nils-herrmann/clean_scirepeval huggingface dataset:
Author’s Reply to Srinivas: “Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection”

is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn’s disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic–pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis.  Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship.  Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib.  Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.
Two years' effectiveness of intravenous pamidronate (APD) versus oral fluoride for osteoporosis occurring in the postmenopause

Bisphosphonates seem to be effective as antiresorptive agents in the prevention and treatment of osteoporosis. However, the optimal dose and route of administration as well as the specific effects on cortical or trabecular bone have not been clarified. To compare pamidronate (APD) with fluoride (F) in the therapy of postmenopausal osteoporosis, 32 osteoporotic women were treated for 2 years either with APD (30 mg as a single intravenous infusion over 1 h every 3 months,n=16, mean age 65 years) or with fluoride orally (20–30 mg F/day,n=16, mean age 67 years) in an open study. Both groups received 1 g calcium and 1000 U vitamin D per day, but no estrogens or other drugs acting on bone. Both groups showed the same initial mean number of fractures per patient (2.8 and 2.7). Bone densitometry was performed every 6 months at three sites: lumbar spine and hip with dual-energy X-ray absorptiometry (BMD), distal forearm with single photon absorptiometry and lumbar spine with quantitative computed tomography. Biochemical assessment was performed in blood and urine every 3 months. Lumbar BMD (g/cm2, mean±SEM) increased from 0.632 (±0.030) at time 0 to 0.696 (±0.028) at 24 months in the APD group (p<0.001), and from 0.684 (±0.025) to 0.769 (±0.028) in the fluoride group (p<0.001). Femoral neck BMD increased significantly from 0.558 (±0.025) to 0.585 (±0.025) (p<0.01) in the APD group, whereas it did not change in the fluoride group. Forearm SPA (g/cm) increased from 0.90 (±0.08) to 0.97 (±0.10) (p<0.01) in the APD group, whereas it decreased from 0.94±(0.06) to 0.90 (±0.06) (p<0.05) in the fluoride group. Plasma calcium, parathormone and creatinine did not change in any group. Urinary hydroxyproline/creatinine, serum osteocalcin and alkaline phosphatase decreased significantly with APD, but did not change with fluoride, except for an increase in osteocalcin. Two new vertebral fractures occurred with APD and 6 with fluoride, plus 1 hip fracture. Side effects were a transient fever with flu-like symptoms in 5 patients after the first infusion of APD, rigors and mild phlebitis in 1 patient. Fluoride was associated with 5 transient arthralgias and 4 mild gastric intolerances, and treatment was interrupted in 2 patients with distal stress fractures. While fluoride increased only lumbar BMD, intermittent intravenous APD increased lumbar, hip and radial BMD in postmenopausal osteoporosis and was well tolerated.
Effect of postural insoles on static and functional balance in children
with cerebral palsy: A randomized controlled study

Improved gait efficiency is one of the goals of therapy for children with cerebral palsy (CP). Postural insoles can allow more efficient gait by improving biomechanical alignment.



The aim of the present study was to determine the effect of the combination of postural insoles and ankle-foot orthoses on static and functional balance in children with CP.



A randomized, controlled, double-blind, clinical trial. After meeting legal requirements and the eligibility criteria, 20 children between four and 12 years of age were randomly allocated either to the control group (CG) (n=10) or the experimental group (EG) (n=10). The CG used placebo insoles and the EG used postural insoles. The Berg Balance Scale, Timed Up-and-Go Test, Six-Minute Walk Test, and Gross Motor Function Measure-88 were used to assess balance as well as the determination of oscillations from the center of pressure in the anteroposterior and mediolateral directions with eyes open and closed. Three evaluations were carried out: 1) immediately following placement of the insoles; 2) after three months of insole use; and 3) one month after suspending insole use.



The EG achieved significantly better results in comparison to the CG on the Timed Up-and-Go Test as well as body sway in the anteroposterior and mediolateral directions.



Postural insoles led to an improvement in static balance among children with cerebral palsy, as demonstrated by the reduction in body sway in the anteroposterior and mediolateral directions. Postural insole use also led to a better performance on the Timed Up-and-Go Test.
Abnormal Brain Activity During a Reward and Loss Task in Opiate-Dependent Patients Receiving Methadone Maintenance Therapy

A core feature of human drug dependency is persistence in seeking and using drugs at the expense of other life goals. It has been hypothesized that addiction is associated with overvaluation of drug-related rewards and undervaluation of natural, nondrug-related rewards. Humans additionally tend to persist in using drugs despite adverse consequences. This suggests that the processing of both rewarding and aversive information may be abnormal in addictions. We used fMRI to examine neural responses to reward and loss events in opiate-dependent patients receiving methadone maintenance treatment (MMT, n=30) and healthy controls (n=23) using nondrug-related stimuli. Half of the patients were scanned after/before daily methadone intake (ADM/BDM patient groups). During reward trials, patients as a whole exhibited decreased neural discrimination between rewarding and nonrewarding outcomes in the dorsal caudate. Patients also showed reduced neural discrimination in the ventral striatum with regard to aversive and nonaversive outcomes and failed to encode successful loss avoidance as a reward signal in the ventral striatum. Patients also showed decreased insula activation during the anticipation/decision phase of loss events. ADM patients exhibited increased loss signals in the midbrain/parahippocampal gyrus, possibly related to a disinhibition of dopamine neurons. This study suggests that patients with opiate dependency on MMT exhibit abnormal brain activations to nondrug-related rewarding and loss events. Our findings add support to proposals that treatments for opiate addiction should aim to increase the reward value of nondrug-related rewarding events and highlight the importance of potential abnormalities in aversive information processing.
Current Integration of Tuberculosis (TB) and HIV Services in South Africa, 2011

Public Health Facilities in South Africa.



To assess the current integration of TB and HIV services in South Africa, 2011.



Cross-sectional study of 49 randomly selected health facilities in South Africa. Trained interviewers administered a standardized questionnaire to one staff member responsible for TB and HIV in each facility on aspects of TB/HIV policy, integration and recording and reporting. We calculated and compared descriptive statistics by province and facility type.



Of the 49 health facilities 35 (71%) provided isoniazid preventive therapy (IPT) and 35 (71%) offered antiretroviral therapy (ART). Among assessed sites in February 2011, 2,512 patients were newly diagnosed with HIV infection, of whom 1,913 (76%) were screened for TB symptoms, and 616 of 1,332 (46%) of those screened negative for TB were initiated on IPT. Of 1,072 patients newly registered with TB in February 2011, 144 (13%) were already on ART prior to Tb clinical diagnosis, and 451 (42%) were newly diagnosed with HIV infection. Of those, 84 (19%) were initiated on ART. Primary health clinics were less likely to offer ART compared to district hospitals or community health centers (p<0.001).



As of February 2011, integration of TB and HIV services is taking place in public medical facilities in South Africa. Among these services, IPT in people living with HIV and ART in TB patients are the least available.
Sequential Markov chain Monte Carlo filter with simultaneous model selection for electrocardiogram signal modeling

Constructing statistical models of electrocardiogram (ECG) signals, whose parameters can be used for automated disease classification, is of great importance in precluding manual annotation and providing prompt diagnosis of cardiac diseases. ECG signals consist of several segments with different morphologies (namely the P wave, QRS complex and the T wave) in a single heart beat, which can vary across individuals and diseases. Also, existing statistical ECG models exhibit a reliance upon obtaining a priori information from the ECG data by using preprocessing algorithms to initialize the filter parameters, or to define the user-specified model parameters. In this paper, we propose an ECG modeling technique using the sequential Markov chain Monte Carlo (SMCMC) filter that can perform simultaneous model selection, by adaptively choosing from different representations depending upon the nature of the data. Our results demonstrate the ability of the algorithm to track various types of ECG morphologies, including intermittently occurring ECG beats. In addition, we use the estimated model parameters as the feature set to classify between ECG signals with normal sinus rhythm and four different types of arrhythmia.
Influence of urate-lowering therapies on renal handling of uric acid

The purpose of this study is to investigate the effect of urate-lowering therapies (ULTs) on renal uric acid excretion in gout patients. This prospective observational study involved 106 primary gout patients and 51 healthy controls. Gout patients received ULT with either xanthine oxidase inhibitors or the uricosuric agent benzbromarone. Parameters such as 24-h urinary uric acid, creatinine clearance, uric acid clearance, glomerular filtration load of uric acid, fractional excretion of uric acid, excretion of uric acid per volume of glomerular filtration, and urinary uric acid to urinary creatinine ratio were used to evaluate the pre- and post-treatment renal capacity for uric acid clearance in gout patients and were compared with the values in the healthy controls. Compared to healthy controls, gout patients had higher glomerular filtration load of uric acid and lower uric acid clearance, creatinine clearance, and fractional uric acid excretion. After ULT, both the xanthine oxidase inhibitor group and benzbromarone group patients showed reduction in glomerular filtration load of uric acid. Creatinine clearance was significantly improved in the xanthine oxidase inhibitor group. Excretion function was remarkably enhanced in patients who reached the treatment target (serum uric acid <6 mg/dl). Changes in glomerular uric acid filtration load were significantly correlated with changes in serum urate levels. Gout patients have impaired renal uric acid excretion. ULTs reduce renal urate load and enhance the renal capacity of uric acid clearance. Xanthine oxidase inhibitors showed superiority over benzbromarone in improving renal function.
Automated electronic reminders to facilitate primary cardiovascular disease prevention: randomised controlled trial.

Primary care databases contain cardiovascular disease risk factor data, but practical tools are required to improve identification of at-risk patients.



To test the effects of a system of electronic reminders (the 'e-Nudge') on cardiovascular events and the adequacy of data for cardiovascular risk estimation.



Randomised controlled trial.



Nineteen general practices in the West Midlands, UK.



The e-Nudge identifies four groups of patients aged over 50 years on the basis of estimated cardiovascular risk and adequacy of risk factor data in general practice computers. Screen messages highlight individuals at raised risk and prompt users to complete risk profiles where necessary. The proportion of the study population in the four groups was measured, as well as the rate of cardiovascular events in each arm after 2 years.



Over 38 000 patients' electronic records were randomised. The intervention led to an increase in the proportion of patients with sufficient data who were identifiably at risk, with a difference of 1.94% compared to the control group (95% confidence interval [CI] = 1.38 to 2.50, P<0.001). A corresponding reduction occurred in the proportion potentially at risk but requiring further data for a risk estimation (difference = -3.68%, 95% CI = -4.53 to -2.84, P<0.001). No significant difference was observed in the incidence of cardiovascular events (rate ratio = 0.96, 95% CI = 0.85 to 1.10, P = 0.59).



Automated electronic reminders using routinely collected primary care data can improve the adequacy of cardiovascular risk factor information during everyday practice and increase the visibility of the at-risk population.
Burden of hospitalizations primarily due to uncontrolled diabetes: implications of inadequate primary health care in the United States.

This study describes the burden of potentially preventable hospitalizations primarily due to uncontrolled diabetes. Uncontrolled diabetes, if not managed properly, often leads to biochemical imbalances that can cause acute life-threatening events and hospitalizations. Since diabetes management relies heavily on ambulatory care, hospitalizations with uncontrolled diabetes largely reflect the quality of the primary health care provided outside the hospital setting. Therefore, the Agency for Healthcare Research and Quality (AHRQ) selected uncontrolled diabetes as a prevention quality indicator (PQI) where timely and appropriate ambulatory care would have prevented a hospitalization (1). To improve primary health care, it is essential to track an outcome of current status of prevention quality indicators. However, the extent of potentially preventable hospitalizations associated with uncontrolled diabetes and its economic burden in the U.S. remains under-investigated.
Comparison of clinical outcomes with the utilization of monitored anesthesia care vs. general anesthesia in patients undergoing transcatheter aortic valve replacement.

There is no clear consensus in regard to the optimal anesthesia utilization during transcatheter aortic valve replacement (TAVR). The aim was to compare outcomes of transfemoral (TF) TAVR under monitored anesthesia care (MAC) vs. general anesthesia (GA) and evaluate the rates and causes of intra-procedural MAC failure.



All consecutive patients who underwent TF TAVR from April 2007 through March 2015 were retrospectively analyzed and dichotomized into two groups: TAVR under MAC vs. GA. The main endpoints of the study included 30-day and 1-year mortality, the rates and reasons for failure of MAC, in-hospital clinical safety outcomes, and post-procedural hospital and intensive care unit length-of-stays.



A total of 533 patients (51% male, mean-age 83years) underwent TF TAVR under MAC (n=467) or GA (n=66). Fifty-six patients (12%) in the MAC group required conversion to GA. The MAC group had significantly shorter post-procedural hospital (6.0 vs. 7.9, p=0.023) and numerically shorter ICU (2.4 vs. 2.8, p=0.355) mean length-of-stays in days. The clinical safety outcomes were similar in both groups. Kaplan-Meier unadjusted cumulative in-hospital and 30-day mortality rates were higher in the GA group but similar in both groups at 1-year.



TF TAVR under MAC is feasible and safe, results in shorter hospital stays, can be performed in the majority of cases, and should be utilized as the default strategy. Trans-esophageal echocardiography utilization during TAVR with MAC is safe and feasible. The most common cause for conversion of MAC to GA is cardiac instability and hypotension. The complete heart team should be available at all times in case the need arises for a rapid conversion to GA.
Increased plasma levels of total homocysteine but not asymmetric dimethylarginine in Hispanic subjects with ischemic stroke FREC-VI sub-study.

Despite sharing some metabolic and pathological mechanisms, the reported association between total homocysteine (tHcy), asymmetric dimethylarginine (ADMA) and stroke remains controversial, particularly in Hispanic populations from developing countries in which genetic, socioeconomic, and nutritional factors are different to those described in developed countries. Our objectives were to determine the relationships of these factors to stroke and to each other independent of other cardiovascular risk factors, and to explore potential sex differences.



This national (Colombia) multicenter case-control study included 238 cases and 238 controls to evaluate traditional and emerging risk factors for ischemic stroke including tHcy and ADMA plasma levels.



The median plasma levels of tHcy were 8.48 μM for controls and 10.01 μM for cases (P<0.0001). Plasma levels of tHcy between 12 and 50μM were considered moderate hyperhomocysteinemia (HtHcy). There were no differences in plasma ADMA concentration between groups (P=0.40). Plasma levels of ADMA and creatinine were not correlated (P=0.47). After adjusting for confounding factors, the presence of HtHcy was strongly associated with stroke (OR 8.97; P<0.0001). The adjusted association between HtHcy and stroke in men (OR 9.98) was comparable to that in women (OR 8.98) (P=0.41).



In this Hispanic population, with relatively normal renal function, plasma levels of tHcy but not ADMA were associated with stroke independent of other cardiovascular risk factors.
A new instrument to describe indicators of well-being in old-old patients with severe dementia – The Vienna List

In patients with very severe dementia self-rating of quality of life usually is not possible and appropriate instruments for proxy-ratings are not available. The aim of this project is to develop an instrument of clinical proxy-ratings for this population.



Using electronic instruments, physicians and nurses recorded patient behaviour and changes of behaviour over a period of one year. Based on these data a list of 65 items was generated and subsequently allocated to 14 categories. This list was tested in 217 patients (61-105 yrs) with dementia diagnosed according to ICD-10 by both physicians and nurses. The severity of dementia was assessed by means of the Global Deterioration Scale (GDS) and the Brief Cognitive Rating Scale (BCRS). The Spitzer-Index (proxy-rating) was used as a global quality of life measure. Activity of daily living was rated using the Barthel Index.



A factor analysis of the original 65 items revealed 5 factors (communication, negative affect, bodily contact, aggression, and mobility). By stepwise removing items we obtained satisfactory internal consistencies of the factors both for nurses' and physicians' ratings. The factors were generally unrelated. The validity of the instrument was proven by correlations of the factors communication and mobility with the Brief Cognitive Rating Scale (BCRS) and the Barthel-Index.



The results demonstrate the reliability and validity of the Vienna List as a proxy rating measurement of quality of life in patients with severe dementia. The psychometric properties of the scale have to be proved in further studies.
Critical appraisal of the Carotid Duplex Consensus criteria in the diagnosis of carotid artery stenosis.

Clinicians have relied on published institutional experience for interpreting carotid duplex ultrasound studies (CDUS). This study will validate the ultrasound imaging consensus criteria published in 2003.



The CDUS and angiography results of 376 carotid arteries were analyzed. Receiver-operating characteristic (ROCs) curves were used to compare peak systolic velocities (PSVs), end-diastolic velocities (EDVs) of the internal carotid artery (ICA), and ICA/common carotid (CCA) ratios in detecting < 50%, 50% to 69% (ICA PSV of 125-230 cm/s), and 70% to 99% (PSV of ≥ 230 cm/s) stenosis according to the consensus criteria.



The consensus criteria uses a PSV of 125 to 230 cm/s for detecting angiographic stenosis of 50% to 69%, which has a sensitivity of 93%, specificity of 68%, and overall accuracy of 85%. A PSV of ≥ 230 cm/s for ≥ 70% stenosis had a sensitivity of 99%, specificity of 86%, and overall accuracy of 95%. ROC curves showed that the ICA PSV was significantly better (area under the curve [AUC], 0.97) than EDV (AUC, 0.94) or ICA/CCA ratio (AUC, 0.84; P = .036) in detecting ≥ 70% stenosis and ≥ 50% stenosis. Pearson correlations showed a statistical difference between the correlation of PSV with angiography (0.833; 95% confidence interval [CI], 0.8-0.86), EDV with angiography (0.755; 95% CI, 0.71-0.80), and ICA/CCA systolic ratio with angiography (0.601; 95% CI, 0.53-0.66; P < .0001) in detecting 70% to 99% stenosis. Adding the EDV values or the ratios to the PSV values did not improve accuracy. The consensus criteria for diagnosing 50% to 69% stenosis can be significantly improved by using an ICA PSV of 140 to 230 cm/s, with a sensitivity of 94%, specificity of 92%, and overall accuracy of 92%.



The consensus criteria can be accurately used for diagnosing ≥ 70% stenosis; however, the accuracy can be improved for detecting 50% to 69% stenosis if the ICA PSV is changed to 140 to < 230 cm/s.