nils-herrmann/clean_scirepeval huggingface dataset:
Clinical and echocardiographic correlates of mortality in medically treated patients with severe isolated aortic stenosis and normal left ventricular ejection fraction.

Many symptomatic patients with severe aortic stenosis (AS) and preserved left ventricular ejection fraction (LVEF) are denied surgery and have a grim prognosis with medical management.



Between 2003 and 2012, among 550 patients with severe isolated AS and preserved LVEF on transthoracic echocardiography, 241 did not undergo aortic valve replacement (mean age, 83.2±7.6 years; 54% female; aortic valve area index, 0.40±0.13cm(2)/m(2); mean LVEF, 64.8±7.6%) and 67% presented with cardiac symptoms. At a mean follow-up of 25.5±25.1 months, 134 patients (56%) had died. Survival at 1, 5 and 9.5 years was 71%, 28% at 12%, respectively. Median survival was 36.3 months (95% confidence interval [CI]: 27.2-42.4 months). In unadjusted analyses, age, heart failure, hypertension, renal insufficiency, left atrial size, pulmonary artery systolic pressure (PASP), relative wall thickness and LV mass/LV end diastolic volume ratio were associated with mortality. On multivariate analysis adjusted for all significant univariate predictors, age ≥78 years, history of hypertension, left atrial diameter ≥40mm and PASP ≥42mmHg gave a joint area under the curve of 0.80 (95% CI: 0.73-0.86) for mortality.



In medically treated patients with severe isolated AS and preserved LVEF, older age, history of hypertension, and echo-Doppler variables reflecting LV diastolic dysfunction are independent predictors of death.
Maintenance of glycaemic control with the evening administration of a long acting sulphonylurea in male type 2 diabetic patients undertaking the Ramadan fast.

In Ramadan, misuse of hypoglycaemic agents, alterations in diet and hypoglycaemia are frequent. This study assessed whether switching to an evening administration of a long acting sulphonylurea during the 29-day, dawn to dusk fast, can maintain glycaemic control in patients with type 2 diabetes.



Male type 2 diabetic patients from Bangladesh, Pakistan and India, under glycaemic control with gliclazide modified release (MR) 60 mg monotherapy, switched to evening administration of the same dose during Ramadan, and reverted to the morning schedule thereafter. The primary outcome was the difference in fasting plasma glucose (FPG) before and after Ramadan.



In 136 patients, mean (95% CI) FPG decreased by 0.01 mmol/l (0-0.2, p = 0.3) with evening medication by the end of the fast, and increased by 0.2 mmol/l (0.1-0.3, p = 0.01) after reverting to morning medication 20 days later. There were 5 (3.7%) hypoglycaemic episodes before, 3 (2.2%) during and 2 (1.5%) after Ramadan.



Male type 2 diabetic patients undertaking the Ramadan fast can safely maintain glycaemic control with evening administration of gliclazide MR 60 mg during the fast, and reverting to a morning schedule thereafter.
Identifying subgroup markers in heterogeneous populations

Traditional methods that aim to identify biomarkers that distinguish between two groups, like Significance Analysis of Microarrays or the t-test, perform optimally when such biomarkers show homogeneous behavior within each group and differential behavior between the groups. However, in many applications, this is not the case. Instead, a subgroup of samples in one group shows differential behavior with respect to all other samples. To successfully detect markers showing such imbalanced patterns of differential signal, a different approach is required. We propose a novel method, specifically designed for the Detection of Imbalanced Differential Signal (DIDS). We use an artificial dataset and a human breast cancer dataset to measure its performance and compare it with three traditional methods and four approaches that take imbalanced signal into account. Supported by extensive experimental results, we show that DIDS outperforms all other approaches in terms of power and positive predictive value. In a mouse breast cancer dataset, DIDS is the only approach that detects a functionally validated marker of chemotherapy resistance. DIDS can be applied to any continuous value data, including gene expression data, and in any context where imbalanced differential signal is manifested.
High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer

A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy.Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m−2, epirubicin 100 mg m−2, cyclophosphamide 500 mg m−2 (FEC 100) followed by three cycles of docetaxel 100 mg m−2 delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis.In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%).Conclusion:Sequential dose-dense FEC 100 followed by docetaxel 100 mg m−2 is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.
Absence of association with DAT1 polymorphism and response to methylphenidate in a sample of adults with ADHD.

A polymorphism in the dopamine transporter gene (DAT1) has been previously associated with ADHD and methylphenidate has been hypothesized to block the dopamine transporter. The goal of this study was to examine whether a 40-bp variable number of tandem repeats (VNTR) of DAT1 moderate response and adverse effects associated with methylphenidate treatment of adults with ADHD. Subjects were 106 adults with ADHD enrolled in 6-week randomized placebo-controlled parallel design trials of methylphenidate (OROS and immediate release preparations). There was no evidence of an association between DAT1 VNTR and response to methylphenidate (F(2,100) = 0.04, P = 0.9). Similarly, there was no pattern of statistically significant association with DAT1 VNTR and cardiovascular or spontaneously reported adverse effects. We failed to identify an association with DAT1 and the response or tolerability of methylphenidate in adults with ADHD.
Long-term comparison of the implantable cardioverter defibrillator versus amiodarone: eleven-year follow-up of a subset of patients in the Canadian Implantable Defibrillator Study (CIDS).

The implantable cardioverter defibrillator (ICD) is superior to amiodarone for secondary prophylaxis of sudden cardiac death. However, the magnitude of this benefit over long-term follow-up is not known. Thus, our objective was to evaluate the long-term consequences of using amiodarone versus an ICD as first-line monotherapy in patients with a prior history of sustained ventricular tachycardia/ventricular fibrillation or cardiac arrest.



A total of 120 patients were enrolled at St Michael's Hospital in the Canadian Implantable Defibrillator Study (CIDS) and were randomly assigned to receive either amiodarone (n=60) or an ICD (n=60). The treatment strategy was not altered after the end of CIDS unless the initial assigned therapy was not effective or was associated with serious side effects. After a mean follow-up of 5.6+/-2.6 years, there were 28 deaths (47%) in the amiodarone group, compared with 16 deaths (27%) in the ICD group (P=0.0213). Total mortality was 5.5% per year in the amiodarone group versus 2.8% per year in the ICD group (hazard ratio of amiodarone: ICD, 2.011; 95% confidence interval, 1.087 to 3.721; P=0.0261). In the amiodarone group, 49 patients (82% of all patients) had side effects related to amiodarone, of which 30 patients (50% of all patients) required discontinuation or dose reduction; 19 patients crossed over to ICD because of amiodarone failure (n=7) or side effects (n=12).



In a subset of CIDS, the benefit of the ICD over amiodarone increases with time; most amiodarone-treated patients eventually develop side effects, have arrhythmia recurrences, or die.
Cost-effectiveness of Spa treatment for fibromyalgia: general health improvement is not for free.

To estimate the cost-effectiveness of an adjuvant treatment course of spa treatment compared with usual care only in patients with fibromyalgia syndrome (FM).



134 patients with FM, selected from a rheumatology outpatient department and from members of the Dutch FM patient association were randomly assigned to a 2(1/2) week spa treatment course in Tunisia or to usual care only. Results are expressed as quality-adjusted life years (QALYs) for a 6-month as well as a 12-month time horizon. Utilities were derived form the Short Form 6D (SF-6D) scores and the visual analogue scale (VAS) rating general health. Costs were reported from societal perspective. Mean incremental cost per patient and the incremental cost utility ratio (ICER) were calculated; 95% confidence intervals (CIs) were estimated using double-sided bootstrapping.



The data of 128 (55 spa and 73 controls) of the 134 patients (96%) could be used for analysis. Improvement in general health was found in the spa group until 6 months of follow-up by both the SF-6D (AUC 0.32 vs 0.30, P < 0.05) and the VAS (AUC 0.23 vs 0.19, P < 0.01). After 1yr no significant between-group differences were found. Mean incremental cost of spa treatment was 1311 Euro per patient (95% CI 369-2439), equalling the cost of the intervention (thalassotherapy including airfare and lodging), or 885 Euro per patient based on a more realistic cost estimate.



The temporary improvement in quality of life due to an adjuvant treatment course of spa therapy for patients with FM is associated with limited incremental costs per patient.
Phase II trial and prediction of response of single agent tipifarnib in patients with relapsed/refractory mantle cell lymphoma: a Groupe d’Etude des Lymphomes de l’Adulte trial

Farnesyltransferase (Ftase) was identified by gene-expression profiling and by preclinical evaluation in in vitro and in vivo mantle cell lymphoma (MCL) models as a rational therapeutic target in MCL, one of the most refractory B-cell lymphomas. We conducted a multicenter phase II study of a potent Ftase inhibitor, tipifarnib, in patients with relapsed or refractory MCL. Tipifarnib was administered at 300 mg orally twice daily for the first 21 days of each 28-day cycle for 4 cycles, and in case of response for 6 cycles. Study endpoints were objective response at 4 and 6 cycles, progression free survival (PFS), overall survival, and toxicity. Prediction of response was retrospectively evaluated in the initial tumor biopsy by the RASGRP1/APTX gene expression ratio, and the AKAP13 expression level. Eleven patients (median age, 71 years) were enrolled. Patients received a median number of three prior therapies (range 1–11). Nine patients completed at least 3 cycles of tipifarnib. No grade III–IV hematological toxicities were recorded. One patient presented a complete response (CR) after 4 and a persistent CR at 6 cycles (ORR = 9%). Median PFS was 3 months (range 0.7–14.2). The RASGRP1/APTX gene expression ratio was higher in the responder (n = 1) while the AKAP13 expression was higher in the non-responders (n = 2). This corresponds to the expected result for predicting response to tipifarnib. Treatment with tipifarnib relapsed or refractory MCL is associated with low response rates. Limited gene expression studies suggest that response may be associated with molecular targets.
Effect of ambient air pollution on pulmonary exacerbations and lung function in cystic fibrosis.

Information concerning the impact of environmental factors on cystic fibrosis (CF) is limited. We conducted a cohort study to assess the impact of air pollutants in CF. The study included patients over the age of 6 years enrolled in the Cystic Fibrosis Foundation National Patient Registry in 1999 and 2000. Exposure was assessed by linking air pollution values from the Aerometric Information Retrieval System with the patients' home zip code. After adjusting for confounders, a 10 microg/m(3) rise in particulate matter (both with a median aerodynamic diameter of 10 microm (PM(10)) or less and with an aerodynamic diameter of 2.5 microm or less (PM(2.5)) was associated with an 8% (95% confidence interval [CI], 2-15%) and 21% (95% CI, 7-33%) increase in the odds of two or more exacerbations, respectively; a 10-ppb rise in ozone was associated with a 10% (95% CI, 3-17%) increase in odds of two or more exacerbations. For every increase in PM(2.5) of 10 microg/m(3), there was an associated fall in FEV(1) of 24 ml (7-40) (95% CI) after adjusting for confounders. PM(2.5)'s association with mortality did not achieve statistical significance (adjusted RR = 1.32 per 10 microg/m(3) 0.91-1.93; 95% CI). Annual average exposures to particulate air pollution was associated with an increased risk of pulmonary exacerbations and a decline in lung function, suggesting a role of environmental exposures on prognosis in CF.
Ezetimibe beneficially influences fasting and postprandial triglyceride-rich lipoproteins in type 2 diabetes.

Type 2 diabetes is associated with atherogenic abnormalities of postprandial triglyceride-rich lipoproteins. This study evaluated whether ezetimibe, by inhibiting intestinal cholesterol absorption, influences chylomicrons and VLDL particles at fasting and after a standard meal.



By a double blind cross-over design 15 subjects with type 2 diabetes and hypercholesterolaemia followed in random order a 6-week treatment with ezetimibe 10mg+simvastatin 20 mg (EZE+S) or placebo+simvastatin 20 mg (P+S) and, after a 6-week wash-out period, crossed over to the other treatment (NCT00699023). At the end of each period lipids, apoB-48, and apoB-100 concentrations in plasma and lipoprotein fractions (separated by discontinuous density gradient ultracentrifugation) were determined before and over 6h following a high-fat test meal.



Compared with P+S, EZE+S induced, (a) beside a greater decrease in LDL cholesterol, (b) a significant decrease in chylomicron lipid content both at fasting and postprandially (4.4 ± 2.7 vs. 8.3 ± 8.7 mg/dl × 6 h total AUC for cholesterol, p < 0.05; 18 ± 12 vs. 29 ± 24 mg/dl triglyceride concentrations at 6h, p < 0.05), (c) a significant decrease in chylomicron postprandial apoB-48 (0.03 ± 0.03 vs. 0.09 ± 0.08 mg/l at 4 h, p < 0.05), and (d) significant fasting and postprandial decreases in the cholesterol content of VLDL, IDL, and LDL, as shown by the significant reduction of the cholesterol/triglyceride ratio in these lipoproteins.



A 6-week treatment with ezetimibe and simvastatin, compared to simvastatin alone, positively influences lipoprotein profile both at fasting and postprandially in type 2 diabetic patients by favouring the production of cholesterol-poor chylomicrons and VLDL particles that have less atherogenic potential.
Subcutaneous methylnaltrexone for treatment of opioid-induced constipation in patients with chronic, nonmalignant pain: a randomized controlled study.

Methylnaltrexone is effective for opioid-induced constipation (OIC) in advanced illness patients. This 4-week, double-blind, randomized, placebo-controlled study investigated the effect of subcutaneous methylnaltrexone on OIC in patients receiving opioids for chronic, nonmalignant pain. Patients (N = 460) received subcutaneous methylnaltrexone 12 mg once daily (QD) or every other day (alternating with placebo) compared with placebo. Assessments included bowel movement count, time of bowel movement, straining, sense of complete evacuation, Bristol Stool Form Scales, and quality of life. Within 4 hours of first dose, 34.2% of patients in both methylnaltrexone groups had rescue-free bowel movements (RFBMs) versus 9.9% on placebo (P < .001). The estimated number needed to treat was about 4. On average, 28.9% of methylnaltrexone QD and 30.2% of methylnaltrexone alternate-day dosing resulted in RFBMs within 4 hours versus 9.4% QD and 9.3% alternate-day placebo injections (both P < .001). Both methylnaltrexone groups had significantly shorter time to first RFBM (P < .001) and greater increase in number of weekly RFBMs (P < .05) versus placebo. Adverse events included abdominal pain, diarrhea, nausea, and hyperhidrosis. Bristol Stool Form Scale scores (P = .002) and sensation of complete evacuation (P < .04) were significantly superior with methylnaltrexone QD; both methylnaltrexone groups reported no or mild straining during RFBMs in the first 2 weeks (P < .02). At 4 weeks, a significantly greater improvement in patient-reported, constipation-specific quality of life was seen in the alternate-day dosing (P < .05) and QD (P < .001) groups.



We present data demonstrating that subcutaneous methylnaltrexone 12 mg given once daily (QD) or every other day provides significant relief of OIC and was generally well tolerated in patients with chronic, nonmalignant pain. These results expand on prior effectiveness observed for the treatment of OIC in advanced illness patients to a broader population.
Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial

Evidence increasingly points to the importance of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal disease (ESRD). Beraprost sodium (BPS) is an orally active prostacyclin (PGI2) analogue demonstrating prevention of the progression of chronic kidney disease (CKD) in various animal models by maintaining renal blood flow and attenuating renal ischemic condition.



This multicenter, randomized, double-blind, placebo-controlled, phase II trial was designed to determine the recommended dose of the sustained-release form of BPS (TRK-100STP 120 μg/day or 240 μg/day) in Japanese patients with CKD. TRK-100STP was administered to a total of 112 patients. The primary efficacy endpoint was the difference in the slope of the regression line of reciprocal of serum creatinine (1/SCr) over time, obtained by the least-squares method.



Regarding the primary endpoint, statistical superiority of TRK-100STP 240 μg over placebo was not confirmed and so a recommended dose was not determined. Compared to placebo, however, the slope of regression line of 1/SCr, elevation of SCr and serum cystatin C during the treatment period revealed greater improvement at 120 μg, at both doses, and at 240 μg, respectively. In terms of safety, both TRK-100STP treatment groups were well tolerated.



Although the study failed to meet the primary endpoint, results indicate that TRK-100STP may potentially prevent the decline in renal function of CKD patients independent of blood pressure or urinary protein levels.
Real-world outcomes of paliperidone palmitate compared to daily oral antipsychotic therapy in schizophrenia: a randomized, open-label, review board-blinded 15-month study.

The Paliperidone Palmitate Research in Demonstrating Effectiveness (PRIDE) study compared the effects of once-monthly paliperidone palmitate with daily oral antipsychotics on treatment failure in adults with schizophrenia.



The PRIDE study is a 15-month, randomized, multicenter study (May 5, 2010, to December 9, 2013) of adult subjects with a DSM-IV diagnosis of schizophrenia and a history of incarceration. Subjects were randomly assigned to once-monthly paliperidone palmitate injections or daily oral antipsychotics (randomly assigned from 7 acceptable, prespecified oral antipsychotics) for 15 months. The primary end point was time to first treatment failure, defined as arrest/incarceration; psychiatric hospitalization; suicide; treatment discontinuation or supplementation due to inadequate efficacy, safety, or tolerability; or increased psychiatric services to prevent hospitalization. Time to first treatment failure was determined by a blinded event-monitoring board and analyzed with the Kaplan-Meier method.



In this study, 450 patients were randomly assigned, and 444 were included in the intent-to-treat population. Paliperidone palmitate was associated with significant delay in time to first treatment failure versus oral antipsychotics (hazard ratio, 1.43; 95% CI, 1.09-1.88; log rank P = .011). Observed treatment failure rates over 15 months were 39.8% and 53.7%, respectively. Arrest/incarceration and psychiatric hospitalization were the most common reasons for treatment failure in the paliperidone palmitate and oral antipsychotic groups (21.2% vs 29.4% and 8.0% vs 11.9%, respectively). The 5 most common treatment-emergent adverse events for the paliperidone palmitate treatment group were injection site pain (18.6% of subjects), insomnia (16.8%), weight increased (11.9%), akathisia (11.1%), and anxiety (10.6%).



In a trial designed to reflect real-world management of schizophrenia, once-monthly paliperidone palmitate demonstrated superiority compared to oral antipsychotics in delaying time to treatment failure.
Phase I trial of simultaneous in-field boost with helical tomotherapy for patients with one to three brain metastases.

Stereotactic radiosurgery is an alternative to surgical resection for selected intracranial lesions. Integrated image-guided intensity-modulated-capable radiotherapy platforms such as helical tomotherapy (HT) could potentially replace traditional radiosurgery apparatus. The present study's objective was to determine the maximally tolerated dose of a simultaneous in-field boost integrated with whole brain radiotherapy for palliative treatment of patients with one to three brain metastases using HT.



The inclusion/exclusion criteria and endpoints were consistent with the Radiation Therapy Oncology Group 9508 radiosurgery trial. The cohorts were constructed with a 3 + 3 design; however, additional patients were enrolled in the lower dose tolerable cohorts during the toxicity assessment periods. Whole brain radiotherapy (30 Gy in 10 fractions) was delivered with a 5-30-Gy (total lesion dose of 35-60 Gy in 10 fractions) simultaneous in-field boost delivered to the brain metastases. The maximally tolerated dose was determined by the frequency of neurologic Grade 3-5 National Cancer Institute Common Toxicity Criteria, version 3.0, dose-limiting toxicity events within each Phase I cohort.



A total of 48 patients received treatment in the 35-Gy (n = 3), 40-Gy (n = 16), 50-Gy (n = 15), 55-Gy (n = 8), and 60-Gy (n = 6) cohorts. No patients experienced dose-limiting toxicity events in any of the trial cohorts. The 3-month RECIST assessments available for 32 of the 48 patients demonstrated a complete response in 2, a partial response in 16, stable disease in 6, and progressive disease in 8 patients.



The delivery of 60 Gy in 10 fractions to one to three brain metastases synchronously with 30 Gy whole brain radiotherapy was achieved without dose-limiting central nervous system toxicity as assessed 3 months after treatment. This approach is being tested in a Phase II efficacy trial.