nils-herrmann/clean_scirepeval huggingface dataset:
A population pharmacokinetic model of valproic acid in pediatric patients with epilepsy: a non-linear pharmacokinetic model based on protein-binding saturation.

Valproic acid (VPA) follows a non-linear pharmacokinetic profile in terms of protein-binding saturation. The total daily dose regarding VPA clearance is a simple power function, which may partially explain the non-linearity of the pharmacokinetic profile; however, it may be confounded by the therapeutic drug monitoring effect. The aim of this study was to develop a population pharmacokinetic model for VPA based on protein-binding saturation in pediatric patients with epilepsy.



A total of 1,107 VPA serum trough concentrations at steady state were collected from 902 epileptic pediatric patients aged from 3 weeks to 14 years at three hospitals. The population pharmacokinetic model was developed using NONMEM(®) software. The ability of three candidate models (the simple power exponent model, the dose-dependent maximum effect [DDE] model, and the protein-binding model) to describe the non-linear pharmacokinetic profile of VPA was investigated, and potential covariates were screened using a stepwise approach. Bootstrap, normalized prediction distribution errors and external evaluations from two independent studies were performed to determine the stability and predictive performance of the candidate models.



The age-dependent exponent model described the effects of body weight and age on the clearance well. Co-medication with carbamazepine was identified as a significant covariate. The DDE model best fitted the aim of this study, although there were no obvious differences in the predictive performances. The condition number was less than 500, and the precision of the parameter estimates was less than 30 %, indicating stability and validity of the final model.



The DDE model successfully described the non-linear pharmacokinetics of VPA. Furthermore, the proposed population pharmacokinetic model of VPA can be used to design rational dosage regimens to achieve desirable serum concentrations.
Estimating peak oxygen uptake in adolescents with cystic fibrosis.

To predict peak oxygen uptake (VO2 peak) from the peak work rate (W peak) obtained during a cycle ergometry test using the Godfrey protocol in adolescents with cystic fibrosis (CF), and assess the accuracy of the model for prognostication clustering.



Out of our database of anthropometric, spirometric and maximal exercise data from adolescents with CF (N=363; 140 girls and 223 boys; age 14.77 ± 1.73 years; mean expiratory volume in 1 s (FEV1%pred) 86.82 ± 17.77%), a regression equation was developed to predict VO2 peak (mL/min). Afterwards, this prediction model was validated with cardiopulmonary exercise data from another 60 adolescents with CF (28 girls, 32 boys; mean age 14.6 ± 1.67 years; mean FEV1%pred 85.43 ± 20.01%).



We developed a regression model VO2 peak (mL/min)=216.3-138.7 × sex (0=male; 1=female)+11.5 × W peak; R(2)=0.91; SE of the estimate (SEE) 172.57. A statistically significant difference (107 mL/min; p<0.001) was found between predicted VO2 peak and measured VO2 peak in the validation group. However, this difference was not clinically relevant because the difference was within the SEE of the model. Furthermore, we found high positive predictive and negative predictive values for the model for prognostication clustering (PPV 50-87% vs NPV 82-94%).



In the absence of direct VO2 peak assessment it is possible to estimate VO2 peak in adolescents with CF using only a cycle ergometer. Furthermore, the regression model showed to be able to discriminate patients in different prognosis clusters based on exercise capacity.
Effects of ACE inhibitors on cardiac angiotensin II and aldosterone in humans: "Relevance of lipophilicity and affinity for ACE".

Angiotensin-converting enzyme (ACE) inhibitors differ in their lipophilic/hydrophilic index that determines their tissue bioavailability and affinity to ACE, which may result in major differences in the degree of blockade of cardiac ACE. We evaluated the hypothesis that in patients with chronic heart failure (CHF) and activated cardiac renin-angiotensin-aldosterone system (RAAS), lipophilic ACE inhibitors with high affinity for ACE (perindopril and quinapril) will cause marked blockade of cardiac angiotensin (Ang) II and aldosterone generation, but not a hydrophilic ACE inhibitor with low affinity for ACE (lisinopril).



Patients were randomized to receive perindopril (8 mg/day), quinapril (40 mg/day), or lisinopril (20 mg/day) for 3-4 weeks before cardiac catheterization. The coronary sinus-aortic root gradients for Ang I and II, and aldosterone were determined.



A total of 19 patients completed the study. Compared to a healthy control group, all three ACE inhibitors decreased circulating Ang II and aldosterone to a similar extent. There were only minor differences between the three ACE inhibitors for the Ang II gradient between the coronary sinus and aortic root. The gradient for aldosterone tended to be positive in the quinapril group and absent/negative in the lisinopril and perindopril groups. Despite the lowest pulmonary capillary wedge pressure (PCWP), gradients between the coronary sinus and aortic root for Ang II and aldosterone were actually the highest in the quinapril group.



These findings do not support the concept that a hydrophilic ACE inhibitor is less effective in blocking the cardiac RAAS as compared to lipophilic ACE inhibitors.
Coiling of very large and giant basilar tip aneurysms: midterm clinical and angiographic results.

The purpose of this study was to report the midterm clinical and angiographic results of coiling of very large (>15 mm) and giant basilar tip aneurysms.



Between January 1995 and October 2005, 44 very large and giant basilar tip aneurysms in 44 patients were coiled. There were 13 men (30%) and 31 women (70%) with a mean age of 51.4 years (median, 51 years; range, 34-72 years). Mean aneurysm size was 19.6 mm (range, 15-30 mm). Of 44 aneurysms, 33 (75%) had ruptured. Of 11 unruptured basilar tip aneurysms, 7 were incidentally discovered, 1 was additional to another ruptured aneurysm, and 3 were symptomatic by mass effect.



Procedural mortality was 2/44 (4.6%, 95% confidence interval (CI), 0.4%-16%) and morbidity 1/44 (2.3%, 95% CI, 0.01%-13%). Of 33 patients with ruptured aneurysms, mean clinical follow-up was 5.2 years (range, 0.5-11.5 years). Two patients had a rebleeding from the coiled basilar tip aneurysm leading to death in 1 patient and to dependency in the other patient (annual rebleeding rate, 1.1%) One other patient died 2 years later of progressive brain stem compression. Mean angiographic follow-up in 41 of 42 surviving patients was 3.1 years. Nineteen aneurysms reopened and were coiled for a second time. Of these, 9 repeatedly reopened with time and were repeatedly coiled up to 6 times. Additional treatments were without complications.



Coiling of very large and giant basilar tip aneurysms is associated with reasonably low morbidity. Although additional treatment during follow-up is frequently necessary, rebleeding is uncommon.
Discovering Excitatory Networks from Discrete Event Streams with Applications to Neuronal Spike Train Analysis

Mining temporal network models from discrete event streams is an important problem with applications in computational neuroscience, physical plant diagnostics, and human-computer interaction modeling. We focus in this paper on temporal models representable as excitatory networks where all connections are stimulative, rather than inhibitory. Through this emphasis on excitatory networks, we show how they can be learned by creating bridges to frequent episode mining. Specifically, we show that frequent episodes help identify nodes with high mutual information relationships and which can be summarized into a dynamic Bayesian network (DBN). To demonstrate the practical feasibility of our approach, we show how excitatory networks can be inferred from both mathematical models of spiking neurons as well as real neuroscience datasets.
FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.

In metastatic colorectal cancer, phase III studies have demonstrated the superiority of fluorouracil (FU) with leucovorin (LV) in combination with irinotecan or oxaliplatin over FU + LV alone. This phase III study investigated two sequences: folinic acid, FU, and irinotecan (FOLFIRI) followed by folinic acid, FU, and oxaliplatin (FOLFOX6; arm A), and FOLFOX6 followed by FOLFIRI (arm B).



Previously untreated patients with assessable disease were randomly assigned to receive a 2-hour infusion of l-LV 200 mg/m(2) or dl-LV 400 mg/m(2) followed by a FU bolus 400 mg/m(2) and 46-hour infusion 2,400 to 3,000 mg/m(2) every 46 hours every 2 weeks, either with irinotecan 180 mg/m(2) or with oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 1. At progression, irinotecan was replaced by oxaliplatin (arm A), or oxaliplatin by irinotecan (arm B).



Median survival was 21.5 months in 109 patients allocated to FOLFIRI then FOLFOX6 versus 20.6 months in 111 patients allocated to FOLFOX6 then FOLFIRI (P =.99). Median second progression-free survival (PFS) was 14.2 months in arm A versus 10.9 in arm B (P =.64). In first-line therapy, FOLFIRI achieved 56% response rate (RR) and 8.5 months median PFS, versus FOLFOX6 which achieved 54% RR and 8.0 months median PFS (P =.26). Second-line FOLFIRI achieved 4% RR and 2.5 months median PFS, versus FOLFOX6 which achieved 15% RR and 4.2 months PFS. In first-line therapy, National Cancer Institute Common Toxicity Criteria grade 3/4 mucositis, nausea/vomiting, and grade 2 alopecia were more frequent with FOLFIRI, and grade 3/4 neutropenia and neurosensory toxicity were more frequent with FOLFOX6.



Both sequences achieved a prolonged survival and similar efficacy. The toxicity profiles were different.
Improving lookup latency in distributed hash table systems using random sampling

Distributed hash table (DHT) systems are an important class of peer-to-peer routing infrastructures. They enable scalable wide-area storage and retrieval of information, and will support the rapid development of a wide variety of Internet-scale applications ranging from naming systems and file systems to application-layer multicast. DHT systems essentially build an overlay network, but a path on the overlay between any two nodes can be significantly different from the unicast path between those two nodes on the underlying network. As such, the lookup latency in these systems can be quite high and can adversely impact the performance of applications built on top of such systems.In this paper, we discuss a random sampling technique that incrementally improves lookup latency in DHT systems. Our sampling can be implemented using information gleaned from lookups traversing the overlay network. For this reason, we call our approach lookup-parasitic random sampling (LPRS). LPRS converges quickly, and requires relatively few modifications to existing DHT systems.For idealized versions of DHT systems like Chord, Tapestry, and Pastry, we analytically prove that LPRS can result in lookup latencies proportional to the average unicast latency of the network, provided the underlying physical topology has a power-law latency expansion. We then validate this analysis by implementing LPRS in the Chord simulator. Our simulations reveal that LPRS-Chord exhibits a qualitatively better latency scaling behavior relative to unmodified Chord. The overhead of LPRS is one sample per lookup hop in the worst case.Finally, we provide evidence which suggests that the Internet router-level topology resembles power-law latency expansion. This finding implies that LPRS has significant practical applicability as a general latency reduction technique for many DHT systems. This finding is also of independent interest since it might inform the design of latency-sensitive topology models for the Internet.
The Effects of Highly Challenging Balance Training in Elderly With Parkinson’s Disease

Highly challenging exercises have been suggested to induce neuroplasticity in individuals with Parkinson's disease (PD); however, its effect on clinical outcomes remains largely unknown.



To evaluate the short-term effects of the HiBalance program, a highly challenging balance-training regimen that incorporates both dual-tasking and PD-specific balance components, compared with usual care in elderly with mild to moderate PD.



Participants with PD (n = 100) were randomized, either to the 10-week HiBalance program (n = 51) or to the control group (n = 49). Participants were evaluated before and after the intervention. The main outcomes were balance performance (Mini-BESTest), gait velocity (during normal and dual-task gait), and concerns about falling (Falls Efficacy Scale-International). Performance of a cognitive task while walking, physical activity level (average steps per day), and activities of daily living were secondary outcomes.



A total of 91 participants completed the study. After the intervention, the between group comparison showed significantly improved balance and gait performance in the training group. Moreover, although no significant between group difference was observed regarding gait performance during dual-tasking; the participants in the training group improved their performance of the cognitive task while walking, as compared with the control group. Regarding physical activity levels and activities of daily living, in comparison to the control group, favorable results were found for the training group. No group differences were found for concerns about falling.



The HiBalance program significantly benefited balance and gait abilities when compared with usual care and showed promising transfer effects to everyday living. Long-term follow-up assessments will further explore these effects.
A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction.



We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤ 35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak Vo₂ (pVo₂), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months. The primary safety end point was a test of noninferiority between groups at 12 months for the composite of all-cause mortality and hospitalizations (12.5% allowable delta).



The groups were comparable for age (58 ± 13 vs 59 ± 12 years), EF (26% ± 7% vs 26% ± 7%), pVo₂ (14.7 ± 2.9 vs 14.8 ± 3.2 mL kg⁻¹ min⁻¹), and other characteristics. While VAT did not improve at 6 months, CCM significantly improved pVo₂ and MLWHFQ (by 0.65 mL kg⁻¹ min⁻¹ [P = .024] and -9.7 points [P < .0001], respectively) over OMT. Forty-eight percent of OMT and 52% of CCM patients experienced a safety end point, which satisfied the noniferiority criterion (P = .03). Post hoc, hypothesis-generating analysis identified a subgroup (characterized by baseline EF ≥ 25% and New York Heart Association class III symptoms) in which all parameters were improved by CCM.



In the overall target population, CCM did not improve VAT (the primary end point) but did improve pVo₂ and MLWHFQ. Cardiac contractility modulation did not have an adverse affect on hospitalizations or mortality within the prespecified boundaries. Further study is required to clarify the role of CCM as a treatment for medically refractory heart failure.
Radioiodine therapy accelerates apoptosis in peripheral blood lymphocytes of patients with differentiated thyroid cancer.

Both apoptosis and micronuclei formation reflect cytogenetic damage in cells and could contribute to cell homeostasis. The aim of this study was to evaluate apoptosis in peripheral blood lymphocytes (PBLs) of patients with differentiated thyroid cancer (DTC) before and after 131-iodine (131-I)-therapy and its correlation with micronuclei (MN) frequency. The study population included 18 DTC patients and 18 healthy donors. Apoptotic cells were detected using the Annexin V-FITC/7-AAD kit and MN frequency by cytokinesis-block MN assay. The difference between early apoptosis in PBLs of DTC patients before therapy and controls (9.88 ± 4.99% vs. 6.64 ± 2.07%, p = 0.003) was significant, as well as between early apoptosis in PBLs of DTC patients before and after 131-I-therapy (9.88 ± 4.99% vs. 13.53 ± 6.57%, p = 0.008). The MN frequency and early apoptosis in PBLs of DTC patients was positively correlated before (r = 0.540, p= 0.021) and after 131-I-therapy (r = 0.585, p= 0.014). Thyroid cancer patients had a significantly increased early apoptosis in PBLs, which further increased after 131-I-therapy in association with MN frequency.
Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes.

To evaluate the efficacy and safety of empagliflozin/linagliptin in subjects with type 2 diabetes.



Subjects not receiving antidiabetes therapy for ≥12 weeks were randomized to empagliflozin 25 mg/linagliptin 5 mg (n = 137), empagliflozin 10 mg/linagliptin 5 mg (n = 136), empagliflozin 25 mg (n = 135), empagliflozin 10 mg (n = 134), or linagliptin 5 mg (n = 135) for 52 weeks. The primary end point was change from baseline in HbA1c at week 24.



Mean HbA1c at baseline was 7.99-8.05% (64 mmol/mol). At week 24, adjusted mean (SE) changes from baseline in HbA1c with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg were -1.08 (0.06)% (-11.8 [0.7] mmol/mol), -1.24 (0.06)% (-13.6 [0.7] mmol/mol), -0.95 (0.06)% (-10.4 [0.7] mmol/mol), -0.83 (0.06)% (-9.1 [0.7] mmol/mol), and -0.67 (0.06)% (-7.3 [0.7] mmol/mol), respectively. Reductions in HbA1c were significantly greater for empagliflozin 25 mg/linagliptin 5 mg compared with linagliptin 5 mg (P < 0.001) but not compared with empagliflozin 25 mg and were significantly greater for empagliflozin 10 mg/linagliptin 5 mg compared with the individual components (P < 0.001 for both). At week 24, 55.4%, 62.3%, 41.5%, 38.8%, and 32.3% of subjects with baseline HbA1c ≥7% (≥53 mmol/mol) reached HbA1c <7% with empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg, respectively. Efficacy was maintained at week 52. The proportion of subjects with adverse events (AEs) over 52 weeks was similar across groups (68.9-81.5%), with no confirmed hypoglycemic AEs.



Reductions from baseline in HbA1c with empagliflozin/linagliptin were significantly different versus linagliptin and empagliflozin 10 mg but not versus empagliflozin 25 mg. Empagliflozin/linagliptin was well tolerated.
Comparison of the effects of metoprolol or carvedilol on serum gamma-glutamyltransferase and uric acid levels among patients with acute coronary syndrome without ST segment elevation

Serum gamma-glutamyltransferase (GGT) and uric acid levels measured in patients with acute coronary syndrome without ST segment elevation (NSTEMI) are important in diagnosis and in predicting the prognosis of the disease. There is a limited number of clinical studies investigating the effects of beta-blockers on GGT and uric acid levels in these patients. In our study, we aimed to investigate the effects of beta-blocker therapy on GGT and uric acid levels.



We conducted a randomized, prospective clinical study. Hundred patients with NSTEMI were included in this study, and they were divided into two groups. Fifty patients were administered metoprolol succinate treatment (1 x 50 mg), whereas the remaining 50 patients were administered carvedilol treatment (2 x 12.5 mg). Thereafter, all of the patients underwent coronary angiography. Blood samples were taken at the time of admission, at the 1st month, and 3rd month to detect GGT and uric acid levels.



There was no statistically significant difference among the metoprolol or carvedilol groups in terms of the GGT levels measured at the baseline, 1st month, and 3rd month (p=0.904 and p=0.573, respectively). In addition, there was no statistically significant difference among the metoprolol or carvedilol groups in terms of uric acid levels measured at the baseline, 1st month, and 3rd month (p=0.601 and p=0.601, respectively).



We found that GGT and uric acid levels did not show any change compared to the baseline values, with metoprolol and carvedilol treatment initiated in the early period in patients with NSTEMI.
Impact of a novel, extended approach of perineal radical prostatectomy on surgical margins in localized prostate cancer.

Therapy (case series) 
To validate the rationale of extended perineal radical prostatectomy (ePRP) for treating localized prostate cancer.



Between December 2000 and May 2007, 196 patients with localized prostate cancer underwent PRP, among which 91 and 105 patients were treated with conventional PRP (cPRP) and ePRP, respectively. The apex, middle, base, and anterior regions of the prostate were separately analysed, and the focus of analysis was on the distribution, size, Gleason score, and positive surgical margins (PSMs) of prostate cancer foci.



The operation time was significantly shorter in ePRP compared with cPRP (161 min vs 188 min; P= 0.001), while there was no significant difference in estimated blood loss between cPRP and ePRP (550 mL vs 500 mL). At the apex and base, there was no significant difference in the PSM rate between cPRP and ePRP. In the middle, there was a lower incidence of PSMs in ePRP (2.4%) than in cPRP (10.9%; P= 0.009). On the anterior side, PSMs were more frequent in cPRP (21.6%) than in ePRP (7.1%; P= 0.029). Logistic regression analysis adjusted by PSA level showed that PSM rate was the most significantly affected by the surgical approach.



We think that ePRP provides an effective treatment strategy for localized prostate cancer in light of excellent cancer control and minimum potential of surgical invasiveness.