INTERNATIONAL JOURNAL OF CANCER, Issue 10 2006
Marie M. Cantwell
Abstract Sex is a consistent predictor of bladder cancer: men experience 2,4-fold higher age-adjusted rates than women in the U.S. and Europe. The objective of this study was to examine whether hormone-related factors are associated with bladder cancer in women. We examined parity, age at menarche, age at first birth, age at menopause, oral contraceptive use and menopausal hormone therapy (HT) use and bladder cancer risk in the Breast Cancer Detection Demonstration Project Follow-Up Study. Endpoint and exposure information was collected on 54,308 women, using annual telephone interviews (1980,86) and 3 mailed, self-administered questionnaires (1987,98). During an average follow-up time of 15.3 years, 167 cases of bladder cancer were identified. Univariate and adjusted rate ratios (RRs) were estimated using Poisson regression. Parity, age at menarche, age at first birth, age at menopause, and oral contraceptive use were not associated with bladder cancer risk. The majority of menopausal women who took HT used estrogen therapy (ET). Postmenopausal women with less than 4 years, 4,9 years, 10,19 years and 20 or more years of ET use had RRs of 1.55 (95% CI = 0.96,2.51), 1.00 (95% CI = 0.49,2.04), 1.23 (95% CI = 0.62,2.43) and 0.57 (95% CI = 0.14,2.34), respectively, compared with nonusers (p = 0.50). Findings from this study are not consistent with the hypothesis that hormone-related factors in women are associated with bladder cancer. © 2006 Wiley-Liss, Inc. [source]

Changes in the Isolated Delayed Component as an Endpoint of Catheter Ablation in Arrhythmogenic Right Ventricular Cardiomyopathy: Predictor for Long-Term Success

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 7 2008
AKIHIKO NOGAMI M.D.
Introduction: Although successful ablation of ventricular tachycardia (VT) is feasible in arrhythmogenic right ventricular cardiomyopathy (ARVC), long-term recurrence is common. The aim of this study was to assess the usefulness of a change in the isolated delayed component (IDC) as an endpoint of the catheter ablation in ARVC. Methods and Results: Eighteen patients (48 ± 11 years) with ARVC were studied. Detailed endocardial mapping of the right ventricle (RV) was performed during sinus rhythm. IDCs were recorded in 16 patients and the latest IDCs were related to the VT circuit. Catheter ablation was carried out in the areas with the IDCs. At the end of the session, the IDC was electrically dissociated in one, disappeared in five, exhibited second-degree block in one, was significantly delayed (,50 ms) in three, and remained unchanged in six. The change in the IDC was correlated with the change in the type II/III late potentials in the signal-averaged electrocardiography (ECG) and the inducibility of the clinical VT after the ablation. During a follow-up of 61 ± 38 months, VT recurred in six. The patients with a changed IDC had a significantly lower VT recurrence than those with no IDC or an unchanged IDC (P < 0.02). Conclusion: In patients with ARVC, (1) the IDCs during sinus rhythm are related to the clinical VT and can be a target for the ablation, (2) a change in the IDC can be used as an endpoint, and (3) qualitative analyses of the serial signal-averaged ECGs may be useful for the long-term follow-up. [source]

Origin and Endpoint of the Olfactory Nerve Fibers: As Described by Santiago Ramón y Cajal,

THE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 7 2008
Catherine Levine
Illustration by author Catherine Levine inspired by the original drawing by Santiago Ramón y Cajal, featured in the article Origin and endpoint of the olfactory nerve fibers: As described by Santiago Ramón y Cajal. Depicted are large tufted cells and granule cells, a large stellate cell, a row of mitral cells and the arborization on the olfactory glomeruli, with olfactory nerve fibers streaming through the cartilage formation of the cribriform plate. See Levine et al., Anatomical Record 291:741,750. [source]

Design and Analysis of Clinical Trials with Time-to-Event Endpoint edited by PEACE, K. E.

BIOMETRICS, Issue 2 2010
Yu Shyr
No abstract is available for this article. [source]

Latent-Model Robustness in Joint Models for a Primary Endpoint and a Longitudinal Process

BIOMETRICS, Issue 3 2009
Xianzheng Huang
Summary Joint modeling of a primary response and a longitudinal process via shared random effects is widely used in many areas of application. Likelihood-based inference on joint models requires model specification of the random effects. Inappropriate model specification of random effects can compromise inference. We present methods to diagnose random effect model misspecification of the type that leads to biased inference on joint models. The methods are illustrated via application to simulated data, and by application to data from a study of bone mineral density in perimenopausal women and data from an HIV clinical trial. [source]

Dynamic Comparison of Kaplan,Meier Proportions: Monitoring a Randomized Clinical Trial with a Long-Term Binary Endpoint

BIOMETRICS, Issue 1 2008
Erica Brittain
Summary The approach to early termination for efficacy in a trial where events occur over time but the primary question of interest relates to a long-term binary endpoint is not straightforward. This article considers comparison of treatment groups with Kaplan,Meier (KM) proportions evaluated at increasing times from randomization, at increasing calendar testing times. This strategy is employed to improve the ability to detect important treatment effects and provide critical treatments to patients in a timely manner. This dynamic Kaplan,Meier (DKM) approach is shown to be robust; that is, it produces high power and early termination time across a wide range of circumstances. In contrast, a fixed time KM comparison and the log-rank test are both shown to be more variable in performance. Practical considerations of implementing the DKM method are discussed. [source]

Reproductive and transgenerational effects of methylmercury or Aroclor 1268 on Fundulus heteroclitus

ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 2 2001
Mary Baker Matta
Abstract This research determined the potential for methylmercury or Aroclor 1268 to disrupt reproduction and sexual differentiation in Fundulus heteroclitus. The research determined whether fish that are exposed to mercury or Aroclor 1268 survive and successfully reproduce; whether offspring of exposed fish hatch, survive, produce eggs, and fertilize them; and whether the secondgeneration offspring of exposed fish hatch and survive. Fundulus heteroclitus were exposed to mercury or Aroclor 1268 via contaminated food. Endpoints evaluated included survival, growth, fecundity, fertilization success, hatch success, larval survival, sex ratios, and the prevalence of gonadal abnormalities. In general, polychlorinated biphenyls were highly bioavailable and accumulated well through feeding. The only statistically significant effect observed as a result of treatment with Aroclor 1268 was an increase in growth in the offspring of exposed fish. Mercury was accumulated in a dose-dependent fashion via food exposures. Exposure to mercury in food increased mortality in male F. heteroclitus, which possibly occurred as a result of behavioral alterations. Increased mortality was observed at body burdens of 0.2 to 0.47 ,g/g. Offspring of F. heteroclitus fed mercury-contaminated food were less able to successfully reproduce, with reduced fertilization success observed at egg concentrations of 0.01 to 0.63 ,g/g, which corresponds with parent whole-body concentrations of 1.1 to 1.2 ,g/g. Offspring of exposed fish also had altered sex ratios, with treatment at moderate concentrations producing fewer females and treatment at the highest concentration producing more females than expected. Alterations in sex ratios were observed at concentrations of less than 0.01 ,g/g in eggs or between 0.44 and 1.1 ,g/g in parents. Offspring of mercury-exposed fish also had increased growth in moderate treatments, when egg concentrations were less than 0.02 ,g/g, or when parent whole bodies contained 0.2 to 0.47 ,g/g. In summary, exposure to mercury reduced male survival, reduced the ability of offspring to successfully reproduce, and altered sex ratios in offspring. Both direct effects on exposed fish and transgenerational effects were observed. [source]

Endpoints of therapy in chronic hepatitis B,

HEPATOLOGY, Issue S5 2009
Jordan J. Feld
Because clearance of hepatitis B virus (HBV) infection is rarely, if ever, achievable, the goals of therapy necessarily focus on prevention of bad clinical outcomes. Ideally, therapies would be shown to prevent tangible clinical endpoints like development of cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, these endpoints typically take years or decades to occur and are therefore impractical targets for clinical trials which last only 1-2 years. As a result, surrogate biomarkers that are believed to correlate with long-term outcome are used to evaluate therapy. Of the clinical, biochemical, serological, virological, and histological endpoints that have been evaluated, none has been shown to be ideal on its own. Symptoms are uncommon and aminotransferase levels fluctuate spontaneously. Loss of hepatitis B e antigen (HBeAg) has been the traditional therapeutic endpoint; however, the indefinite durability off treatment and the emergence of HBeAg-negative disease have made it inadequate as the sole goal of therapy. Loss of hepatitis B surface antigen is associated with improved clinical outcomes, but it is rarely achieved with current therapies. Suppression of viral replication, as measured by serum HBV DNA levels, has become the major goal of therapy, particularly if maintained off therapy. Although useful, the significance of viral levels depends on the stage of disease, degree of liver damage, and the type of therapy. Finally, liver biopsy, often considered the gold standard, is invasive, prone to sampling error, and may take years to change significantly. At present, there is no ideal biomarker for evaluation of therapies for hepatitis B. Future research should be directed at development and validation of surrogate markers that accurately predict or reflect clinically relevant outcomes of chronic hepatitis B. (HEPATOLOGY 2009;49:S96,S102.) [source]

Predicting short-term disease progression among HIV-infected patients in Asia and the Pacific region: preliminary results from the TREAT Asia HIV Observational Database (TAHOD)

HIV MEDICINE, Issue 3 2005
J Zhou
Objectives HIV disease progression has been well documented in Western populations. This study aimed to estimate the short-term risk of AIDS and death from the TREAT Asia HIV Observational Database (TAHOD), a prospective, multicentre cohort study in Asia and the Pacific region. Methods Prospective data were analysed to estimate short-term disease progression. Endpoints were defined as the time from study entry to diagnosis with AIDS or death. Antiretroviral treatment was fitted as a time-dependent variable. Predictors of disease progression were assessed using Cox proportional hazards models, and prognostic models were developed using Weibull models. Results A total of 1260 patients with prospective follow-up data contributed 477 person-years of follow-up, during which 18 patients died and 34 were diagnosed with AIDS, a combined rate of 10.1 per 100 person-years. Compared with patients receiving antiretroviral treatment, patients not on treatment had a higher rate of disease progression (17.6 vs. 8.1 per 100 person-years, respectively). Baseline CD4 count was the strongest predictor of disease progression. Prognostic models, using either a baseline CD4 count as the sole marker or markers including baseline haemoglobin, AIDS-related symptoms and previous or current antiretroviral treatment, were successful at identifying patients at high risk of short-term disease progression. Conclusions Similar to the situation in Western countries, baseline CD4 count was the strongest predictor of short-term disease progression. Prognostic models based on readily available clinical data and haemoglobin level should be useful in estimating short-term clinical risk in HIV-infected patients in Asia and the Pacific region. [source]

Considerations for Development of Surrogate Endpoints for Antifracture Efficacy of New Treatments in Osteoporosis: A Perspective,,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2008
Mary L Bouxsein
Abstract Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance. [source]

Endpoints in Ablation of Paroxysmal Atrial Fibrillation: When is Enough Enough?

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2010
GEOFFREY LEE M.B.Ch.B.
First page of article [source]

The Clinical Implications of Cumulative Right Ventricular Pacing in the Multicenter Automatic Defibrillator Trial II

JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2005
JONATHAN S. STEINBERG M.D.
Introduction: This study was designed to assess whether right ventricular pacing in the implantable cardioverter defibrillator (ICD) arm of the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II was associated with an unfavorable outcome. Methods and Results: Data on the number of ventricular paced beats were available in 567 (76%) of 742 MADIT II patients with ICDs. The number of ventricular paced beats over the total number of beats showed a bimodal distribution with patients being predominantly paced or nonpaced. Therefore, patients were dichotomized at 0,50% and 51,100% of cumulative pacing with median pacing rate 0.2% and 95.6%, respectively. Endpoints included new or worsening heart failure, appropriate ICD therapy for VT/VF, and the combined endpoint of heart failure or death. Clinical features associated with frequent ventricular pacing included age ,65 years, advanced NYHA heart failure class, LVEF < 0.25, first degree AV and bundle branch block, and amiodarone use. During follow-up, 119 patients (21%) had new or worsened heart failure, 130 (23%) had new or worsened heart failure or death, and 142 (25%) had appropriate therapy for VT/VF. In comparison to patients with infrequent pacing, those with frequent pacing had significantly higher risk of new or worsened heart failure (hazard ratio = 1.93; P = 0.002) and VT/VF requiring ICD therapy (HR = 1.50; P = 0.02). Conclusions: Patients in MADIT II who were predominantly paced had a higher rate of new or worsened heart failure and were more likely to receive therapy for VT/VF. These results suggest the deleterious consequences of RV pacing, particularly in the setting of severe LV dysfunction. [source]

Clinical trial: a nutritional supplement Viusid, in combination with diet and exercise, in patients with nonalcoholic fatty liver disease

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2009
E. VILAR GOMEZ
Summary Background, Nonalcoholic fatty liver disease (NAFLD) is a significant health problem for which there is no universally accepted pharmacological treatment. The combination of weight loss and antioxidant drugs to ameliorate insulin resistance and improve steatosis, inflammation and fibrosis provides the rational for therapeutic trials. Aim, To evaluate the efficacy and safety of a nutritional supplement Viusid in association with diet and exercise for NAFLD. Methods, A randomized, controlled and parallel-group trial was conducted at a tertiary care academic centre (National Institute of Gastroenterology, Havana, Cuba). We randomly assigned 60 patients with liver biopsy-proven NAFLD to 6 months of treatment with a hypocaloric diet plus aerobic exercise daily and three Viusid sachets daily or a hypocaloric diet and exercise. Endpoints were improvement in the NAFLD activity score (NAS), fibrosis and normalization of serum aminotransferase levels. Results, A significant improvement in steatosis, necroinflammation and fibrosis was seen in each group of treatment (P < 0.01 for each feature). The Viusid group, as compared with the control group, significantly reduced the mean of NAS [from 4.18 to 0.54 points in the Viusid group vs. 4.45 to 2.2 points in the control group (P < 0.001)]. On between-group comparison, Viusid was found to be associated with a significantly greater improvement in steatosis (P < 0.001), ballooning (P = 0.002) and lobular inflammation (P = 0.025), but not in fibrosis (P = 0.07). Viusid was well tolerated. Conclusions, Our results indicate that treatment with diet and exercise leads to a notable improvement in the histological features of NAFLD; however, the administration of Viusid intensifies the improvements of histological findings, especially of steatosis and inflammation. [source]

Clinical trial: lansoprazole 15 or 30 mg once daily vs. placebo for treatment of frequent nighttime heartburn in self-treating subjects

ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 5 2009
D. A. PEURA
Summary Background, Frequent nighttime heartburn is common. Lansoprazole 15 mg is indicated for treatment of heartburn and other gastro-oesophageal reflux disease-related symptoms. Aim, To evaluate the efficacy and safety of lansoprazole in self-treating subjects with frequent nocturnal heartburn. Methods, A total of 864 subjects with heartburn on ,2 days/week over the past month were randomized to double-blind treatment with lansoprazole 15 or 30 mg or placebo each morning. Endpoints were percentage of nighttimes without heartburn (primary), percentage of 24-h days without heartburn and percentage of subjects without heartburn on day 1. Results, Mean percentage of nighttimes without heartburn was significantly greater with lansoprazole 15 mg (61.3%) or lansoprazole 30 mg (61.7%) vs. placebo (47.8%) over 14 days (P < 0.0001 vs. placebo for both doses). Percentage of 24-h days without heartburn and percentage of subjects without heartburn on day 1 were significantly greater with lansoprazole 15 or 30 mg vs. placebo. Conclusions, Both lansoprazole 15 and 30 mg were highly effective and well tolerated in reducing symptoms in subjects with frequent nighttime heartburn. The benefit of therapy on 24-h heartburn and nighttime heartburn on day 1 of treatment was also evident. Lansoprazole 15 mg is a suitable choice for management of frequent nighttime heartburn. [source]

Long-term study of fluticasone propionate aqueous nasal spray in acute and maintenance therapy of nasal polyposis

ALLERGY, Issue 6 2009
R. Jankowski
Background:, Topical steroids are first-line medication to control nasal polyposis (NP), a disease with long-term clinical course. Objective:, The aim of this study was to evaluate the efficacy and safety of fluticasone propionate aqueous nasal spray (FPANS) 200 ,g twice a day (bd) after 1 month of treatment, and to compare FPANS 200 ,g bd and FPANS 200 ,g once a day (od) in maintenance and long-term treatment. Methods:, Double-blind, placebo-controlled, 8-month study with three treatment periods (1-month acute period followed with 1-month maintenance period and 6-month follow-up period) was carried out. Group 1 received FPANS 200 ,g bd, during acute, maintenance and follow-up periods, Group 2 received FPANS 200 ,g bd during acute period and FPANS 200 ,g od during maintenance and follow-up periods, and Group 3 received placebo during acute and maintenance periods and FPANS 200 ,g bd during follow-up period. Endpoints were change from baseline in clinic peak nasal inspiratory flow (PNIF), domiciliary evening PNIF, intensity of symptoms and polyposis grade. Results:, After acute period and maintenance periods, FPANS 200 ,g bd was significantly more effective than placebo on all endpoints and more effective than FPANS 200 ,g od after 1-month maintenance period on clinic PNIF, evening PNIF, obstruction, percentage of days with no sense of smell and percentage of nights with no disturbances. The two doses were similar on other endpoints. After the 6-month follow-up period, there was no difference between the two doses of FPANS at all efficacy endpoints. The safety profile of FPANS did not highlight any new or unanticipated adverse events. Conclusion:, The study demonstrated the efficacy of FPANS 200 ,g bd in acute treatment and FPANS 200 ,g od as a sufficient dose to maintain a long-term efficacy in the treatment for NP. [source]

Surrogate endpoints and emerging surrogate endpoints for risk reduction of cardiovascular disease

NUTRITION REVIEWS, Issue 2 2008
Crystal M Rasnake
This article reviews surrogate endpoints and emerging biomarkers that were discussed at the annual "Cardiovascular Biomarkers and Surrogate Endpoints" symposium cosponsored by the US Food and Drug Administration (FDA) and the Montreal Heart Institute. The FDA's Center for Food Safety and Applied Nutrition (CFSAN) uses surrogate endpoints in its scientific review of a substance/disease relationship for a health claim. CFSAN currently recognizes three validated surrogate endpoints: blood pressure, blood total cholesterol, and blood low-density lipoprotein (LDL) concentration in its review of a health claim for cardiovascular disease (CVD). Numerous potential surrogate endpoints of CVD are being evaluated as the pathophysiology of heart disease is becoming better understood. However, these emerging biomarkers need to be validated as surrogate endpoints before they are used by CFSAN in the evaluation of a CVD health claim. [source]

Green Tea Polyphenols and Cancer Chemoprevention: Multiple Mechanisms and Endpoints for Phase II Trials

NUTRITION REVIEWS, Issue 5 2004
M.P.H., Susan B. Moyers Ph.D.
Among the numerous polyphenols isolated from green tea, the catechin EGCG predominates and is the target of anticancer research. But studies suggest that EGCG and other catechins are poorly absorbed and undergo substantial biotransformation to species that include glucuronides, sulfates, and methylated compounds. Numerous studies relate the antioxidant properties of the catechins with anticancer effects, but recent research proposes other mechanisms of action, including those involving methyl transfers that are subject to allelic variability in the enzyme catechol O-methyl transferase. However, preclinical research is promising and EGCG appears to be ready for further study in phase II and III trials. [source]

Cardiac Effects of Electrical Stun Guns: Does Position of Barbs Contact Make a Difference?

PACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 4 2008
DHANUNJAYA LAKKIREDDY M.D.
Background:The use of electrical stun guns has been rising among law enforcement authorities for subduing violent subjects. Multiple reports have raised concerns over their safety. The cardiovascular safety profile of these devices in relationship to the position of delivery on the torso has not been well studied. Methods:We tested 13 adult pigs using a custom device built to deliver neuromuscular incapacitating (NMI) discharge of increasing intensity that matched the waveform of a commercially available stun gun (TASER® X-26, TASER International, Scottsdale, AZ, USA). Discharges with increasing multiples of output capacitances were applied in a step-up and step-down fashion, using two-tethered barbs at five locations: (1) Sternal notch to cardiac apex (position-1), (2) sternal notch to supraumbilical area (position-2), (3) sternal notch to infraumbilical area (position-3), (4) side to side on the chest (position-4), and (5) upper to lower mid-posterior torso (position-5). Endpoints included determination of maximum safe multiple (MaxSM), ventricular fibrillation threshold (VFT), and minimum ventricular fibrillation induction multiple (MinVFIM). Results:Standard TASER discharges repeated three times did not cause ventricular fibrillation (VF) at any of the five locations. When the barbs were applied in the axis of the heart (position-1), MaxSM and MinVFIM were significantly lower than when applied away from the heart, on the dorsum (position-5) (4.31 ± 1.11 vs 40.77 ± 9.54, P< 0.001 and 8.31 ± 2.69 vs 50.77 ± 9.54, P< 0.001, respectively). The values of these endpoints at position-2, position-3, and position-4 were progressively higher and ranged in between those of position-1 and position-5. Presence of ventricular capture at a 2:1 ratio to the delivered TASER impulses correlated with induction of VF. No significant metabolic changes were seen after standard NMI TASER discharge. There was no evidence of myocardial damage based on serum cardiac markers, electrocardiography, echocardiography, and histopathologic findings confirming the absence of significant cardiac effects. Conclusions: Standard TASER discharges did not cause VF at any of the positions. Induction of VF at higher output multiples appear to be sensitive to electrode distance from the heart, giving highest ventricular fibrillation safety margin when the electrodes are placed on the dorsum. Rapid ventricular capture appears to be a likely mechanism of VF induction by higher output TASER discharges. [source]

Mortality and Revascularization Following Admission for Acute Myocardial Infarction: Implication for Rural Veterans

THE JOURNAL OF RURAL HEALTH, Issue 4 2010
Thad E. Abrams MD
Abstract Introduction: Annually, over 3,000 rural veterans are admitted to Veterans Health Administration (VA) hospitals for acute myocardial infarction (AMI), yet no studies of AMI have utilized the VA rural definition. Methods: This retrospective cohort study identified 15,870 patients admitted for AMI to all VA hospitals. Rural residence was identified by either Rural-Urban Commuting Area (RUCA) codes or the VA Urban/Rural/Highly Rural (URH) system. Endpoints of mortality and coronary revascularization were adjusted using administrative laboratory and clinical variables. Results: URH codes identified 184 (1%) veterans as highly rural, 6,046 (39%) as rural, and 9,378 (60%) as urban; RUCA codes identified 1,350 (9%) veterans from an isolated town, 3,505 (22%) from a small or large town, and 10,345 (65%) from urban areas. Adjusted mortality analyses demonstrated similar risk of mortality for rural veterans using either URH or RUCA systems. Hazards of revascularization using the URH classification demonstrated no difference for rural (HR, 0.96; 95% CI, 0.94-1.00) and highly rural veterans (HR, 1.13; 0.96-1.31) relative to urban veterans. In contrast, rural (relative to urban) veterans designated by the RUCA system had lower rates of revascularization; this was true for veterans from small or large towns (HR, 0.89; 0.83-0.95) as well as veterans from isolated towns (HR, 0.86; 0.78-0.93). Conclusion: Rural veterans admitted for AMI care have a similar risk of 30-day mortality but the adjusted hazard for receipt of revascularization for rural veterans was dependent upon the rural classification system utilized. These findings suggest potentially lower rates of revascularization for rural veterans. [source]

The Elephant in the Room: Failings of Current Clinical Endpoints in Kidney Transplantation

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 5 2010
J. D. Schold
In this opinion piece, we address the limitations of the two most common clinical endpoints in kidney transplantation trials (acute rejection and renal function) and attempt to offer a reasonable framework by which to find true and reliable early endpoints that reflect long-term outcomes. Other potential endpoints tested in recent years, including the use of genomic and proteomic markers are still in development. Until other reliable endpoints are established, it is important to understand what can be inferred from ongoing studies that utilize these endpoints and what further information we need to derive ,true' surrogate endpoints. We consider evaluation of current markers using the ,Prentice criteria', which bases assessment of endpoints as true surrogates on four primary rules. Based on our assessment, progress in understanding the safety and efficacy of new therapies and interventions in kidney transplantation will remain limited with current makers. Prospectively, we advocate: (i) significant caution in extrapolating long-term outcomes from currently utilized clinical markers, (ii) use of traditional hard endpoints whenever feasible and (iii) dedication of efforts for more data collection on specific disease entities and greater diligence in determining the onset of deleterious processes. [source]

Geographic Variation in Organ Availability Is Responsible for Disparities in Liver Transplantation between Hispanics and Caucasians

AMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2009
M. L. Volk
The aims of this study were to determine whether disparities in waiting list outcomes exist for Hispanics and African Americans during the post-MELD era, and to investigate interactions between disparities and geography. Scientific Registry of Transplant Recipients data were used to compare Hispanics and African Americans to Caucasians listed between 2003 and 2008. Endpoints included (i) receipt of a liver transplant and (ii) death or removal from the waiting list for being too sick or medically unsuitable. Adjustment for possible confounders was performed using multivariate Cox regression, with adjustment for geographic variation using a fixed-effects multilevel model. In multivariate analysis, African Americans have similar hazard of transplantation and death/removal as Caucasians during the post-MELD era. However, Hispanics are less likely to receive a transplant than Caucasians despite adjustment for potential confounders (HR 0.80, 95% CI 0.77,0.83), while having a similar hazard of death/removal. This effect disappeared after adjusting for unequal regional distribution of Hispanics, who represent 8% of patients in donation service areas (DSAs) having median waiting times of ,155 days versus 19% in DSAs with median waiting times of >155 days. In conclusion, disparities in liver transplantation exist for Hispanics during the post-MELD era, caused by geographic variation in organ availability. [source]

Safety and Efficacy of Bivalirudin in High-risk Patients Admitted Through the Emergency Department

ACADEMIC EMERGENCY MEDICINE, Issue 8 2009
Chadwick D. Miller MD
Abstract Objectives:, The objective was to assess the safety and efficacy of bivalirudin monotherapy in patients with high-risk acute coronary syndrome (ACS) presenting to the emergency department (ED). Methods:, Data from the Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial were used to conduct a post hoc subgroup analysis of high-risk ACS patients (cardiac biomarker elevation or ST-segment deviation) who initially presented to the ED. The ACUITY trial randomized patients to receive heparin (unfractionated [UFH] or enoxaparin) plus glycoprotein IIb/IIIa inhibition (GPI), bivalirudin plus GPI, or bivalirudin monotherapy. Endpoints included composite ischemia, major bleeding (not coronary artery bypass graft (CABG) related), and net clinical outcome (major bleeding plus composite ischemia). Results:, Of 13,819 participants in the ACUITY trial, 6,441 presented initially to the ED, met high-risk criteria, and were included in the primary analysis. Bivalirudin alone when compared to heparin plus GPI, after adjusting for covariates, was associated with an improvement in net clinical outcome (12.3% vs. 14.3%, adjusted odds ratio [OR] = 0.81, 95% confidence interval [CI] = 0.66 to 0.99), similar composite ischemia (9.3% vs. 9.1%, adjusted OR = 0.98, 95% CI = 0.77 to 1.24), and less major bleeding (4.0% vs. 6.8%, adjusted OR = 0.57, 95% CI = 0.42 to 0.75). Bivalirudin plus GPI when compared to heparin plus GPI had similar net clinical outcome (13.8% vs. 14.3%, adjusted OR = 0.91, 95% CI = 0.75 to 1.11), composite ischemia (8.8% vs. 9.1%, adjusted OR = 0.87, 95% CI = 0.69 to 1.11), and major bleeding (6.8% vs. 6.8%, adjusted OR = 1.01, 95% CI = 0.79 to 1.30). Conclusions: Bivalirudin monotherapy decreases major bleeding while providing similar protection from ischemic events compared to heparin plus GPI in patients with high-risk ACS admitted through the ED. [source]

Beating-Heart Coronary Artery Bypass Grafting With Miniaturized Cardiopulmonary Bypass Results in a More Complete Revascularization When Compared to Off-Pump Grafting

ARTIFICIAL ORGANS, Issue 3 2010
Delawer Reber
Abstract The technique of miniaturized cardiopulmonary bypass (M-CPB) for beating-heart coronary artery bypass grafting (CABG) is relatively new and has potential advantages when compared to conventional cardiopulmonary bypass (CPB). M-CPB consists of less tubing length and requires less priming volume. The system is phosphorylcholine coated and results in minimal pump-related inflammatory response and organ injury. Finally, this technique combines the advantages of the off-pump CABG (OPCAB) with the better exposure provided by CPB to facilitate complete revascularization. The hypothesis is that CABG with M-CPB has a better outcome in terms of complete coronary revascularization and perioperative results as that compared to off-pump CABG (OPCAB). In a retrospective study, 302 patients underwent beating-heart CABG, 117 (39%) of them with the use of M-CPB and 185 (61%) with OPCAB. After propensity score matching 62 patients in both groups were demographically similar. The most important intra- and early-postoperative parameters were analyzed. Endpoints were hospital mortality and complete revascularization. Hospital mortality was comparable between the groups. The revascularization was significantly more complete in M-CPB patients than in patients in the OPCAB group. Beating-heart CABG with M-CPB is a safe procedure and it provides an optimal operative exposure with significantly more complete coronary revascularization when compared to OPCAB. Beating-heart CABG with the support of a M-CPB is the operation of choice when total coronary revascularization is needed. [source]

Humane Endpoints in Animal Experiments for Biomedical Research.

AUSTRALIAN VETERINARY JOURNAL, Issue 7 2000
HV Smith
No abstract is available for this article. [source]

Assessment of Multiple Ordinal Endpoints

BIOMETRICAL JOURNAL, Issue 1 2009
Lothar Häberle
Abstract Ranking multivariate ordinal data and applying a non-parametric test is an analytical approach commonly employed to compare treatments. We study three types of ranking and demonstrate how to combine them. The ranking methods rest upon partial orders of the multidimensional measurements or upon the sum of ranks. Since their usage is simple as regards statistical assumptions and technical realization, they are also adapted for health professionals without deep statistical knowledge. Our goal is discussing differences between the approaches and disclosing possible statistical consequences of their usage (© 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source]

Blinded Sample Size Reestimation in Non-Inferiority Trials with Binary Endpoints

BIOMETRICAL JOURNAL, Issue 6 2007
Tim Friede
Abstract Sample size calculations in the planning of clinical trials depend on good estimates of the model parameters involved. When the estimates of these parameters have a high degree of uncertainty attached to them, it is advantageous to reestimate the sample size after an internal pilot study. For non-inferiority trials with binary outcome we compare the performance of Type I error rate and power between fixed-size designs and designs with sample size reestimation. The latter design shows itself to be effective in correcting sample size and power of the tests when misspecification of nuisance parameters occurs with the former design. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [source]

A Note on One-Sided Tests with Multiple Endpoints

BIOMETRICS, Issue 1 2004
Michael D. Perlman
Summary. Testing problems with multivariate one-sided alternative hypotheses are common in clinical trials with multiple endpoints. In the case of comparing two treatments, treatment 1 is often preferred if it is superior for at least one of the endpoints and not biologically inferior for the remaining endpoints. Bloch et al. (2001, Biometrics57, 1039,1047) propose an intersection,union test (IUT) for this testing problem, but their test does not utilize the appropriate multivariate one-sided test. In this note we modify their test by an alternative IUT that does utilize the appropriate one-sided test. Empirical and graphical evidence show that the proposed test is more appropriate for this testing problem. [source]

Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head-to-head placebo-controlled trial

BJU INTERNATIONAL, Issue 1 2010
Sender Herschorn
Study Type , Therapy (RCT) Level of Evidence 1b OBJECTIVE To compare the efficacy and tolerability of fesoterodine 8 mg with tolterodine extended-release (ER) 4 mg and placebo in a randomized clinical trial of patients with an overactive bladder (OAB). PATIENTS AND METHODS In this 12-week double-blind, double-dummy, placebo-controlled, randomized clinical trial, eligible patients reported OAB symptoms for ,3 months and recorded ,8 voids and ,1 urgency urinary incontinence (UUI) episode per 24 h in 3-day bladder diaries at baseline. Patients were randomized in a 2:2:1 ratio to fesoterodine (4 mg for 1 week then 8 mg for 11 weeks); tolterodine ER 4 mg; or placebo (with sham dose escalation for tolterodine ER and placebo). Endpoints were changes from baseline to week 12 in UUI episodes (primary endpoint), total and nocturnal voids, urgency episodes, severe urgency episodes, and frequency-urgency sum per 24 h; mean voided volume per void (MVV); and the OAB questionnaire (OAB-q), Patient Perception of Bladder Condition (PPBC), and Urgency Perception Scale (UPS). Safety and tolerability were assessed and summarized over the 12-week study period. RESULTS Fesoterodine (636 patients) significantly improved UUI episodes at week 12 (primary endpoint) compared with tolterodine ER (641 patients; P = 0.017) and placebo (313 patients; P < 0.001). Fesoterodine also produced significantly greater improvements than tolterodine ER in MVV (P = 0.005). Fesoterodine significantly improved all diary endpoints compared with placebo (P < 0.001), except for nocturnal voids (P = 0.327). Tolterodine ER significantly improved all diary endpoints vs placebo (P < 0.001), except for nocturnal voids (P = 0.506) and MVV (P = 0.103). Diary dry rates (the proportion of patients reporting no UUI episodes at endpoint among those with one or more UUI episodes at baseline) were significantly higher with fesoterodine (64%) than with tolterodine ER (57%; P = 0.015) and placebo (45%; P < 0.001). Improvements in PPBC, UPS and OAB-q scale and domain scores at week 12 were all significantly better with fesoterodine than placebo (all P < 0.001) and tolterodine ER (all P < 0.05) except for the OAB-q Sleep domain vs tolterodine ER (P = 0.081). Dry mouth and constipation rates were 28% and 5% in the fesoterodine group, 16% and 4% in the tolterodine ER group, and 6% and 3% with placebo, respectively. Discontinuations due to treatment-emergent adverse events were 6%, 4% and 2% in the fesoterodine, tolterodine ER, and placebo groups, respectively. CONCLUSION In patients with OAB, fesoterodine 8 mg showed superior efficacy over tolterodine ER 4 mg and placebo in reducing UUI episodes (primary endpoint) and in improving most patient-reported outcome measures. Both active treatments were well tolerated. [source]

High-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patients

BRITISH JOURNAL OF HAEMATOLOGY, Issue 4 2009
Mars B. Van't Veer
Summary Mantle cell lymphoma (MCL) has a dismal outcome when treated with conventional chemotherapy. This single arm phase 2 study evaluated intensive consolidation treatment of patients with newly diagnosed MCL up to the age of 65 years, responsive to R-CHOP (rituximab, cyclophosphamide, oncovin, adriamycin, prednisolone). Endpoints for evaluation were toxicity, failure-free survival (FFS) and overall survival (OS). Eighty-seven patients were treated with three cycles of R,CHOP. Sixty-six patients responded to R-CHOP with at least a partial response, 62 continued protocol treatment with high-dose cytarabine (Ara-C; 2000 mg/m2, bid. over 4 d) and 61 patients received rituximab and stem cell harvest, followed by BEAM (carmustine, etoposide, Ara-C, melphalan) and autologous stem cell rescue. Non-haematological toxicity, grades III and IV, was seen in 8% of the patients after R-CHOP, in 22% after high-dose Ara-C and in 55% after BEAM. The overall response rate was 70% (complete response rate 64%, partial response rate 6%), FFS and OS at 4 years were 36 ± 7% and 66 ± 6%, respectively. The FFS and OS at 4 years from the evaluation after BEAM in the 61 R-CHOP responsive patients was 46 ± 9% and 79 ± 7%, respectively. In conclusion, high-dose Ara-C and BEAM with stem cell rescue in newly diagnosed MCL patients responsive to R-CHOP is a manageable treatment with respect to toxicity. This regimen leads to long-term, but probably not durable, remissions. [source]

Case,control comparison of profundaplasty and femoropopliteal supragenicular bypass for peripheral arterial disease,

BRITISH JOURNAL OF SURGERY (NOW INCLUDES EUROPEAN JOURNAL OF SURGERY), Issue 3 2010
A. Koscielny
Background: The aim of this study was to compare preoperative and postoperative findings, and clinical progress in patients with peripheral arterial occlusive disease undergoing femoropopliteal supragenicular bypass or profundaplasty in a case,control study. Methods: Between January 2001 and June 2004, 171 patients with occlusion of the superficial femoral artery underwent surgery. A retrospective analysis of 28 matched patient pairs was performed. Endpoints were bypass occlusion, surgical revision, amputation and death. Mean length of follow-up was 36 months. Results: At 3 years after surgery there was no statistically significant difference in outcome between femoropopliteal bypass surgery and profundaplasty. There was a trend towards improved results in patients who had bypass surgery for critical leg ischaemia. Preoperative patency of the crural outflow arteries was an independent prognostic factor in multivariable analysis. Conclusion: There were no significant outcome differences between supragenicular bypass surgery or profundaplasty in patients who had surgery for intermittent claudication or ischaemic rest pain. Patients with a single patent tibial artery and gangrene or ulceration appeared to benefit more from bypass surgery. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. [source]