tbuckley/cabot-search huggingface dataset:
Abstract 12465: Association of Markers of Electrical Heterogeneity With Premature Ventricular Contractions on 12-Lead Electrocardiogram
Authors: Abhishek Maan, Jonathan W Waks, David German, Muammar Kabir, Jason Thomas, Golriz Sedhaghat, Colleen Sitlani, Mary Biggs, Nona Sotoodehnia, David Siscovick, Tor Biering-Soresen, Elsayed Z Soliman, E. Kevin Heist, Scott Solomon, Wendy Post, Alfred E Buxton, Mark Josephson, Larisa Tereshchenko
Journal: Circulation (2016)

Introduction: It was recently shown that independent electrophysiological substrate, quantified by global electrical heterogeneity (GEH) measures on ECG, is associated with Sudden Cardiac Death (SCD). However, mechanisms of GEH development are incompletely understood. Hypothesis: We hypothesized that the presence of premature ventricular contractions (PVCs) on 12-lead ECG is associated with GEH. Methods: We analyzed 20,288 participants from the Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Studies (CHS). Linear regression models were adjusted for demographics, structural heart disease and its risk factors to assess the association between PVCs and GEH. In a subsequent analysis, we included only those participants (n =478) who had both (a): monomorphic (if multiple) or single PVCs and (b): normal median sinus beat . The distance between PVC’s QRS vector and sinus T vector was calculated assuming the heart as a global structure. Prematurity index (PI) was defined as coupling interval (CI) divided by mean sinus-beat RR interval. SAI QRST (sum absolute interval of QRST interval) was measured as the arithmetic sum of areas under the QRST curve. Results: After adjusting for structural heart disease and its risk factors, the presence of PVCs was associated with a QRS-T angle widening by 6.9 (95% CI: 4.41-9.41) degrees (p &lt; 0.0001), and SAI QRST increase by 7.03 mV*ms (95% CI: 2.58-11.48, p = 0.002). On comprehensive adjustment using our linear regression model, among those with PVCs, 1 standard deviation of decrease in the distance between PVC’s QRS-vector and sinus beat’s T-vector was associated with spatial QRS-T angle increase by 3.6 (95% CI: 0.3-7.2) degrees (p =0.048). In the same model increase in PI by 10% was associated with spatial QRS-T angle increase by 3.0 (95%CI 0.7-4.9) degrees (P=0.010). Conclusions: The presence of PVCs is independently associated with an increase in the GEH. Better alignment between PVC’s QRS-vector and sinus beat’s T-vector (presumed cardiac memory) and less premature PVC was independently associated with wider spatial QRS-T angle.
Foxp3+ T reg cells control psoriasiform inflammation by restraining an IFN-I–driven CD8+ T cell response
Authors: Krista Stockenhuber, Ahmed N. Hegazy, Nathaniel R. West, Nicholas E. Ilott, Alexander Stockenhuber, Samuel J. Bullers, Emily E. Thornton, Isabelle C. Arnold, Andrea Tucci, Herman Waldmann, Graham S. Ogg, Fiona Powrie
Journal: The Journal of Experimental Medicine (2018)

Psoriasis is a complex inflammatory skin disease affecting ∼3% of the population worldwide. Although type I interferons (IFN-I) are thought to be involved in its pathogenesis, the details of this relationship remain elusive. Here we show that in a murine model of imiquimod-driven psoriatic skin inflammation, Foxp3+ regulatory T cells (T reg cells) control inflammation severity by restraining IFN-I. Depletion of T reg cells induces IFN-I and IFN-stimulated gene expression, and leads to accumulation of CD8+ T cells in lesional skin. Mononuclear phagocytes (MNPs) were the source of IFN-I, and their depletion reversed the effect of T reg cell depletion. Blockade of IFN-I signaling abolished CD8+ T cell infiltration and excess inflammation in the skin of T reg cell–depleted mice. Depletion of CD8+ T cells attenuated pathology, confirming their role as critical effector cells downstream of IFN-I. Our results describe an unexpected role for T reg cells in restraint of an MNP–IFN-I–driven CD8+ T cell response during psoriasiform skin inflammation. These findings highlight a pathway with potential relevance for the treatment of early-stage disease.
Second signals rescue B cells from activation-induced mitochondrial dysfunction and death
Authors: Munir Akkaya, Javier Traba, Alexander S. Roesler, Pietro Miozzo, Billur Akkaya, Brandon P. Theall, Haewon Sohn, Mirna Pena, Margery Smelkinson, Juraj Kabat, Eric Dahlstrom, David W. Dorward, Jeff Skinner, Michael N. Sack, Susan K. Pierce
Journal: Nature Immunology (2018)
Improving the career prospects of international medical graduates
Authors: Rahul Tony Rao
Journal: BMJ (2018)

Simpson’s essay on the role of international medical graduates is a surreal biography of my own personal life and medical career.1

In the late 1960s, an acute shortage of doctors in certain specialties across England led to recruitment of doctors from outside Europe, mostly from the Asian subcontinent.2 As the son of two such doctors, the reality of how they were treated is ingrained …
REPAIRING A GASTROCUTANEOUS FISTULA AFTER PEG-TUBE REMOVAL
Authors: G Grajales-Figueroa, AI Ramirez Polo, LE Zamora Nava, F Valdovinos Andraca
Journal: Endoscopy (2018)

A 69-year-old man was evaluated at the unit because of dysphagia. The upper endoscopy revealed an esophageal mass with exophytic growth in the lower third, which was obstructing 70% of the esophageal lumen. The biopsy concluded the diagnosis of adenocarcinoma originated in Barrett's esophagus. Because of the inability of per oral intake, a percutaneous endoscopic gastrostomy was placed, with the “pull” technique. After 17 days, a delimitated zone of erythema was identified around the site of gastrostomy tube placement in the abdominal wall with leaking of alimentary and gastric content. A new upper endoscopy revealed a 2 cm defect in the anterior gastric wall with visualization of the internal bumper through the gastric wall. The diagnosis of “buried bumper syndrome” was made and the gastrostomy tube was removed. After 7 days of the removal, persistence of the defect both in the skin and in the gastric wall with leakage of gastric content was identified. There were multiple attempts to close the 2-cm defect with endoscopic hemoclips. Using a double-channel scope (GIF 2T160, Olympus Medical Co, Tokyo, Japan), the procedure for closing the defect began with the placement of a 3 cm detachable snare around the defect site. Then, the snare was anchored and with hemostatic clips and tightened in order to close the defect. An air leak test revealed that the wall defect was not fully closed. In order to achieve complete endoscopic closure, N-butyl-2-cyanoacrylate was applied over the defect site among the clips. One week later, an upper endoscopy showed the complete healing of the defect.
Response by Ibrahim et al to Letter Regarding Article, “Effect of Intravenous Fentanyl on Ticagrelor Absorption and Platelet Inhibition Among Patients Undergoing Percutaneous Coronary Intervention: The PACIFY Randomized Clinical Trial (Platelet Aggregation With Ticagrelor Inhibition and Fentanyl)”
Authors: Khalil Ibrahim, Rohan Shah, John W. McEvoy
Journal: Circulation (2018)
Protein Kinase Cθ Via Activating Transcription Factor 2-Mediated CD36 Expression and Foam Cell Formation of Ly6C <sup>hi</sup> Cells Contributes to Atherosclerosis
Authors: Somasundaram Raghavan, Nikhlesh K. Singh, Sivaiah Gali, Arul M. Mani, Gadiparthi N. Rao
Journal: Circulation (2018)

Although the role of thrombin in atherothrombosis is well studied, its role in the pathogenesis of diet-induced atherosclerosis is not known.Using a mouse model of diet-induced atherosclerosis and molecular biological approaches, here we have explored the role of thrombin and its G protein-coupled receptor signaling in diet-induced atherosclerosis.In exploring the role of G protein-coupled receptor signaling in atherogenesis, we found that thrombin triggers foam cell formation via inducing CD36 expression, and these events require Par1-mediated Gα12-Pyk2-Gab1-protein kinase C (PKC)θ-dependent ATF2 activation. Genetic deletion of PKCθ in apolipoprotein E (ApoE)-/- mice reduced Western diet-induced plaque formation. Furthermore, thrombin induced Pyk2, Gab1, PKCθ, and ATF2 phosphorylation, CD36 expression, and foam cell formation in peritoneal macrophages of ApoE-/- mice. In contrast, thrombin only stimulated Pyk2 and Gab1 but not ATF2 phosphorylation or its target gene CD36 expression in the peritoneal macrophages of ApoE-/-:PKCθ-/- mice, and it had no effect on foam cell formation. In addition, the aortic root cross-sections of Western diet-fed ApoE-/- mice showed increased Pyk2, Gab1, PKCθ, and ATF2 phosphorylation and CD36 expression as compared with ApoE-/-:PKCθ-/- mice. Furthermore, although the monocytes from peripheral blood and the aorta of Western diet-fed ApoE-/- mice were found to contain more of Ly6Chi cells than Ly6Clo cells, the monocytes from Western diet-fed ApoE-/-:PKCθ-/- mice were found to contain more Ly6Clo cells than Ly6Chi cells. It is interesting to note that the Ly6Chi cells showed higher CD36 expression with enhanced capacity to form foam cells as compared with Ly6Clo cells.These findings reveal for the first time that thrombin-mediated Par1-Gα12 signaling via targeting Pyk2-Gab1-PKCθ-ATF2-dependent CD36 expression might be playing a crucial role in diet-induced atherogenesis.
Eradication of Helicobacter pylori in functional dyspepsia
Authors: K. E L McColl, D. Gillen, A. S Dickson, N. J Talley, K. Lauritsen, E. Bolling-Sternevald
Journal: BMJ (1999)

Editor—Several weaknesses in Talley et al’s study may explain its failure to detect symptomatic benefit from eradicating infection with Helicobacter pylori in functional dyspepsia.1 The first is inadequate follow up. Of the three quarters of patients said to have completed the study, some did not reach their one year assessment. The outcome measurement even in those reaching the one year end point seems to have been inadequate as symptom diary cards in which only three fifths were completed were considered acceptable. The proportion of randomised patients reaching the one year end point with complete outcome documentation needs to be reported.

In our study, funded by the Medical Research Council, 318 patients were randomised and 97% were fully reassessed one year after treatment.2 This reassessment showed a significant benefit of active compared with placebo treatment of 14% (95% confidence interval 7% to 22%; P<0.001). Even before the problems with follow up are taken into account, Talley et al’s study only had the power to detect a benefit of 20%, and its negative result in no way refutes the findings of our study.

Another problem in the authors’ study is that, despite functional dyspepsia being common, half of the 40 centres recruited fewer than six patients. How representative were these patients of patients with the disorder? The symptom characteristics indicate that patients with the motility type of functional dyspepsia—the group least likely to benefit from eradication treatment—were overrepresented, making up most of those randomised. In our study every patient fulfilling the entry criteria was randomised apart from nine (3%) who did not consent.

Despite the above shortcomings, there are several pointers in Talley et al’s study towards symptomatic benefit from eradicating H pylori. Resolution of symptoms was 8% greater in those who became negative for H pylori than in those who remained positive for it, and the use of antacids was 18% less. Furthermore, symptoms resolved in 15% more of those with little or no persisting H pylori gastritis, and this was highly significant (P=0.008) even on secondary analysis.

The magnitude of benefit of 14% over placebo treatment detected by our study, but missed by studies of inadequate power, is clinically important. The treatments currently used, such as anti-secretory agents and anti-nociceptive agents, produce a benefit of only 10% over placebo.3,4 Consequently, the benefit of treatment to eradicate H pylori is at least as great as that of any other currently available treatment. Moreover, the benefit is achieved by a single week’s course of treatment rather than by long term, expensive maintenance treatment.
DIAGNOSTIC YIELD OF NEW 20-GAUGE FORWARD-BEVEL CORE BIOPSY NEEDLE FOR EUS-GUIDED TISSUE ACQUISITION FROM PANCREATIC LESIONS IN COMPARISON WITH STANDARD 22G NEEDLE
Authors: H Ishiwatari, S Fujie, K Sasaki, J Sato, H Matsubayashi, M Yoshida, K Imai, S Ito, N Kawata, N Kakushima, K Takizawa, K Hotta, H Ono
Journal: Endoscopy (2018)

A 20G forward-bevel core biopsy needle (CBN) characterized by an antegrade core trap has been developed to obtain histological core tissue during endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). We evaluated diagnostic yield of the needle for EUS-FNA of a solid pancreatic mass ≥10 mm in comparison with standard 22G needle.
Strain-Level Analysis of Mother-to-Child Bacterial Transmission during the First Few Months of Life
Authors: Moran Yassour, Eeva Jason, Larson J. Hogstrom, Timothy D. Arthur, Surya Tripathi, Heli Siljander, Jenni Selvenius, Sami Oikarinen, Heikki Hyöty, Suvi M. Virtanen, Jorma Ilonen, Pamela Ferretti, Edoardo Pasolli, Adrian Tett, Francesco Asnicar, Nicola Segata, Hera Vlamakis, Eric S. Lander, Curtis Huttenhower, Mikael Knip, Ramnik J. Xavier
Journal: Cell Host & Microbe (2018)
Competing Risks in Older Patients With Cancer: A Systematic Review of Geriatric Oncology Trials
Authors: Nikki Burdett, Andrew D Vincent, Michael O’Callaghan, Ganessan Kichenadasse
Journal: JNCI Journal of the National Cancer Institute (2018)

It is increasingly recognized that older adults with cancer represent a diverse cohort of patients and that other comorbidities may have an equal impact on survival and quality of life as any diagnosis of malignancy. Competing risk has consequently emerged as an important concept in the design and reporting of geriatric oncology trials.We performed a systematic review of phase II and III oncology trials for systemic therapy in older patients with solid organ malignancy from the year 2000 until April 30, 2017. Forty-one trials including 7864 patients were identified for evaluation.Only 15 trials (36.6%) employed disease-related end points to account for death from other causes, and only one study used statistical analysis that addressed competing risk. Seventeen studies (41.5%) of trials included some assessment of comorbidity or frailty. Twenty-one trials (51.2%) included any assessment of quality of life.This review demonstrates clear areas for improvement for future studies and highlights the need for careful consideration of trial design, data collection, and appropriate statistical methodology for reporting of competing risks in geriatric oncology trials.
Concomitant Oral Anticoagulant and Nonsteroidal Anti-Inflammatory Drug Therapy in Patients With Atrial Fibrillation
Authors: Anthony P. Kent, Martina Brueckmann, Mandy Fraessdorf, Stuart J. Connolly, Salim Yusuf, John W. Eikelboom, Jonas Oldgren, Paul A. Reilly, Lars Wallentin, Michael D. Ezekowitz
Journal: Journal of the American College of Cardiology (2018)
Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin For Patients With Relapsed/Refractory Multiple Myeloma: Results From a Phase 1/2 Trial
Authors: James R. Berenson, James D. Hilger, Leonard Klein, Alberto Bessudo, Peter J. Rosen, Shahrooz Eshaghian, Youram Nassir, Regina A. Swift, Robert Vescio
Journal: Blood (2013)
The impact of continuing medical education (CME) programs in metastatic castration-resistant prostate cancer (CRPC).
Authors: Hamsa Jaganathan, Anne Roc, Andrew J. Armstrong, Daniel J. George, Wendy Turell
Journal: Journal of Clinical Oncology (2017)

e18280 Background: The concurrent development of many CRPC treatments within a short period of time has made prospective data on their sequential use and efficacy complicated, which have challenged clinician confidence, knowledge, and competency. Four hours of CME focused on the therapeutic management of CRPC were developed and participant responses analyzed to determine if these challenges were addressed. Methods: PlatformQ Health developed and executed 4 hours of virtual CME programs in CRPC. The 1st 2-hours, broadcast in May 2015 and offered online for 6 months, attracted a total of 545 learners. The 2nd 2-hours, broadcast in July 2016 and offered for 12 months, attracted a total of 345* learners. Survey-based evaluations targeted self-reported clinician data on satisfaction, clinical practice change and observed patient outcome. Clinician participation data and self-reported patients with CRPC seen per week were used in extrapolations of patients impacted by the CME education per week. Results: Between the 2015 and 2016 CME programs, learners gained confidence in their ability to employ a personalized, sequential approach to treat CRPC (12% vs 35%). Overall, 68% of all learners reported a positive clinical practice impact and 59% reported a positive impact on patient experience and/or outcomes as a result of CME participation. Learner commitment to change was consistently observed in both 2015 and 2016 programs in: medical and practice knowledge (90% and 94%, respectively), care attitudes (83% and 85%), practice behavior (79% and 77%), and their patients’ clinical outcomes (76% and 78%). An estimated 4,066 patients in 2015 and 3,374 patients in 2016 were impacted as a result of the education. Conclusions: Outcomes results of 2 years of education on evolving treatment paradigms of metastatic CRPC demonstrate learner improvements in both clinical practice and patient outcomes. Continuing education in the management of CRPC is recommended, particularly on strategies to appropriately sequence treatments, treatment of bone metastases, keeping abreast of new data, and understanding the rationale for investigational agents. *As of Jan 2017, data collection is ongoing
Metabolic phenotype of skeletal muscle in early critical illness
Authors: Zudin A Puthucheary, Ronan Astin, Mark J W Mcphail, Saima Saeed, Yasmin Pasha, Danielle E Bear, Despina Constantin, Cristiana Velloso, Sean Manning, Lori Calvert, Mervyn Singer, Rachel L Batterham, Maria Gomez-Romero, Elaine Holmes, Michael C Steiner, Philip J Atherton, Paul Greenhaff, Lindsay M Edwards, Kenneth Smith, Stephen D Harridge, Nicholas Hart, Hugh E Montgomery
Journal: Thorax (2018)

To characterise the sketetal muscle metabolic phenotype during early critical illness.Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5).From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (-27.4CN (95% CI -123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (-1859CN (IQR -5557-1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (-4.8 mmol/kg dw (IQR -8.0-1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR -0.09-2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5-1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR -0.44-3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4-39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR -7-100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered.Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting.NCT01106300.
Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells
Authors: Fiamma Salerno, Sander Engels, Maartje van den Biggelaar, Floris P. J. van Alphen, Aurelie Guislain, Wanqi Zhao, Deborah L. Hodge, Sarah E. Bell, Jan Paul Medema, Marieke von Lindern, Martin Turner, Howard A. Young, Monika C. Wolkers
Journal: Nature Immunology (2018)
miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential
Authors: Sara E. Meyer, David E. Muench, Andrew M. Rogers, Tess J. Newkold, Emily Orr, Eric O’Brien, John P. Perentesis, John G. Doench, Ashish Lal, Patrick J. Morris, Craig J. Thomas, Judy Lieberman, Edwina McGlinn, Bruce J. Aronow, Nathan Salomonis, H. Leighton Grimes
Journal: The Journal of Experimental Medicine (2018)

We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found Cdkn1b (p27Kip1) is a direct miR-196b target whose repression enhanced an embryonic stem cell–like signature associated with decreased leukemia latency and increased numbers of leukemia stem cells in vivo. Conversely, elevation of p27Kip1 significantly reduced MLL-r leukemia self-renewal, promoted monocytic differentiation of leukemic blasts, and induced cell death. Antagonism of miR-196b activity or pharmacologic inhibition of the Cks1-Skp2–containing SCF E3-ubiquitin ligase complex increased p27Kip1 and inhibited human AML growth. This work illustrates that understanding oncogenic miRNA target pathways can identify actionable targets in leukemia.
To what are we trying to generalize?
Authors: Robin M. Hogarth
Journal: Behavioral and Brain Sciences (2001)

In conducting experiments, economists take more care than psychologists in specifying characteristics of people and tasks and are clearer about the conditions to which results can be generalized. Psychologists could learn much from this practice. They should also think in terms of programs of research – involving laboratory and field studies – that will allow them to test the generality of their theories.
Beyond Primary Tumor Location and <i>RAS/BRAF</i> Mutational Status as Prognostic Factor in Stage III Colon Cancer—Reply
Authors: Julien Taieb
Journal: JAMA Oncology (2018)

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