The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale

Background The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA.CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. Trial design TRA.CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least I year. The TRA.CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. Conclusion TRA.CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies. (Am Heart J 2009; 158:327-34.)

Double-blind, Randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: Results from EFECT

Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR +) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR + advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane ( n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups ( hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate ( 7.4% v 6.7%; P = .736) and clinical benefit rate ( 32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.

Accuracy of store-and-forward diagnosis in leproy

Telemedicine might increase the speed of diagnosis for leprosy and reduce the development of disabilities. We compared the accuracy of diagnosis made by telemedicine with that made by in-person examination. The cases were patients with suspected leprosy at eight public health clinics in outlying areas of the city of Sao Paulo. The case history and clinical examination data, and at least two clinical images for each patient, were stored in a web-based system developed for teledermatology. After the examination in the public clinic, patients then attended a teaching hospital for an in-person examination. The benchmark was the clinical examination of two dermatologists at the university hospital. From August 2005 to April 2006, 142 suspected cases of leprosy were forwarded to the website by the doctors at the clinics. Of these, 36 cases were excluded. There was overall agreement in the diagnosis of leprosy in 74% of the 106 remaining cases. The sensitivity was 78% and the specificity was 31%. Although the specificity was low, the study suggests that telemedicine may be a useful low-cost method for obtaining second opinions in programmes to control leprosy.

Peginterferon alfa-2b and Ribavirin: Effective in Patients With Hepatitis C Who Failed Interferon alfa/Ribavirin Therapy

Background & Aims: Treatment with peginterferon alfa and ribavirin produces a sustained virologic response (SVR) in approximately 60% of hepatitis C virus (HCV)-infected patients. Alternate options are needed for patients who relapse or do not respond to therapy. Methods: This prospective, international, multicenter, open-label study evaluated efficacy and safety of peginterferon alfa-2b (1.5 mu g/kg/wk) plus weight-based ribavirin (800-1400 mg/day) in 2333 chronic HCV-infected patients with significant fibrosis/cirrhosis whose previous interferon alfa/ribavirin therapy failed. Patients with undetectable HCV-RNA at treatment week (TW) 12 received 48 weeks of therapy; patients with detectable HCV-RNA at TW12 could enter maintenance studies at TW18; 188 patients with low/detectable HCV-RNA at TW12 continued therapy at the investigator`s request. Results: Overall, 22% of the patients attained SVR (56% with undetectable HCV-RNA and 12% with low/detectable HCV-RNA at TW12). SVR was better in relapsers (38%) than nonresponders (14%), regardless of previous treatment, and in patients previously treated with interferon-alfa/ribavirin (25%) than peginterferon alfa-ribavirin (17%). Predictors of response in patients with undetectable HCV-RNA at TW12 were genotype (2/3 vs 1, respectively; odds ratio [OR] 2.4; P < .0001), fibrosis score (F2 vs F4; OR, 2.2; F3 vs F4; OR, 1.7; P < .0001), and baseline viral load (<= 600,000 vs >600,000 IU/mL; OR, 1.4; P = .0223). These factors plus previous treatment and response were overall predictors of SVR. Safety was similar among fibrosis groups. Conclusions: Peginterferon alfa-2b plus weight-based ribavirin is effective and safe in patients who failed interferon alfa/ribavirin therapy. Genotype, baseline viral load, and fibrosis stage were predictors of response.

Factors associated with mortality in patients with bloodstream infection and pneumonia due to Stenotrophomonas maltophilia

Severe infections caused by Stenotrophomonas maltophilia are associated with high mortality, and strategies to improve the clinical outcome for infected patients are needed. A retrospective cohort study of patients with bloodstream infection (BSIs) and pneumonia caused by S. maltophilia was conducted. Multivariate analysis was performed to access factors associated with 14-day mortality. A total of 60 infections were identified. Among these, eight (13%) were pneumonias and 52 were BSIs; 33.3% were primary, 13% were central venous catheter (CVC)-related and 40% were secondary BSIs. Fifty-seven (85%) patients had received previous antimicrobial therapy; 88% had CVC, 57% mechanical ventilation and 75% were in the intensive care unit at the onset of infection. Malignancy (45%) was the most frequent underlying disease. The mean of the Acute Physiology and Chronic Health Evaluation II (APACHE II) scores was 17 and for the Sepsis-related Organ Failure Assessment (SOFA) score, it was 7 points. The overall and 14-day mortality were, respectively, 75% and 48%. Forty-seven (78%) patients were treated and, of these, 74% received trimethoprim-sulfamethoxazole. Independent risk factors associated with mortality were SOFA index > 6 points (0.005) and septic shock (0.03). The Kaplan-Meier estimations curves showed that patients with APACHE II score > 20 and SOFA score > 10 had a survival chance of, respectively, less than 8% and less than 10% (P <= 0.001) at 21 days after the first positive S. maltophilia culture. Our results suggest that the independent factors associated with outcome in patients with infection caused by S. maltophilia are septic shock and higher SOFA index.

Effects of Somatosensory Stimulation on Motor Function After Subacute Stroke

Background. Previous works showed potentially beneficial effects of a single session of peripheral nerve sensory stimulation (PSS) on motor function of a paretic hand in patients with subacute and chronic stroke. Objective. To investigate the influence of the use of different stimulus intensities over multiple sessions (repetitive PSS [RPSS]) paired with motor training. Methods. To address this question, 22 patients were randomized within the second month after a single hemispheric stroke in a parallel design to application of 2-hour RPSS at 1 of 2 stimulus intensities immediately preceding motor training, 3 times a week, for 1 month. Jebsen-Taylor test (JTT, primary endpoint measure), pinch force, Functional Independence Measure (FIM), and corticomotor excitability to transcranial magnetic stimulation were measured before and after the end of the treatment month. JTT, FIM scores, and pinch force were reevaluated 2 to 3 months after the end of the treatment. Results. Baseline motor function tests were comparable across the 2 RPSS intensity groups. JTT improved significantly in the lower intensity RPSS group but not in the higher intensity RPSS group at month 1. This difference between the 2 groups reduced by months 2 to 3. Conclusions. These results indicate that multiple sessions of RPSS could facilitate training effects on motor function after subacute stroke depending on the intensity of stimulation. It is proposed that careful dose-response studies are needed to optimize parameters of RPSS stimulation before designing costly, larger, double-blind, multicenter clinical trials.

STANDARDIZATION OF SPINAL CORD INJURY IN WISTAR RATS

Objective: To standardize an experimental model of spinal cord injury in Wistar rats, computerized weight fall impact equipment were used and the parameters were used determined by the multicenter animal spinal cord injury study - MASCIS. Methods: Thirty rats were used, with age varying between 20 and 25 weeks, and weight ranging from 200 to 300g for females, and from 232 to 430g for males. The impacts were done with weights of 10g starting from 12.5, 25 and 50 mm of height, and the impact speed and compression coefficient were obtained. The impact occurred on the surface of the spinal cord at the level of the tenth thoracic vertebra after laminectomy. Vital signs were monitored and gas analysis was made before and after the spinal cord injury. The lesion volume was evaluated by the quantitative analysis of sodium and potassium ions. Results: Statistically significant correlations were verified among the lesion volume and the mechanical parameters. The lesion volume caused by the fall from 50mm height was superior to that of the 12.5 and 25mm, which didn`t differ from each other. Conclusion: The model demonstrated itself to be effective and capable of generating standard spinal cord injuries on Wistar rats.

A randomized controlled trial comparing a computer-assisted insulin infusion protocol with a strict and a conventional protocol for glucose control in critically ill patients

Purpose: The objective of this study is to evaluate blood glucose (BG) control efficacy and safety of 3 insulin protocols in medical intensive care unit (MICU) patients. Methods: This was a multicenter randomized controlled trial involving 167 MICU patients with at least one BG measurement +/- 150 mg/dL and one or more of the following: mechanical ventilation, systemic inflammatory response syndrome, trauma, or burns. The interventions were computer-assisted insulin protocol (CAIP), with insulin infusion maintaining BG between 100 and 130 mg/dL; Leuven protocol, with insulin maintaining BG between 80 and 110 mg/dL; or conventional treatment-subcutaneous insulin if glucose > 150 mg/dL. The main efficacy outcome was the mean of patients` median BG, and the safety outcome was the incidence of hypoglycemia (<= 40 mg/dL). Results: The mean of patients` median BG was 125.0, 127.1, and 158.5 mg/dL for CAIP, Leuven, and conventional treatment, respectively (P = .34, CAIP vs Leuven; P < .001, CAIP vs conventional). In CAIP, 12 patients (21.4%) had at least one episode of hypoglycemia vs 24 (41.4%) in Leuven and 2 (3.8%) in conventional treatment (P = .02, CAIP vs Leuven; P = .006, CAIP vs conventional). Conclusions: The CAIP is safer than and as effective as the standard strict protocol for controlling glucose in MICU patients. Hypoglycemia was rare under conventional treatment. However, BG levels were higher than with IV insulin protocols. (C) 2009 Elsevier Inc. All rights reserved.

Incidence of stroke subtypes, prognosis and prevalence of risk factors in Joinville, Brazil: a 2 year community based study

Background: There have been few population based studies on stroke risk factors and prognosis conducted in Brazil. The objective of this study was to evaluate, over a 2 year period, the incidence of the subtypes of first ever stroke, the prevalence of cardiovascular risk factors and functional prognosis in a city located in the south of Brazil. Methods: The period from January 2005 to December 2006 was evaluated prospectively by compiling data on first ever stroke cases, medications used prior to the morbidity and the incidence of traditional risk factors. The annual incidence was adjusted for age using the direct method. Patients were monitored for at least 6 months following the event. Results: Of 1323 stroke cases, 759 were first ever stroke cases. Of these, 610 were classified as infarctions, 94 as intracerebral haemorrhage and 55 as subarachnoid haemorrhage. The crude incidence rate per 100 000 inhabitants was 61.8 for infarction (95% CI 57.0 to 66.9), 9.5 for intracerebral haemorrhage (95% CI 7.7 to 11.6) and 5.6 for subarachnoid haemorrhage (95% CI 4.2 to 7.3). The 30 day case fatality was 19.1%. The most prevalent cardiovascular risk factor was arterial hypertension. By post-stroke month 6, 25% had died (95% CI 21.4 to 29.1) whereas 61.5% had regained their independence (95% CI 56.2 to 68.3). Conclusions: Case fatality rate, prognosis and incidence adjusted for stroke subtypes were similar to those found in other population based studies. The prevalence rates of ischaemic heart disease, dyslipidaemia, arterial hypertension and diabetes suggest that Joinville presents a mixed pattern of cardiovascular risk, a pattern seen in developed and developing countries alike.

Interaction between Tobacco and Alcohol Use and the Risk of Head and Neck Cancer: Pooled Analysis in the International Head and Neck Cancer Epidemiology Consortium

Background: The magnitude of risk conferred by the interaction between tobacco and alcohol use on the risk of head and neck cancers is not clear because studies have used various methods to quantify the excess head and neck cancer burden. Methods: We analyzed individual-level pooled data from 17 European and American case-control studies (11,221 cases and 16,168 controls) participating in the International Head and Neck Cancer Epidemiology consortium. We estimated the multiplicative interaction parameter (psi) and population attributable risks (PAR). Results: A greater than multiplicative joint effect between ever tobacco and alcohol use was observed for head and neck cancer risk (psi = 2.15; 95% confidence interval, 1.53-3.04). The PAR for tobacco or alcohol was 72% (95% confidence interval, 61-79%) for head and neck cancer, of which 4% was due to alcohol alone, 33% was due to tobacco alone, and 35% was due to tobacco and alcohol combined. The total PAR differed by subsite (64% for oral cavity cancer, 72% for pharyngeal cancer, 89% for laryngeal cancer), by sex (74% for men, 57% for women), by age (33% for cases < 45 years, 73% for cases > 60 years), and by region (84% in Europe, 51% in North America, 83% in Latin America). Conclusions: Our results confirm that the joint effect between tobacco and alcohol use is greater than multiplicative on head and neck cancer risk. However, a substantial proportion of head and neck cancers cannot be attributed to tobacco or alcohol use, particularly for oral cavity cancer and for head and neck cancer among women and among young-onset cases. (Cancer Epidemiol Biomarkers Prev 2009;18(2):541-50)

Suicidality in Obsessive-Compulsive Disorder: Prevalence and Relation to Symptom Dimensions and Comorbid Conditions

Background: Suicidal thoughts and behaviors, also known as suicidality, are a fairly neglected area of study in patients with obsessive-compulsive disorder (OCD). Objective: To evaluate several aspects of suicidality in a large multicenter sample of OCD patients and to compare those with and without suicidal ideation, plans, and attempts according to demographic and clinical variables, including symptom dimensions and comorbid disorders. Method: This cross-sectional study included 582 outpatients with primary OCD (DSM-IV) recruited between August 2003 and March 2008 from 7 centers of the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders. The following assessment instruments were used: the Yale-Brown Obsessive Compulsive Scale, the Dimensional Yale-Brown Obsessive Compulsive Scale, the Beck Depression and Anxiety Inventories, the Structured Clinical Interview for DSM-IV Axis I Disorders, and 6 specific questions to investigate suicidality. After univariate analyses, logistic regression analyses were performed to adjust the associations between the dependent and explanatory variables for possible confounders. Results: Thirty-six percent of the patients reported lifetime suicidal thoughts, 20% had made suicidal plans, 11% had already attempted suicide, and 10% presented current suicidal thoughts. In the logistic regression, only lifetime major depressive disorder and posttraumatic stress disorder (PTSD) remained independently associated with all aspects of suicidal behaviors. The sexual/religious dimension and comorbid substance use disorders remained associated with suicidal thoughts and plans, while impulse-control disorders were associated with current suicidal thoughts and with suicide plans and attempts. Conclusions: The risk of suicidal behaviors must be carefully investigated in OCD patients, particularly those with symptoms of the sexual/religious dimension and comorbid major depressive disorder, PTSD, substance use disorders, and impulse-control disorders. J Clin Psychiatry 2011;72(1):17-26 (C) Copyright 2011 Physicians Postgraduate Press, Inc.

Aripiprazole for Patients with Schizophrenia and Schizoaffective Disorder: An Open-Label, Randomized, Study Versus Haloperidol

Introduction: Aripiprazole, a dopamine D(2) receptor partial agonist, has also partial agonist activity at serotonin (5-HT)(1A) receptors and antagonist activity at 5-HT(2A) receptors. Methods: In this 8-week, multicenter, randomized, parallel-group, open-label, flexible-dose study, patients diagnosed with schizophrenia or schizoaffective disorder were randomized to aripiprazole 15-30 mg/day or haloperidol 10-15 mg/day. Results: Patients treated with both aripiprazole and haloperidol improved from baseline in Positive and Negative Syndrome Scale total, positive, and negative scores as well as in Clinical Global Impressions scores (all P<.001). At the end of the study, the percentage of patients classified as responders-according to >= 40% reduction in the Positive and Negative Syndrome Scale negative subscale score-was significantly higher in the aripiprazole group (20%) than in the haloperidol group (0%) (P<.05). Additionally, a higher number of patients receiving haloperidol required more anticholinergic medications (P<.001) than aripiprazole-treated patients, whereas more aripiprazole (45.5%) than haloperidol-treated patients (12.9%) required benzodiazepines (P=.002). At endpoint, rates of preference of medication were higher in the aripiprazole group (63.2%) than in the haloperidol group (21.7%), as expressed by patients and caregivers (P=.001). Conclusion: Aripiprazole and haloperidol had similar efficacy in terms of reduction of overall psychopathology. Although aripiprazole has been demonstrated to be superior concerning negative symptoms and in terms of tolerability (extrapyramidal symptoms) and preferred by patients and caregivers than haloperidol, significantly more aripiprazole-treated patients required benzodiazepines.

Self-Esteem, Confidence, and Relationships in Brazilian Men with Erectile Dysfunction Receiving Sildenafil Citrate: A Randomized, Parallel-Group, Double-Blind, Placebo-Controlled Study in Brazil

Psychosocial manifestations of erectile dysfunction (ED) differ across cultures. Understanding the treatment response to ED medications within cultural groups can aid in resource allocation and in developing treatment strategies. Evaluate the effect of sildenafil treatment on self-esteem, confidence, and sexual relationship satisfaction in Brazilian men with ED. The Self-Esteem and Relationship (SEAR) questionnaire, a validated, 14-question instrument developed to specifically address self-esteem and relationship issues within the context of ED. Men aged 18 years or older with a clinical diagnosis of ED (<= 21 on the Sexual Health Inventory for Men) and in a stable relationship with a partner during the study were eligible. The primary end point was a change from baseline in the self-esteem subscale of the SEAR questionnaire. Thirteen Brazilian sites participated in a randomized, double-blind, placebo-controlled trial of sildenafil treatment for ED. Patients were randomized to receive either 50 mg of sildenafil (adjustable to 25 mg or 100 mg based on patient response) or matching placebo approximately 1 hour before anticipated sexual activity but not more than once a day. At the end of double-blind treatment, 63 and 66 patients in the placebo and sildenafil groups, respectively, from 13 Brazilian sites were assessed for efficacy. Brazilian patients receiving sildenafil had significantly greater improvements in their scores on the SEAR self-esteem subscale (42.9 [95% confidence interval 35.7-50.0]) compared with placebo (21.1 [95% confidence interval 13.7-28.6]; P < 0.0001). Effect sizes ranged from 0.91 to 1.25 for individual SEAR components. The psychosocial parameters in Brazilian men with ED assessed by the SEAR questionnaire showed significant improvements in self-esteem, confidence, and relationships after treatment with sildenafil. Glina S, Damiao R, Abdo C, Afif-Abdo J, Tseng L-J, and Stecher V. Self-esteem, confidence, and relationships in Brazilian men with erectile dysfunction receiving sildenafil citrate: A randomized, parallel-group, double-blind, placebo-controlled study in Brazil. J Sex Med 2009;6:268-275.

Comparing topiramate with naltrexone in the treatment of alcohol dependence

To compare the efficacy of topiramate with naltrexone in the treatment of alcohol dependence. The investigation was a double-blind, placebo-controlled, 12-week study carried out at the University of Sao Paulo, Brazil. A total of 155 patients, 18-60 years of age, with an International Classification of Diseases (ICD-10) diagnosis of alcohol dependence. After a 1-week detoxification period, patients were assigned randomly to receive topiramate (induction to 300 mg/day), naltrexone (50 mg/day) or placebo. Time to first relapse (consumption of > 60 g ethyl alcohol), cumulative abstinence duration and weeks of heavy drinking. In intention-to-treat analyses, topiramate was statistically superior to placebo on a number of measures including time to first relapse (7.8 versus 5.0 weeks), cumulative abstinence duration (8.2 versus 5.6 weeks), weeks of heavy drinking (3.4 versus 5.9) and percentage of subjects abstinent at 4 weeks (67.3 versus 42.6) and 8 weeks (61.5 versus 31.5), but not 12 weeks (46.2 versus 27.8). Results remained significant after controlling for Alcoholics Anonymous attendance, which was higher in topiramate than in other groups. There were no significant differences between naltrexone versus placebo or naltrexone versus topiramate groups, but naltrexone showed trends toward inferior outcomes when compared to topiramate. The results of this study support the efficacy of topiramate in the relapse prevention of alcoholism. Suggestive evidence was also obtained for superiority of topiramate versus naltrexone, but this needs to be verified in future research with larger sample sizes.

Individual risk prediction of nodal and distant metastasis for patients with typical bronchial carcinoid tumors

Objective: Bronchial typical carcinoid tumors are tow-grade malignancies. However, metastases are diagnosed in some patients. Predicting the individual risk of these metastases to determine patients eligible for a radical lymphadenectomy and patients to be followed-up because of distant metastasis risk is relevant. Our objective was to screen for predictive criteria of bronchial typical carcinoid tumor aggressiveness based on a logistic regression model using clinical, pathological and biomolecular data. Methods: A multicenter retrospective cohort study, including 330 consecutive patients operated on for bronchial typical carcinoid tumors and followed-up during a period more than 10 years in two university hospitals was performed. Selected data to predict the individual risk for both nodal and distant metastasis were: age, gender, TNM staging, tumor diameter and location (central/peripheral), tumor immunostaining index of p53 and Ki67, Bcl2 and the extracellular density of neoformed microvessels and of collagen/elastic extracellular fibers. Results: Nodal and distant metastasis incidence was 11% and 5%, respectively. Univariate analysis identified all the studied biomarkers as related to nodal metastasis. Multivariate analysis identified a predictive variable for nodal metastasis: neo angiogenesis, quantified by the neoformed pathological microvessels density. Distant metastasis was related to mate gender. Discussion: Predictive models based on clinical and biomolecular data could be used to predict individual risk for metastasis. Patients under a high individual risk for lymph node metastasis should be considered as candidates to mediastinal lymphadenectomy. Those under a high risk of distant metastasis should be followed-up as having an aggressive disease. Conclusion: Individual risk prediction of bronchial typical carcinoid tumor metastasis for patients operated on can be calculated in function of biomolecular data. Prediction models can detect high-risk patients and help surgeons to identify patients requiring radical lymphadenectomy and help oncologists to identify those as having an aggressive disease requiring prolonged follow-up. (C) 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.