nils-herrmann/clean_scirepeval huggingface dataset:
Bioinformatic identification of FGF, p38-MAPK, and calcium signalling pathways associated with carcinoma in situ in the urinary bladder

Carcinoma in situ (CIS) is believed to be a precursor of invasive bladder cancer. Identification of CIS is a valuable prognostic factor since radical treatment strategies can be offered these patients before the disease becomes invasive. We developed a pathway based classifier approach to predict presence or absence of CIS in patients suffering from non muscle invasive bladder cancer. From Ingenuity Pathway Analysis we considered four canonical signalling pathways (p38 MAPK, FGF, Calcium, and cAMP pathways) with most coherent expression of transcription factors (TFs) across samples in a set of twenty-eight non muscle invasive bladder carcinomas. These pathways contained twelve TFs in total. We used the expression of the TFs to predict presence or absence of CIS in a Leave-One-Out Cross Validation classification. We showed that TF expression levels in three pathways (FGF, p38 MAPK, and calcium signalling) or the expression of the twelve TFs together could be used to predict presence or absence of concomitant CIS. A cluster analysis based on expression of the twelve TFs separated the samples in two main clusters: one branch contained 11 of the 15 patients without concomitant CIS and with the majority of the genes being down regulated; the other branch contained 10 of 13 patients with concomitant CIS, and here genes were mostly up regulated. The expression in the CIS group was comparable to the expression of twenty-three patients suffering from muscle-invasive bladder carcinoma. Finally, we validated our results in an independent test set and found that prediction of CIS status was possible using TF expression of the p38 MAPK pathway. We conclude that it is possible to use pathway analysis for molecular classification of bladder tumors.
Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation.

There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma.



Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated.



Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y).



Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.
Function after spinal treatment, exercise and rehabilitation (FASTER): improving the functional outcome of spinal surgery

The life-time incidence of low back pain is high and diagnoses of spinal stenosis and disc prolapse are increasing. Consequently, there is a steady rise in surgical interventions for these conditions. Current evidence suggests that while the success of surgery is incomplete, it is superior to conservative interventions. A recent survey indicates that there are large differences in the type and intensity of rehabilitation, if any, provided after spinal surgery as well as in the restrictions and advice given to patients in the post-operative period. This trial will test the hypothesis that functional outcome following two common spinal operations can be improved by a programme of post-operative rehabilitation that combines professional support and advice with graded active exercise and/or an educational booklet based on evidence-based messages and advice.



The study design is a multi-centre, factorial, randomised controlled trial with patients stratified by surgeon and operative procedure. The trial will compare the effectiveness and cost-effectiveness of a rehabilitation programme and an education booklet for the postoperative management of patients undergoing discectomy or lateral nerve root decompression, each compared with "usual care"using a 2 x 2 factorial design. The trial will create 4 sub-groups; rehabilitation-only, booklet-only, rehabilitation-plus-booklet, and usual care only. The trial aims to recruit 344 patients, which equates to 86 patients in each of the four sub-groups. All patients will be assessed for functional ability (through the Oswestry Disability Index - a disease specific functional questionnaire), pain (using visual analogue scales), and satisfaction pre-operatively and then at 6 weeks, 3, 6 and 9 months and 1 year post-operatively. This will be complemented by a formal analysis of cost-effectiveness.



This trial will determine whether the outcome of spinal surgery can be enhanced by either a post-operative rehabilitation programme or an evidence-based advice booklet or a combination of the two and as such will contribute to our knowledge on how to manage spinal surgery patients in the post-operative period.
Women’s Experiences with Oral and Vaginal Pre-Exposure Prophylaxis: The VOICE-C Qualitative Study in Johannesburg, South Africa

In VOICE, a multisite HIV pre-exposure prophylaxis (PrEP) trial, plasma drug levels pointed to widespread product nonuse, despite high adherence estimated by self-reports and clinic product counts. Using a socio-ecological framework (SEF), we explored socio-cultural and contextual factors that influenced participants' experience of daily vaginal gel and oral tablet regimens in VOICE.



In Johannesburg, a qualitative ancillary study was concurrently conducted among randomly selected VOICE participants assigned to in-depth interviews (n = 41), serial ethnographic interviews (n = 21), or focus group discussions (n = 40). Audiotaped interviews were transcribed, translated, and coded thematically for analysis.



Of the 102 participants, the mean age was 27 years, and 96% had a primary sex partner with whom 43% cohabitated. Few women reported lasting nonuse, which they typically attributed to missed visits, lack of product replenishments, and family-related travel or work. Women acknowledged occasionally skipping or mistiming doses because they forgot, were busy, felt lazy or bored, feared or experienced side effects. However, nearly all knew or heard of other study participants who did not use products daily. Three overarching themes emerged from further analyses: ambivalence toward research, preserving a healthy status, and managing social relationships. These themes highlighted the profound and complex meanings associated with participating in a blinded HIV PrEP trial and taking antiretroviral-based products. The unknown efficacy of products, their connection with HIV infection, challenges with daily regimen given social risks, lack of support-from partners and significant others-and the relationship tradeoffs entailed by using the products appear to discourage adequate product use.



Personal acknowledgment of product nonuse was challenging. This qualitative inquiry highlighted key influences at all SEF levels that shaped women's perceptions of trial participation and experiences with investigational products. Whether these impacted women's behaviors and may have contributed to ineffective trial results warrants further investigation.
Detection of EGFR mutations in plasma and biopsies from non-small cell lung cancer patients by allele-specific PCR assays

Lung cancer patients with mutations in the epidermal growth factor receptor (EGFR) are primary candidates for EGFR-targeted therapy. Reliable analyses of such mutations have previously been possible only in tumour tissue. Here, we demonstrate that mutations can be detected in plasma samples with allele-specific PCR assays. Pairs of the diagnostic biopsy and plasma obtained just prior to start of erlotinib treatment were collected from 199 patients with adenocarcinoma of non-small-cell lung cancer. DNA from both sample types was isolated and examined for the presence of mutations in exons 18–21 of the EGFR gene, employing the cobas® EGFR Tissue Test and cobas® EGFR Blood Test (in development, Roche Molecular Systems, Inc., CA, USA). Test results were obtained in all 199 (100%) plasma samples and 196/199 (98%) of the biopsies. EGFR-activating mutations were identified in 24/199 (12%) plasma samples and 28/196 (14%) biopsy samples, and 17/196 (9%) matched pairs contained the same mutation. Six EGFR mutations were present only in plasma samples but not in the biopsy samples. The overall concordance of the EGFR gene mutations detected in plasma and biopsy tissue was 179/196 (91%) (kappa value: 0.621). Mutational analysis of the EGFR gene in plasma samples is feasible with allele-specific PCR assays and represents a non-invasive supplement to biopsy analysis. M-20080012 from March 10, 2008 and reported to ClinicalTrials.gov: NCT00815971 .
Incorporation of inhaled insulin into the FDA accepted University of Virginia/Padova Type 1 Diabetes Simulator

The University of Virginia/Padova Type 1 Diabetes (T1DM) Simulator has been extensively used in artificial pancreas research mostly for testing and design of control algorithms. However, it also offers the possibility of testing new insulin analogs and alternative routes of delivery given that subcutaneous insulin administration present significant delays & variability. Inhaled insulin appears an important candidate to improve post-prandial glucose control given its rapid appearance in plasma. In this contribution, we present the results of incorporating a pharmacokinetic model of inhaled Technosphere® Insulin (TI) into the T1DM simulator. In particular, we successfully reproduced in silico the post-prandial glucose control observed in T1DM subjects treated with TI given at meal time, and the post-prandial glucose dynamics in response to different timing of TI dose.
The foundation of a generic theorem prover

Isabelle [28, 30] is an interactive theorem prover that supports a variety of logics. It represents rules as propositions (not as functions) and builds proofs by combining rules. These operations constitute a meta-logic (or ‘logical framework’) in which the object-logics are formalized. Isabelle is now based on higher-order logic-a precise and well-understood foundation. Examples illustrate the use of this meta-logic to formalize logics and proofs. Axioms for first-order logic are shown to be sound and complete. Backwards proof is formalized by meta-reasoning about object-level entailment. Higher-order logic has several practical advantages over other meta-logics. Many proof techniques are known, such as Huet's higher-order unification procedure.
Clinical response to 2 dosing regimens of lansoprazole in infants with gastroesophageal reflux.

Proton pump inhibitors such as lansoprazole are used in the treatment of gastroesophageal reflux disease (GERD), but dosing guidelines for infants have not been determined. The objective of this study was to assess the clinical efficacy of 2 dosing regimens of lansoprazole in infants with GERD using the revised infant gastroesophageal reflux questionnaire scores (I-GERQ-R). Thirty consecutive infants (3-7 months) with GERD, whose conditions were diagnosed by I-GERQ-R scores of > or =16, were randomly assigned to receive 1 of 2 lansoprazole dosing regimens: 15 mg given once per day (group A) or approximately 7.5 mg given 2 times per day (group B). Matched infants in a control group were treated with an extensively hydrolyzed formula (group C). Daily I-GERQ-R scores were gathered, and the scores after 1 and 2 weeks of treatment were used for analysis. The mean pretreatment scores were similar in groups A, B, and C (26.6, 26.9, and 25.9, respectively). After treatment there was a similar drop in the mean scores in groups A and B (20.6 and 20.0, respectively), but not in group C (25.8). At the end of the first week of treatment, in group A, 5 of 15 infants (33%) had a significant reduction in their I-GERQ-R scores, whereas in group B, 10 of 15 infants (67%) had a significant reduction in their I-GERQ-R scores (P < 0.05). At the end of the second week of treatment, groups A and B had similar numbers of patients with significant improvement (60% and 67%), which was higher than in group C (3/15, 20%). Overall, there was no difference in the symptom response, as measured by I-GERQ-R scores, between 15 mg of lansoprazole given once per day and 7.5 mg given twice per day in infants with GERD, but the twice-daily regimen produced a faster symptom response. Both regimens were significantly better than treatment of infants with an extensively hydrolyzed formula.
Automatic segmentation and plaque characterization in atherosclerotic carotid artery MR images

In vivo MRI provides a means to non-invasively image and assess the morphological features of atherosclerotic carotid arteries. To assess quantitatively the degree of vulnerability and the type of plaque, the contours of the lumen, outer boundary of the vessel wall and plaque components, need to be traced. Currently this is done manually, which is time-consuming and sensitive to inter- and intra-observer variability. The goal of this work was to develop an automated contour detection technique for tracing the lumen, outer boundary and plaque contours in carotid MR short-axis black-blood images. Seventeen patients with carotid atherosclerosis were imaged using high-resolution in vivo MRI, generating a total of 50 PD- and T1-weighted MR images. These images were automatically segmented using the algorithm presented in this work, which combines model-based segmentation and fuzzy clustering to detect the vessel wall, lumen and lipid core boundaries. The results demonstrate excellent correspondence between automatic and manual area measurements for lumen (r=0.92) and outer (r=0.91), and acceptable correspondence for fibrous cap thickness (r=0.71). Though further optimization is required, our algorithm is a powerful tool for automatic detection of lumen and outer boundaries, and characterization of plaque in atherosclerotic vessels.
The Lipid Research Clinics Coronary Primary Prevention Trial

The Lipid Research Clinics Coronary Primary Prevention Trial tested the efficacy of cholesterol lowering in reducing the risk of coronary heart disease in 3806 asymptomatic, middle-aged men with primary hypercholesterolaemia. The cholestyramine group experienced 8.5 and 12.6% greater reductions in total and low density lipoprotein (LDL), respectively, than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (p < 0.05) of the primary end-point of definite coronary heart disease death and/or definite non-fatal myocardial infarction. Corresponding and significant reductions were also seen for angina, development of a positive exercise test, and coronary bypass surgery. All-cause mortality was only slightly, and not significantly, reduced in the cholestyramine group, reflecting more violent and accidental deaths in the cholestyramine subjects. When the cholestyramine group was analysed separately, a 19% reduction in coronary heart disease risk was also associated with each decrement of 8% in total cholesterol. Moreover, coronary heart disease incidence in men in sustaining a fall of 25% in total cholesterol, a typical response to the prescribed dosage (24 g/day) of cholestyramine resin, was half that of men who remained at pretreatment level. The Lipid Research Clinics Coronary Primary Prevention Trial findings show that reducing total cholesterol by lowering LDL cholesterol levels, can diminish the incidence of coronary heart disease morbidity and mortality in men at high risk for the disease because of raised LDL cholesterol levels. These results have considerable importance for the prevention of coronary heart disease through cholesterol lowering, at both the clinical and public health levels.
A Novel MDR1 GT1292-3TG (Cys431Leu) Genetic Variation and Its Effect on P-glycoprotein Biologic Functions

P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood–brain barrier. MDR1 genetic variation can lead to changes in P-gp function and may have implications on drug pharmacokinetics. We have identified a novel MDR1 GT1292-3TG (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. The cellular and transport function of this variation was investigated with recombinant human embryonic kidney cells expressing MDR1. Compared with the wild type, MDR1 GT1292-3TG recombinant cells exhibited a lower drug resistance phenotype for a panel of chemotherapeutic agents. When compared with wild type, MDR1 GT1292-3TG recombinant cells exposed exhibited a 75% decrease in IC50 for doxorubicin (162.6 ± 17.4 to 37.9 ± 2.6 nM) and a 50% decrease in IC50 for paclitaxel (155.7 ± 27.5 to 87.7 ± 9.2 nM), vinblastine (128.0 ± 15.9 to 65.9 ± 5.1 nM), and vincristine (593.7 ± 61.8 to 307.3 ± 17.0 nM). The effects of the Cys431Leu variation, due to MDR1 GT1292-3TG nucleotide transition, on P-gp-dependent intracellular substrate accumulation appeared to be substrate dependent where doxorubicin, vinblastine, and paclitaxel exhibit an increased accumulation (p < 0.05), while verapamil and Hoechst33342 exhibit a decreased intracellular concentration compared with wild type (p < 0.05). Collectively, these data suggest MDR1 GT1292-3TG variation of P-gp may reduce drug resistance and that subjects with this genotype undergoing chemotherapy with drugs that are transported by P-gp could potentially be more responsive to therapy than those with MDR1 wild-type genotype.
Use of idarubicin in pre-transplant conditioning in children with high-risk acute leukaemia

The major cause of treatment failure following allogeneic bone marrow transplantation for acute leukaemia is disease relapse. In an attempt to reduce post- transplant relapse in 33 children with high-risk acute leukaemia who received a related or unrelated bone marrow transplant, the pre-transplant conditioning regimen was intensified by the addition of idarubicin. Its toxicity and effects on survival were evaluated over a 57-month period. Toxicity, largely gastrointestinal, was increased but acceptable, and there was no specific regimen-related toxicity. Relapse rates were low (24%) in this high risk group, but mortality was increased in those receiving unrelated donor grafts, largely due to sepsis. Idarubicin does appear to have a role to play in the conditioning regimen of patients with high-risk acute leukaemia undergoing BMT, and may reduce relapse rates without increasing transplant-related mortality.
Effect of a low dose whey/guar preload on glycemic control in people with type 2 diabetes-a randomised controlled trial

Large preloads of protein and fat have been shown to lower glucose after a carbohydrate-rich meal in people with type 2 diabetes but add a considerable energy burden. Low calorie preloads [<5% of daily energy intake] have been tested in this study in people with prediabetes and with type 2 diabetes.



This was an unblinded randomised crossover study with two placebo days and two active treatment days. Glucose was measured for 3 hours with fingerprick samples as well as continuous glucose monitoring [CGMS]. Twenty-four subjects with pre-diabetes or moderately controlled type 2 diabetes [fasting glucose < 10 and HbA1c < 8.5%] were recruited. The preload contained 17 g whey protein plus 3 g lactose and 5 g guar, and 1 g flavour material [including sucralose] dissolved in 150 ml cold water or 150 ml cold water with no additives. The breakfast test meal consisted of 2 slices of bread, margarine and jam [3 slices for men] with the test drink 15 minutes beforehand.



Peak fingerprick glucose was reduced by 2.1 mmol/L at 45 min [p < 0.0001]. Average fingerprick glucose over 3 hours was reduced by 0.8 mmol/L [p = 0.0003]. There was no difference between those with diabetes or prediabetes or those on medication or not on medication.



An 80 kcal whey protein/fibre preload can lower average glucose over 3 hours by 0.8 mmol/L. If used long term before at least two carbohydrate-rich meals/day this preload could lower HbA1c by up to 1%.
Epidural anesthesia and analgesia decrease the postoperative incidence of insulin resistance in preoperative insulin-resistant subjects only.

Insulin resistance (IR) is a feature of the endocrine stress response to surgery. It is not known whether a preoperative state of IR would affect the postoperative endocrine response. We sought to characterize the preoperative state of IR in a group of patients undergoing elective hip and knee arthroplasty, and to determine to what extent perioperative epidural analgesia modifies the postoperative state of IR in those who are and are not insulin-resistant before surgery.



Sixty patients undergoing either hip or knee arthroplasty were screened by using the homeostatic model assessment (HOMA) in two populations: insulin-resistant patients and noninsulin-resistant patients, whereas HOMA is fasting insulin (microU/mL) x fasting glucose (mmol/L)/22.5. The patients belonging to each population were then randomly assigned to receive either intraoperative epidural blockade followed by postoperative epidural analgesia (epidural group) or general anesthesia followed by patient-controlled analgesia (control group). Analgesia was assessed with visual analog scale up to 48 h after surgery and HOMA was repeated at the end of surgery and 48 h after surgery to determine the postoperative state of IR.



Epidural anesthesia and analgesia significantly influenced the postoperative HOMA score (smaller proportion of IR) in the postoperative period only in those patients who were insulin-resistant before surgery (P < 0.01). In contrast, noninsulin-resistant patients had a similar postoperative proportion of IR between the epidural and control groups (P > 0.05). At rest and during movement, visual analog scale scores were not different between groups at the end of surgery and in the first and second days after surgery.



Epidural anesthesia and analgesia compared to general anesthesia followed by patient-controlled analgesia decreased the incidence of IR soon after surgery and 48 h after surgery only in patients who were insulin-resistant before surgery.