tbuckley/cabot-search huggingface dataset:
Temporal Trends in Rates of Patient Harm Resulting from Medical Care
Authors: Christopher P. Landrigan, Gareth J. Parry, Catherine B. Bones, Andrew D. Hackbarth, Donald A. Goldmann, Paul J. Sharek
Journal: New England Journal of Medicine (2010)

In the 10 years since publication of the Institute of Medicine's report To Err Is Human, extensive efforts have been undertaken to improve patient safety. The success of these efforts remains unclear.We conducted a retrospective study of a stratified random sample of 10 hospitals in North Carolina. A total of 100 admissions per quarter from January 2002 through December 2007 were reviewed in random order by teams of nurse reviewers both within the hospitals (internal reviewers) and outside the hospitals (external reviewers) with the use of the Institute for Healthcare Improvement's Global Trigger Tool for Measuring Adverse Events. Suspected harms that were identified on initial review were evaluated by two independent physician reviewers. We evaluated changes in the rates of harm, using a random-effects Poisson regression model with adjustment for hospital-level clustering, demographic characteristics of patients, hospital service, and high-risk conditions.Among 2341 admissions, internal reviewers identified 588 harms (25.1 harms per 100 admissions; 95% confidence interval [CI], 23.1 to 27.2) [corrected]. Multivariate analyses of harms identified by internal reviewers showed no significant changes in the overall rate of harms per 1000 patient-days (reduction factor, 0.99 per year; 95% CI, 0.94 to 1.04; P=0.61) or the rate of preventable harms. There was a reduction in preventable harms identified by external reviewers that did not reach statistical significance (reduction factor, 0.92; 95% CI, 0.85 to 1.00; P=0.06), with no significant change in the overall rate of harms (reduction factor, 0.98; 95% CI, 0.93 to 1.04; P=0.47).In a study of 10 North Carolina hospitals, we found that harms remain common, with little evidence of widespread improvement. Further efforts are needed to translate effective safety interventions into routine practice and to monitor health care safety over time. (Funded by the Rx Foundation.).
HLA-B27 in patients with a permanent pacemaker
Authors: J Bruges-Armas
Journal: Annals of the Rheumatic Diseases (2003)

Paired two tailed Student's t test used to test differences between baseline and six month follow up values for both patient groups.ESR, erythrocyte sedimentation rate (normal value 5-15 mm/1st h); CRP, C reactive protein (normal value <10 mg/l); VAS, visual analogue score; BASFI, Bath Ankylosing Spondylitis Functional Index (0-100); BASDAI, Bath Ankylosing Spondylitis Disease Activity Index (0-100).
Neurocognitive Consequences of Risk-Adapted Therapy for Childhood Medulloblastoma
Authors: Raymond K. Mulhern, Shawna L. Palmer, Thomas E. Merchant, Dana Wallace, Mehmet Kocak, Pim Brouwers, Kevin Krull, Murali Chintagumpala, Robyn Stargatt, David M. Ashley, Vida L. Tyc, Larry Kun, James Boyett, Amar Gajjar
Journal: Journal of Clinical Oncology (2005)

This prospective, longitudinal study examined the effects of risk-adapted craniospinal irradiation (CSI) dose and the interactions of dose with age and time from diagnosis on intelligence quotient (IQ) and academic achievement (reading, spelling, and math) among patients treated for medulloblastoma (MB).Patients received serial neurocognitive testing spanning from 0 to 6.03 years after diagnosis (median, 3.14 years). The multi-institutional study included 111 patients, who were 3 to 20 years of age at diagnosis (median age, 7.4 years), treated for MB with risk-adapted CSI followed by four cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, and vincristine) with stem-cell support. High-risk patients (HR; n = 37) received CSI to 36 to 39.6 Gy and conformal boost treatment of the primary site to 55.8 to 59.4 Gy. Average-risk patients (AR; n = 74) received CSI to 23.4 Gy and conformal boost treatment of the posterior fossa to 36.0 Gy and primary site to 55.8 Gy.Multivariate modeling revealed statistically significant declines in mean IQ (-1.59 points/yr; P = .006), reading (-2.95 points/yr; P < .0001), spelling (-2.94 points/yr; P < .0001), and math (-1.87 points/yr; P = .003) scores for the entire group. The effects of risk-adapted radiation therapy on IQ, reading, and spelling were moderated by age, with the greatest rates of decline observed for the HR patients who were younger (< 7 years old) at diagnosis.Young age at diagnosis was the most prominent risk factor for neurocognitive deficits among survivors of MB despite reductions in CSI dosing and efforts to limit the boost volume. Younger patients exhibited substantial problems with the development of reading skills.
A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization
Authors: Dan E Arking, Arne Pfeufer, Wendy Post, W H Linda Kao, Christopher Newton-Cheh, Morna Ikeda, Kristen West, Carl Kashuk, Mahmut Akyol, Siegfried Perz, Shapour Jalilzadeh, Thomas Illig, Christian Gieger, Chao-Yu Guo, Martin G Larson, H Erich Wichmann, Eduardo Marbán, Christopher J O'Donnell, Joel N Hirschhorn, Stefan Kääb, Peter M Spooner, Thomas Meitinger, Aravinda Chakravarti
Journal: Nature Genetics (2006)
Outcomes of Critically Ill Patients Who Received Cardiopulmonary Resuscitation
Authors: Jianmin Tian, David A. Kaufman, Stuart Zarich, Paul S. Chan, Philip Ong, Yaw Amoateng-Adjepong, Constantine A. Manthous
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Studies examining survival outcomes after in-hospital cardiopulmonary arrest (CPA) among intensive care unit (ICU) patients requiring medications for hemodynamic support are limited.To examine outcomes of ICU patients who received cardiopulmonary resusitation.We identified 49,656 adult patients with a first CPA occurring in an ICU between January 1, 2000 and August 26, 2008 within the National Registry of Cardiopulmonary Resuscitation. Survival outcomes of patients requiring hemodynamic support immediately before CPA were compared with those of patients who did not receive hemodynamic support (pressors), using multivariable logistic regression analyses to adjust for differences in demographics and clinical characteristics. Pressor medications included epinephrine, norepinephrine, phenylephrine, dopamine, dobutamine, and vasopressin.The overall rate of survival to hospital discharge was 15.9%. Patients taking pressors before CPA were less likely to survive to discharge (9.3 vs. 21.2%; P < 0.0001). After multivariable adjustment, patients taking pressors before pulseless CPA were 55% less likely to survive to discharge (adjusted odds ratio [OR], 0.45; 95% confidence interval [CI], 0.42-0.48). Age equal to or greater than 65 years (adjusted OR, 0.77; 95% CI, 0.73-0.82), nonwhite race (adjusted OR, 0.58; 95% CI, 0.54-0.62), and mechanical ventilation (adjusted OR, 0.60; 95% CI, 0.56-0.63) were also variables that could be identified before CPA that were independently associated with lower survival. More than half of survivors were discharged to rehabilitation or extended care facilities. Only 3.9% of patients who had CPA despite pressors were discharged home from the hospital, as compared with 8.5% of patients with a CPA and not taking pressors (adjusted OR, 0.53; 95% CI, 0.49-0.59).Although overall survival of ICU patients was 15.9%, patients requiring pressors and who experienced a CPA in an ICU were half as likely to survive to discharge and to be discharged home than patients not taking pressors. This study provides robust estimates of CPR outcomes of critically ill patients, and may assist clinicians to inform consent for this procedure.
Correlates and Causes of Death in Patients With Severe Symptomatic Aortic Stenosis Who Are Not Eligible to Participate in a Clinical Trial of Transcatheter Aortic Valve Implantation
Authors: Itsik Ben-Dor, Augusto D. Pichard, Manuel A. Gonzalez, Gaby Weissman, Yanlin Li, Steven A. Goldstein, Petros Okubagzi, Asmir I. Syed, Gabriel Maluenda, Sara D. Collins, Cedric Delhaye, Kohei Wakabayashi, Michael A. Gaglia, Rebecca Torguson, Zhenyi Xue, Lowell F. Satler, William O. Suddath, Kenneth M. Kent, Joseph Lindsay, Ron Waksman
Journal: Circulation (2010)

Background— Transcatheter aortic valve implantation is currently being evaluated in patients with severe aortic stenosis who are considered high-risk surgical candidates. This study aimed to detect incidences, causes, and correlates of mortality in patients ineligible to participate in transcatheter aortic valve implantation studies. Methods and Results— From April 2007 to July 2009, a cohort of 362 patients with severe aortic stenosis were screened and did not meet the inclusion/exclusion criteria necessary to participate in a transcatheter aortic valve implantation trial. These patients were classified into 2 groups: group 1 (medical): 274 (75.7%): 97 (35.4%) treated medically and 177 (64.6%) treated with balloon aortic valvuloplasty; and group 2 (surgical): 88 (24.3%). The medical/balloon aortic valvuloplasty group had significantly higher clinical risk compared with the surgical group, with significantly higher Society of Thoracic Surgeons score (12.8±7.0 versus 8.5±5.1; P &lt;0.001) and logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) (42.4±22.8 versus 24.4±18.1; P &lt;0.001). The medical/balloon aortic valvuloplasty group had a higher New York Heart Association functional class, incidence of renal failure, and lower ejection fraction. During median follow-up of 377.5 days, mortality in the medical/balloon aortic valvuloplasty group was 102 (37.2%), and during median follow-up of 386 days, mortality in the surgical group was 19 (21.5%). Multivariable adjustment analysis identified renal failure (hazard ratio [HR]: 5.60), New York Heart Association class IV (HR: 5.88), and aortic systolic pressure (HR: 0.99) as independent correlates for mortality in the medical group, whereas renal failure (HR: 7.45), Society of Thoracic Surgeons score (STS; HR: 1.09) and logistic EuroSCORE (HR: 1.45) were correlates of mortality in the in the surgical group. Conclusion— Patients with severe symptomatic aortic stenosis not included in transcatheter aortic valve implantation trials do poorly and have extremely high mortality rates, especially in nonsurgical groups, and loss of quality of life in surgical groups.
Prevention of Atrial Fibrillation
Authors: Emelia J. Benjamin, Peng-Sheng Chen, Diane E. Bild, Alice M. Mascette, Christine M. Albert, Alvaro Alonso, Hugh Calkins, Stuart J. Connolly, Anne B. Curtis, Dawood Darbar, Patrick T. Ellinor, Alan S. Go, Nora F. Goldschlager, Susan R. Heckbert, José Jalife, Charles R. Kerr, Daniel Levy, Donald M. Lloyd-Jones, Barry M. Massie, Stanley Nattel, Jeffrey E. Olgin, Douglas L. Packer, Sunny S. Po, Teresa S.M. Tsang, David R. Van Wagoner, Albert L. Waldo, D. George Wyse
Journal: Circulation (2009)

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.
Randomized, Double-Blind, Placebo-Controlled, International Trial of the Oral IIb/IIIa Antagonist Lotrafiban in Coronary and Cerebrovascular Disease
Authors: Eric J. Topol, Donald Easton, Robert A. Harrington, Pierre Amarenco, Robert M. Califf, Carmen Graffagnino, Stephen Davis, Hans-Christophe Diener, James Ferguson, Desmond Fitzgerald, Jeffrey Granett, Ashfaq Shuaib, Peter J. Koudstaal, Pierre Theroux, Frans Van de Werf, Kristina Sigmon, Karen Pieper, Marc Vallee, James T. Willerson
Journal: Circulation (2003)

This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.
Sensitization for γ-Irradiation–Induced Apoptosis by Second Mitochondria-Derived Activator of Caspase
Authors: Stavros Giagkousiklidis, Meike Vogler, Mike-Andrew Westhoff, Hubert Kasperczyk, Klaus-Michael Debatin, Simone Fulda
Journal: Cancer Research (2005)

Abstract Resistance to current treatment regimens, such as radiation therapy, remains a major concern in oncology and may be caused by defects in apoptosis programs. Because inhibitor of apoptosis proteins (IAPs), which are expressed at high levels in many tumors, block apoptosis at the core of the apoptotic machinery by inhibiting caspases, therapeutic modulation of IAPs could target a key control point in resistance. Here, we report for the first time that full-length or mature second mitochondria-derived activator of caspase (Smac), an inhibitor of IAPs, significantly enhanced γ-irradiation–induced apoptosis and reduced clonogenic survival in neuroblastoma, glioblastoma, or pancreatic carcinoma cells. Notably, Smac had no effect on DNA damage/DNA repair, activation of nuclear factor-κB, up-regulation of p53 and p21 proteins, or cell cycle arrest following γ-irradiation, indicating that Smac did not alter the initial damage and/or cellular stress response. Smac enhanced activation of caspase-2, caspase-3, caspase-8, and caspase-9, loss of mitochondrial membrane potential, and cytochrome c release on γ-irradiation. Inhibition of caspases also blocked γ-irradiation–induced mitochondrial perturbations, indicating that Smac facilitated caspase activation, which in turn triggered a mitochondrial amplification loop. Interestingly, mitochondrial perturbations were completely blocked by the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone or the relatively selective caspase-2 inhibitor N-benzyloxycarbonyl-Val-Asp-Val-Ala-Asp-fluoromethylketone, whereas caspase-8 or caspase-3 inhibitors only inhibited the increased drop of mitochondrial membrane potential provided by Smac, suggesting that caspase-2 was acting upstream of mitochondria after γ-irradiation. In conclusion, our findings provide evidence that targeting IAPs (e.g., by Smac agonists) is a promising strategy to enhance radiosensitivity in human cancers.
Epigenetic tethering of AID to the donor switch region during immunoglobulin class switch recombination
Authors: Beena Patricia Jeevan-Raj, Isabelle Robert, Vincent Heyer, Adeline Page, Jing H. Wang, Florence Cammas, Frederick W. Alt, Régine Losson, Bernardo Reina-San-Martin
Journal: The Journal of Experimental Medicine (2011)

Immunoglobulin class switch recombination (CSR) is initiated by double-stranded DNA breaks (DSBs) in switch regions triggered by activation-induced cytidine deaminase (AID). Although CSR correlates with epigenetic modifications at the IgH locus, the relationship between these modifications and AID remains unknown. In this study, we show that during CSR, AID forms a complex with KAP1 (KRAB domain-associated protein 1) and HP1 (heterochromatin protein 1) that is tethered to the donor switch region (Sμ) bearing H3K9me3 (trimethylated histone H3 at lysine 9) in vivo. Furthermore, in vivo disruption of this complex results in impaired AID recruitment to Sμ, inefficient DSB formation, and a concomitant defect in CSR but not in somatic hypermutation. We propose that KAP1 and HP1 tether AID to H3K9me3 residues at the donor switch region, thus providing a mechanism linking AID to epigenetic modifications during CSR.
Hypertrophy of Intramyocardial Arteriolar Smooth Muscle Cells in Experimental Renal Failure
Authors: JOHANNES TÖRNIG, MARIE-LUISE GROSS, AURELIA SIMONAVICIENE, GERHARD MALL, EBERHARD RITZ, KERSTIN AMANN
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Wall thickening of intramyocardial arteries in patients with chronic renal failure may contribute to the increased susceptibility of the uremic heart to ischemic injury. In this context, the following questions arise: ( 1 ) Is intramyocardial wall thickening in experimental renal failure due to hypertrophy, hyperplasia or both? ( 2 ) Which stimuli trigger wall thickening? Using novel stereologic techniques (Nucleator, Selector), intramyocardial arteries were examined in sham-operated and subtotally nephrectomized (SNX) Sprague Dawley rats with moderate renal failure of 8 wk duration. Systolic BP during the experiment was not significantly different in both groups. Absolute and relative left ventricular weight, wall thickness (5.69 ± 1.11 μm versus 4.42 ± 0.99 μm), and wall-to-lumen ratio of intramyocardial arteries (0.117 ± 0.03 μm/μm versus 0.089 ± 0.01 μm/μm) were significantly greater in SNX than in sham-operated rats. The mean cell and nuclear volume of intramyocardial arteriolar smooth muscle cells was significantly increased in SNX rats (650 ± 230 μm 3 versus 430 ± 90 μm 3 and 26 ± 4.5 versus 19.9 ± 2.2 μm 3 , respectively). In parallel, the total arteriolar wall volume was significantly greater in the left ventricle of SNX (+ 58%) compared with sham rats. In contrast, the total length of all left ventricular arteries was comparable in both groups. The increase in mean cell volume without significant change in cell number indicates that arteriolar wall thickening in the heart of SNX rats is explained by hypertrophy rather than hyperplasia of arterial smooth muscle cells. This finding in a nonhypertensive experimental model of chronic renal failure contrasts with findings in spontaneously hypertensive rats. Independent of BP and left ventricular hypertrophy, specific growth signals must act on cardiac arteriolar smooth muscle cells.
Chronic Renal Allograft Dysfunction
Authors: Jeremy R. Chapman, Philip J. O’Connell, Brian J. Nankivell
Journal: Journal of the American Society of Nephrology (2005)

The major causes of renal transplant loss are death from vascular, malignant or infectious disease, and loss of the allograft from chronic renal dysfunction associated with the development of graft fibrosis and glomerulosclerosis. Chronic allograft nephropathy (CAN) is the histologic description of the fibrosis, vascular and glomerular damage occurring in renal allografts. Clinical programs rely on monitoring change in serum creatinine for identification of patients at risk of CAN, but this change occurs late in the course of the disease, and underestimates the severity of pathologic change. CAN has several causes: ischemia-reperfusion injury, ineffectively or untreated clinical and subclinical rejection, and superimposed calcineurin inhibitor nephrotoxicity, exacerbating pre-existing donor disease. Once established, interstitial fibrosis and arteriolar hyalinosis lead to progressive glomerulosclerosis over the subsequent years. There have been a number of approaches to treatment aimed at reducing the impact of CAN, mostly centered around avoidance of calcineurin inhibitors through their elimination in all, or just selected, patients. These immunosuppression strategies combine corticosteroids with azathioprine or mycophenolate mofetil, and/or sirolimus and everolimus. Late identification of CAN in individual patients has meant that strategies for intervening to prevent chronic renal allograft dysfunction and subsequent graft loss tend to be "too little and far too late."
CRP discriminates primary from secondary necrosis
Authors: C. Janko, C. Schorn, L. E Munoz, M. Rauh, G. Schett, M. Herrmann
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background and objectives</h3> C-reactive protein (CRP) is an acute-phase protein whose serum concentration increases massively in response to tissue injury or inflammation. Beside membranes of bacteria CRP is known to bind calcium dependent to altered mammalian membranes (as occurring in cell death) via phosphocholine, the polar headgroup of phosphatidylcholine and its derivatives. CRP also opsonises intracellular components leaking from necrotic cells. This study was performed to analyse whether CRP differentially binds to primary and secondary necrotic cells. Primary necrosis is defined as immediate cell death appearing after severe death stimuli, whereas secondary necrosis follows after an apoptotic stadium. <h3>Materials and methods</h3> We prepared directly Fitc-labelled CRP to determine the binding of CRP to primary and secondary necrotic cells by flow cytometry and confocal microscopy. The release of a CRP target from dying cells was detected in the supernatant by inhibition assays. The released CRP antagonist was identified by enzymatic cleavage and by mass spectrometry. <h3>Results</h3> The binding of CRP to primary necrotic cells was significantly stronger compared to secondary necrotic ones. We detected a CRP antagonistic activity in supernatants of secondary necrotic cells, which was identified as glycerophosphocholine (GlyceroPC). Actually, CRP binding to necrotic cells was blocked by synthetic GlyceroPC. The release of the CRP antagonist was significantly reduced by inhibitors of Phospholipase A2 and Caspases. <h3>Conclusions</h3> Secondary necrotic cells show a weaker binding of CRP resulting from the release of the CRP target during late apoptosis. That may have implications for opsonisation with CRP of dying and dead cells and for CRP-mediated effects in clearance. Secondary necrotic cells, for example in SLE patients, may release high amounts of the CRP antagonist with the following consequences (1) missing CRP binding targets on the dead cells and (2) neutralising of circulating CRP, both possibly contributing to clearance failure.