A new clinical scoring system to define pneumonia following esophagectomy for cancer.

BACKGROUND: Pneumonia is a frequently observed complication following esophagectomy. The lack of a uniform definition of pneumonia leads to large variations of pneumonia rates in literature. This study was designed to develop a scoring system for diagnosing pneumonia following esophagectomy at the hospital ward. METHODS: In a prospective cohort study of esophagectomy patients, known risk factors for pneumonia, temperature, leukocyte count, pulmonary radiography and sputum culture added were evaluated. Primary outcome was defined as the decision to treat suspected pneumonia. Multivariate Cox regression analysis with backward selection was used to identify predictors of pneumonia treatment. RESULTS: The majority of postoperative pneumonia treatments (88.2%) occurred at the hospital ward, where treatment was observed in 67 (36.2%) of 185 patients. Independent diagnostic determinants for pneumonia treatment were temperature (hazard ratio (HR) = 1.283, p = 0.073), leukocyte count (HR = 1.040, p = 0.078) and pulmonary radiography (HR >11.0, p = 0.000). Sputum culture did not influence the decision to treat pneumonia. These findings were used to develop a scoring system which includes temperature, leukocyte count and pulmonary radiography. CONCLUSION: The decision to treat pneumonia is based on temperature, leukocyte count and pulmonary radiography findings. The proposed clinical scoring system for pneumonia following esophagectomy at the hospital ward has the potential to aid clinical practice and improve comparability of future research in esophageal cancer surgery.

Short-term dose-response characteristics of 2-iminobiotin immediately postinsult in the neonatal piglet after hypoxia-ischemia.

BACKGROUND AND PURPOSE: To determine the optimal dose of 2-iminobiotin (2-IB) for the treatment of moderate to severe asphyxia in a neonatal piglet model of hypoxia-ischemia. METHODS: Newborn piglets were subjected to a 30-minute hypoxia-ischemia insult and randomly treated with vehicle or 2-IB (0.1 mg/kg, 0.2 mg/kg, or 1.0 mg/kg). aEEG background and seizure activity were scored after hypoxia-ischemia every 4 h until 24 h and at 48 h and neurobehavioral scores were obtained. Brain tissue was collected and processed for analysis of caspase-3 activity, histology, and tyrosine nitration. RESULTS: A dose range of 0.1 to 1.0 mg/kg/dose of 2-IB improved short-term outcome as demonstrated by an increased survival with a normal aEEG and decreased nitrotyrosine staining in the 2-IB-treated animals, indicating decreased cellular damage. Neurobehavior, caspase-3 activity in thalamus, and histology scores were not significantly different. CONCLUSIONS: Based on survival with a normal aEEG, 0.2 mg/kg 2-IB is likely to be the most appropriate dose for use in future clinical trials in neonates with perinatal hypoxia-ischemia.

Genistein in Sanfilippo disease: a randomized controlled crossover trial.

OBJECTIVE: Sanfilippo disease (mucopolysaccharidosis type III [MPS III]) is a rare neurodegenerative metabolic disease caused by a deficiency of 1 of the 4 enzymes involved in the degradation of heparan sulfate (HS), a glycosaminoglycan (GAG). Genistein has been proposed as potential therapy but its efficacy remains uncertain. We aimed to determine the efficacy of genistein in MPS III. METHODS: Thirty patients were enrolled. Effects of genistein were determined in a randomized, crossover, placebo-controlled intervention with a genistein-rich soy isoflavone extract (10mg/kg/day of genistein) followed by an open-label extension study for patients who were on genistein during the last part of the crossover. RESULTS: Genistein resulted in a significant decrease in urinary excretion of total GAGs (p = 0.02, slope -0.68 mg GAGs/mmol creatinine/mo) and in plasma concentrations of HS (p = 0.01, slope -15.85 ng HS/ml/mo). No effects on total behavior scores or on hair morphology were observed. Parents or caregivers could not predict correctly during which period of the crossover a patient was on genistein. INTERPRETATION: Genistein at 10mg/kg/day effectively reduces urinary excretion of GAGs and plasma HS concentration in patients with MPS III. However, the absolute reduction in GAGs and in HS is small and values after 12 months of treatment remain within the range as observed in untreated patients. No clinical efficacy was detected. Substantially higher doses of genistein might be more effective as suggested by recent studies in animal models.

Plasma and urinary levels of dermatan sulfate and heparan sulfate derived disaccharides after long-term enzyme replacement therapy (ERT) in MPS I: correlation with the timing of ERT and with total urinary excretion of glycosaminoglycans.

INTRODUCTION: Mucopolysaccharidosis type I (MPS I) results in a defective breakdown of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, which leads to a progressive disease. Enzyme replacement therapy (ERT) results in clearance of these GAGs from a range of tissues and can significantly ameliorate several symptoms. The biochemical efficacy of ERT is generally assessed by the determination of the total urinary excretion of GAGs. However, this has limitations. We studied the concentrations of heparan sulfate and dermatan sulfate derived disaccharides (HS and DS, respectively) in the plasma and urine of seven patients and compared these levels with total urinary GAGs (uGAGs) levels. METHODS: Plasma and urine samples were collected at different time points relative to the weekly ERT for three non-consecutive weeks in seven MPS I patients who had been treated with ERT for at least 2.5 years. Heparan and dermatan sulfate in plasma and urine were enzymatically digested into disaccharides, and HS and DS levels were determined by HPLC-MS/MS analysis. uGAGs were measured by the DMB test. RESULTS: The levels of HS and DS were markedly decreased compared with the levels before the initiation of ERT. However, the concentrations of DS in plasma and of both HS and DS in urine remained significantly elevated in all studied patients, while in six patients the level of total uGAGs had normalized. The concentrations of plasma and urinary HS during the weekly ERT followed a U-shaped curve. However, the effect size is small. The concentrations of plasma and urinary DS and uGAGs appeared to be in a steady state. CONCLUSIONS: HS and DS are sensitive biomarkers for monitoring the biochemical treatment efficacy of ERT and remain elevated despite long-term treatment. This finding may be related to the labeled dose or antibody status of the patient. The timing of the sample collection is not relevant, at least at the current dose of 100 IU/kg/weekly.

An analytical approach to assess the predictive value of biomarkers in Phase II decision making.

Early Phase II clinical trials typically have a biomarker as a primary outcome. The extent to which a positive result for such a Phase II trial is predictive for Phase III success is of obvious concern. In this article we extend existing approaches for assessing the probability of success in Phase III. We address the case that a dichotomous clinical endpoint of interest is to be measured in Phase III. A Beta prior distribution is suggested that quantifies information from both the data observed on the biomarker and its predictive accuracy. Based on the quantification of the impact of the predictive ability of biomarkers, it is shown that the predictive quality of a biomarker needs to be substantial to support the full development decision. The approach is illustrated with a practical example. A simulation study is presented to illustrate the findings more generally.

Full loss of residual renal function causes higher mortality in dialysis patients; findings from a marginal structural model.

BACKGROUND: Declining residual renal function, as indicated by the glomerular filtration rate (GFR), is associated with an increased mortality risk in patients with end-stage renal disease (ESRD) on dialysis. METHODS: We monitored GFR and mortality in 1800 haemodialysis (HD) and peritoneal dialysis (PD) patients in 1996-2006. We used a marginal structural model to estimate the causal effects both of GFR when it was not completely lost and of the subsequent full loss of GFR on mortality, avoiding the drawbacks of standard regression models that include covariates to adjust for confounding. Instead, effect estimates were adjusted for possible baseline and time-varying confounders using inverse probability weighting. RESULTS: We estimated a hazard ratio (HR) corresponding to the effect of the full loss of GFR on mortality, as compared to not having fully lost GFR, of 1.50 [95% confidence interval (CI) 1.09-2.07]. The HR corresponding to the effect of GFR when GFR is not (yet) fully lost on mortality was 0.97 (95% CI 0.92-1.02) (per mL/min/1.73 m(2)). We found no significant difference in the effect of GFR on mortality between patients starting on PD and HD. CONCLUSIONS: Preventing or delaying the full loss of GFR can improve survival in dialysis patients. This supports the importance that is given to the effect of treatment options for patients with ESRD on the rate of decline of the residual renal function.

ICE COLD ERIC--International collaborative effort on chronic obstructive lung disease: exacerbation risk index cohorts--study protocol for an international COPD cohort study.

BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is a systemic disease; morbidity and mortality due to COPD are on the increase, and it has great impact on patients' lives. Most COPD patients are managed by general practitioners (GP). Too often, GPs base their initial assessment of patient's disease severity mainly on lung function. However, lung function correlates poorly with COPD-specific health-related quality of life and exacerbation frequency. A validated COPD disease risk index that better represents the clinical manifestations of COPD and is feasible in primary care seems to be useful. The objective of this study is to develop and validate a practical COPD disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2-4. METHODS/DESIGN: We will conduct 2 linked prospective cohort studies with COPD patients from GPs in Switzerland and the Netherlands. We will perform a baseline assessment including detailed patient history, questionnaires, lung function, history of exacerbations, measurement of exercise capacity and blood sampling. During the follow-up of at least 2 years, we will update the patients' profile by registering exacerbations, health-related quality of life and any changes in the use of medication. The primary outcome will be health-related quality of life. Secondary outcomes will be exacerbation frequency and mortality. Using multivariable regression analysis, we will identify the best combination of variables predicting these outcomes over one and two years and, depending on funding, even more years. DISCUSSION: Despite the diversity of clinical manifestations and available treatments, assessment and management today do not reflect the multifaceted character of the disease. This is in contrast to preventive cardiology where, nowadays, the treatment in primary care is based on patient-specific and fairly refined cardiovascular risk profile corresponding to differences in prognosis. After completion of this study, we will have a practical COPD-disease risk index that predicts the clinical course of COPD in primary care patients with GOLD stages 2-4. In a second step we will incorporate evidence-based treatment effects into this model, such that the instrument may guide physicians in selecting treatment based on the individual patients' prognosis. TRIAL REGISTRATION: ClinicalTrials.gov Archive NCT00706602.

Prediction and treatment of asthma in preschool children at risk: study design and baseline data of a prospective cohort study in general practice (ARCADE).

BACKGROUND: Asthma is a difficult diagnosis to establish in preschool children. A few years ago, our group presented a prediction rule for young children at risk for asthma in general practice. Before this prediction rule can safely be used in practice, cross-validation is required. In addition, general practitioners face many therapeutic management decisions in children at risk for asthma. The objectives of the study are: (1) identification of predictors for asthma in preschool children at risk for asthma with the aim of cross-validating an earlier derived prediction rule; (2) compare the effects of different treatment strategies in preschool children. DESIGN: In this prospective cohort study one to five year old children at risk of developing asthma were selected from general practices. At risk was defined as 'visited the general practitioner with recurrent coughing (>or= 2 visits), wheezing (>or=1) or shortness of breath (>or=1) in the previous 12 months'. All children in this prospective cohort study will be followed until the age of six. For our prediction rule, demographic data, data with respect to clinical history and additional tests (specific immunoglobulin E (IgE), fractional exhaled nitric oxide (FENO), peak expiratory flow (PEF)) are collected. History of airway specific medication use, symptom severity and health-related quality of life (QoL) are collected to estimate the effect of different treatment intensities (as expressed in GINA levels) using recently developed statistical techniques. In total, 1,938 children at risk of asthma were selected from general practice and 771 children (40%) were enrolled. At the time of writing, follow-up for all 5-year olds and the majority of the 4-year olds is complete. The total and specific IgE measurements at baseline were carried out by 87% of the children. Response rates to the repeated questionnaires varied from 93% at baseline to 73% after 18 months follow-up; 89% and 87% performed PEF and FENO measurements, respectively. DISCUSSION: In this study a prediction rule for asthma in young children, to be used in (general) practice, will be cross-validated. Our study will also provide more insight in the effect of treatment of asthma in preschool children.

Lactobacilli vs antibiotics to prevent urinary tract infections: a randomized, double-blind, noninferiority trial in postmenopausal women.

BACKGROUND: Growing antibiotic resistance warrants studying nonantibiotic prophylaxis for recurrent urinary tract infections (UTIs). Use of lactobacilli appears to be promising. METHODS: Between January 2005 and August 2007, we randomized 252 postmenopausal women with recurrent UTIs taking part in a double-blind noninferiority trial to receive 12 months of prophylaxis with trimethoprim-sulfamethoxazole, 480 mg, once daily or oral capsules containing 109 colony-forming units of Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 twice daily. Primary end points were the mean number of symptomatic UTIs, proportion of participants with at least 1 UTI during 12 months, time to first UTI, and development of antibiotic resistance by Escherichia coli. RESULTS: The mean number of symptomatic UTIs in the year preceding randomization was 7.0 in the trimethoprim-sulfamethoxazole group and 6.8 in the lactobacilli group. In the intention-to-treat analysis, after 12 months of prophylaxis, these numbers were 2.9 and 3.3, respectively. The between-treatment difference of 0.4 UTIs per year (95% CI, -0.4 to 1.5) was outside our noninferiority margin. At least 1 symptomatic UTI occurred in 69.3% and 79.1% of the trimethoprim-sulfamethoxazole and lactobacilli participants, respectively; median times to the first UTI were 6 and 3 months, respectively. After 1 month of trimethoprim-sulfamethoxazole prophylaxis, resistance to trimethoprim-sulfamethoxazole, trimethoprim, and amoxicillin had increased from approximately 20% to 40% to approximately 80% to 95% in E coli from the feces and urine of asymptomatic women and among E coli causing a UTI. During the 3 months after trimethoprim-sulfamethoxazole discontinuation, resistance levels gradually decreased. Resistance did not increase during lactobacilli prophylaxis. CONCLUSIONS: In postmenopausal women with recurrent UTIs, L rhamnosus GR-1 and L reuteri RC-14 do not meet the noninferiority criteria in the prevention of UTIs when compared with trimethoprim-sulfamethoxazole. However, unlike trimethoprim-sulfamethoxazole, lactobacilli do not increase antibiotic resistance. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN50717094.

Cranberries vs antibiotics to prevent urinary tract infections: a randomized double-blind noninferiority trial in premenopausal women.

BACKGROUND: The increasing prevalence of uropathogens resistant to antimicrobial agents has stimulated interest in cranberries to prevent recurrent urinary tract infections (UTIs). METHODS: In a double-blind, double-dummy noninferiority trial, 221 premenopausal women with recurrent UTIs were randomized to 12-month prophylaxis use of trimethoprim-sulfamethoxazole (TMP-SMX), 480 mg once daily, or cranberry capsules, 500 mg twice daily. Primary end points were the mean number of symptomatic UTIs over 12 months, the proportion of patients with at least 1 symptomatic UTI, the median time to first UTI, and development of antibiotic resistance in indigenous Escherichia coli. RESULTS: After 12 months, the mean number of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (4.0 vs 1.8; P = .02), and the proportion of patients with at least 1 symptomatic UTI was higher in the cranberry than in the TMP-SMX group (78.2% vs 71.1%). Median time to the first symptomatic UTI was 4 months for the cranberry and 8 months for the TMP-SMX group. After 1 month, in the cranberry group, 23.7% of fecal and 28.1% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant, whereas in the TMP-SMX group, 86.3% of fecal and 90.5% of asymptomatic bacteriuria E coli isolates were TMP-SMX resistant. Similarly, we found increased resistance rates for trimethoprim, amoxicillin, and ciprofloxacin in these E coli isolates after 1 month in the TMP-SMX group. After discontinuation of TMP-SMX, resistance reached baseline levels after 3 months. Antibiotic resistance did not increase in the cranberry group. Cranberries and TMP-SMX were equally well tolerated. CONCLUSION: In premenopausal women, TMP-SMX, 480 mg once daily, is more effective than cranberry capsules, 500 mg twice daily, to prevent recurrent UTIs, at the expense of emerging antibiotic resistance. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN50717094.

Comparing mortality in renal patients on hemodialysis versus peritoneal dialysis using a marginal structural model.

When comparing the causal effect of peritoneal dialysis (PD) and hemodialysis (HD) treatment on lowering mortality in renal patients, using observational data, it is necessary to adjust for different forms of confounding and informative censoring. Both the type of dialysis treatment that is started with and mortality are affected by baseline covariates. Longitudinal and baseline variables can affect both the probability of switching from one type of dialysis to the other, and mortality. Longitudinal and baseline variables can also affect the probability of receiving a kidney transplant, possibly causing informative censoring. Adjusting for longitudinal variables by including them as covariates in a regression model potentially causes bias, for instance by losing a possible indirect effect of dialysis on mortality via these longitudinal variables. Instead, we fitted a marginal structural model (MSM) to estimate the causal effect of dialysis type, adjusted for confounding and informative censoring. We used the MSM to compare the hazard of death as well as cumulative survival between the potential treatment trajectories "always PD" and "always HD" over time, conditional on age and diabetes mellitus status. We used inverse probability weighting (IPW) to fit the MSM.