nils-herrmann/clean_scirepeval huggingface dataset:
Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis.

Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir.



We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed.



Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C(max)) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C(max) values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C(max) values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance.



The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.
Extended evaluation of the safety and efficacy of GAD treatment of children and adolescents with recent-onset type 1 diabetes: a randomised controlled trial

The aim of this study was to investigate the safety and efficacy of alum formulated glutamic acid decarboxylase GAD65 (GAD-alum) treatment of children and adolescents with type 1 diabetes after 4 years of follow-up. Seventy children and adolescents aged 10–18 years with recent onset type 1 diabetes participated in a phase II, double-blind, randomised placebo-controlled clinical trial. Patients identified as possible participants attended one of eight clinics in Sweden to receive information about the study and for an eligibility check, including a medical history. Participants were randomised to one of the two treatment groups and received either a subcutaneous injection of 20 μg of GAD-alum or placebo at baseline and 1 month later. The study was blinded to participants and investigators until month 30. The study was unblinded at 15 months to the sponsor and statistician in order to evaluate the data. At follow-up after 30 months there was a significant preservation of residual insulin secretion, as measured by C-peptide, in the group receiving GAD-alum compared with placebo. This was particularly evident in patients with <6 months disease duration at baseline. There were no treatment-related serious adverse events. We have now followed these patients for 4 years. Overall, 59 patients, 29 who had been treated with GAD-alum and 30 who had received placebo, gave their informed consent. One patient in each treatment group experienced an episode of keto-acidosis between months 30 and 48. There were no treatment-related adverse events. The primary efficacy endpoint was the change in fasting C-peptide concentration from baseline to 15 months after the prime injection for all participants per protocol set. In the GAD-alum group fasting C-peptide was 0.332 ± 0.032 nmol/l at day 1 and 0.215 ± 0.031 nmol/l at month 15. The corresponding figures for the placebo group were 0.354 ± 0.039 and 0.184 ± 0.033 nmol/l, respectively. The decline in fasting C-peptide levels between day 1 and month 1, was smaller in the GAD-alum group than the placebo group. The difference between the treatment groups was not statistically significant. In those patients who were treated within 6 months of diabetes diagnosis, fasting C-peptide had decreased significantly less in the GAD-alum group than in the placebo-treated group after 4 years. Four years after treatment with GAD-alum, children and adolescents with recent-onset type 1 diabetes continue to show no adverse events and possibly to show clinically relevant preservation of C-peptide.  The study was funded by The Swedish Research Council K2008-55X-20652-01-3, Barndiabetesfonden (The Swedish Child Diabetes Foundation), the Research Council of Southeast Sweden, and an unrestricted grant from Diamyd Medical AB.
Pravastatin decreases wall shear stress and blood velocity in the internal carotid artery without affecting flow volume: results from the PROSPER MRI study.

Despite speculations, it is unknown whether statins affect wall shear stress (WSS). Therefore, the effect of pravastatin on WSS was investigated.



In 355 elderly individuals participating in the PROSPER study (follow up after 3 years), the effect of 40 mg pravastatin on WSS was assessed in the internal carotid artery using magnetic resonance imaging.



WSS and blood velocity decreased both in the pravastatin group and in the placebo group but decreased faster in the pravastatin group (P<0.04, P<0.02). Blood volume flow did not differ between the groups.



In elderly subjects, the WSS and blood velocity of the internal carotid artery declines significantly over time and this decline is more pronounced in subjects treated with 40 mg pravastatin compared with the placebo group.
Apixaban for extended treatment of venous thromboembolism.

Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism.



In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months.



A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group.



Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).
Cardiac arrest patients have an impaired immune response, which is not influenced by induced hypothermia

Induced hypothermia is increasingly applied as a therapeutic intervention in ICUs. One of the underlying mechanisms of the beneficial effects of hypothermia is proposed to be reduction of the inflammatory response. However, a fear of reducing the inflammatory response is an increased infection risk. Therefore, we studied the effect of induced hypothermia on immune response after cardiac arrest.



A prospective observational cohort study in a mixed surgical-medical ICU. Patients admitted at the ICU after surviving cardiac arrest were included and during 24 hours body temperature was strictly regulated at 33°C or 36°C. Blood was drawn at three time points: after reaching target temperature, at the end of the target temperature protocol and after rewarming to 37°C. Plasma cytokine levels and response of blood leucocytes to stimulation with toll-like receptor (TLR) ligands lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteicoic acid (LTA) from Gram-positive bacteria were measured. Also, monocyte HLA-DR expression was determined.



In total, 20 patients were enrolled in the study. Compared to healthy controls, cardiac arrest patients kept at 36°C (n = 9) had increased plasma cytokines levels, which was not apparent in patients kept at 33°C (n = 11). Immune response to TLR ligands in patients after cardiac arrest was generally reduced and associated with lower HLA-DR expression. Patients kept at 33°C had preserved ability of immune cells to respond to LPS and LTA compared to patients kept at 36°C. These differences disappeared over time. HLA-DR expression did not differ between 33°C and 36°C.



Patients after cardiac arrest have a modest systemic inflammatory response compared to healthy controls, associated with lower HLA-DR expression and attenuated immune response to Gram-negative and Gram-positive antigens, the latter indicative of an impaired immune response to bacteria. Patients with a body temperature of 33°C did not differ from patients with a body temperature of 36°C, suggesting induced hypothermia does not affect immune response in patients with cardiac arrest.
Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial.

Patients with chronic hepatitis C and low serum and hepatic iron stores may have an improved response to interferon (IFN). We tested whether iron reduction before and during IFN therapy would lead to an improved sustained biochemical and virological response compared with IFN alone. Eighty-two previously untreated patients with chronic hepatitis C were randomized to either: group A IFN-alpha2b 3 MU 3 times per week for 6 months, or group B iron reduction before and during IFN-alpha2b 3 MU 3 times per week for 6 months. Group B patients had lower mean serum alanine transaminase (ALT) levels than group A patients during treatment and follow-up. Group B patients had significantly lower mean hepatitis C virus (HCV)-RNA levels at treatment weeks 4 and 12 (P <.05). Serum HCV RNA was undetectable at the end of treatment in 15 group B patients compared with 7 group A patients (P =.03); 7 group B patients and 3 group A patients had persistently undetectable serum HCV RNA 24 weeks after the end of therapy (P =.20). Paired pre- and posttreatment liver biopsies in 18 group B patients demonstrated significant improvements in 2 of the 3 inflammation scores of the Knodell histological activity index (P <. 05). No changes occurred in the paired biopsies from 15 group A patients. We conclude that iron reduction via therapeutic phlebotomy improves the end-of-treatment virological and histological response to short-term IFN therapy. Additional studies are needed to determine if iron reduction in combination with higher doses or longer duration of IFN may be of benefit.
Bone texture analysis is correlated with three-dimensional microarchitecture and mechanical properties of trabecular bone in osteoporotic femurs

Fracture of the proximal femur is a major public health problem in elderly persons. It has recently been suggested that combining texture analysis and bone mineral density measurement improves the failure load prediction in human femurs. In this study, we aimed to compare bone texture analysis with three-dimensional (3D) microarchitecture and mechanical properties of trabecular bone in osteoporotic femurs. Eight femoral heads from osteoporotic patients who fractured their femoral neck provided 31 bone cores. Bone samples were studied using a new high-resolution digital X-ray device (BMA™, D3A Medical Systems) allowing for texture analysis with fractal parameter H mean, and were examined using micro-computed tomography (microCT) for 3D microarchitecture. Finally, uniaxial compression tests to failure were performed to estimate failure load and apparent modulus of bone samples. The fractal parameter H mean was strongly correlated with bone volume fraction (BV/TV) (r = 0.84) and trabecular thickness (Tb.Th) (r = 0.91) (p < 0.01). H mean was also markedly correlated with failure load (r = 0.84) and apparent modulus (r = 0.71) of core samples (p < 0.01). Bone volume fraction (BV/TV) and trabecular thickness (Tb.Th) demonstrated significant correlations with failure load (r = 0.85 and 0.72, respectively) and apparent modulus (r = 0.72 and 0.64, respectively) (p < 0.01). Overall, the best predictors of failure load were H mean, bone volume fraction, and trabecular thickness, with r 2 coefficients of 0.83, 0.76, and 0.80 respectively. This study shows that the fractal parameter H mean is correlated with 3D microCT parameters and mechanical properties of femoral head bone samples, which suggests that radiographic texture analysis is a suitable approach for trabecular bone microarchitecture assessment in osteoporotic femurs.
Bronchodilatation after inhalation of the antihistamine clemastine.

H1 receptor blocking antihistamines administered by mouth have not found a clear place in the management of bronchial asthma. We investigated the possibility that higher concentrations of these drugs, administered directly to the bronchial tree, might produce bronchodilatation. Twelve asthmatic patients inhaled aerosols generated from solutions of clemastine (0.05%), salbutamol (0.5%), and placebo. Bronchodilatation was assessed by changes in the forced expiratory volume in one second (FEV1) and peak expiratory flow rate (PEFR) over four hours. Both clemastine and salbutamol caused significant bronchodilatation. The mean maximum percentage increases in FEV1 for clemastine and salbutamol were 21.1% and 29.2% respectively. The mean maximum percentage increases in PEFR were 31.2% and 35.2% respectively. There was no significant difference in the maximum bronchodilatation produced by the two drugs. Clemastine, when administered by aerosol inhalation, appears to be an effective bronchodilator.
Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome

Hurler syndrome (mucopolysaccharidosis type I, MPS IH) is characterized by a deficiency of α-L-iduronidase resulting in progressive multiorgan dysfunction. We sought to determine whether enzyme replacement therapy (ERT) with iduronidase in the peritransplant period affects outcome of hematopoietic stem cell transplantation (HSCT) for MPS IH. Seven children with MPS IH at a median age of 1.5 years at the time of myeloablative HSCT were eligible. All patients had null mutations in IDUA gene. Iduronidase (0.58 mg/kg per dose) was administered intravenously in 11–14 weekly doses before HSCT and 8 weekly doses after HSCT. The infusions were well tolerated. All patients developed antibodies to iduronidase but all engrafted with >90% donor hematopoiesis. A majority of patients had significant pulmonary complications before ERT and HSCT but all are alive and well with a median follow-up of more than 1 year after HSCT. This suggests that ERT prior to HSCT is unlikely to alter engraftment. In addition, morbidity was acceptable, despite a previous history of pulmonary difficulties that suggested that these patients were high risk for these complications. Therefore, we recommend treatment of MPS IH patients with combination of ERT and HSCT therapy to further investigate its potential to enhance outcomes with HSCT.
Angiogenesis in skeletal muscle precede improvements in peak oxygen uptake in peripheral artery disease patients.

Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, causing claudication and exercise intolerance. The mechanism(s) by which exercise training improves functional capacity is not understood. This study tested the hypothesis that in PAD patients who undergo supervised exercise training, increases in capillary density (CD) in calf muscle take place before improvements in peak oxygen uptake (VO(2)).



Thirty-five PAD patients were randomly assigned to 12 weeks of directly supervised or home-based exercise training. Peak VO(2) testing and gastrocnemius muscle biopsies were performed at baseline and after training. CD (endothelial cells/mm(2)) was measured using immunofluorescence staining. After 3 weeks of directly supervised training, patients had an increase in CD (216±66 versus 284±77, P<0.01) but no increase in peak VO(2). However, after 12 weeks, peak VO(2) increased (15.3±2.8 versus 16.8±3.8, P<0.01), whereas in muscle, CD remained increased over baseline, but there were no changes in markers of oxidative capacity. Within subjects, CD was related to peak VO(2) before and after directly supervised training.



Changes in CD in ischemic muscle with training may modulate the response to training, and those changes precede the increase in VO(2).
A pilot study of methylphenidate preference assessment in children diagnosed with attention-deficit/hyperactivity disorder.

The use of methylphenidate (MPH) in the treatment of attention-deficit/hyperactivity disorder (ADHD) is widely accepted; however, there is increased concern regarding its abuse potential. Few studies have examined the reinforcing effects of drugs in individuals receiving them for clinical purposes. This study attempts to assess MPH preference in children with ADHD using a choice procedure in order to explore the relationship among drug preference, clinical efficacy, and abuse potential.



Participants were 5 children (10-14 years of age) receiving MPH for the treatment of ADHD. Reinforcing effects were assessed using a double-blind choice procedure, with six sampling sessions and six choice sessions. Participant-rated effects were measured using self-report questionnaires. Clinical effects were measured using direct observations and behavior ratings.



Differences between the number of MPH, Placebo, and Neither choices across participants were significant (chi2 = 9.6; p < 0.01). Three of five participants reliably chose MPH more often than placebo. MPH produced idiosyncratic patterns of participant-rated effects but failed to produce significant clinical effects.



These findings add to the literature on the reinforcing effects of MPH and are the first reported in a clinical sample of children. Further research exploring the role of clinical efficacy in MPH preference is warranted.
The reasons for triple therapy in stable COPD patients in Japanese clinical practice

Triple combination therapy involving long-acting muscarinic antagonists long-acting β2 agonists, and inhaled corticosteroids has recently become an option for maintenance treatment of COPD. Some add-on clinical trials have reported the benefits of these combinations. However, the process to step up to triple therapy varies for individual cases.



Keio University and affiliated hospitals conducted an observational COPD cohort study, recruiting patients diagnosed as having COPD by pulmonary physicians and those referred for investigation of possible COPD. Their prescription history and clinical course were retrospectively analyzed based on the physicians' medical records and patient questionnaires. 
A total of 95 of the 445 COPD patients (21%) were treated with inhaled corticosteroids/long-acting β2 agonists/long-acting muscarinic antagonists as maintenance therapy, including 12 in COPD Grade I, 31 in Grade II, 38 in Grade III, and 14 in Grade IV, based on the Global Initiative for Chronic Obstructive Lung Disease spirometric grading. For more than half of the patients on triple therapy, the treatment had been intensified due to unsatisfactory improvement of symptoms, and 32% were treated with triple therapy due to comorbid asthma. In contrast, there were COPD patients whose therapy was maintained after starting with triple therapy because of their serious conditions or concurrent exacerbation at diagnosis (8%).



Triple therapy was often prescribed in the real-life management of COPD, even in patients whose airflow limitation was not severe. To better control symptoms was the major reason for choosing triple therapy, regardless of the severity of COPD, in Japan.
Lidoflazine: Double-blind trial of a new coronary vasodilator in angina pectoris

Lidoflazine, a new coronary vasodilator, has been tested in 31 cases of angina pectoris in a double-blind cross-over study. It diminished significantly the frequency of attacks and nitroglycerine consumption of the more severe cases, but its effects were less marked in milder cases. The results are discussed in relation to other anti-anginal drugs. The necessity for a preliminary run-in period in studies of angina pectoris is emphasized and the occurrence of carry-over effects between lidoflazine and the placebo is discussed.
The impact of numeracy on reactions to different graphic risk presentation formats: An experimental analogue study.

Numeracy, the ability to process basic mathematical concepts, may affect responses to graphical displays of health risk information. Displays of probabilistic risk information using grouped dots are easier to understand than displays using dispersed dots. However, dispersed dots may better convey the randomness with which health threats occur, so increasing perceived susceptibility. We hypothesized that low numeracy participants would better understand risks presented using grouped dot displays, while high numeracy participants would have good understanding, regardless of display type. Moreover, we predicted that dispersed dot displays, in contrast to grouped dot displays, would increase risk perceptions and worry only for highly numerate individuals.



One hundred and forty smokers read vignettes asking them to imagine being at risk of Crohn's disease, in a 2(display type: dispersed/grouped dots) x 3(risk magnitude: 3%/6%/50%) x 2(numeracy: high/low) design. They completed measures of risk comprehension, perceived susceptibility and worry.



More numerate participants had better objective risk comprehension, but this effect was not moderated by display type. There was marginally significant support for the predicted numeracy x display type interaction for worry about Crohn's disease, but not for perceived susceptibility to the condition.



Dispersed dot displays somewhat increase worry in highly numerate individuals, but only numeracy influenced objective risk comprehension. The most effective display type for communicating risk information will depend on the numeracy of the population and the goal(s) of the communication.