann Brenner, Melanie Waldenberger, M. Arfan Ikram, Joyce B.J. van Meurs, Oscar H. Franco, Trudy Voortman, John Chambers, Bruno H. Stricker, Taulant Muka
Journal: Diabetes Care (2020)

OBJECTIVE To investigate the role of epigenetics in statins’ diabetogenic effect comparing DNA methylation (DNAm) between statin users and nonusers in an epigenome-wide association study in blood. RESEARCH DESIGN AND METHODS Five cohort studies’ participants (n = 8,270) were classified as statin users when they were on statin therapy at the time of DNAm assessment with Illumina 450K or EPIC array or noncurrent users otherwise. Associations of DNAm with various outcomes like incident type 2 diabetes, plasma glucose, insulin, and insulin resistance (HOMA of insulin resistance [HOMA-IR]) as well as with gene expression were investigated. RESULTS Discovery (n = 6,820) and replication (n = 1,450) phases associated five DNAm sites with statin use: cg17901584 (1.12 × 10−25 [DHCR24]), cg10177197 (3.94 × 10−08 [DHCR24]), cg06500161 (2.67 × 10−23 [ABCG1]), cg27243685 (6.01 × 10−09 [ABCG1]), and cg05119988 (7.26 × 10−12 [SC4MOL]). Two sites were associated with at least one glycemic trait or type 2 diabetes. Higher cg06500161 methylation was associated with higher fasting glucose, insulin, HOMA-IR, and type 2 diabetes (odds ratio 1.34 [95% CI 1.22, 1.47]). Mediation analyses suggested that ABCG1 methylation partially mediates the effect of statins on high insulin and HOMA-IR. Gene expression analyses showed that statin exposure and ABCG1 methylation were associated with ABCG1 downregulation, suggesting epigenetic regulation of ABCG1 expression. Further, outcomes insulin and HOMA-IR were significantly associated with ABCG1 expression. CONCLUSIONS This study sheds light on potential mechanisms linking statins with type 2 diabetes risk, providing evidence on DNAm partially mediating statins’ effects on insulin traits. Further efforts shall disentangle the molecular mechanisms through which statins may induce DNAm changes, potentially leading to ABCG1 epigenetic regulation.
Abstract 14351: Increased Levels of IgM Autoantibodies to Oxidation-Specific Epitopes are Inversely Associated With Coronary Heart Disease: Analyses of Data From 204,257 Participants
Authors: Adam Taleb, Wei Zhao, Amir Shahzada, Asif Rasheed, Christoph J Binder, Joseph L Witztum, John Danesh, Daniel J Rader, Sotirios Tsimikas, Danish Saleheen
Journal: Circulation (2015)

Background: Immunoglobulin M (IgM) autoantibodies to oxidation-specific epitopes (OSE) have been shown to be protective against atherosclerosis in animal models, but the data in human studies is controversial. Objectives: This study sought to determine the association between IgM autoantibodies to OSE and apolipoprotein B-100-immune complexes (apoB-IC) and risk of coronary heart disease through a Mendelian Randomization study design. Methods: IgM autoantibodies to malondialdehyde-low density lipoprotein (MDA-LDL), phosphocholine-modified bovine serum albumin (PC-BSA) and IgM apoB-IC were measured in 9,830 participants (4966 first-onset cases with myocardial infarction [MI] and 4864 age and sex-matched controls) in the Pakistan Risk of Myocardial Infarction Study (PROMIS). Analyses in association with MI were conducted using logistic regression models progressively adjusted for age, sex, center, self-reported ethnicity, tobacco use, waist-to-hip ratio, history of diabetes and hypertension and LDL-C levels. Genetic analyses (GWAS and exome-chip) were also conducted using additive models. Variants associated with GWAS levels of significance were further assessed for pleiotropy and used as instruments to assess causality with CHD risk using genetic data on 63,746 CHD cases and 130,681 controls from the CARDIoGRAMplusC4D consortium. Results: In PROMIS, compared to the bottom quintile, the odds ratio for MI among participants in the top quintiles of IgM MDA-LDL, IgM PC-BSA and IgM apoB-IC were: 0.62 ([95% CI. 0.55-0.70], p&lt;0.001), 0.60 ([95% CI. 0.53-0.68], p&lt;0.001) and 0.64 ([95% CI. 0.56-0.73], p&lt;0.001], respectively. Genetic analyses identified several novel variants associated with circulating IgM MDA-LDL, IgM PC-BSA and IgM apoB-IC at GWAS levels of significance. In CARDIoGRAMplusC4D variants that exclusively increased circulating IgM autoantibodies were causally associated with reduced CHD risk (P&lt;1x10-5). Conclusions: Increased levels of IgM autoantibodies to MDA-LDL and PC-BSA and IgM apoB-IC are likely causally associated with a protective effect on CHD. This inverse association supports the hypothesis of the atheroprotective role of IgM autoantibodies.
Clinical significance of neutrophil-lymphocyte ratio to the patients with locally advanced rectal cancer who received preoperative chemoradiation therapy.
Authors: Joo Hwan Lee, Jong Hoon Lee, Sung Hwan Kim, Hyo Chun Lee
Journal: Journal of Clinical Oncology (2020)

138 Background: Preoperative chemoradiation therapy (CRT) and total mesorectal excision have been the standard care of the patients with locally advanced rectal cancer. Response to the preop CRT varied from patient to patient, approximately 10-15% of the patients achieved complete response, on the contrary, nearly 40% of the patients still showed ypT4 disease. The aim of this study is to assess the prognostic value of NLR and suggest the optimal cut-off value to predict tumor response to the preoperative chemoradiation therapy in the patients with locally advanced rectal cancer. Methods: We analyzed the medical records of 1134 patients who diagnosed with locally advanced rectal cancer and treated with preop CRT followed by radical surgery at St. Vincent hospital, Seoul St. Mary’s hospital, Chonnam National University Hwasun Hospital, Gyeongsang National University Hospital and Dongsan Medical Center from 1998 to 2015. All patients had histologically confirmed rectal adenocarcinoma within 10 cm from anal verge. All patients received preoperative CRT to the pelvis followed by TME. Complete blood count was performed at initial workup before treatment and NLR was calculated with differential count. Results: An optimal cut-off value of the NLR was revealed as 1.98. The NLR showed average value for predicting death (AUC 0.516, p &lt; 0.001). According to the cut-off value, patients were divided into two groups; high NLR (NLR≥2.0, n = 530) and low NLR (NLR &lt; 2.0, n = 604). The patients with low NLR achieved pathologic complete response more frequently. 105 patients of total 604 patients (17.4%) with low NLR showed no remnant tumor cells, compared to 63 patients of the 530 patients (11.9%) with high NLR did (p = 0.012). The proportion of the patients who were downstaged to T1-2N0 was evaluated. In the low NLR group, 258 patients (42.7%) were downstaged, while 199 patients (37.5%) in the high NLR group were, which showed a tendency but did not reach statistical significance (p = 0.087). Conclusions: In this large-scale multi-center analysis, NLR was once again identified as a predictor of treatment response of preop CRT in patients with locally advanced rectal cancer.
<i>RAS</i> status in circulating-tumor DNA (ctDNA) and outcomes during rechallenge treatments with anti-EGFR antibodies in metastatic colorectal cancer (mCRC).
Authors: Yu Sunakawa, Masato Nakamura, Masahiro Ishizaki, Masato Kataoka, Hironaga Satake, Masaki Kitazono, Hideyuki Yanagisawa, Yasuyuki Kawamoto, Hidekazu Kuramochi, Hisatsugu Ohori, Michio Nakamura, Fumiyo Maeda, Chihiro Komeno, Masahiro Takeuchi, Masashi Fujii, Takayuki Yoshino, Wataru Ichikawa, Akihito Tsuji
Journal: Journal of Clinical Oncology (2020)

166 Background: We have evaluated rechallenge treatment with irinotecan plus cetuximab (JACCRO CC-08, n = 36) or panitumumab (JACCRO CC-09, n = 25) in patients (pts) with KRAS wild-type mCRC [Tsuji A, WCGC 2018], and the primary endpoint of PFS rate at 3 months was met in both trials. RAS status in ctDNA may potentially predict responders of the rechallenge treatment in mCRC resistant to anti-EGFR antibody [Cremolini C, JAMA Oncol 2018]. Methods: A post-hoc biomarker study was performed to investigate an association between RAS status in ctDNA and clinical outcomes in the JACCRO phase II trials comprised mCRC pts who achieved a clinical benefit from 1st-line anti-EGFR antibody-based therapy, then had a disease progression at 2nd-line treatment. RAS status in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC Kit for specific KRAS/ NRAS mutations, using cut-off value defined as the number of beads with amplified-mutant molecules specifically set per each codon. Results: Sixteen pts (median 67.5-y old, 50% of PS0, 25% of right-sided primary, cet/pani: 4/12) were enrolled in this study, with response rate of 0% and disease control rate (DCR) of 62.5%. RAS mutations (mt) were found at the baseline in 6 out of 16 pts (all left-sided pts with KRAS codon 12, codon 61 and/or NRAS codon 61 mt simultaneously). Pts without RAS mt at baseline experienced longer PFS in 1st-line treatment (11.5 vs. 9.0 m). The DCR was 33% in pts with RAS mt in ctDNA, while it was 80% in pts without RAS mt at baseline. Pts with RAS mt at baseline had significantly shorter PFS and OS than pts without RAS mt [median PFS 2.3 vs 4.7 m, HR 6.2 (95%CI 1.6-30.5), p = 0.013; median OS 3.8 vs. 16.0 m, HR 12.4 (95%CI 2.7-87.7), p = 0.0028]. Six of 10 pts without RAS mt at baseline acquired RAS mt ( KRAS/ NRAS codon 12 or 61) in ctDNA at progression, however there was no difference in survival between pts with/without RAS mt at progression. Conclusions: Our study demonstrated that RAS status in ctDNA using OncoBEAM RAS CRC Kit predicts survival of rechallenge treatment with anti-EGFR antibody in mCRC pts. These data can support the application of RAS monitoring into clinical practice. Clinical trial information: UMIN000015914/UMIN000015916.
Algorithm based smartphone apps to assess risk of skin cancer in adults: systematic review of diagnostic accuracy studies
Authors: Karoline Freeman, Jacqueline Dinnes, Naomi Chuchu, Yemisi Takwoingi, Sue E Bayliss, Rubeta N Matin, Abhilash Jain, Fiona M Walter, Hywel C Williams, Jonathan J Deeks
Journal: BMJ (2020)

Abstract Objective To examine the validity and findings of studies that examine the accuracy of algorithm based smartphone applications (“apps”) to assess risk of skin cancer in suspicious skin lesions. Design Systematic review of diagnostic accuracy studies. Data sources Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, CPCI, Zetoc, Science Citation Index, and online trial registers (from database inception to 10 April 2019). Eligibility criteria for selecting studies Studies of any design that evaluated algorithm based smartphone apps to assess images of skin lesions suspicious for skin cancer. Reference standards included histological diagnosis or follow-up, and expert recommendation for further investigation or intervention. Two authors independently extracted data and assessed validity using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2 tool). Estimates of sensitivity and specificity were reported for each app. Results Nine studies that evaluated six different identifiable smartphone apps were included. Six verified results by using histology or follow-up (n=725 lesions), and three verified results by using expert recommendations (n=407 lesions). Studies were small and of poor methodological quality, with selective recruitment, high rates of unevaluable images, and differential verification. Lesion selection and image acquisition were performed by clinicians rather than smartphone users. Two CE (Conformit Europenne) marked apps are available for download. No published peer reviewed study was found evaluating the TeleSkin skinScan app. SkinVision was evaluated in three studies (n=267, 66 malignant or premalignant lesions) and achieved a sensitivity of 80% (95% confidence interval 63% to 92%) and a specificity of 78% (67% to 87%) for the detection of malignant or premalignant lesions. Accuracy of the SkinVision app verified against expert recommendations was poor (three studies). Conclusions Current algorithm based smartphone apps cannot be relied on to detect all cases of melanoma or other skin cancers. Test performance is likely to be poorer than reported here when used in clinically relevant populations and by the intended users of the apps. The current regulatory process for awarding the CE marking for algorithm based apps does not provide adequate protection to the public. Systematic review registration PROSPERO CRD42016033595.
Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk
Authors: Iris E. Jansen, Jeanne E. Savage, Kyoko Watanabe, Julien Bryois, Dylan M. Williams, Stacy Steinberg, Julia Sealock, Ida K. Karlsson, Sara Hägg, Lavinia Athanasiu, Nicola Voyle, Petroula Proitsi, Aree Witoelar, Sven Stringer, Dag Aarsland, Ina S. Almdahl, Fred Andersen, Sverre Bergh, Francesco Bettella, Sigurbjorn Bjornsson, Anne Brækhus, Geir Bråthen, Christiaan de Leeuw, Rahul S. Desikan, Srdjan Djurovic, Logan Dumitrescu, Tormod Fladby, Timothy J. Hohman, Palmi V. Jonsson, Steven J. Kiddle, Arvid Rongve, Ingvild Saltvedt, Sigrid B. Sando, Geir Selbæk, Maryam Shoai, Nathan G. Skene, Jon Snaedal, Eystein Stordal, Ingun D. Ulstein, Yunpeng Wang, Linda R. White, John Hardy, Jens Hjerling-Leffler, Patrick F. Sullivan, Wiesje M. van der Flier, Richard Dobson, Lea K. Davis, Hreinn Stefansson, Kari Stefansson, Nancy L. Pedersen, Stephan Ripke, Ole A. Andreassen, Danielle Posthuma
Journal: Nature Genetics (2020)
Whole-Gene Sequencing of <i>CFTR</i> Reveals a High Prevalence of the Intronic Variant c.3874-4522A&gt;G in Cystic Fibrosis
Authors: Deborah J. Morris-Rosendahl, Matthew Edwards, Melissa J. McDonnell, Shibu John, Eric W. F. W. Alton, Jane C. Davies, Nicholas J. Simmonds
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Synergistic Combination of Oncolytic Virotherapy and Immunotherapy for Glioma
Authors: Bingtao Tang, Zong Sheng Guo, David L. Bartlett, David Z. Yan, Claire P. Schane, Diana L. Thomas, Jia Liu, Grant McFadden, Joanna L. Shisler, Edward J. Roy
Journal: Clinical Cancer Research (2020)

We hypothesized that the combination of a local stimulus for activating tumor-specific T cells and an anti-immunosuppressant would improve treatment of gliomas. Virally encoded IL15Rα-IL15 as the T-cell activating stimulus and a prostaglandin synthesis inhibitor as the anti-immunosuppressant were combined with adoptive transfer of tumor-specific T cells.Two oncolytic poxviruses, vvDD vaccinia virus and myxoma virus, were each engineered to express the fusion protein IL15Rα-IL15 and a fluorescent protein. Viral gene expression (YFP or tdTomato Red) was confirmed in the murine glioma GL261 in vitro and in vivo. GL261 tumors in immunocompetent C57BL/6J mice were treated with vvDD-IL15Rα-YFP vaccinia virus or vMyx-IL15Rα-tdTr combined with other treatments, including vaccination with GARC-1 peptide (a neoantigen for GL261), rapamycin, celecoxib, and adoptive T-cell therapy.vvDD-IL15Rα-YFP and vMyx-IL15Rα-tdTr each infected and killed GL261 cells in vitro. In vivo, NK cells and CD8+ T cells were increased in the tumor due to the expression of IL15Rα-IL15. Each component of a combination treatment contributed to prolonging survival: an oncolytic virus, the IL15Rα-IL15 expressed by the virus, a source of T cells (whether by prevaccination or adoptive transfer), and prostaglandin inhibition all synergized to produce elimination of gliomas in a majority of mice. vvDD-IL15Rα-YFP occasionally caused ventriculitis-meningitis, but vMyx-IL15Rα-tdTr was safe and effective, causing a strong infiltration of tumor-specific T cells and eliminating gliomas in 83% of treated mice.IL15Rα-IL15-armed oncolytic poxviruses provide potent antitumor effects against brain tumors when combined with adoptive T-cell therapy, rapamycin, and celecoxib.
Tumor size and the risk for lymph node metastases in T1 esophageal adenocarcinoma.
Authors: Meena Sadaps, Neal Mehta, Michael J. McNamara, Alok A. Khorana, Amit Bhatt
Journal: Journal of Clinical Oncology (2020)

332 Background: Adjuvant therapy after endoscopic resection (ER) of T1 EAC in non-surgical candidates is largely based on the risk of LNM. Risk factors for LNM in T1 EAC are not clearly defined. Our aim is to evaluate risk factors for LNM in T1 EAC patients following esophagectomy or ER with ≥ 5 years of follow-up. Methods: This is a retrospective analysis at a large tertiary referral center. Our pathology database identified patients who underwent esophagectomy or ER with ≥ 5 years follow-up, with histologically proven T1 EAC from 2010-2017. Patients were excluded if they (a) received chemoradiation prior to esophagectomy or before/after ER (b) had any other primary cancer treated within the previous 5 years. Specimens were reviewed by an expert GI pathologist for accuracy. Results: Of 80 patients [85% males], 61 (76%) underwent esophagectomy and 19 (24%) underwent ER. Twelve (15%) developed LNM per study criteria. Tumor size was significantly (p-value 0.014) associated with risk of LNM (Table). No other factors including lymphovascular invasion, differentiation on pathology, macroscopic appearance, infiltration growth pattern, or tumor distance from the gastroesophageal junction were significant risk factors for LNM. Conclusions: In T1 EAC, tumor size appears to be a significant risk factor for LNM at five years following surgical or endoscopic resection. Adjuvant therapy should be considered in patients with larger tumor size. [Table: see text]
Can We Really Stop Pediatric Migraine?
Authors: Boris Zernikow
Journal: JAMA Pediatrics (2020)

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Abstract 11388: Calmodulin-Dependent Protein Kinase II Activation Promotes Cardiac Structural Remolding and Kidney Mesangial Expansion in Streptozotocin-Induced Diabetic Mice
Authors: Alexei V Mikhailov, Jen-Jar Lin, Yixi Liu, Heng-Jie Cheng, David Herrington, David Zhao, Che Ping Cheng
Journal: Circulation (2019)

Background: Cardiorenal syndrome is a complication of diabetes mellitus (DM) and a cause of declining function in both organs. Calmodulin-dependent protein kinase II (CaMKII) is upregulated in DM a...
Abstract 10175: The Impact of Anticoagulation During Intra-Aortic Balloon Counterpulsation Pump Placement on In-Hospital Outcomes in 18,875 Patients Undergoing Cardiac Revascularization
Authors: Chee Tang Chin, Robert V Kelly, Mauricio G Cohen, Marc Cohen, J R Trout, Gregg W Stone, Jan T Christenson, Robert J Freedman, Ramachandra C Reddy, Debra Joseph, E M Ohman
Journal: Circulation (2010)

Background: Anticoagulation during intra aortic balloon counterpulsation pumping (IABP) is widely considered standard adjunctive therapy to prevent catheter thrombosis and embolic events. However, ...
Identification and validation of biomarkers of persistent acute kidney injury: the RUBY study
Authors: Eric Hoste, Azra Bihorac, Ali Al-Khafaji, Luis M. Ortega, Marlies Ostermann, Michael Haase, Kai Zacharowski, Richard Wunderink, Michael Heung, Matthew Lissauer, Wesley H. Self, Jay L. Koyner, Patrick M. Honore, John R. Prowle, Michael Joannidis, Lui G. Forni, J. Patrick Kampf, Paul McPherson, John A. Kellum, Lakhmir S. Chawla
Journal: Intensive Care Medicine (2020)

The aim of the RUBY study was to evaluate novel candidate biomarkers to enable prediction of persistence of renal dysfunction as well as further understand potential mechanisms of kidney tissue damage and repair in acute kidney injury (AKI). The RUBY study was a multi-center international prospective observational study to identify biomarkers of the persistence of stage 3 AKI as defined by the KDIGO criteria. Patients in the intensive care unit (ICU) with moderate or severe AKI (KDIGO stage 2 or 3) were enrolled. Patients were to be enrolled within 36 h of meeting KDIGO stage 2 criteria. The primary study endpoint was the development of persistent severe AKI (KDIGO stage 3) lasting for 72 h or more (NCT01868724). 364 patients were enrolled of whom 331 (91%) were available for the primary analysis. One hundred ten (33%) of the analysis cohort met the primary endpoint of persistent stage 3 AKI. Of the biomarkers tested in this study, urinary C–C motif chemokine ligand 14 (CCL14) was the most predictive of persistent stage 3 AKI with an area under the receiver operating characteristic curve (AUC) (95% CI) of 0.83 (0.78–0.87). This AUC was significantly greater than values for other biomarkers associated with AKI including urinary KIM-1, plasma cystatin C, and urinary NGAL, none of which achieved an AUC > 0.75. Elevated urinary CCL14 predicts persistent AKI in a large heterogeneous cohort of critically ill patients with severe AKI. The discovery of CCL14 as a predictor of persistent AKI and thus, renal non-recovery, is novel and could help identify new therapeutic approaches to AKI.