tbuckley/cabot-search huggingface dataset:
Improving, and auditing, access to clinical trial results
Authors: B. Goldacre, C. Heneghan
Journal: BMJ (2014)

The House of Commons Public Accounts Committee delivered a remarkable report on 3 January.Its initial remit was the United Kingdom's £424m (€510m; $697m) stockpile of oseltamivir (Tamiflu), but the committee soon broadened out-with evident surprise-into the ongoing problem of clinical trial results being routinely and legally withheld from doctors, researchers, and patients.This situation has persisted for too long.The first quantitative evidence on publication bias was published in 1986. 1 Iain Chalmers described in 2006 how progress in the 1990s soon deteriorated into broken promises. 2Recent years have seen extensive denial.The Association of the British Pharmaceutical Industry (ABPI) has claimed that these problems are historic, and that results are now posted on clinicaltrials.gov.The recently defunct Ethical Standards in Health and Life Sciences Group, 3 which most UK medical and academic professional bodies signed up to, falsely claimed that a "robust regulatory framework" ensures access to trial results. 4US legislation requiring all results to be posted on clinicaltrials.govwithin 12 months of completion has been widely ignored, 5 with no enforcement.There has also been covert activity from industry-a leaked memo on its "advocacy" strategy included "mobilising patient groups" to campaign against transparency.
Abstract 4638: NVP-CGM097: a novel p53-Mdm2 inhibitor exhibiting potent antitumor activity in mouse models of human cancer
Authors: Stéphane Ferretti, Marjorie Berger, Ramona Rebmann, Francesca Santacroce, Dario Sterker, Michael Jensen, Keiichi Masuya, Sébastien Jeay
Journal: Cancer Research (2014)

Abstract Although functional inactivation of the tumor suppressor p53 is a frequent genetic event, half of all human tumors express wild-type p53. Stabilization of p53 by antagonizing its negative regulator mouse double minute 2 (Mdm2) leads to selective induction of the p53 pathway, thus offering a promising therapeutic opportunity. NVP-CGM097 binds in the p53 pocket on the surface of Mdm2 and effectively disrupts the interaction between p53 and Mdm2. The aim of this study was to determine the pharmacokinetic (PK), pharmacodynamic (PD) and efficacy profile of this novel p53-Mdm2 inhibitor in mouse models of human cancer. During the medicinal chemistry discovery efforts, the compound series was optimized for oral administration. The selected compound, NVP-CGM097, was well absorbed in mice where the maximum plasma concentration (Tmax) was observed about 3 hours post dose followed by a prolonged absorption phase. PD effects were determined by measuring the expression levels of p53 target genes including p21, PUMA and Mdm2 in tumors. The expression levels of p53 target genes correlated with the concentrations of NVP-CGM097 demonstrating a good PK/PD relationship. Optimal treatment schedules were investigated in the Mdm2-amplified, p53 wild-type osteosarcoma xenograft model SJSA-1. Interestingly, various schedules were highly efficacious at well-tolerated dose levels. Tumor regression was observed when NVP-CGM097 was administered in schedules ranging from daily to twice per week with no adverse effects. Following dose optimization studies, potent anti-tumor efficacy was observed in a range of p53 wild-type expressing xenograft models including Mdm2 non-amplified orthotopic AML as well as well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcomas. Overall, we demonstrate that the novel p53-Mdm2 inhibitor NVP-CGM097 has a good PK profile and affects PD markers in human tumors leading to tumor regression at well-tolerated dose levels. These data strongly support clinical development of NVP-CGM097. Citation Format: Stéphane Ferretti, Marjorie Berger, Ramona Rebmann, Francesca Santacroce, Dario Sterker, Michael Jensen, Keiichi Masuya, Sébastien Jeay. NVP-CGM097: a novel p53-Mdm2 inhibitor exhibiting potent antitumor activity in mouse models of human cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4638. doi:10.1158/1538-7445.AM2014-4638
Mechanisms of Contraction of the Normal and Failing Heart
Authors: David H. Spodick
Journal: JAMA (1968)

From the discoveries of Harvey and Hales through the pioneering advances of Frank, Starling, Wiggers, and Hill, the way the heart works has never been as extensively studied as in the last decade. Among the outstanding contributors is the now centrifugal NIH team who here present a review of recent work (largely their own) on myocardial function. The authors largely bypass hemodynamics to seek, in the actual mechanics of muscle action, more fundamental explanations of the events and control of normal cardiac activity and its disruption by disease processes. Similarly, electromechanical and chemical-mechanical transformations are only briefly noted as the text concentrates on the movements of demonstrable structural elements and their relationship to contractile function. A brief introduction to myocardial ultrastructure forms the background for integrating experimental results in muscle strips, isolated hearts, and intact animals, with observations in normal and diseased human beings. The performance of the heart as
Surgical Repair of Ventricular Septal Defect Due to Myocardial Infarction
Authors: W. Spencer Payne, James C. Hunt, John W. Kirklin
Journal: JAMA (1963)

RUPTURE of the ventricular septum following myocardial infarction has been estimated to occur in 1% to 2% of the patients who have died from acute infarction.<sup>1-3</sup>Until recent years the diagnosis of postinfarction rupture of the heart was usually made only at necropsy. Following rupture of the myocardium, the patient seldom survives more than a few hours or days. However, rupture of the ventricular septum may, on occasion, be associated with more prolonged survival. At present this complication of myocardial infarction is being recognized more frequently.<sup>3,4</sup> Survival of patients with postmyocardial-infarction rupture of the interventricular septum beyond the immediate postinfarction period is complicated by the development of a left-to-right shunt and cardiac decompensation. Reports of operations for the closure of such defects are rare.<sup>5,6</sup>For this reason the following case is reported. <h3>Report of a Case</h3> A man, 60 yr of age, was seen initially at the
Persistence of Childhood Eczema Into Adulthood
Authors: Jonathan I. Silverberg
Journal: JAMA Dermatology (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Dermatology journal
Should children who have a cardiac arrest be treated with therapeutic hypothermia?
Authors: B. R. Scholefield, G. D. Perkins, H. P. Duncan, F. Gao, K. P. Morris
Journal: BMJ (2014)

The International Liaison Committee for Resuscitation recommends that comatose adult patients with spontaneous circulation after cardiac arrest are cooled to 32-34°C for 12-24 hours based on analysis of data from two randomised controlled trials and 17 observational studies.1 However, these studies were mostly in a specific subgroup of cardiac arrest patients with witnessed, out-of-hospital ventricular fibrillation, and evidence of benefit in the general population of cardiac arrest patients has been less certain.2 The rationale for therapeutic hypothermia is that it can reduce cerebral metabolism, attenuate biosynthesis of excitotoxic compounds, reduce free radical production, reduce inflammation, and regulate gene and protein expressions associated with necrotic and apoptotic pathways during ischaemia and reperfusion.3

Recommendations for treatment in children4 (box 1) are based almost solely on adult data. However, the aetiology of cardiac arrest is very different in children,5 possibly altering the pattern of neuronal injury. Most cardiac arrests are secondary to a respiratory cause with profound hypoxia, and primary cardiac causes of arrests, including ventricular fibrillation, are rare. In other clinical situations, therapeutic hypothermia has been seen to be both beneficial (newborns with hypoxic brain injury within 6 hours of birth)6 and potentially harmful (traumatic brain injury).7 It is therefore important that the question of whether children with cardiac arrest should be treated with therapeutic hypothermia is addressed.

#### Box 1: Recommendations for use of therapeutic hypothermia after paediatric cardiac arrest (International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science with Treatment Recommendations4)

Our recent Cochrane systematic …
OC-078 Coeliac disease and persisting symptoms: should capsule be the next investigation?: Abstract OC-078 Table 1
Authors: M Kurien, K E Evans, K Drew, M E McAlindon, R H Sidhu, D S Sanders
Journal: Gut (2012)

<h3>Introduction</h3> Up to a third of patients with coeliac disease fail to have a symptomatic response to a gluten-free diet (GFD), or relapse after initial response. Causes include inadvertent gluten exposure and complications of coeliac disease such as lymphoma. There are limited published data assessing the role of capsule endoscopy (CE) in patients with coeliac disease and persisting symptoms. For this reason we evaluated our experience of CE in this group of coeliac patients. <h3>Methods</h3> Data from all patients with established, biopsy-proven coeliac disease and persisting symptoms despite 12 months GFD, who underwent CE between 2004 and 2011 in a tertiary gastroenterology department were analysed. Concurrently we performed serology (endomysial antibody [EMA] and tissue transglutaminase [tTG]), and a duodenal biopsy (Marsh grading, and where appropriate T cell clonality). At CE changes of coeliac disease such as scalloping, mosaic pattern and loss of folds were assessed including extent of disease (proximal or diffuse). Concordance between serology, histology and CE was assessed using Spearman9s coefficient. <h3>Results</h3> 69 patients (47 female, median age 56 years, range 22–83 y) were identified. 8/69 (13.0%) had significantly abnormal CE findings with either mass lesions, extensive disease or ulceration. In these eight cases: two had enteropathy associated lymphoma (EATL), four Type 1 refractory disease, one fibroepithelial polyp, one had ulcerative jejunitis. Of the 4 (4/69, 5.8%) refractory Type 1 cases, two were started on immunosuppressants, one died of unrelated causes and another was a tertiary referral case in whom outcome data are unknown. There was no correlation between the likelihood of having complicated coeliac disease and the serological titres (either a positive EMA or significantly raised tTG). However, there was a positive correlation between more extensive changes at CE (diffuse) and the level of tTG (<i>r</i>=0.448, p=0.001). A similar observation was made for the relationship between diffuse involvement at CE and EMA positivity (<i>r</i>=0.351, p=0.003). There was also a correlation between the extent of disease observed at CE and histology (<i>r</i>=0.455, p&lt;0.0001). <h3>Conclusion</h3> This is the largest internationally reported series demonstrating a role for CE in coeliac disease patients with persisting symptoms. A significant proportion are found to have complicated or refractory coeliac disease. Extensive changes of coeliac disease seen on CE should prompt clinicians to investigate for refractory disease, request PCR on duodenal biopsy (for monoclonality) and consider immunosuppressive therapy. <h3>Competing interests</h3> None declared.
Propranolol and prednisolone combination for the treatment of segmental haemangioma in PHACES syndrome
Authors: M. Gnarra, L. Solman, J. Harper, S. Batul Syed
Journal: British Journal of Dermatology (2015)

Posterior fossa malformations-haemangiomas-arterial anomalies-cardiac defects-eye abnormalities-sternal cleft and supraumbilical raphe syndrome (also known as PHACES syndrome) is a rare neurocutaneous disorder. Children presenting with these manifestations need careful ophthalmological, cardiac and neurological assessment. They may have one or more of these extracutaneous manifestations, the most common being cerebral and cardiovascular anomalies. There is controversy about treating these children with propranolol especially if they have cerebrovascular involvement with narrow, dysplastic or absent blood vessels. The concern with propranolol is that hypotension may lead to reduced cerebral blood flow and neurological consequences. Prior to propranolol the systemic treatment for haemangiomas was prednisolone and then the concern was the opposite, namely hypertension. Our proposal was whether a combination of these two drugs would provide a safer and faster recovery. We report three retrospective cases of PHACES syndrome, each of whom received treatment with a combination of propranolol and prednisolone: two children were started on prednisolone and propranolol was added because the haemangiomas failed to respond adequately; the third child was started on propranolol and developed peripheral ischaemia and ulceration necessitating a reduction in dose addition of a low dose of prednisolone. All three patients, who failed on the one treatment, responded well to combination therapy without any significant complications. These outcomes suggest that for some patients with PHACES syndrome the use of combination treatment with propranolol and prednisolone could be advantageous, potentially allowing for the introduction of low doses of each with an enhanced combined effect. The doses can be increased gradually depending on the magnetic resonance imaging findings.
How to obtain the confidence interval from a P value
Authors: D. G. Altman, J. M. Bland
Journal: BMJ (2011)

Confidence intervals (CIs) are widely used in reporting statistical analyses of research data, and are usually considered to be more informative than P values from significance tests.1 2 Some published articles, however, report estimated effects and P values, but do not give CIs (a practice BMJ now strongly discourages). Here we show how to obtain the confidence interval when only the observed effect and the P value were reported. The method is outlined in the box below in which we have distinguished two cases. #### Steps to obtain the confidence interval (CI) for an estimate of effect from the P value and the estimate ( Est ) ##### (a) CI for a difference ##### (b) CI for a ratio
Abstract P3-10-11: Clinical Significance of Progesterone Receptor and HER2 Status in Estrogen Receptor-Positive, Operable Breast Cancer with Adjuvant Tamoxifen: Consistent Prognostic Impact of HER2 Status Over Time
Authors: YW Moon, S Park, JH Sohn, DR Kang, JS Koo, HS Park, HC Chung, B-W Park
Journal: Cancer Research (2010)

Abstract Purpose: To evaluate prognostic factors in estrogen receptor (ER)-positive, operable breast cancer, focusing on the progesterone receptor (PR) and HER2 over time. Patients and Methods: A total of 819 patients with ER-positive, operable breast cancer were enrolled. All received adjuvant tamoxifen. Prognostic value of the PR status and HER2 status was evaluated using Cox regression before and after 5 years post-surgery. Results: PR and HER2 status were inversely correlated (P = .014). PR-negativity was a time-dependent poor prognostic factor for recurrence before 5 years post-surgery (P = .049), but not after 5 years post-surgery (P = .566). However, HER2 overexpression and younger age (35 years or less) were consistent prognostic factors for recurrence over all time periods, whereas N stage and histologic grade, which are known prognostic factors, were no longer informative after 5 years post-surgery, except for N3 disease. Conclusion: In ER-positive, operable breast cancer, the prognostic impact of PR status along with N stage and histologic grade were strong for the first 5 years post-surgery, but disappeared thereafter. However, HER2 overexpression was a consistent poor prognostic factor, suggesting that an alternative adjuvant strategy, possibly involving incorporation of prolonged HER2-targeted therapy should be evaluated for HER2-overexpressing tumors. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-11.
Journal Clubs — Science as Conversation
Authors: Joe Wright
Journal: New England Journal of Medicine (2004)

I had forgotten about it amidst the other tasks of medical-student life: exams, patient write-ups, the shirt I needed to iron. But an e-mail from my fellow student John reminded me that it was my turn to lead the journal club for our HIV–AIDS interest group. I had no idea what article I would bring. I bumbled through PubMed in search of a paper, wandering through several topics before landing on an article about the high prevalence of chlamydia in China,1 along with an editorial2 arguing for a particular strategy for preventing a new explosion of human immunodeficiency virus (HIV) . . .
2009 Sol Sherry Distinguished Lecture in Thrombosis—Hemostasis and Thrombosis—Two Sides of the Same Coin?
Authors: Nigel Mackman
Journal: Circulation (2009)

Blood coagulation is essential for life. The clotting cascade is divided into extrinsic (tissue factor and factor VIIa), intrinsic (factors XIIa, XIa, IXa, and FVIIIa), and common (factor Xa, factor Va, and thrombin) pathways that generate cross-linked fibrin. Hemostasis is a physiological process that prevents excess bleeding after vessel injury. Under normal conditions, all coagulation factors, except tissue factor, reside in the blood. Tissue factor is expressed in the vessel wall and activates the clotting system after injury. Thrombosis is a pathological process that leads to occlusion of blood vessels. Thrombosis can be triggered by rupture of an atherosclerotic plaque or by tissue factor–positive microparticles in the blood. Mice lacking components of the extrinsic or common pathways do not survive, which indicates that these pathways are essential for hemostasis. In contrast, mice lacking either factor XI or factor XII have no hemostatic defects, which suggests that these factors are not required for hemostasis. Mice deficient in either factor VIII or IX survive but exsanguinate after tail transection, consistent with a role in amplification of the cascade. Surprisingly, mice lacking either factor XII or factor XI were protected in thrombosis models demonstrating a role in thrombosis. These results reveal mechanistic differences between hemostasis and thrombosis. At present, the identity of the activators of the intrinsic pathway has not been defined but may include extracellular RNA released from damaged cells and polyphosphate secreted from activated platelets. A better understanding of the different pathways may lead to the development of novel antithrombotic drugs. These designations were based on the “ex vivo” activation of coagulation. An “extrinsic” factor called tissue thromboplastin (also known as factor III or tissue factor) initiated clotting via the extrinsic pathway, and this reaction formed the basis of the prothrombin time assay. In contrast, addition of blood to a negatively charged surface, such as kaolin, activated the clotting cascade via the intrinsic pathway. This is called the activated partial thromboplastin time and is driven by factor XIIa (also known as Hageman factor). However, individuals deficient in factor XII, such as John Hageman, were not bleeders. This suggested that factor XIIa was not required for in vivo clotting. In 1991, Gailani and Broze found that thrombin could activate factor XI and factor XII was largely removed from diagrams of the clotting cascade. Studies on mice lacking different clotting factors demonstrated essential roles in hemostasis for components of the extrinsic and common pathways.
BASELINE NT–PROBNP AND THE IMPACT OF AORTIC REGURGITATION AFTER TRANSCATHETER AORTIC VALVE REPLACEMENT
Authors: Bogdan Lucian Borz, Eric Durand, Camille Hauville, Christophe Tron, Matthieu Godin, Alexandre Canville, Fabrice Bauer, Pierre–Yves Litzler, Jean–Paul Bessou, Alain Cribier, Hélène Eltchaninoff
Journal: Journal of the American College of Cardiology (2013)
The Relationship Between Serum Lipoprotein(a) and Insulinemia in Healthy Nondiabetic Adult Men
Authors: P Barton Duell, Fay Hagemenas, William E Connor
Journal: Diabetes Care (1994)

OBJECTIVE To test the hypothesis that variations in serum insulin concentrations and insulin action may influence serum concentrations of lipoprotein(a) [Lp(a)]. RESEARCH DESIGN AND METHODS A cross-sectional analysis of fasting serum insulin and Lp(a) concentrations were conducted in a group of 54 healthy adult men 23–61 years of age. Measures of dietary intake, exercise, smoking, alcohol ingestion, body mass index (BMI), fasting plasma lipoprotein lipid concentrations, and serum sex hormone and fasting glucose levels were also determined. RESULTS The fasting serum concentrations of insulin and Lp(a) were negatively correlated (r = −0.339, P = 0.014) by univariate regression analysis. Several confounding variables were also significantly correlated with Lp(a) concentrations: testosterone (r = 0.348, P = 0.012), strenuous exercise (r = 0.287, P = 0.041), and BMI (r = −0.276, P = 0.050). As expected, these additional variables and serum insulin concentrations were highly interrelated. In a stepwise regression model, the serum insulin level was identified as the single best predictor of Lp(a) levels. Nearly 25% of the heterogeneity in serum concentrations of Lp(a) could be predicted by serum levels of insulin and testosterone, BMI, and the amount of strenuous exercise. CONCLUSIONS The results of these studies have shown that serum concentrations of insulin and testosterone, BMI, and strenuous exercise appear to account for the majority of predicted nongenetic variability in serum levels of Lp(a). These observations suggest the possibility in this group of healthy men that serum concentrations of Lp(a) may be modulated by a complex interplay between insulin action, obesity, androgen levels, and strenuous exercise.