tbuckley/cabot-search huggingface dataset:
Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss
Authors: Johann S. de Bono, Ugo De Giorgi, Daniel Nava Rodrigues, Christophe Massard, Sergio Bracarda, Albert Font, Jose Angel Arranz Arija, Kent C. Shih, George Daniel Radavoi, Na Xu, Wai Y. Chan, Han Ma, Steven Gendreau, Ruth Riisnaes, Premal H. Patel, Daniel J. Maslyar, Viorel Jinga
Journal: Clinical Cancer Research (2018)

Abstract Purpose: PI3K–Akt–mTOR and androgen receptor (AR) signaling are commonly aberrantly activated in metastatic castration-resistant prostate cancer (mCRPC), with PTEN loss associating with poor prognosis. We therefore conducted a phase Ib/II study of the combination of ipatasertib, an Akt inhibitor, with the CYP17 inhibitor abiraterone in patients with mCRPC. Patients and Methods: Patients were randomized 1:1:1 to ipatasertib 400 mg, ipatasertib 200 mg, or placebo, with abiraterone 1,000 mg orally. Coprimary efficacy endpoints were radiographic progression-free survival (rPFS) in the intent-to-treat population and in patients with PTEN-loss tumors. Results: rPFS was prolonged in the ipatasertib cohort versus placebo, with similar trends in overall survival and time-to-PSA progression. A larger rPFS prolongation for the combination was demonstrated in PTEN-loss tumors versus those without. The combination was well tolerated, with no treatment-related deaths. Conclusions: In mCRPC, combined blockade with abiraterone and ipatasertib showed superior antitumor activity to abiraterone alone, especially in patients with PTEN-loss tumors. See related commentary by Zhang et al., p. 901
Multi-family therapy for veteran and refugee families: a Delphi study
Authors: Elisa van Ee
Journal: Military Medical Research (2018)

Research indicates that Posttraumatic stress disorder (PTSD) has an extensive impact on family relationships. Nevertheless, there is a dearth of empirically supported interventions addressing family functioning and PTSD. In the Netherlands, it is considered good clinical practice to offer multi-family therapy (MFT) to veteran and refugee families. MFT for traumatized families aims to address the dysfunctional family patterns that have evolved to address the consequences with trauma. The aim of this study is to generate a common framework for the practical impact and active ingredients of MFT in families confronted with trauma. The Delphi method was used to study the expert opinion of 11 therapists in Dutch expert trauma institutes. The results indicate that MFT is a promising treatment for families dealing with the consequences of trauma. According to experts, positive outcomes include an increased understanding between family members, particularly visible in the de-escalation of conflicts within the family, and improved parenting. One explanation for the effectiveness of MFT with these target groups is its defining feature of therapy with several families. The findings support the importance of considering family relationships and the family context in interventions for traumatized individuals.
Face Masks Reduce the Release of <i>Pseudomonas aeruginosa</i> Cough Aerosols When Worn for Clinically Relevant Periods
Authors: Rebecca E. Stockwell, Michelle E. Wood, Congrong He, Laura J. Sherrard, Emma L. Ballard, Timothy J. Kidd, Graham R. Johnson, Luke D. Knibbs, Lidia Morawska, Scott C. Bell, Maureen Peasey, Christine Duplancic, Kay A. Ramsay, Nassib Jabbour, Peter O’Rourke, Claire E. Wainwright, Peter D. Sly
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Occult blood in faeces is associated with all-cause and non-colorectal cancer mortality
Authors: Gillian Libby, Callum G Fraser, Frank A Carey, David H Brewster, Robert J C Steele
Journal: Gut (2018)

Objective An association between detectable faecal haemoglobin (f-Hb) and both the risk of death from colorectal cancer (CRC) and all-cause mortality has been reported. We set out to confirm or refute this observation in a UK population and to explore the association between f-Hb, as indicated by a positive guaiac faecal occult blood test (gFOBT) result, and different causes of death. Design All individuals (134 192) who participated in gFOBT screening in Tayside, Scotland between 29/03/2000 and 29/03/2016 were studied by linking their test result (positive or negative) with mortality data from the National Records of Scotland database and following to 30/03/2016. Results Those with a positive test result (n=2714) had a higher risk of dying than those with a negative result, from CRC: HR 7.79 (95% CI 6.13 to 9.89), p&lt;0.0001, (adjusted for, gender, age, deprivation quintile and medication that can cause bleeding) and all non-CRC causes: HR 1.58 (95% CI 1.45 to 1.73), p&lt;0·0001.· In addition, f-Hb detectable by gFOBT was significantly associated with increased risk of dying from circulatory disease, respiratory disease, digestive diseases (excluding CRC), neuropsychological disease, blood and endocrine disease and non-CRC. Conclusion The presence of detectable f-Hb is associated with increased risk of death from a wide range of causes.
What the replication reformation wrought
Authors: Barbara A. Spellman, Daniel Kahneman
Journal: Behavioral and Brain Sciences (2018)

Abstract Replication failures were among the triggers of a reform movement which, in a very short time, has been enormously useful in raising standards and improving methods. As a result, the massive multilab multi-experiment replication projects have served their purpose and will die out. We describe other types of replications – both friendly and adversarial – that should continue to be beneficial.
The adenosine monophosphate–activated protein kinase—vacuolar adenosine triphosphatase–pH axis: A key regulator of the profibrogenic phenotype of human hepatic stellate cells
Authors: Giusi Marrone, Francesco De Chiara, Katrin Böttcher, Ana Levi, Dipok Dhar, Lisa Longato, Giuseppe Mazza, Zhenzhen Zhang, Martina Marrali, Anabel Fernández‐Iglesias, Andrew Hall, Tu Vinh Luong, Benoit Viollet, Massimo Pinzani, Krista Rombouts
Journal: Hepatology (2018)

Liver fibrosis and cirrhosis are characterized by activation of hepatic stellate cells (HSCs), which is associated with higher intracellular pH (pHi). The vacuolar H + adenosine‐triphosphatase (v‐ATPase) multisubunit complex is a key regulator of pHi homeostasis. The present work investigated the functional role of v‐ATPase in primary human HSC (hHSC) activation and its modulation by specific adenosine monophosphate–activated protein kinase (AMPK) subunits. We demonstrate that the expression of different v‐ATPase subunits was increased in in vivo and in vitro activated hHSCs compared to nonactivated hHSCs. Specific inhibition of v‐ATPase with bafilomycin and KM91104 induced a down‐regulation of the HSC fibrogenic gene profile, which coincided with increased lysosomal pH, decreased pHi, activation of AMPK, reduced proliferation, and lower metabolic activity. Similarly, pharmacological activation of AMPK by treatment with diflunisal, A769662, and ZLN024 reduced the expression of v‐ATPase subunits and profibrogenic markers. v‐ATPase expression was differently regulated by the AMPK α1 subunit (AMPKα1) and AMPKα2, as demonstrated in mouse embryo fibroblasts specifically deficient for AMPK α subunits. In addition, activation of v‐ATPase in hHSCs was shown to be AMPKα1‐dependent. Accordingly, pharmacological activation of AMPK in AMPKα1‐depleted hHSCs prevented v‐ATPase down‐regulation. Finally, we showed that v‐ATPase expression was increased in fibrotic livers from bile duct–ligated mice and in human cirrhotic livers. Conclusion: The down‐regulation of v‐ATPase might represent a promising target for the development of antifibrotic strategies. (H epatology 2018).
Comparing image analysis approaches versus expert readers: the relation of knee radiograph features to knee pain
Authors: Luca Minciullo, Matthew J Parkes, David T Felson, Timothy F Cootes
Journal: Annals of the Rheumatic Diseases (2018)

Objectives The relationship between radiographic evidence of osteoarthritis and knee pain has been weak. This may be because features that best discriminate knees with pain have not been included in analyses. We tested the correlation between knee pain and radiographic features taking into account both image analysis features and manual scores. Methods Using data of the Multicentre Osteoarthritis Study, we tested in a cross-sectional design how well X-ray features discriminated those with frequent knee pain (one question at one time) or consistent frequent knee pain (three questions at three times during the 2 weeks prior to imaging) from those without it. We trained random forest models on features from two radiographic views for classification. Results X-rays were better at classifying those with pain using three questions compared with one. When we used all manual radiographic features, the area under the curve (AUC) was 73.9%. Using the best model from automated image analyses or a combination of these and manual grades, no improvement over manual grading was found. Conclusions X-ray changes of OA are more strongly associated with repeated reports of knee pain than pain reported once. In addition, a fully automated system that assessed features not scored on X-ray performed no better than manual grading of features.
Abstract 18926: Serum Resistin is not Associated with the Response to Lipid-Lowering Therapy in Non-Diabetic Patients with Coronary Artery Disease
Authors: Sahmin Lee, Yoon-Ki Kim, Yoo-Wook Kwon, Han-Mo Yang, Hyun-Jai Cho, Byung-Hee Oh, Young-Bae Park, Hyo-Soo Kim
Journal: Circulation (2012)

Background : Resistin is an adipokine that mediates insulin resistance in obese mice. In human, however, circulating resistin levels are not associated with obesity or insulin resistance. Although the function of human resistin is enigmatic, it has recently been reported that human resistin plays a role in hepatocyte low-density lipoprotein (LDL) receptor suppression. Objectives : Aim of this study was to determine if serum levels of resistin are associated with the response to lipid-lowering therapy and the prognosis in coronary artery disease (CAD). Methods : One hundred and eighty two patients without diabetes who underwent percutaneous coronary intervention for CAD participated in this study. We measured pre-procedural serum resistin levels. After procedures, we treated the patients with atorvastatin 20mg and evaluated response to the statin therapy at 6-month follow-up. We also performed 6-month follow-up coronary angiography (CAG) in all patients and quantitative coronary angiographic analysis was conducted. Results : After adjusting age, sex, BMI, hypertension and smoking, serum levels of resistin had positive correlation with total cholesterol (Pearson’s partial correlation coefficient (r)=0.170, p =0.015) and LDL (r=0.159, p =0.023) at baseline. However, there was no correlation between baseline serum levels of resistin and the decrement of LDL after statin therapy (r= 0.07, p =0.36). Although, serum resistin (odds ratio 1.714, 95%CI 1.266-2.319) and hypertension (odds ratio 4.617, 95%CI 1.535-13.887) were independent predictors of coronary artery disease in multivariate logistic regression analysis, we found no relationship between baseline serum levels of resistin and decrement in minimal lumen diameter of target vessel at follow-up CAG (r=0.003, p =0.96). Conclusions : Higher baseline serum resistin levels and the positive correlation between serum resistin and baseline LDL in CAD patients suggest that resistin may affect coronary atherosclerosis via lipid metabolism pathway. However, serum resistin is not associated with the response to lipid-lowering therapy and the prognosis in CAD. The different mechanism of restenosis after DES implantation might explain the irrelevance of resistin level and restenosis.
Incidence of Atrial Fibrillation and Mineralocorticoid Receptor Activity in Patients With Medically and Surgically Treated Primary Aldosteronism
Authors: Gregory L. Hundemer, Gary C. Curhan, Nicholas Yozamp, Molin Wang, Anand Vaidya
Journal: JAMA Cardiology (2018)

Primary aldosteronism (PA) is an ideal condition to evaluate the role of the mineralocorticoid receptor (MR) in the pathogenesis of atrial fibrillation (AF).To investigate whether MR antagonist therapy or surgical adrenalectomy in PA influence the risk for incident AF.This cohort study included patients aged 18 years and older. Patients with PA and age-matched patients with essential hypertension were identified via electronic health records. Patients with a history of AF, myocardial infarction, congestive heart failure, or stroke were excluded. Data were collected between 1991 and the end of 2016 in an academic medical center, with a mean follow-up duration of approximately 8 years.Patients with PA treated with MR antagonists or surgical adrenalectomy were compared with patients with essential hypertension. Patients with PA who were treated with MR antagonists were categorized by whether their plasma renin activity remained suppressed (< 1 ng/mL/h) or substantially increased (≥ 1 ng/mL/h), as proxies for insufficient or sufficient MR blockade.Incident AF.A total of 195 patients with PA who were treated with MR antagonists and 201 patients with PA treated with surgical adrenalectomy were included, as well as 40 092 age-matched patients with essential hypertension. Despite similar blood pressure at study entry and throughout follow-up, patients with PA who were treated with MR antagonists whose renin remained suppressed had a higher risk for incident AF than patients with essential hypertension (adjusted HR, 2.55 [95% CI, 1.75-3.71]). They also had an adjusted 10-year cumulative AF incidence difference of 14.1 (95% CI, 6.7-21.5) excess cases per 100 persons compared with patients with essential hypertension. In contrast, patients with PA who were treated with MR antagonists and whose renin increased and patients with PA who were treated with surgical adrenalectomy had no statistically significant difference in risk for incident AF compared with patients with essential hypertension.When compared with patients with essential hypertension, patients with PA treated with MR antagonists such that renin remained suppressed (as a proxy for insufficient MR blockade) had a significantly higher risk for incident AF; however, treatment of PA with MR antagonists to substantially increase renin (suggesting sufficient MR blockade), or with surgical adrenalectomy (to remove the source of aldosteronism), was associated with no significant difference in risk for developing AF. These findings add to the growing body of evidence suggesting that MR blockade may be a potential therapy to decrease the incidence of AF.
PTU-009 Competency of endoscopic non-technical skills (ents) during endoscopy training
Authors: K Siau, P Dunckley, J Anderson, I Beales, R Broughton, M Feeney, N Hawkes, B McKaig, R Valori, C Wells, S Thomas-Gibson, G Johnson, A Haycock
Journal: Gut (2017)

Introduction  Endoscopic non-technical skills (ENTS), comprising of communication and teamwork, situation awareness, leadership, and judgement and decision-making, are recognised indicators of quality endoscopy and patient safety. Since July 2016, electronic assessment forms (DOPS) for UK trainee endoscopists have been updated to include ENTS as an assessable domain. We aimed to explore the uptake and distribution of ENTS scoring in DOPS and their correlation with other endoscopic skills.  Method  We identified all DOPS submitted between July 2016 and Feb 2017 from the national trainee database (JETS) and acquired data on trainees, procedures and scores. We collated scores for each of the 4 assessable domains (pre-procedural, procedural, post-procedural and ENTs) into overall outcomes of “not competent” (if any domain items required supervision) or “competent”, and compared this to the overall competence rating. Statistical analysis was performed using chi2 and regression modelling.  Results  8601 DOPS were prospectively collected, with ENTS assessed in 99.3%. Overall competency rates in ENTS varied across procedures (p  Conclusion  ENTS is an assessable domain within endoscopy training, with scores that correlate with other procedure-related skills, demonstrating construct validity of the ENTS scoring system. Competency of ENTS develop with procedural count, and vary with trainee seniority and specialty. Longer term data are required to assess the impact of ENTS on certification.  Disclosure of Interest  None Declared
Different Effects Of Pulmonary Rehabilitation In Anxious Vs. Non-Anxious Patients With Idiopathic Pulmonary Fibrosis - A Pilot Study
Authors: I. Jarosch, T. Schneeberger, R. Gloeckl, M. Kreuter, J. Benstz, M. Frankenberger, C. Neurohr, A. Prasse, J. Behr, K. Kenn
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Dynamic Upper Airway Imaging during Wakefulness in Obese Subjects with and without Sleep Apnea
Authors: Yuan Feng, Brendan T. Keenan, Stephen Wang, Sarah Leinwand, Andrew Wiemken, Allan I. Pack, Richard J. Schwab
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Obesity is a major risk factor for obstructive sleep apnea. Although greater dimensional changes in the upper airway during wake respiration have been noted in patients with apnea compared with control subjects, whether these differences remain in the presence of obesity is unknown.Objectives: To evaluate upper airway anatomic characteristics and airway compliance (distensibility) in obese subjects with obstructive sleep apnea compared with obese control subjects.Methods: Dynamic magnetic resonance imaging was performed in 157 obese subjects with apnea and 46 obese control subjects during wakefulness in the midsagittal and three axial upper airway regions (retropalatal, retroglossal, epiglottal). Differences in measurements between subjects with apnea and control subjects, and correlations with apnea–hypopnea index among subjects with apnea, were examined.Measurements and Main Results: Measurements included airway areas and linear dimensions. Subject-specific coefficients of variation were calculated to examine variability in airway size. Controlling for covariates, the retropalatal area during respiration was significantly smaller in subjects with apnea than control subjects, based on the average (P = 0.003), maximum (P = 0.004), and minimum (P = 0.001) airway area. Airway narrowing was observed in anteroposterior and lateral dimensions (adjusted P < 0.05). Results were similar in an age, sex, and body mass index–matched subsample. There were significant correlations between apnea–hypopnea index and dynamic measures of airway caliber in the retropalatal and retroglossal regions among subjects with apnea.Conclusions: Upper airway caliber during respiration was significantly narrower in obese subjects with apnea than obese control subjects in the retropalatal region. These findings provide further evidence that retropalatal airway narrowing plays an important role in the pathogenesis of obstructive sleep apnea in obese subjects.
Allograft rejection is associated with development of functional IgE specific for donor MHC antigens
Authors: Andreas M. Farkas, Ulrike Baranyi, Georg A. Böhmig, Lukas Unger, Stefan Hopf, Markus Wahrmann, Heinz Regele, Benedikt Mahr, Christoph Schwarz, Karin Hock, Nina Pilat, Ivan Kristo, Jasmin Mraz, Christian Lupinek, Josef Thalhamer, Gregor Bond, Lorenz Kuessel, Elizabeth Wlodek, Jack Martin, Menna Clatworthy, Gavin Pettigrew, Rudolf Valenta, Thomas Wekerle
Journal: Journal of Allergy and Clinical Immunology (2018)

Donor-specific antibodies of the IgG isotype are measured routinely for diagnostic purposes in renal transplant recipients and are associated with antibody-mediated rejection and long-term graft loss.
Colon cleansing efficacy and safety with 1 L NER1006 versus sodium picosulfate with magnesium citrate: a randomized phase 3 trial
Authors: Stefan Schreiber, Daniel Baumgart, Joost Drenth, Rafał Filip, Lucy Clayton, Kerry Hylands, Alessandro Repici, Cesare Hassan
Journal: Endoscopy (2018)

Abstract Background Polyethylene glycol (PEG) bowel preparations are widely used for precolonoscopy bowel cleansing. This phase 3 trial assessed the efficacy, safety, and tolerability of the novel 1 L PEG-based NER1006 vs. sodium picosulfate plus magnesium citrate (SP + MC) in day-before dosing. Methods Patients requiring colonoscopy were randomized (1 : 1) to receive NER1006 or SP + MC. Cleansing was assessed on the Harefield Cleansing Scale (HCS) and Boston Bowel Preparation Scale (BBPS) using central readers. Two primary end points were assessed: overall colon cleansing success and high-quality cleansing of the right colon. Intention-to-treat (modified full analysis set [mFAS]) and per protocol (PP) analyses were performed. Results Of 515 patients, efficacy was analyzed in 501 (NER1006, n = 250; SP + MC, n = 251) and 379 patients (NER1006, n = 172; SP + MC, n = 207) in the mFAS and PP analyses, respectively. Non-inferiority of NER1006 vs. SP + MC was established in the mFAS for both overall cleansing (62.0 % vs. 53.8 %; P = 0.04) and high-quality cleansing in the right colon (4.4 % vs. 1.2 %; P = 0.03). Superiority of NER1006 was demonstrated using HCS in the PP set for overall cleansing success (68.0 % vs. 57.5 %; P = 0.02) and right colon high-quality cleansing (5.2 % vs. 1.0 %; P = 0.02) and using BBPS in the mFAS for overall cleansing success (58.4 % vs. 45.8 %; P = 0.003) and right colon high-quality cleansing (4.0 % vs. 0.8 %; P = 0.02). Mean segmental scores for 4/5 segments were higher with NER1006 (P ≤ 0.04). Both treatments were well tolerated, with more mild adverse events for NER1006 (17.0 % vs. 10.0 %; P = 0.03). Conclusions Colon cleansing with NER1006 vs. SP + MC was non-inferior (mFAS) and superior (PP), with acceptable safety. European Clinical Trials Database (EudraCT) 2014-002186-30 TRIAL REGISTRATION: Multicenter, randomized, parallel group, phase 3 study 2014-002186-30 at https://eudract.ema.europa.eu/