nils-herrmann/clean_scirepeval huggingface dataset:
A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors

(also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies.  Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state.  Forty-six patients were treated across nine dose levels (12.5–750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d.  VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.
Inhaled fluticasone furoate/vilanterol does not affect hypothalamic-pituitary-adrenal axis function in adolescent and adult asthma: randomised, double-blind, placebo-controlled study

Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24-h activity. FF is in development as a once-daily treatment for asthma as monotherapy and in combination with vilanterol (VI), a long-acting β2 agonist. Corticosteroids can have systemic effects on hypothalamic-pituitary-adrenal (HPA) axis function, potentially resulting in cortisol suppression.



To assess the effect of FF/VI compared with placebo on the HPA axis by evaluating 24-h weighted mean serum cortisol levels in adolescent and adult patients with persistent asthma.



One hundred eighty-five patients with >12 weeks history of asthma were randomised in a 4:4:4:1 ratio to one of two once-daily FF/VI treatments (100/25 μg or 200/25 μg), placebo or an active control group that received inhaled placebo plus one prednisolone 10 mg capsule daily for the last 7 days of the study. Twenty-four-hour serum and urinary cortisol was measured at baseline and on day 42.



Non-inferiority in 24-h weighted mean serum cortisol after 6 weeks of treatment with once-daily FF/VI at either strength was shown. Treatment ratios [95% confidence interval (CI)] to placebo for FF/VI 100/25 μg [0.99 (0.87-1.12)] or FF/VI 200/25 μg [0.97 (0.86-1.10)] indicated non-inferiority of both FF/VI doses to placebo as the lower limit of the 95% CI was greater than the predefined 0.8. Prednisolone substantially reduced 24-h weighted mean serum cortisol [treatment ratio to placebo 0.34 (0.28-0.41)]. FF/VI was well-tolerated, and no safety concerns were identified.



FF/VI was found to be non-inferior to placebo on HPA axis function, with no indication of significant cortisol suppression after 42 days.
No negative effects of a multi-factorial, intensified treatment on self-reported health status, treatment satisfaction, and diabetes-related distress in screen-detected type 2 diabetes patients. The ADDITION-Netherlands study

To examine the effects of a multi-factorial, intensified treatment on self-reported health status, treatment satisfaction, and diabetes-related distress in screen-detected type 2 diabetes patients. Cluster-randomised controlled trial; A total of 498 screen-detected type 2 diabetes patients from 79 general practices were assigned to intensified (n = 255) or routine treatment according to Dutch guidelines (n = 243). At baseline and after 3 years, patients completed the Short Form-36 and the European Quality of Life-5 Dimensions questionnaires. After 4.5 years, patients completed the Diabetes Treatment Satisfaction Questionnaire and the Problem Areas In Diabetes scale. We analysed the effects of intensified treatment on self-rated health status, treatment satisfaction, and diabetes-related distress, using random effects models to account for clustering at practice level. Three to 5 years after type 2 diabetes was detected by screening, there were no differences between intensified and routine treatment in self-reported health status, treatment satisfaction, and diabetes-related distress. Multi-factorial, intensified treatment did not influence self-rated health status, treatment satisfaction, and distress in screen-detected type 2 diabetes patients. Therefore, health care professionals do not have to fear negative effects of an intensified treatment on these psychological outcomes.
Discovering intermediate entities from two examples by using web search engine indices

We propose a system for finding intermediate entities from two examples by using web search engine indices. For example, a user wants to find recipients of the Nobel Peace Prize in the thirty years between Mother Teresa in 1979 and Barack Obama in 2009. In this example, the answer is, for example, Kofi Atta Annan. In this situation, the user wants to find something intermediate between two entities. We first describe the problem of finding entities between two examples. We then propose a system for extracting intermediate entities between two inputs by using a Web search engine indices. The system focuses on the positions of terms in Web pages and then extracts candidate terms that are likely to appear between the two inputs. Then, our system ranks candidate terms based on term frequencies and positions. Finally, we conducted experiments to show the usefulness of our system.
Improving lesion localisation at colonoscopy: an analysis of influencing factors

Colonoscopy detects colorectal cancer and determines lesion localisation that influences surgical planning. However, published work suggests that the accuracy of lesion localisation can be low as 60 %, with implications for both the surgeon and the patient. This work aims to identify potential influencing factors at colonoscopy that could lead to improved lesion localisation accuracy. A multi-centred, prospective, observational study was performed that identified patients who were undergoing planned curative resection for a colorectal lesion. Localisation of a lesion at colonoscopy was compared to the intra-operative lesion localisation to determine accuracy of colonoscopic localisation. Patient factors and colonoscopic factors were recorded to determine any influencing factors on lesion localisation at colonoscopy. One hundred and eleven patients were analysed: mean age 67.4 years (range 27–89); male:female ratio 1.3:1; symptomatic referrals (n = 78, 70.3 %); and previous abdominal surgery in 27 patients (24.3 %). Complete colonoscopy was recorded in 78 patients (70.3 %). In 88 patients (79.3 %), colonoscopic lesion localisation matched the intra-operative location. Pre-operative CT imaging was unable to identify the tumour in 24 cases (21.8 %). Potential influencing patient and colonoscopic factors on accurate lesion localisation at colonoscopy found complete colonoscopy to be the only significant factor (p = 0.008). Colonoscopic lesion localisation was found to be inaccurate in 79.3 % cases, and with pre-operative CT unable to detect all lesions, this study confirms that accurate lesion localisation in the modern era is increasingly reliant on colonoscopy. Incomplete colonoscopy was the only significant factor that influenced inaccurate lesion localisation at colonoscopy.
Jejunal Infusion of Levodopa–Carbidopa Intestinal Gel Versus Oral Administration of Levodopa–Carbidopa Tablets in Japanese Subjects with Advanced Parkinson’s Disease: Pharmacokinetics and Pilot Efficacy and Safety

Oral levodopa-carbidopa (LC-oral) treatment in advanced Parkinson's disease (PD) is associated with motor complications due to large fluctuations in levodopa plasma concentrations. Levodopa-carbidopa intestinal gel (LCIG) provides individualized continuous levodopa-carbidopa delivery through intrajejunal infusion. This study evaluated the pharmacokinetics, safety, and efficacy of LCIG relative to LC-oral in Japanese subjects with advanced PD.



Subjects with advanced PD were converted from their anti-PD medications to individually optimized doses of LC-oral (10:1 levodopa:carbidopa ratio) for 28 days (baseline; period 1) followed by switching to intrajejunal infusion of LCIG (4:1 ratio) for 21 days (period 2). Pharmacokinetics, adverse events (AEs), and efficacy were assessed.



Eight patients were enrolled. Six received LCIG and four reported at least one AE [most common: fall (33.3 %), dyskinesia (33.3 %)]; one discontinued due to an AE. The average daily dose was 1230/123 and 1370/342 mg levodopa/carbidopa for LC-oral and LCIG, respectively, at the end of each period. The degree of fluctuation and intra-subject variability of levodopa plasma concentrations were 5.5- and 4-fold lower, respectively, with LCIG than with LC-oral. Levodopa bioavailability was 99 % for LCIG relative to LC-oral. Compared with baseline, LCIG decreased "Off" time (2.68 h, P = 0.002) and increased "On" time without troublesome dyskinesia (2.35 h, P = 0.006) in the PD Diary(©). With the small sample size, no statistically significant changes were seen on other efficacy endpoints.



In Japanese subjects with advanced PD, LCIG resulted in an improved pharmacokinetic profile that appeared to be associated with reduced motor complications compared with LC-oral. These results extend previous findings in mainly Caucasian populations.
Clinical Implementations of Preoperative Computed Tomography Lymphography in Gastric Cancer: A Comparison with Dual Tracer Methods in Sentinel Node Navigation Surgery

Current sentinel node (SN) detection techniques require a learning period and tracers have many disadvantages for practical use. The purpose of this study was to evaluate the feasibility of preoperative computed tomography (CT) lymphography using lipiodol for detecting SNs in gastric cancer. A total of 24 patients who underwent laparoscopic surgery for early gastric cancer were enrolled in this study. Noncontrast CT images were obtained 1–2 h after endoscopic submucosal peritumoral injection of 1 mL of lipiodol the day before surgery. The final sentinel basins (SBs) were decided by the dual tracer method (indocyanine green plus 99mTc-antimony sulfur colloid) during laparoscopic gastrectomy. SN detection rate by preoperative CT lymphography using lipiodol and agreement between CT lymphography versus dual tracer method were evaluated. The agreement was confirmed with soft X-ray radiography of detected SBs. Technical failure of endoscopic lipiodol injection occurred in one patient. SNs were successfully detected in the remaining 23 patients (95.8 %), whereas the intraoperative SB detection rate using the dual method was 100 %. The agreement rate, defined as the concordance between two methods or inclusion of SNs detected by CT lymphography in SBs by the dual tracer method, was 87 %. Our initial experience of CT lymphography using lipiodol shows good potential in predicting SBs of gastric cancer preoperatively. However, SN detection by CT lymphography and the dual method should be applied complementarily in gastric cancer because discrepancies between these methods occur.
Reconstruction of full-thickness buccal defects with folded radial forearm flaps

Our goal was to describe our experience of the folded radial forearm flap (RFF) flap in through-and-through buccal defect reconstructions.Patients who had received a folded RFF flap for full-thickness cheek defect reconstruction were included. The flap success rate and functional results were evaluated.Six patients were enrolled. All flaps survived totally without any complication; the mean flap size was 75.5 (range 32-135) cm. The mean mouth-open width was 4.2 (range 3.5-4.7) cm at 6 months after operation. All patients were satisfied with the appearance and were capable of maintaining a regular oral diet, and no patients complained of an inability to eat in a public setting, microstomia, or drooling.Radial forearm flap was a reliable method for through-and-through buccal reconstruction with high success rate and good functional result.
[Long-term results of lung cancer surgery in octogenarians].

This retrospective study was undertaken to evaluate late results of lung cancer surgery in octogenerians.



All patients 80years old or more who underwent a lung resection for cancer from 2000 to 2010 at Lyon University Hospital were included. No patients were treated with video-assisted surgery. Wedge resections were excluded.



Sixty-three patients (42 men, 21 women) were operated. The median age was 82years. Operative mortality was 4.7%. The rate of perioperative complications was 49%. The late survival was 34% at 5years. Five-year survival by nodal involvement was N0, 36%; N1, 29%; N2 20%, P<0.05. Patients with a squamous cell carcinoma (24) had a better long-term survival than patients with an adenocarcinoma (30), 33% and 25% respectively at 5years, P<0.05. The rate of recurrence was 33.9%.



Surgical treatment of lung cancer in selected population of octogenerians is associated with satisfactory early and long-term results. Survival is influenced by nodal involvement and by the pathologic type of the cancer.
Antiretroviral regimens in pregnancy and breast-feeding in Botswana.

The most effective highly active antiretroviral therapy (HAART) to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) in pregnancy and its efficacy during breast-feeding are unknown.



We randomly assigned 560 HIV-1-infected pregnant women (CD4+ count, > or = 200 cells per cubic millimeter) to receive coformulated abacavir, zidovudine, and lamivudine (the nucleoside reverse-transcriptase inhibitor [NRTI] group) or lopinavir-ritonavir plus zidovudine-lamivudine (the protease-inhibitor group) from 26 to 34 weeks' gestation through planned weaning by 6 months post partum. A total of 170 women with CD4+ counts of less than 200 cells per cubic millimeter received nevirapine plus zidovudine-lamivudine (the observational group). Infants received single-dose nevirapine and 4 weeks of zidovudine.



The rate of virologic suppression to less than 400 copies per milliliter was high and did not differ significantly among the three groups at delivery (96% in the NRTI group, 93% in the protease-inhibitor group, and 94% in the observational group) or throughout the breast-feeding period (92% in the NRTI group, 93% in the protease-inhibitor group, and 95% in the observational group). By 6 months of age, 8 of 709 live-born infants (1.1%) were infected (95% confidence interval [CI], 0.5 to 2.2): 6 were infected in utero (4 in the NRTI group, 1 in the protease-inhibitor group, and 1 in the observational group), and 2 were infected during the breast-feeding period (in the NRTI group). Treatment-limiting adverse events occurred in 2% of women in the NRTI group, 2% of women in the protease-inhibitor group, and 11% of women in the observational group.



All regimens of HAART from pregnancy through 6 months post partum resulted in high rates of virologic suppression, with an overall rate of mother-to-child transmission of 1.1%.
Coadministration of ritonavir strongly enhances the apparent oral bioavailability of docetaxel in patients with solid tumors.

To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer.



A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel.



The area under the plasma concentration-time curve in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 +/- 1.5 and 2.8 +/- 1.4 mg/h/L, respectively, compared with 1.9 +/- 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% +/- 90% and 161% +/- 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated.



Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.
A hierarchical model for BGP routing policies

BGP routing policies are mainly used by network operators to enforce business relationships between Autonomous Systems (AS), and to prefer some routes over others. In this paper, we propose a hierarchical policy model to express each policy at the most appropriate level of abstraction. The model is structured around chains of filters that apply at a specific level of abstraction. To validate our approach, we implemented the model in a Java prototype and used it to reproduce several network-wide routing policies. In all studied networks, the model produced a high-level view of routing policies while preserving their semantics. Our model offers numerous advantages to network operators including, but not limited to, a better network documentation, an improved understanding of routing policies, redundancy suppression, and an easier way of managing their network.
Point of care troponin decreases time in the emergency department for patients with possible acute coronary syndrome: a randomised controlled trial.

To determine the effect of cardiac troponin I testing with a point-of-care (POC) device versus central laboratory on length of stay (LOS) in emergency department (ED) patients presenting with possible acute coronary syndromes (ACS).



A 12-week randomised controlled trial at two metropolitan ED in eastern Australia with a combined annual census of 80,000. Participants were all patients presenting with possible ACS. Exclusions were a diagnosis of ACS before arrival, ST elevation and failure to wait for complete assessment. Randomisation was by week when POC was made available. Primary outcome was LOS from patient arrival to physical departure from the ED. The proportion of patients meeting a government target of less than 8 h stay was compared. Analysis was by intention to treat.



Despite underutilisation of POC, LOS was shorter during weeks when it was available. The time savings translates into approximately 48 minutes (95% CI 12 to 84) per average LOS of almost 7 h, which did not reach statistical significance (p=0.063), or an absolute increase of 10% (95% CI 4.3 to 16.6) in the number of people discharged from the ED within the target LOS of less than 8 h, which did reach significance (p=0.007). These savings were more pronounced in the setting without 24 h central laboratory availability.



POC testing for troponin in the ED tended to reduce the LOS for possible ACS patients. The degree of this benefit is likely to be markedly dependent on its acceptance and uptake by attending personnel, and on the ED setting in which it is used.
Multiple levels of regulation of the interleukin-6 system in stroke.

Serum levels of the cytokine interleukin-6 (IL-6) rise markedly in stroke. IL-6 is a key regulator of inflammatory mechanisms that play an important part in stroke pathophysiology. The action of IL-6 is modified by its soluble receptor subunits sgp130 and sIL-6R. The purpose of this study was to investigate whether serum levels of the receptor subunits are changed after ischemic stroke and to define the role of genetic influences on IL-6 expression in acute stroke.



In 48 patients with acute stroke and 48 age- and sex-matched control subjects, serum concentrations of IL-6, sgp130, and sIL-6R were measured by enzyme-linked immunosorbent assay. Furthermore, IL-6 promoter haplotypes comprising 4 different polymorphisms (-597G-->A, -572G-->C, -373A(n)T(n), -174G-->C) were determined by DNA sequencing and allele-specific oligonucleotide polymerase chain reaction. The effect of the common haplotypes on IL-6 gene transcription was tested by transfecting reporter fusion genes in the astrocytelike cell line U373.



Whereas serum concentrations of IL-6 significantly rose (P<0.001), sgp130 levels were transiently reduced after stroke (P<0.05), and sIL-6R levels remained unchanged. IL-6 levels depended on the infarct size and the haplotype of the promoter region. The common haplotype A-G-8/12-C was associated with low IL-6 levels after stroke and a reduced induction of IL-6 transcription on stimulation with an adenosine analog in vitro.



The data demonstrate genetic variation in the expression of IL-6 in stroke. Induction of the inflammatory response by IL-6 might be enhanced by a transient downregulation of the potential IL-6 antagonist sgp130.
Ankle Brachial Index Values, Leg Symptoms, and Functional Performance Among Community‐Dwelling Older Men and Women in the Lifestyle Interventions and Independence for Elders Study

The prevalence and significance of low normal and abnormal ankle brachial index (ABI) values in a community-dwelling population of sedentary, older individuals is unknown. We describe the prevalence of categories of definite peripheral artery disease (PAD), borderline ABI, low normal ABI, and no PAD and their association with lower-extremity functional performance in the LIFE Study population.



Participants age 70 to 89 in the LIFE Study underwent baseline measurement of the ABI, 400-m walk, and 4-m walking velocity. Participants were classified as follows: definite PAD (ABI <0.90), borderline PAD (ABI 0.90 to 0.99), low normal ABI (ABI 1.00 to 1.09), and no PAD (ABI 1.10 to 1.40). Of 1566 participants, 220 (14%) had definite PAD, 250 (16%) had borderline PAD, 509 (33%) had low normal ABI, and 587 (37%) had no PAD. Among those with definite PAD, 65% were asymptomatic. Adjusting for age, sex, race, body mass index, smoking, and comorbidities, lower ABI was associated with longer mean 400-m walk time: (definite PAD=533 seconds; borderline PAD=514 seconds; low normal ABI=503 seconds; and no PAD=498 seconds [P<0.001]). Among asymptomatic participants with and without PAD, lower ABI values were also associated with longer 400-m walk time (P<0.001) and slower walking velocity (P=0.042).



Among older community-dwelling men and women, 14% had PAD and 49% had borderline or low normal ABI values. Lower ABI values were associated with greater functional impairment, suggesting that lower extremity atherosclerosis may be a common preventable cause of functional limitations in older people.