nils-herrmann/clean_scirepeval huggingface dataset:
Dose-finding study of imatinib in combination with intravenous cytarabine: feasibility in newly diagnosed patients with chronic myeloid leukemia.

The HOVON cooperative study group performed a feasibility study of escalated imatinib and intravenous cytarabine in 165 patients with early chronic-phase chronic myeloid leukemia (CML). Patients received 2 cycles of intravenous cytarabine (200 mg/m(2) or 1000 mg/m(2) days 1-7) in conjunction with imatinib (200 mg, 400 mg, 600 mg, or 800 mg), according to predefined, successive dose levels. All dose levels proved feasible. Seven dose-limiting toxicities (DLTs) were observed in 302 cycles of chemotherapy, which were caused by streptococcal bacteremia in 5 cases. Intermediate-dose cytarabine (1000 mg/m(2)) prolonged time to neutrophil recovery and platelet recovery compared with a standard dose (200 mg/m(2)). High-dose imatinib (600 mg or 800 mg) extended the time to platelet recovery compared with a standard dose (400 mg). More infectious complications common toxicity criteria (CTC) grade 3 or 4 were observed after intermediate-dose cytarabine compared with a standard-dose of cytarabine. Early response data after combination therapy included a complete cytogenetic response in 48% and a major molecular response in 30% of patients, which increased to 46% major molecular responses at 1 year, including 13% complete molecular responses. We conclude that combination therapy of escalating dosages of imatinib and cytarabine is feasible.
Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia.

Ghrelin is a novel enteric hormone that stimulates growth hormone (GH), ACTH, and epinephrine; augments plasma glucose; and increases food intake by inducing the feeling of hunger. These characteristics make ghrelin a potential counterregulatory hormone. At present, it is not known whether ghrelin increases in response to insulin-induced hypoglycemia. To answer this question, we compared plasma ghrelin concentrations after a short-term insulin infusion that was allowed or not (euglycemic clamp) to cause hypoglycemia (2.7 +/- 0.2 mmol/l at 30 min) in five healthy volunteers. In both studies, plasma ghrelin concentrations decreased (P < 0.01) after insulin infusion (hypoglycemia by 14%, euglycemia by 22%), reached a nadir at 30 min, and returned to baseline at 60 min, without differences between the hypoglycemia and the euglycemia studies. Glucagon, cortisol, and GH increased in response to hypoglycemia despite the decreased ghrelin. There was a strong correlation (R(2) = 0.91, P < 0.002) between the insulin sensitivity of the subjects and the percentage suppression of ghrelin from baseline. These data demonstrate that ghrelin is not required for the hormonal defenses against insulin-induced hypoglycemia and that insulin can suppress ghrelin levels in healthy humans. These results raise the possibility that postprandial hyperinsulinemia is responsible for the reduction of plasma ghrelin that occurs during meal intake.
A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates

We recently reported the clinical results of a Phase I trial combining ipilimumab with a vaccine containing transgenes for prostate-specific antigen (PSA) and for a triad of costimulatory molecules (PROSTVAC) in patients with metastatic castration-resistant prostate cancer. Thirty patients were treated with escalating ipilimumab and a fixed dose of vaccine. Of 24 chemotherapy-naïve patients, 58 % had a PSA decline. Combination therapy did not exacerbate the immune-related adverse events associated with ipilimumab. Here, we present updated survival data and an evaluation of 36 immune cell subsets pre- and post-therapy. Peripheral blood mononuclear cells were collected before therapy, at 13 days and at 70 days post-initiation of therapy, and phenotyped by flow cytometry for the subsets of T cells, regulatory T cells, natural killer cells, and myeloid-derived suppressor cells. Associations between overall survival (OS) and immune cell subsets prior to treatment, and the change in a given immune cell subset 70 days post-initiation of therapy, were evaluated. The median OS was 2.63 years (1.77–3.45). There were trends toward associations for longer OS and certain immune cell subsets before immunotherapy: lower PD-1+Tim-3NEGCD4EM (P = 0.005, adjusted P = 0.010), higher PD-1NEGTim-3+CD8 (P = 0.002, adjusted P = 0.004), and a higher number of CTLA-4NEG Tregs (P = 0.005, adjusted P = 0.010). We also found that an increase in Tim-3+ natural killer cells post- versus pre-vaccination associated with longer OS (P = 0.0074, adjusted P = 0.015). These results should be considered as hypothesis generating and should be further evaluated in larger immunotherapy trials.
Surgically Managed Clinical Stage IIIA-Clinical N2 Lung Cancer in The Society of Thoracic Surgeons Database.

The role of surgical resection in patients with clinical stage IIIA-N2 positive (cIIIA-N2) lung cancer is controversial, partly because of the variability in short- and long-term outcomes. The objective of this study was to characterize the management of cIIIA-N2 lung cancer in The Society of Thoracic Surgeons General Thoracic Surgery Database (STS-GTSD).



The STS-GTSD was queried for patients who underwent operations for cIIIA-N2 lung cancer between 2002 and 2012. A subset of patients aged older than 65 years was linked to Medicare data.



Identified were 3,319 surgically managed, cIIIA-N2 patients, including 1,784 (54%) treated with upfront resection (treatment naïve upfront surgery group, and 1,535 (46%) with induction therapy. A positron emission tomography scan was documented in 93% of patients, and 51% of patients were coded in STS-GTSD as having undergone invasive mediastinal staging. Nodal overstaging (cN2→pN0/N1) was observed in 43% of upfront surgery patients. Lobectomy was performed in 69% of patients and pneumonectomy in 11%. Operative mortality was similar between patients treated with upfront surgery (1.9%) and induction therapy (2.5%, p = .2583). The unadjusted Kaplan-Meier estimate of 5-year survival of cIII-N2 patients treated with induction therapy then resection was 35%.



STS surgeons achieve excellent short- and long-term results treating predominantly lobectomy-amenable cIIIA-N2 lung cancer. However, prevalent overstaging and abstention from induction therapy suggest "overcoding" of false positives on imaging or variable compliance with current guidelines for cIIIA-N2 lung cancer. Efforts are needed to improve clinical stage determination and guideline compliance in the GTSD for this cohort.
Development and psychometric evaluation of the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) in patients with upper gastrointestinal disorders

Describe the development and evaluation of a new self-report instrument, the patient assessment of upper gastrointestinal disorders-symptom severity index (PAGI-SYM) in subjects with gastroesophageal reflux disease (GERD), dyspepsia, or gastroparesis.  Recruited subjects with GERD (n=810), dyspepsia (n=767), or gastroparesis (n=169) from the US, France, Germany, Italy, the Netherlands, and Poland. Subjects completed the PAGI-SYM, SF-36, a disease-specific HRQL measure (PAGI-QOL), and disability day questions. Two-week reproducibility was evaluated in 277 stable subjects. We evaluated construct validity by correlating subscale scores with SF-36, PAGI-QOL, disability days, and global symptom severity scores.  The final 20-item PAGI-SYM has six subscales: heartburn/regurgitation, fullness/early satiety, nausea/vomiting, bloating, upper abdominal pain, and lower abdominal pain. Internal consistency reliability was good (α =0.79 0.91); test–retest reliability was acceptable (Intraclass correlation coefficients α =0.60 0.82). PAGI-SYM subscale scores correlated significantly with SF-36 scores (all p < 0.0001), PAGI-QOL scores (all p < 0.0001), disability days (p< 0.0001), and global symptom severity (p < 0.0001). Mean PAGI-SYM scores varied significantly in groups defined by disability days (all p < 0.0001), where greater symptom severity was associated with more disability days.  Results suggest the PAGI-SYM, a brief symptom severity instrument, has good reliability and evidence supporting construct validity in subjects with GERD, dyspepsia, or gastroparesis.
Do the risk factors of age, family history of prostate cancer or a higher prostate specific antigen level raise anxiety at prostate biopsy?

To date, little is known of the impact knowledge of personal risk factors has on anxiety in men undergoing biopsy tests for prostate cancer. This analysis explores anxiety scores of men at higher risk due to age, family history of prostate cancer and a higher prostate specific antigen (PSA) level when proceeding from PSA test to prostate biopsy. A prospective cohort of 4198 men aged 50-69 years with a PSA result of >3ng/ml was studied, recruited for the Prostate testing for cancer and Treatment study . Anxiety scores at the time of biopsy were lower in older men (p<0.001). No age group showed an increase in anxiety as the men proceeded from PSA testing to biopsy, although older men did not show the same level of decrease in anxiety as younger men (p=0.035). There was no difference in anxiety scores at biopsy between men with or without a family history of prostate cancer (p=0.68), or between those with a raised PSA of 10-<20ng/ml compared to a PSA result of 3-<10ng/ml (p=0.46). Change in scores since the initial PSA test appeared unaffected by family history (p=0.995) or by PSA result (p=0.76). Within the context of a research study, the increased risk of prostate cancer through older age, having a family history of prostate cancer, or having a significantly elevated PSA level appears to have no detrimental effect on men's anxiety level when proceeding to biopsy.
The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: A randomised, double-blind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults

Some studies have suggested an association between omega-3 long-chain polyunsaturated fatty acids (n-3 LC PUFAs) and better cognitive outcomes in older adults. To date, only two randomised, controlled trials have assessed the effect of n-3 LC PUFA supplementation on cognitive function in older cognitively healthy populations. Of these trials only one found a benefit, in the subgroup carrying the ApoE-ε4 allele. The benefits of n-3 LC PUFA supplementation on cognitive function in older normal populations thus still remain unclear. The main objective of the current study was to provide a comprehensive assessment of the potential of n-3 LC PUFAs to slow cognitive decline in normal elderly people, and included ApoE-ε4 allele carriage as a potential moderating factor. The detailed methodology of the trial is reported herein.



The study was a parallel, 18-month, randomised, double-blind, placebo-controlled intervention with assessment at baseline and repeated 6-monthly. Participants (N = 391, 53.7% female) aged 65-90 years, English-speaking and with normal cognitive function, were recruited from metropolitan Adelaide, South Australia. Participants in the intervention arm received capsules containing fish-oil at a daily dosage of 1720 mg of docosahexaenoic acid and 600 mg of eicosapentaenoic acid while the placebo arm received the equivalent amount of olive oil in their capsules. The primary outcome is rate of change in cognitive performance, as measured by latent variables for the cognitive constructs (encompassing Reasoning, Working Memory, Short-term Memory, Retrieval Fluency, Inhibition, Simple and Choice-Reaction Time, Perceptual Speed, Odd-man-out Reaction Time, Speed of Memory Scanning, and Psychomotor Speed) and assessed by latent growth curve modeling. Secondary outcomes are change in the Mini-mental State Examination, functional capacity and well-being (including health status, depression, mood, and self-report cognitive functioning), blood pressure, and biomarkers of n-3 LC PUFA status, glucose, lipid metabolism, inflammation, oxidative stress, and DNA damage.
Double-blind comparison of eprosartan and enalapril on cough and blood pressure in unselected hypertensive patients

The effects of a new angiotensin receptor antagonist, eprosartan (200 or 300 mg b.i.d.) and enalapril (5–20 mg u.i.d.) on cough and blood pressure were compared in a 26-week, double-blind, randomised, parallel-group, multicentre, international study involving 528 patients with hypertension. Uptitration of doses was based on clinic blood pressure measurements during the first 12 weeks, after which hydrochlorothiazide (12.5–25 mg/day) could be added. The frequency and intensity of cough was assessed by a standardised questionnaire administered at each clinic visit. The primary end-point was the incidence of persistent, dry cough not due to upper respiratory infection; change in sitting diastolic blood pressure and overall incidence of cough were secondary end-points. During the first 12 weeks of double-blind therapy, enalapril treatment was associated with a 3.45-fold higher risk of definite cough (14/261 vs 4/259, P = 0.018). Overall cough incidence (from spontaneous reports from patients, or investigator’s observation) was also more frequent with enalapril, as compared to eprosartan. Both agents reduced blood pressure significantly compared to baseline, although the eprosartan-treated group had a slightly higher response rate (defined as sitting diastolic blood pressure <90 mm hg, or at least a 10 mm hg reduction from baseline), both at end of titration (70.3% vs 62.6%, P < 0.05) and after 26 weeks (81.7% vs 73.5%, P = 0.018). These data suggest that, in unselected hypertensive patients, eprosartan is associated with less cough and a somewhat higher responder rate than enalapril.
SRC/ABL inhibition disrupts CRLF2-driven signaling to induce cell death in B-cell acute lymphoblastic leukemia

Children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) overexpressing the CRLF2 gene (hiCRLF2) have poor prognosis. CRLF2 protein overexpression leads to activated JAK/STAT signaling and trials are underway using JAK inhibitors to overcome treatment failure. Pre-clinical studies indicated limited efficacy of single JAK inhibitors, thus additional pathways must be targeted in hiCRLF2 cells. To identify additional activated networks, we used single-cell mass cytometry to examine 15 BCP-ALL primary patient samples. We uncovered a coordinated signaling network downstream of CRLF2 characterized by co-activation of JAK/STAT, PI3K, and CREB pathways. This CRLF2-driven network could be more effectively disrupted by SRC/ABL inhibition than single-agent JAK or PI3K inhibition, and this could be demonstrated even in primary minimal residual disease (MRD) cells. Our study suggests SCR/ABL inhibition as effective in disrupting the cooperative functional networks present in hiCRLF2 BCP-ALL patients, supporting further investigation of this strategy in pre-clinical studies.
Reliability and validity of the Women's Health Initiative Insomnia Rating Scale.

The reliability and construct validity of the 5-item Women's Health Initiative Insomnia Rating Scale (WHIIRS) were evaluated in 2 studies. In Study 1, using a sample of 66,269 postmenopausal women, validity of the WHIIRS was assessed by examining its relationship to other measures known to be related to sleep quality. Reliability of the WHIIRS was estimated using a resampling approach; the mean alpha coefficient was .78. Test-retest reliability coefficients were .96 for same-day administration and .66 after a year or more. Correlations of the WHIIRS with the other measures were in the predicted directions. Study 2 used a sample of 459 women and compared the WHIIRS with objective indicators of sleep quality. Results showed that differences in the objective indicators could be detected by the WHIIRS. Findings suggest that a between-group mean difference of approximately 0.50 of a standard deviation on the WHIIRS may be clinically meaningful.
Primary complement and antibody deficiencies in autoimmune rheumatologic diseases with juvenile onset: a prospective study at two centers

Our aim was to investigate the prevalence and clinical relevance of inherited complement and antibody deficiency states in a large series of patients with various autoimmune rheumatologic diseases (ARD) with juvenile onset.



A total number of 117 consecutive patients from 2 tertiary referral hospitals were included in the study. All patients underwent genetic screening for type I C2 deficiency and C4 allotyping. Serum levels of immunoglobulin classes measured systematically throughout their regular medical care were recorded retrospectively.



Our cohort of patients included 84 with juvenile idiopathic arthritis (JIA), 21 with systemic lupus erythematosus (SLE), 6 with systemic vasculitis, 2 with juvenile scleroderma, 2 with idiopathic uveitis, 1 with mixed connective tissue disease and 1 with SLE/scleroderma overlap syndrome. We have found 16 patients with evidence of primary immunodeficiency in our series (13.7%), including 7 with C4 deficiency, 5 with selective IgA deficiency, 3 with C2 deficiency and 2 with unclassified hypogammaglobulinemia (one also presented C4D). Of the 84 patients with JIA, 4 (4.8%) had a complement deficiency, which was less prevalent than in the SLE cohort (23.8%), but all of them have exhibited an aggressive disease. Most of our patients with primary antibody deficiencies showed a more complicated and severe disease course and even the co-occurrence of two associated autoimmune diseases (SLE/scleroderma overlap syndrome and SLE/autoimmune hepatitis type 1 overlap).



Our findings among others demonstrate that complement and immunoglobulin immunodeficiencies need careful consideration in patients with ARD, as they are common and might contribute to a more severe clinical course of the disease.
On credibility of simulation studies of telecommunication networks

In telecommunicationnetworks,asin many otherareasof scienceandengineering,proliferation of computersasresearchtools hasresultedin the adoptionof computersimulationasthe most commonlyusedparadigmof scientific investigations.This, togetherwith a plethoraof existing simulationlanguagesandpackages,hascreateda popularopinion that simulationis mainly an exercisein computerprogramming.In new computingenvironments,programmingcanbeminimised,or evenfully replaced,by themanipulationof icons(representingpre-built programming objectscontainingbasicfunctionalblocksof simulatedsystems)on a computermonitor. Onecan saythatwe have witnessedanothersuccessof modernscienceandtechnology:theemergenceof wonderfulandpowerful toolsfor exploringandpredictingthebehaviour of suchcomplex, stochastic dynamicsystemsastelecommunicationetworks. But this enthusiasmis not sharedby all researchersin this area. An opinion is spreading thatonecannotrely on themajority of thepublishedresultson performanceevaluationstudiesof telecommunicationnetworks basedon stochasticsimulation,sincethey lack credibility. Indeed, thespreadof this phenomenonis sowide thatonecanspeakabouta deepcrisisof credibility. In this paper , this claim is supportedby theresultsof asurvey of over2200publicationson telecommunicationnetworksin recentproceedingsof theIEEEINFOCOMandsuchjournalsastheIEEE Transactionson Communications,the IEEE/ACM Transactionson Networking, andthe PerformanceEvaluationJournal. Thiswork waspartiallysupportedby theUniversityof Canterbury’sGrantno.  Status:a revisionof thepapersubmittedto theIEEECommunicationsMagazinein April 2000 Credibility of simulationstudies 2 Our discussionfocuseson two importantnecessaryconditionsof a crediblesimulationstudy: useof appropriatepseudo-randomgeneratorsof independent uniformly distributednumbers,and appropriateanalysisof simulationoutput data. Having consideredtheir perils and pitfalls, we formulateguidelinesthat,if observed,couldhelpto assureabasiclevel of credibility of simulation studiesof telecommunicationetworks.
Fasting serum taurine-conjugated bile acids are elevated in type 2 diabetes and do not change with intensification of insulin.

Bile acids (BAs) are newly recognized signaling molecules in glucose and energy homeostasis. Differences in BA profiles with type 2 diabetes mellitus (T2D) remain incompletely understood.



The objective of the study was to assess serum BA composition in impaired glucose-tolerant, T2D, and normal glucose-tolerant persons and to monitor the effects of improving glycemia on serum BA composition in T2D patients.



This was a cross-sectional cohort study in a general population (cohort 1) and nonrandomized intervention (cohort 2).



Ninety-nine volunteers underwent oral glucose tolerance testing, and 12 persons with T2D and hyperglycemia underwent 8 weeks of intensification of treatment.



Serum free BA and respective taurine and glycine conjugates were measured by HPLC tandem mass spectrometry.



Oral glucose tolerance testing identified 62 normal-, 25 impaired glucose-tolerant, and 12 T2D persons. Concentrations of total taurine-conjugated BA were higher in T2D and intermediate in impaired- compared with normal glucose-tolerant persons (P = .009). Univariate regression revealed a positive association between total taurine-BA and fasting glucose (R = 0.37, P < .001), postload glucose (R = 0.31, P < .002), hemoglobin A1c (R = 0.26, P < .001), fasting insulin (R = 0.21, P = .03), and homeostatic model assessment-estimated insulin resistance (R = 0.26, P = .01) and an inverse association with oral disposition index (R = -0.36, P < .001). Insulin-mediated glycemic improvement in T2D patients did not change fasting serum total BA or BA composition.



Fasting taurine-conjugated BA concentrations are higher in T2D and intermediate in impaired compared with normal glucose-tolerant persons and are associated with fasting and postload glucose. Serum BAs are not altered in T2D in response to improved glycemia. Further study may elucidate whether this pattern of taurine-BA conjugation can be targeted to provide novel therapeutic approaches to treat T2D.
Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG).

We sought to determine whether a high-risk group could be defined among patients with operable breast cancer in whom a search of occult central nervous system (CNS) metastases was justified.



We evaluated data from 9524 women with early breast cancer (42% node-negative) who were randomized in International Breast Cancer Study Group clinical trials between 1978 and 1999, and treated without anthracyclines, taxanes, or trastuzumab. We identified patients whose site of first event was CNS and those who had a CNS event at any time.



Median follow-up was 13 years. The 10-year incidence (10-yr) of CNS relapse was 5.2% (1.3% as first recurrence). Factors predictive of CNS as first recurrence included: node-positive disease (10-yr = 2.2% for > 3 N+), estrogen receptor-negative (2.3%), tumor size > 2 cm (1.7%), tumor grade 3 (2.0%), < 35 years old (2.2%), HER2-positive (2.7%), and estrogen receptor-negative and node-positive (2.6%). The risk of subsequent CNS recurrence was elevated in patients experiencing lung metastases (10-yr = 16.4%).



Based on this large cohort we were able to define risk factors for CNS metastases, but could not define a group at sufficient risk to justify routine screening for occult CNS metastases.