tbuckley/cabot-search huggingface dataset:
Using patient identifiable data without consent
Authors: P. Cox
Journal: BMJ (2001)

Editor—The editorial by Al-Shahi and Warlow is timely and well argued.1 The implications of a strict requirement for written consent from patients in observational and epidemiological research are extremely serious. Research in histopathology would be particularly severely affected. It is essential that patients' consent is obtained in interventional studies or where information, or, in the case of pathology, tissue, is collected solely for the purpose of research. However, applying this requirement for every study of archived biopsy, surgical or necropsy tissue blocks, or review of patient records, where diagnosis has been made and where patient management will not be affected, is impracticable.

Studies of archival material have been the core of research in histopathology. A glance at the methods section of the papers of any pathology journal reveals that most have used archival tissue with no indication that specific patient consent has been obtained. For recent issues of the Journal of Pathology, Histopathology, and the Journal of Clinical Pathology the proportions of archival, non-consented research were 9/16, 9/9, and 11/13 papers, respectively.

Until now, this form of research has been simple and cheap to undertake, and has provided valuable information on the causes and pathology of many human diseases. It is unlikely that any of the large studies of gastric biopsies, cancers, etc would have been conducted had every patient or their relatives had to be contacted to obtain consent. We would be left with only anecdotal information on which to base prognosis and treatment for many common cancers and we would know much less about many common diseases. Despite considerable problems in obtaining funding for research in histopathology, authors in the United Kingdom continue to produce papers of high quality, but it is doubtful that this will continue if individual consent for each study becomes a legal requirement.

Either a general consent for use of residual tissues for research should be allowed or alternatively the NHS needs to fund the staff necessary to obtain the consent from central or regional research and development budgets, which could be accessed by researchers wishing to undertake archival studies. This would, however, be both cumbersome and costly. If observational research in pathology or other subjects and epidemiological studies are to be outlawed, the public interest will be damaged and patients in the future will be the losers.
Abstract 2420: Effect of Rosiglitazone on Left Ventricular Systolic and Diastolic Function and on NT-proBNP: Results of the Echocardiographic and Biomarker Substudy of the DREAM Trial
Authors: Mahmoud A Sharaf, Mahadevan Rajaram, Patrick Sheridan, Gilles Dagenais, Raphael Diaz, Salim Yusuf, Herztel C Gerstein, Eva Lonn
Journal: Circulation (2008)
Abstract 17238: Hematopoietic Deficiency of the Catalytic PI 3-Kinase Isoform PI3Kdelta Aggravates the Development of Atherosclerosis in LDLR-/- Mice
Authors: Mario Zierden, Christopher Millarg, Marius Vantler, Christine Herbers, Eva Berghausen, Stephan Rosenkranz
Journal: Circulation (2013)

Atherosclerosis is a chronic inflammatory disease of arterial blood vessels underlying myocardial infarction and ischemic stroke. Atherogenesis is characterized by infiltration of the arterial wall by macrophages, dendritic cells and T lymphocytes. Although different cell types of the innate and adaptive immune system play central pro-inflammatory roles, they exert regulatory functions in different stages of this complex disease as well. Leukocytes express the catalytic phosphoinositide 3-kinase isoform p110δ (PI3Kδ), a key enzyme involved in the regulation of immune responses. Therefore, PI3Kδ represents an interesting target for the modulation of atherogenesis.  To investigate the role of PI3Kδ in leukocytes for the orchestration of atherogenesis, lethally irradiated LDLR -/-  mice were either transplanted with bone marrow from PI3Kδ -/-  or PI3Kδ +/+  mice. After 4 weeks of recovery, recipient mice were challenged for 6 weeks with atherogenic diet. PI3Kδ -/-  recipient LDLR -/-  mice displayed a profound reduction of peripheral B and T cells as well as strongly impaired CD4 +  T-cell activation and regulatory T-cell numbers in paraaortic lymph nodes and spleen compared with PI3Kδ +/+  transplanted recipients. Surprisingly, the profound impairment of the immune system by PI3Kδ-deficiency caused a considerable exacerbation of atherosclerosis in LDLR -/-  mice. Atherosclerotic lesion area / aortic root area in PI3Kδ -/-  recipient LDLR -/-  mice was significantly augmented compared with PI3Kδ +/+  transplanted controls (0.26 ± 0.07 vs. 0.16 ± 0.04;  P  -/-  recipients was also significantly higher than in PI3Kδ +/+  transplanted LDLR -/-  mice (0.023 ± 0.009 vs. 0.01 ± 0.005;  P  en face  analysis of Sudan IV-stained whole aortas.  In summary, we demonstrate that hematopoietic PI3Kδ plays a crucial role in regulating immune responses within the arterial wall by exerting protective functions during the development and progression of atherosclerosis. Current studies aim to dissect PI3Kδ-dependent mechanisms that modulate inflammatory processes in multiple stages of atherosclerotic lesion formation.
Detection of a variant protein in hair: new diagnostic method in Portuguese type familial amyloid polyneuropathy Commentary: A new hair test for rare antigens
Authors: Y. Ando, I. Anan, O. Suhr, G. Holmgren, P. M P Costa, R S Pereira
Journal: BMJ (1998)

Portuguese type familial amyloid polyneuropathy is a hereditary amyloidosis caused by a variant form of transthyretin in which valine is replaced by methionine at position 30. 1 2 Transthyretin is produced predominantly in the liver and circulates in the blood as a carrier protein for thyroid hormones and retinol binding protein. 1 2 All carriers of this transthyretin variant have large amounts of the variant protein in their blood, so it may be present in the hair just as A and B blood group antigens are.To test this possibility, we examined the immunoreactivity of hair from carriers and control subjects. Subjects, methods, and resultsWe tested the immunoreactivity of hair using a monoclonal antibody specific to the methionine variant of transthyretin that does not react with normal transthyretin. 3 4We investigated hair from five Japanese patients with familial amyloid polyneuropathy (age range 28-51 years; all black hair), one carrier of the gene for familial amyloid polyneuropathy who was symptom free (61 year old Swedish woman; grey hair), and eight healthy controls (age range 25-48; five were Japanese (black hair), two were Swedish (one blond, one brown hair), and one was Iranian (black hair)).Hair was embedded directly in epoxy resin without being treated, and sections were cut at 3 m.Sections were immersed in 0.01% hydrogen TRIS buffer (pH 7.4) for 10 minutes to inhibit endogenous peroxidase and then treated with 1% bovine serum albumin to occupy nonspecific binding sites.The sections were incubated overnight at room temperature with the monoclonal transthyretin antibody.Immunoreactivity to the antibody was detected by the avidin-biotin complex method (Dakopatts, Glostrup, Denmark).Finally, hairs Immunoreactivity for variant transthyretin in healthy male volunteer aged 43 (left) and male patient with familial amyloid polyneuropathy aged 36 (right).Arrows indicate medulla of hair
Abstract 1375: The Role of Nitric Oxide Synthase Uncoupling in Right Ventricular Hypertrophy and Failure
Authors: Hazim El-Haddad, Ari L Zaiman, Shehzin Mozammel, Priya Kesari, Paul Hassoun, Rubin M Tuder, Michael T Crow, Hunter C Champion
Journal: Circulation (2008)

Right ventricular failure (RVF) is the leading cause of death in patients with severe pulmonary hypertension (PH). Despite its profound clinical consequences, little is known about right ventricular (RV) adaptation and failure within the context of PH. NOS uncoupling has been identified as a potential cause of LV failure. In this study, we hypothesized that NOS uncoupling plays an important early role in the RVH/RVF. We studied the mechanisms of RV failure in Dahl Salt-Sensitive (SS) rats using a RV pressure overload model produced by banding the main pulmonary artery (PAB). 11 days following PAB there was marked RV hypertrophy (0.24 vs 0.36) with marked reduction of both systolic and diastolic functions (RVESP 48 vs 22 mmHg, dP/dt IP 46 vs 80, Tau 29.7 vs 19.4 ms). Analysis of NOS activity and dimerization demonstrated that NOS uncoupling (shift from dimer to monomeric NOS with a concomitant drop in NOS activity) occurred within 4 days of PAB and persisted through day 11. To test the hypothesis that NOS uncoupling is secondary to BH4 oxidation, thus limiting NOS cofactor availability, we treated rats with supplemental BH4 (36 mg/kg/d po). We observed that NOS coupling was improved by BH4 treatment 4 days after PAB. Interestingly, we also observed that treatment with the phosphodiesterase 5 inhibitor sildenafil (100 mg/kg/d po) preserved NOS coupling at day 4 and the improvement persisted. Sildenafil treatment also resulted in a marked reduction in luminal chemiluminescence suggesting reduced ROS signaling and there was also a concomitant improvement in RV systolic (dP/dt/IP 74 vs 46) and diastolic (Tau 14.5 vs 29.7 ms) function and a reduction in cardiac hypertrophy (RV/(LV+septum) 0.28 vs 0.36). These data provide the first evidence that RV hypertrophy and failure are associated with NOS uncoupling that can be prevented by BH4 supplementation. Moreover, these data also provide the first evidence that NOS coupling can be prevented in the RV with sildenafil. These data suggest that sildenafil (likely via cGMP/PKG signaling) modulates NOS coupling, possibly via ROS reduction and preventing BH4 oxidation, or that BH4 synthesis itself is regulated by PKG signaling.
Increasing prevalence of ESBL-producing Enterobacteriaceae in Europe
Authors: T M Coque, F Baquero, R Cantón
Journal: Eurosurveillance (2008)

Extended-spectrum beta-lactamases (ESBLs) have been increasingly reported in Europe since their first description in 1983. During the 1990s, they were described mainly as members of the TEM- and SHV-beta-lactamase families in Klebsiella pneumoniae causing nosocomial outbreaks. Nowadays, they are mostly found in Escherichia coli that cause community-acquired infections and with increasing frequency contain CTX-M enzymes. Dissemination of specific clones or clonal groups and epidemic plasmids in community and nosocomial settings has been the main reason for the increase in most of the widespread ESBLs belonging to the TEM (TEM-24, TEM-4, TEM-52), SHV (SHV-5, SHV-12) and CTX-M (CTX-M-9, CTX-M-3, CTX-M-14 or CTX-M-15) families in Europe. Co-selection with other resistances, especially to fluoroquinolones, aminoglycosides and sulfonamides, seems to have contributed to the problem. The emergence of epidemic clones harbouring several beta-lactamases simultaneously (ESBLs, metallo-beta-lactamases or cephamycinases) and of new mechanisms of resistance to fluoroquinolones and aminoglycosides warrants future surveillance studies.
Abstract 1680: Spatial Distribution of Myocardial Infarction in Patients with Diabetes Mellitus
Authors: Pallav Garg, Susana Candia, John C Wang, Richard E Kuntz, Laura Mauri
Journal: Circulation (2007)

BACKGROUND: Acute coronary occlusions occur most frequently as a result of rupture of an atherosclerotic plaque. Previous studies have found greater extent of atherosclerotic disease in the coronary arteries of diabetic patients. While the burden of disease is higher in diabetics, less is known about the spatial distribution of myocardial infarction in this population. METHODS: We sought to compare the spatial distribution of myocardial infarction (STEMI and Non-STEMI) in patients with diabetes mellitus and in those without, based on quantitative coronary and statistical analysis. We analyzed 756 patients with STEMI (n = 556) and NSTEMI (n=200), of which 175 patients comprised the diabetic cohort, and mapped the location of the acute coronary occlusion. RESULTS: Coronary occlusions were not uniformly distributed throughout each of the major epicardial coronary arteries but tended to cluster within the proximal third of each of the vessels in both cohorts. There was no difference in the distribution of occlusions in diabetics vs. non-diabetics in any of the vessels (left anterior descending artery, P=0.35; left circumflex artery; P=0.33 right coronary artery, P=0.20; Figure). CONCLUSIONS: Acute coronary occlusions leading to STEMI and NSTEMI in both diabetics and non-diabetics tend to cluster in predictable “hot spots” within the proximal third of the coronary arteries. Identification of these high-risk zones for acute coronary occlusions will lead to future advances in vulnerable plaque detection technology and potentially locally directed preventive strategies. Spatial distribution of myocardial infarction in diabetics vs. non-diabetics using distance to lesion from the ostium of the coronary artery.
Abstract 10435: Coronary Artery Calcium Scores and Coronary Risk - Coronary Artery Calcium Thresholds Are Not Consistent Across Baseline Risk Levels: The Multi-Ethnic Study of Atherosclerosis
Authors: Tamar S Polonsky, Robyn L McClelland, Neal W Jorgensen, Diane E Bild, Gregory L Burke, Alan D Guerci, Philip Greenland
Journal: Circulation (2010)
Abstract 3646: Supplement with Omega-3 Fatty Acids Lowers Pulse Wave Velocity in Obese Adolescents
Authors: Frida Dangardt, Walter Osika, Yun Chen, Eva Gronowitz, Birgitta Strandvik, Peter Friberg
Journal: Circulation (2007)

Introduction: Compared with normal-weight adolescents, obese adolescents show higher ratio between omega-6 (n6) and omega-3 (n3) polyunsaturated fatty acids (PUFA) in plasma phospholipids. They also show increased arterial stiffness, which is related to development of atherosclerosis. Regular diet and lifestyle interventions have low compliance, while a standardized supplement of fish-oil is easy to define and administer. Hypothesis: Supplementation of n3 lowers the plasma n6/n3 PUFA ratio and lowers arterial stiffness measured by pulse wave velocity (PWV) in obese adolescents. Methods: 25 obese adolescents (13 females, 12 males, age 15.4 ±1.1 yrs, BMI 34.1 ±4.3) were recruited and randomized to intake of capsules containing either n3 (186 mg eicosapentaenoic acid and 58 mg docosahexaenoic acid), or placebo (palmitic acid), 2x5 capsules, for 3 months. The study was performed in a double-blind, cross-over design with 6 weeks washout period. Weight, height, waist, hip and blood pressure measurements as well as fasting blood samples were obtained before and after each treatment period. PWV was measured after each respective treatment period. Results: The plasma n6/n3 PUFA ratio was reduced by 43 % from 6.8 ± 2.1 (p&lt;0.0001) with n3 treatment, and was not affected by placebo treatment. The plasma triglycerides were reduced by 21% from 1.2 ±0.5 (p=0.001) with n3 treatment, but not placebo. The plasma n6/n3 PUFA ratio difference between n3 and placebo treatment was correlated to the difference in PWV (r=0.43, p=0.03) indicating that the lowering of n6/n3 ratio results in lowering PWV. There were no changes in weight, height, waist, hip or blood pressure. Conclusion: Supplementation with n3 capsules of 5 g/day decreases the ratio between n6/n3 PUFA and triglycerides in plasma and is associated with a lowering of arterial stiffness in obese adolescents.
Characteristics, Treatments, and Outcomes of Patients With Preserved Systolic Function Hospitalized for Heart Failure
Authors: Gregg C. Fonarow, Wendy Gattis Stough, William T. Abraham, Nancy M. Albert, Mihai Gheorghiade, Barry H. Greenberg, Christopher M. O’Connor, Jie Lena Sun, Clyde W. Yancy, James B. Young
Journal: Journal of the American College of Cardiology (2007)
Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages
Authors: JB Weinberg, MA Misukonis, PJ Shami, SN Mason, DL Sauls, WA Dittman, ER Wood, GK Smith, B McDonald, KE Bachus
Journal: Blood (1995)
Therapeutic Hypothermia in Children
Authors: Matthias L. Riess, Tom P. Aufderheide, Demetris Yannopoulos
Journal: New England Journal of Medicine (2015)

We commend the authors for this challenging multicenter randomized study on the use of therapeutic hypothermia (TH) in comatose children after cardiac arrest. 1 Indeed, 1355 patients were screened to eventually lead to 260 evaluations of the primary outcome, 1-year survival with a VABS-II score of ≥70.Conclusions from this study, however, are hampered by its limited power.It was designed to detect an absolute survival difference of 15-20% assuming a survival rate of 15-35% in normothermic patients with a power of 85%; under these overly optimistic and unfounded conditions despite pertinent literature, 2-4 only 276 patients were calculated to be needed.An absolute difference of 8%, however, still corresponding to >50% relative increase in neurologically acceptable survival, and a 0.14 p-value strongly suggest that the study was severely underpowered (42%) to rightfully reject the null-hypothesis under these conditions.Therefore, it would be premature to conclude that withholding TH from pediatric patients does not make a difference in outcome.A >50% increased survival, though not significant due to suboptimal study design, points in a very different direction.
Abstract 001: Quantity and Variety in Fruit and Vegetable Intake and Risk of Coronary Heart Disease
Authors: Shilpa N Bhupathiraju, Nicole M Wedick, An Pan, JoAnn E Manson, Kathryn M Rexrode, Walter C Willett, Eric B Rimm, Frank B Hu
Journal: Circulation (2013)

Epidemiological data have consistently documented a protective effect of fruit and vegetable intake on risk of coronary heart disease (CHD). Consequently, dietary guidelines recommend increasing fruit and vegetable intake and, most recently, have also suggested increasing variety. Our objective was to examine the independent roles of quantity and variety in fruit and vegetable intake in relation to incident CHD. We prospectively observed 71,157 women from the Nurses’ Health Study (NHS, 1984-2008) and 39,752 men from the Health Professionals Follow-up Study (HPFS, 1986-2008) who were free of diabetes, cardiovascular diseases, and cancer at baseline. We documented 2585 incident CHD cases in women during 24 years of follow-up and 3408 cases in men during 22 years of follow-up. Diet was assessed using a standardized and validated questionnaire and updated every 4 years. Variety was defined as the number of unique fruits and vegetables consumed at least once per week. To account for minor differences in the number of fruit and vegetable items administered at each follow-up cycle, we standardized our variety score to 30 (11 for fruit score and 19 for vegetable score). Potatoes, soy, or other legumes were not included in our analyses. Because the AHA does not consider fruit juice to be equivalent to whole fruit, fruit juice was also not included in our analyses. Quantity (servings/day) and variety in fruit and vegetable intake were correlated (r=0.68, P&lt;0.0001). We, therefore, regressed variety on quantity to assess their independent effects on CHD risk. In multivariable analyses, after adjusting for dietary and non-dietary covariates, those in the highest fifth of fruit and vegetable intake (median intake=7.80 servings/day) had a 13% lower risk (95% CI, 0.79 to 0.95) of CHD compared to those in the lowest fifth (median intake=2.14 servings/day). Conversely, quantity-adjusted variety was not associated with CHD risk (RR for highest fifth compared to lowest fifth=1.04, 95% CI, 0.92 to 1.19). Further, within each category of quantity, higher variety was not associated with CHD risk. Our data suggest that absolute quantity, rather than variety, in fruit and vegetable intake is associated with a significantly lower risk of CHD. Future work should examine the role of variety in reducing biological markers of inflammation and endothelial dysfunction. Meanwhile, policy efforts should continue to focus on increasing overall fruit and vegetable intake.
Abstract 14149: Gender Differences in the Association of Diabetes with Incident Coronary Heart Disease in Two Populations
Authors: Rita R Kalyani, Mariana Lazo, Evrim Turkbey, Karinne Chevalier, Frederick Brancati, Pamela Ouyang, Diane Becker, Dhananjay Vaidya
Journal: Circulation (2012)

Objective: Controversy exists about the coronary disease risk conveyed by diabetes in women vs men. We explored gender differences in risk of CHD conveyed by diabetes among high-risk adults and a r...
<i>WNK1</i> haplotypes and bevacizumab-induced hypertension
Authors: M. K. Frey, N. Olvera, F. Bogomolniy, F. Dao, L. Borsu, J. A. Konner, N. A. Rizvi, R. R. Barakat, M. N. Dickler, D. A. Levine
Journal: Journal of Clinical Oncology (2008)

11003 Background: Bevacizumab, a monoclonal antibody to vascular endothelial growth factor, has shown a survival advantage in treating several solid tumors. Reported serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension. Methods: Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from one of six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using Sequenom® mass spectrometry assays. Bevacizumab toxicities were identified from clinical trial reports and graded according to common toxicity criteria. Bayesian statistical methods were used to reconstruct haplotypes from diploid genotyping data. Single loci genotypes and haplotype frequencies were compared using standard two-sided statistical tests. Results: The study population included 102 patients with the following solid tumors: breast cancer, 53; non-small cell lung cancer, 25; serous ovarian cancer, 11; and other, 13. Of these patients, 28 developed grade 1–4 bevacizumab-induced hypertension. Of the 10 hypertension-associated candidate genes, WNK1 was found to be most strongly associated with bevacizumab-induced hypertension. Single loci testing identified 2 of 22 WNK1 htSNPs, rs11064560 and rs2158501, that were individually associated with bevacizumab- induced hypertension (P = 0.0026 and P = 0.013, respectively; trend test). Haplotype analyses of WNK1 identified three risk haplotypes for bevacizumab-induced hypertension. Patients who carried at least one of these risk haplotypes had an increased risk of bevacizumab-induced hypertension (OR, 4.7; P = 0.002; 95% CI, 1.67–13.1). Conclusions: The data suggest that genetic variation in WNK1 is associated with bevacizumab-induced hypertension. WNK1 is a biologically plausible mediator due to its role in blood pressure control, regulating sodium re-absorption in the distal nephron of the kidney. Genetic predisposition to bevacizumab-induced hypertension can help risk stratify patients prior to initiating therapy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech
ACCF/AHA/ACP 2009 Competence and Training Statement: A Curriculum on Prevention of Cardiovascular Disease
Authors: C. Noel Bairey Merz, Mark J. Alberts, Gary J. Balady, Christie M. Ballantyne, Kathy Berra, Henry R. Black, Roger S. Blumenthal, Michael H. Davidson, Sara B. Fazio, Keith C. Ferdinand, Lawrence J. Fine, Vivian Fonseca, Barry A. Franklin, Patrick E. McBride, George A. Mensah, Geno J. Merli, Patrick T. O'Gara, Paul D. Thompson, James A. Underberg
Journal: Circulation (2009)