bluuebunny/crossref_metadata_2025_split huggingface dataset:
Applying Hodges-Lehmann scale parameter estimates to hospital discharge times
Authors: Shuster Jonathan J , Theriaque Douglas W , Ilfeld Brian M 
Published: November 2008

Background: Clinical trials aimed at shortening the time-to-discharge need to have rational and easily understood effect size estimates for health care management organizations. A natural choice is a scale model, where the distribution of time to discharge on one treatment is assumed to be the same as ρ times that on the other. If, for example ρ=0.6, then one treatment is associated with a 40% reduction in discharge time. In designing and analyzing these studies, we need to have the capability to accommodate right censored data, as it is plausible that some patients may never meet the discharge criteria, even though they do get discharged. Purpose: Utilizing the ideas of Hodges and Lehmann, to provide methods for analysis of trials aimed at shortening hospital discharge times, using point and interval estimates of scale parameters based on the Gehan generalization of the Mann—Whitney—Wilcoxon test, which accommodates right censoring for situations where patients never meet discharge criteria (+∞). Methods: For every value of ρ > 0, we shall test the null hypothesis that the distribution of discharge times on one treatment is the same ρ times that on the other. The values of ρ that we fail to reject form the confidence interval for the true ρ. Results: The methods were developed and applied to a real clinical trial for times to meet the three objective discharge criteria in knee replacement surgery for two post-operative pain control strategies (usual care plus a perineural infusion of either placebo or 0.2% ropivocaine, until the morning following surgery). Based on 48 randomized patients, the point estimate (95% confidence limits) for ρ was 0.47 (0.32—0.67), favoring ropivocaine. Limitations: The methods cannot as yet be applied to group sequential designs or studies with more than two treatments. Conclusion: This methodology is an effective way to analyze two-arm trials involving continuous hospital discharge time data.
An analysis of the controversy over classical one-sided tests
Authors: Freedman Laurence S 
Published: November 2008

Background When applying classical tests of the null hypothesis in clinical trials, there has been considerable controversy over the choice between a one-sided versus a two-sided test. The choice between a one-sided and two-sided test still impacts on sample size calculations, assessment of study results by regulatory authorities, and publication of study results in academic journals. Purpose To analyze the main elements in the controversy, and examine the procedures from both a Bayesian and classical viewpoint. Methods and Results Using a Bayesian decision framework, it is shown that there is no reason to double the p-value when moving from a one-sided to a two-sided test. Within the classical framework, it is shown that the doubling of the p-value results from a discontinuity due to testing a point null hypothesis. A three-decision rule, credited to Neyman or Wald, is presented that does not require the doubling of the p-value, and is consistent with a Bayesian approach. Conclusions For most comparative clinical trials the three-decision rule is appropriate, and its use would abolish the controversy over one-sided tests. Clinical Trials 2008; 5: 635—640. http://ctj.sagepub.com
Graft-versus-leukemia effects of transplantation and donor lymphocytes
Authors: Kolb Hans-Jochem 
Published: November 2008

AbstractAllogeneic transplantation of hematopoietic cells is an effective treatment of leukemia, even in advanced stages. Allogeneic lymphocytes produce a strong graft-versus-leukemia (GVL) effect, but the beneficial effect is limited by graft-versus-host disease (GVHD). Depletion of T cells abrogates GVHD and GVL effects. Delayed transfusion of donor lymphocytes into chimeras after T cell–depleted stem cell transplantation produces a GVL effect without necessarily producing GVHD. Chimerism and tolerance provide a platform for immunotherapy using donor lymphocytes. The allogeneic GVL effects vary from one disease to another, the stage of the disease, donor histocompatibility, the degree of chimerism, and additional treatment. Immunosuppressive therapy before donor lymphocyte transfusions may augment the effect as well as concomitant cytokine treatment. Possible target antigens are histocompatibility antigens and tumor-associated antigens. Immune escape of tumor cells and changes in the reactivity of T cells are to be considered. Durable responses may be the result of the elimination of leukemia stem cells or the establishment of a durable immune control on their progeny. Recently, we have learned from adoptive immunotherapy of viral diseases and HLA-haploidentical stem cell transplantation that T-cell memory may be essential for the effective treatment of leukemia and other malignancies.
Microglia: gatekeepers of central nervous system immunology
Authors: Tambuyzer Bart R , Ponsaerts Peter , Nouwen Etienne J 
Published: November 2008

AbstractMicroglia are perhaps the most underestimated cell type of our immune system. Not only were immunologists unaware of their capabilities until recently, but also, some neuroscientists denied their actual existence until the late 20th century. Nowadays, their presence is confirmed extensively, as demonstrated by numerous reports describing their involvement in virtually all neuropathologies. However, despite distinct approaches, their origin remains a point of controversy. Although many agree about their myeloid-monocytic ancestry, the precise progenitor cells and the differentiation mechanisms, which give rise to microglia in the different developmental stages of the CNS, are not unraveled yet. Mostly, this can be attributed to their versatile phenotype. Indeed, microglia show a high morphological plasticity, which is related to their functional state. This review about microglia aims to introduce the reader extensively into their ontogeny, cell biology, and involvement in different neuropathologies.
Autologous Stem-Cell Transplantation As First-Line Therapy in Peripheral T-Cell Lymphomas: Results of a Prospective Multicenter Study
Authors: Reimer Peter , Rüdiger Thomas , Geissinger Eva , Weissinger Florian , Nerl Christoph , Schmitz Norbert , Engert Andreas , Einsele Hermann , Müller-Hermelink Hans Konrad , Wilhelm Martin 
Published: November 2008

Purpose Peripheral T-cell lymphomas (PTCLs) are rare malignancies with poor outcome after conventional chemotherapy. The role of myeloablative therapy and autologous stem-cell transplantation (autoSCT) is still unclear. Therefore, we initiated the first prospective multicenter study on upfront autoSCT in PTCL and recently reported good feasibility and efficacy of this approach. Here, we present the final analysis of the study. Patients and Methods The treatment regimen consisted of four to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by mobilizing therapy with either the dexamethasone, carmustine, melphalan, etoposide, and cytarabine protocol or the etoposide, methylprednisolone, cytarabine, and cisplatin protocol and stem-cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemoradiotherapy (fractionated total-body irradiation and high-dose cyclophosphamide) and autoSCT. Results From June 2000 to April 2006, 83 patients were enrolled onto the study. Main subgroups were PTCL not specified (n = 32) and angioimmunoblastic T-cell lymphoma (n = 27). Fifty-five (66%) of the 83 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the overall response rate after myeloablative therapy was 66% (56% CR and 8% PR). With a median follow-up time of 33 months, 43 patients are alive; the estimated 3-year overall and disease-free survival rates for patients in CR (calculated from CR to the date of relapse) and 3-year progression-free survival rate were 48%, 53%, and 36%, respectively. Conclusion The results of this prospective study suggest a substantial impact on outcome for upfront autoSCT in PTCL and should be further evaluated in randomized trials. Pretransplantation treatment needs to be improved to increase the transplantation rate.
Inpatient mental healthcare in England and Wales: patterns in NHS and independent healthcare providers
Authors: Raleigh Veena S , Polato Giovanna M , Bremner Stephen A , Dhillon Sunderjit , Deery Anthony 
Published: November 2008

Summary Objectives Independent healthcare, most of it NHS-funded, provides a significant and growing proportion of inpatient mental healthcare in the UK, but information about patients in these providers is limited. This paper examines differences in the profiles of mental health inpatients in NHS and independent providers in England and Wales, and assesses whether current information systems are adequate for monitoring patient flows and care, given the plurality of service provision. Design Data from the national censuses of inpatients in mental health services in England and Wales in 2006 and 2007 were analysed to examine differences in demographic and other characteristics between inpatients in NHS and independent providers. Setting All NHS and independent providers of inpatient mental health services in England and Wales in 2006 and 2007. Main outcome measures Patients in independent providers were younger, 60% were on low/medium secure wards (compared with 16% in the NHS), they were 44% more likely to be detained and referrals were predominantly from NHS inpatient services. For all ethnic groups, ratios of detention on admission were higher in independent providers. Conclusions This analysis highlights differences between inpatients in NHS and independent providers of mental health services. We also highlight the inadequacy of current information systems for monitoring care, and the urgent need for standardized data across all NHS-commissioned mental healthcare, irrespective of whether it is publicly or privately provided. This is especially important in view of the increases in independent sector provision, and the specialist nature of their services. Such information is critical for commissioners, regulators of health and social care, and other audiences for monitoring patient flows, the quality of care provided, usage of the Mental Health Act 2007 and compliance with equality legislation.
Tips for teaching evidence-based medicine in a clinical setting: lessons from adult learning theory. Part two
Authors: Malick Sadia , Das Kausik , Khan Khalid S 
Published: November 2008

Summary Evidence-based medicine (EBM) is the clinical use of current best available evidence from relevant, valid research. Provision of evidence-based healthcare is the most ethical way to practise as it integrates up-to-date patient-oriented research into the clinical decision-making to improve patients' outcomes. This article provides tips for teachers to teach clinical trainees the final two steps of EBM: integrating evidence with clinical judgement and bringing about change.
Impact of simulated visual impairment on the cognitive test performance of young adults
Authors: Wood Joanne M. , Chaparro Alex , Anstey Kaarin J. , Hsing Y. Eve , Johnsson Alexia K. , Morse Anna L. , Wainwright Sara E. 
Published: November 2008

Aims. This study investigated the effect of simulated visual impairment on the speed and accuracy of performance on a series of commonly used cognitive tests.Methods. Cognitive performance was assessed for 30 young, visually normal subjects (M=22.0±3.1 years) using the Digit Symbol Substitution Test (DSST), Trail Making Test (TMT) A and B and the Stroop Colour Word Test under three visual conditions: normal vision and two levels of visually degrading filters (VistechTM) administered in a random order. Distance visual acuity and contrast sensitivity were also assessed for each filter condition.Results. The visual filters, which degraded contrast sensitivity to a greater extent than visual acuity, significantly increased the time to complete (p<.05), but not the number of errors made, on the DSST and the TMT A and B and affected only some components of the Stroop test.Conclusions. Reduced contrast sensitivity had a marked effect on the speed but not the accuracy of performance on commonly used cognitive tests, even in young individuals; the implications of these findings are discussed.
Assessment of the Multiple-Biomarker Approach for Diagnosis of Myocardial Infarction in Patients Presenting with Symptoms Suggestive of Acute Coronary Syndrome
Authors: Apple Fred S , Smith Stephen W , Pearce Lesly A , Murakami MaryAnn M 
Published: November 2008

Abstract
Background: Cardiac troponin is the preferred biomarker for detecting acute myocardial injury and infarction (MI). We studied whether multiple biomarkers of numerous pathophysiological pathways would increase the diagnostic accuracy for detecting MI.
Methods: Seven biomarkers [myeloperoxidase, soluble CD40 ligand, placental growth factor, matrix metalloproteinase 9 (MMP-9), high-sensitivity C-reactive protein (hsCRP), cardiac troponin I (cTnI), N-terminal pro–B-type natriuretic peptide] and estimated glomerular filtration rate were measured in 457 patients presenting on admission with symptoms suggestive of acute coronary syndrome. Twenty-five patients (5.4%) received MI diagnoses. Clinical sensitivities and specificities were evaluated from 99th-percentile reference values. Forward and backward stepwise logistic regression modeling techniques were used to identify biomarkers that were independently predictive of MI.
Results: Biomarker sensitivities ranged from 20% to 96%, and specificities ranged from 19% to 89%. MMP-9 had the highest sensitivity, but its specificity was 19%. cTnI demonstrated a sensitivity of 72% (95% CI, 51%–88%) and a specificity of 89% (95% CI, 85%–92%). In multivariate models, cTnI (P &lt; 0.001) and either hsCRP (P = 0.009) or MMP-9 (P = 0.03) were independently predictive of MI. Addition of hsCRP or MMP-9 increased the specificity to 95% (95% CI, 92%–97%) or 91% (95% CI, 88%–94%), respectively, but reduced the sensitivity to 56% (95% CI, 35%–76%) and 68% (95% CI, 47%–85%) relative to cTnI alone.
Conclusions: Our findings indicate that the most clinically accurate biomarker for the early diagnosis of MI is the use of cTnI alone, rather than a multiple-biomarker approach, when an analytically robust cardiac troponin assay based on the 99th percentile is used.
Clinical Utility of an LC-MS/MS Seizure Panel for Common Drugs Involved in Drug-Induced Seizures
Authors: Drees Julia C , Stone Judy A , Olson Kent R , Meier Kathryn H , Gelb Alan M , Wu Alan H B 
Published: November 2008

AbstractBackground: Approximately 6% of new-onset seizures are drug-related, but there is currently no reliable way to determine if a seizure is drug-induced. Liquid chromatography–tandem mass spectrometry (LC-MS/MS) is a powerful tool that allows simultaneous detection of numerous analytes of diverse chemical nature in patient samples. This allows a single analysis to incorporate many compounds relevant to a particular clinical presentation, such as suspected drug-induced seizures. We investigated whether results from a seizure panel using LC-MS/MS could affect patient care.Methods: We developed a semiquantitative LC-MS/MS assay to detect 12 chemically diverse drugs implicated in drug-related seizures. We collected leftover serum and plasma samples from patients who had seized, performed solid-phase extraction, and analyzed the samples using a hybrid triple quadrupole/linear ion trap mass spectrometer. After assembling a team of medical and toxicology experts, we developed and used a scoring system to determine whether the results of the seizure panel would have affected patient treatment in each case where a drug was detected.Results: In an analysis of 157 samples from patients who seized, 17 (11%) were found to be positive for a drug on the seizure panel. The team of experts determined that the test results probably or definitely would have affected treatment in 7 (41%) of these cases.Conclusions: A test that detects the presence of drugs implicated in drug-induced seizures can help physicians determine if an unexplained seizure is drug-related and thus potentially better direct patient care. Additionally, LC-MS/MS is an effective tool for answering clinically driven questions.
Analysis of Radial Consolidation Test Data Using a log-log Method
Authors: Robinson Retnamony G. 
Published: November 2008

Abstract
Vertical drains are extensively used to accelerate the consolidation of soft clay deposits. Barron’s theory is usually used to analyze this problem, in which the drainage occurs in the radial direction. The important input parameter in Barron’s theory is the coefficient of radial consolidation (cr) and a rational assessment of cr is necessary for the economic design of vertical drains. While several methods exist for the determination of the coefficient of consolidation (cv) under vertical drainage, very few methods are available for the determination of cr. In this paper, a log-log method is proposed for the determination of cr from the experimental data obtained from consolidation tests under radial drainage, based on the characteristic feature observed from a log Ur versus log Tr plot for the equal strain condition. The validity of the method is evaluated by comparing the experimental data with the theory and comparing with the existing methods, such as the t method and the inflection point method. In addition, the parameters obtained based on the proposed method are used to analyze a large-scale experiment with a prefabricated vertical drain.
Prioritizing Future Research on Off‐Label Prescribing: Results of a Quantitative Evaluation
Authors: Walton Surrey M. , Schumock Glen T. , Lee Ky‐Van , Alexander G. Caleb , Meltzer David , Stafford Randall S. 
Published: November 2008

Study Objective. To develop a prioritized list of individual drugs for which future research regarding off‐label uses is warranted.Design. Retrospective, cross‐sectional study.Data Sources. Commercial database that provides ongoing estimates of drug prescribing practices of office‐based physicians in the United States and an Internet database of comprehensive evidence‐based drug information.Measurements and Main Results. The base analyses incorporated three key factors based on the theory of value of information: volume of off‐label use with inadequate evidence, drug safety, and cost and market considerations. Nationally representative prescribing data were used to estimate the number of off‐label drug uses by indication from January 1, 2005‐June 30, 2007, in the United States, and these indications were then categorized according to the adequacy of scientific support. Black‐box warnings and safety alerts, drug cost, date of market entry, and marketing expenditures were also incorporated into the final model to produce a priority score. Sensitivity analyses were conducted by varying key model parameters. Our findings identified a high volume of off‐label prescribing in the absence of good evidence for a substantial number of drugs, particularly antidepressants, antipsychotics, and anxiolytic‐sedatives. Drugs that consistently ranked high in both our base model and sensitivity analyses were quetiapine, warfarin, escitalopram, risperidone, montelukast, bupropion, sertraline, venlafaxine, celecoxib, lisinopril, duloxetine, trazodone, olanzapine, and epoetin alfa.Conclusion. Future research into off‐label drug use should focus on drugs used frequently with inadequate supporting evidence, particularly if further concerns are raised by known safety issues, high drug cost, recent market entry, and extensive marketing. Our quantitative analysis identified particular concerns with the off‐label use of antipsychotic and antidepressant drugs. Targeted research and policy activities on our list of prioritized drugs have high potential value.
Effect of Atorvastatin on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel in Healthy Subjects
Authors: Farid Nagy A. , Small David S. , Payne Christopher D. , Jakubowski Joseph A. , Brandt John T. , Li Ying G. , Ernest C. Steven , Salazar Daniel E. , Konkoy Christopher S. , Winters Kenneth J. 
Published: November 2008

Study Objective. To investigate the potential effect of atorvastatin 80 mg/day on the pharmacokinetics and pharmacodynamics of the thienopyridines prasugrel and clopidogrel.Design. Open‐label, randomized, crossover, two‐arm, parallel‐group study.Setting. Single clinical research center in the United Kingdom.Participants. Sixty‐nine healthy men aged 18–60 years.Intervention. Subjects received either a loading dose of prasugrel 60 mg followed by a maintenance dose of 10 mg/day or a loading dose of clopidogrel 300 mg followed by 75 mg/day. The drug was given as monotherapy for 10 days, and after a 6‐day run‐in period with atorvastatin 80 mg/day, the same dosage of atorvastatin was continued with the respective thienopyridine for 10 days. A 14‐day washout period separated the treatment regimens.Measurements and Main Results. Blood samples were collected before and at various time points after dosing on days 1 and 11 for determination of plasma concentrations of metabolites and for measurement of platelet aggregation induced by adenosine 5′‐diphosphate 20 μM and vasodilator‐stimulated phosphoprotein (VASP). Coadministration of atorvastatin did not alter exposure to active metabolites of prasugrel or clopidogrel after the loading dose and thus did not alter inhibition of platelet aggregation (IPA). During maintenance dosing, atorvastatin administration resulted in 17% and 28% increases in the area under the plasma concentration‐time curve (AUC) values of prasugrel's and clopidogrel's active metabolites, respectively. These small changes in AUC did not result in a significant change in IPA response to prasugrel but did result in a significant increase in IPA during clopidogrel maintenance dosing at some, but not all, of the time points on day 11. Coadministration of atorvastatin with either prasugrel or clopidogrel had no effect on VASP phosphorylation relative to the thienopyridine alone after the loading dose.Conclusion. Coadministration of atorvastatin 80 mg/day with prasugrel or clopidogrel did not negatively affect the antiplatelet response to either drug after a loading dose or during maintenance dosing. The lack of a clinically meaningful effect of high‐dose atorvastatin on the pharmacodynamic response to prasugrel after the loading or maintenance dose indicates that no dosage adjustment should be necessary in patients receiving these drugs concomitantly.