nils-herrmann/clean_scirepeval huggingface dataset:
A phase I trial of twice-weekly 17-allylamino-demethoxy-geldanamycin in patients with advanced cancer.

To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins.



A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one.



Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m2. Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m2. There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells.



The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m2. Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.
Safety behaviors and judgmental biases in social anxiety disorder.

Two experiments were conducted to examine the link between safety behaviors and social judgments in social anxiety disorder (SAD). Safety behaviors were manipulated in the context of a controlled laboratory-based social interaction, and subsequent effects of the manipulation on the social judgments of socially anxious participants (N = 50, Study 1) and individuals meeting diagnostic criteria for generalized SAD (N = 80, Study 2) were examined. Participants were randomly assigned to either a safety behavior reduction plus exposure condition (SB + EXP) or a graduated exposure (EXP) control condition, and then took part in a conversation with a trained experimental confederate. Results revealed across both studies that participants in the SB + EXP group were less negative and more accurate in judgments of their performance following safety behavior reduction relative to EXP participants. Study 2 also demonstrated that participants in the SB + EXP group displayed lower judgments about the likelihood of negative outcomes in a subsequent social event compared to controls. Moreover, reduction in safety behaviors mediated change in participant self-judgments and future social predictions. The current findings are consistent with cognitive theories of anxiety, and support the causal role of safety behaviors in the persistence of negative social judgments in SAD.
Nicotine dependence and symptoms in schizophrenia: naturalistic study of complex interactions.

Smoking may have a beneficial effect on either schizophrenic symptoms or antipsychotic side-effects, but studies are hampered by the lack of control of confounding factors.



To explore the self-medication hypothesis in a large sample of stable out-patients with schizophrenia.



Symptoms, assessed with the Positive and Negative Syndrome Scale (PANSS), and number of hospitalisations were compared in 250 out-patients with DSM-IV schizophrenia classified into three categories: highly dependent smokers, mildly dependent smokers and non-smokers. Log-linear analysis was used to control for potential confounding and interacting variables.



High PANSS total scores and positive symptoms were less frequent in mildly dependent smokers than in non-smokers or highly dependent smokers. The highly dependent smokers had the worst outcome.



The data do not generally support the self-medication hypothesis but rather suggest a complex interaction between nicotine dependence and nicotine dependence and schizophrenic symptoms.
Self-reported symptoms in patients on hemodialysis with moderate to severe secondary hyperparathyroidism receiving combined therapy with cinacalcet and low-dose vitamin D sterols.

Patients with secondary hyperparathyroidism experience a variety of clinical symptoms which may adversely affect physical and mental function. As part of a multicenter, open-label clinical trial, subjects completed a questionnaire that included the Medical Outcomes Study Short Form-36 and 14 kidney disease-related symptoms at multiple time points during the study. Out of the 567 subjects who received at least one dose of cinacalcet, 528 to 535 (93.8-94.4%) completed all or portions of the questionnaire at baseline. The median bioactive parathyroid hormone (PTH) was 294 pg/mL (10%, 90% range, 172-655 pg/mL). Following treatment with cinacalcet and low-dose vitamin D sterols, subjects reported significant improvement in the frequency of pain in muscles, joints and bones, stiff joints, dry skin, itchy skin, excessive thirst, and trouble with memory. At end of the efficacy assessment phase (Weeks 16 to 22), the magnitude of improvement was the greatest in joint pain, bone pain, dry skin, and excessive thirst (>5 on a 0-100 scale; P < 0.001). There were no clinically or statistically significant changes in any of the Short Form-36 subscales or in the physical or mental health composite scores. Among patients on hemodialysis with moderate to severe secondary hyperparathyroidism, treatment with cinacalcet and low-dose vitamin D sterols results in significant improvement in pain in the muscles, joints and bones, joint stiffness, dry and itchy skin, excessive thirst, and trouble with memory.
Intraoperative transesophageal two-dimensional echocardiography in total hip replacement

A number of studies in medical literature suggest that during implantation of hip prostheses pulmonary embolism of medullary contents and of air may occur. Proof of this suggestion was based on histological examination of lung tissue in animal experiments as well as on post mortem examinations of human tissue. In vivo evidence of this suspected embolism has been lacking so far, since an appropriate technique has not been available. Using transesophageal two-dimensional echocardiography, continuous imaging of the right atrium and the right ventricle can be performed in order to prove this suspected embolization in vivo. Thus, in a prospective randomized study of 26 patients undergoing hip surgery, the right atrium and right ventricle were continuously imaged. Simultaneously, the end-expiratory CO2 partial pressure was recorded. The medical literature suggests that a venting hole in the shaft of the femur prevents the rise in pressure in the medullary space and thus also averts embolism. Therefore, prior to the implantation of the shaft prosthesis, and in order to vent the medullary space, in 13 patients a 4.5-mm lateral borehole was drilled into the femoral shaft, located two finger breadths distal to the point were the end of the prosthesis would be positioned. In 12 of 13 patients in the control group without boreholes, transesophageal two-dimensional echocardiography revealed that air bubbles formed during the implantation of the shaft. In the group with boreholes, however, presence of air could be demonstrated in only four patients (P < 0.01). Emboli were detectable in eight patients in the control of group, but in only two patients in the group with boreholes (P < 0.05). In the control group the median end-expiratory CO2 partial pressure dropped from 35 to 33 mmHG (P < 0.01) because of embolism, but in the group with venting holes this value was 35 mm Hg before as well as after implantation. Transesophageal two-dimensional echocardiography proves that embolization of air and medullary space contents occurs during the implantation of hip prostheses. A venting hole in the shaft of the femur may help to reduce the incidence of intraoperative embolization of air and medullary space contents occuring during shaft implantation, but it cannot eliminate this completely.
Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial.

: Osteoarthritis (OA) is the most widespread musculoskeletal disorder in adults. It leads to cartilage damage associated with subchondral bone changes and synovial inflammation, causing pain and disability. The present study aimed at evaluating the safety of a dose-escalation protocol of intra-articular injected adipose-derived stromal cells (ASCs) in patients with knee OA, as well as clinical efficacy as secondary endpoint. A bicentric, uncontrolled, open phase I clinical trial was conducted in France and Germany with regulatory agency approval for ASC expansion procedure in both countries. From April 2012 to December 2013, 18 consecutive patients with symptomatic and severe knee OA were treated with a single intra-articular injection of autologous ASCs. The study design consisted of three consecutive cohorts (six patients each) with dose escalation: low dose (2 × 10(6) cells), medium dose (10 × 10(6)), and high dose (50 × 10(6)). The primary outcome parameter was safety evaluated by recording adverse events throughout the trial, and secondary parameters were pain and function subscales of the Western Ontario and McMaster Universities Arthritis Index. After 6 months of follow-up, the procedure was found to be safe, and no serious adverse events were reported. Four patients experienced transient knee joint pain and swelling after local injection. Interestingly, patients treated with low-dose ASCs experienced significant improvements in pain levels and function compared with baseline. Our data suggest that the intra-articular injection of ASCs is a safe therapeutic alternative to treat severe knee OA patients. A placebo-controlled double-blind phase IIb study is being initiated to assess clinical and structural efficacy.



Although this phase I study included a limited number of patients without a placebo arm, it showed that local injection of autologous adipose-derived stem cells was safe and well tolerated in patients with knee osteoarthritis. This study also provides encouraging preliminary evidence of efficacy. Larger and controlled long-term studies are now mandatory to confirm whether this new strategy of cell therapy can improve pain and induce structural benefit in osteoarthritis.
Acute changes in electromechanical parameters during different pacing configurations using a quadripolar left ventricular lead

Quadripolar left ventricular (LV) leads allow for several pacing configurations in candidates for cardiac resynchronization therapy (CRT). Whether different pacing configurations may affect LV dyssynchrony and systolic function is not completely known. We aimed to evaluate the acute effects of different pacing vectors on LV electromechanical parameters in patients implanted with a quadripolar LV lead. In this two-centre study, within 1 month of implantation 21 CRT patients (65 ± 8 years, 76 % men, 38 % ischemic) receiving a quadripolar LV lead (Quartet 1458Q, St Jude Medical) underwent LV capture threshold assessment, intracardiac electrogram optimization, and two-dimensional echocardiography during four pacing configurations: D1-P4, P4-RV coil, D1-RV coil, and P4-M2. LV dyssynchrony and contractile function were expressed by septal-to-lateral delay and global longitudinal strain (GLS). LV capture threshold varied between the configurations (P < 0.001), showing higher values in the configurations P4-RV coil and P4-M2. Septal-to-lateral delay decreased in the configurations D1-P4 and D1-RV coil (P = 0.003 and P = 0.033 vs. spontaneous rhythm, respectively). GLS improved significantly vs. spontaneous rhythm only in the configuration D1-P4 (from −8.6 ± 3.5 to −11.0 ± 3.2 %, P = 0.001). Accordingly, an increase in stroke volume and a decrease in mitral regurgitation were observed in the configuration D1-P4 (P ≤ 0.001 vs. spontaneous rhythm). In CRT patients receiving a quadripolar LV lead, significant variations in electromechanical parameters were observed by changing pacing vector. Individually targeting the optimal pacing site may enhance the acute haemodynamic response to CRT.
Does anaesthesia cause postoperative cognitive dysfunction? A randomised study of regional versus general anaesthesia in 438 elderly patients.

Postoperative cognitive dysfunction (POCD) is a common complication after cardiac and major non-cardiac surgery with general anaesthesia in the elderly. We hypothesized that the incidence of POCD would be less with regional anaesthesia rather than general.



We included patients aged over 60 years undergoing major non-cardiac surgery. After giving written informed consent, patients were randomly allocated to general or regional anaesthesia. Cognitive function was assessed using four neuropsychological tests undertaken preoperatively and at 7 days and 3 months postoperatively. POCD was defined as a combined Z score >1.96 or a Z score >1.96 in two or more test parameters.



At 7 days, POCD was found in 37/188 patients (19.7%, [14.3-26.1%]) after general anaesthesia and in 22/176 (12.5%, [8.0-18.3%]) after regional anaesthesia, P = 0.06. After 3 months, POCD was present in 25/175 patients (14.3%, [9.5-20.4%]) after general anaesthesia vs. 23/165 (13.9%, [9.0-20.2%]) after regional anaesthesia, P = 0.93. The incidence of POCD after 1 week was significantly greater after general anaesthesia when we excluded patients who did not receive the allocated anaesthetic: 33/156 (21.2%[15.0-28.4%]) vs. 20/158 (12.7%[7.9-18.9%]) (P = 0.04). Mortality was significantly greater after general anaesthesia (4/217 vs. 0/211 (P < 0.05)).



No significant difference was found in the incidence of cognitive dysfunction 3 months after either general or regional anaesthesia in elderly patients. Thus, there seems to be no causative relationship between general anaesthesia and long-term POCD. Regional anaesthesia may decrease mortality and the incidence of POCD early after surgery.
Population pharmacokinetics of intravenous and oral panobinostat in patients with hematologic and solid tumors

The study aimed to characterize the population pharmacokinetics of panobinostat, a pan-deacetylase inhibitor that has demonstrated efficacy in combination with bortezomib and dexamethasone in patients with multiple myeloma. A nonlinear mixed-effect model was used to fit plasma panobinostat concentration-time data collected from patients across 14 phase 1 and phase 2 trials following either oral or intravenous (IV) administration. The model was used to estimate bioavailabilities of the two oral formulations and the effects of demographic and clinical covariates on the central volume of distribution and clearance of panobinostat. A total of 7834 samples from 581 patients were analyzed. Panobinostat pharmacokinetic parameters were best characterized by a three-compartment model with first-order absorption and elimination. Bioavailability was 21.4 %. Median clearance was 33.1 L/h. Interindividual variability in clearance was 74 %. For Caucasian patients of median age 61 years, area under the curve (AUC) decreased from 104 to 88 ng· h/mL as body surface area (BSA) increased from the first to third quartiles, 1.8 to 2.1 m2. For Caucasian patients of median BSA 1.9 m2, AUC decreased from 102 to 95 ng· h/mL as age increased from the first to third quartiles, 51 to 70 years. For patients of median BSA and median age, AUC ranged across the four race categories from 80 to 116 ng· h/mL. Covariate analysis showed no impact on panobinostat clearance and volume by patients’ sex, tumor type, kidney function, liver markers, or coadministered medications. However, separate analyses of dedicated studies have demonstrated effects of liver impairment and CYP3A4 inhibition. Although covariate analyses revealed significant effects of body size, age, and race on panobinostat pharmacokinetics, these effects were minor compared to the interindividual variability and therefore not clinically relevant when dosing panobinostat in populations similar to those studied.
Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study.

Long-term results at week 96 are needed to evaluate the capacity of the darunavir/ritonavir monotherapy strategy to maintain a sustained control of the HIV-1 viral load.



MONOI is a prospective, open-label, non-inferiority, randomized, 96 week trial comparing darunavir/ritonavir monotherapy versus a darunavir/ritonavir triple-therapy strategy to maintain HIV-1 viral load suppression in HIV-1-infected patients.



From 225 randomized patients, 219 patients reached the 48 week follow-up and 211 reached the 96 week follow-up (106 patients in the darunavir monotherapy arm and 105 in the darunavir triple-therapy arm). Baseline characteristics were well balanced between the two treatment groups. At week 96, in intent-to-treat analysis, 91/103 patients (88%, 95% CI 81-94) allocated to the darunavir/ritonavir monotherapy arm and 87/104 patients (84%, 95% CI 75-90) allocated to the darunavir triple-therapy arm achieved an HIV-1 viral load <50 copies/mL, with no statistical difference between the two groups. Throughout the 96 week follow-up, 66/112 patients (59%, 95% CI 49-68) and 79/113 patients (70%, 95% CI 61-78) consistently had HIV-1 RNA <50 copies/mL with darunavir/ritonavir monotherapy and darunavir/ritonavir triple therapy, respectively.



The MONOI study establishes darunavir/ritonavir monotherapy as durable and efficacious for maintaining virological suppression in HIV-1 patients. Darunavir/ritonavir monotherapy should be considered as a (tailored) treatment option for standard triple-therapy patients who have had a substantial period of viral suppression.
Temporal changes in blood product usage in preterm neonates born at less than 30 weeks' gestation in Canada.

Knowledge of neonatal transfusion practices remains limited to local cohorts or survey-based studies. This study evaluated the pattern and temporal changes in the types and frequency of blood product use among preterm neonates born at less than 30 weeks' gestation in Canada.



A retrospective cohort study of preterm neonates born at less than 30 weeks' gestation and admitted to participating neonatal intensive care units in the Canadian Neonatal Network from 2004 to 2012 was conducted to evaluate blood product usage. The temporal change in red blood cell (RBC) use was evaluated by dividing the study period into three epochs: 2004 to 2006, 2007 to 2009, and 2010 to 2012.



Of 14,868 eligible neonates admitted to participating units in Canada during the overall study period, 8252 (56%) received RBCs, 2151 (15%) platelets, 1556 (11%) fresh-frozen plasma, 915 (6%) albumin, and 302 (2%) cryoprecipitate. Temporal evaluation over three epochs revealed a trend toward fewer RBC transfusions among neonates born at 26 to 29 weeks' gestation (p = <0.01-0.04) but use remained unchanged or increased for neonates born at 23 to 25 weeks' gestation (p = 0.02-0.54).



Blood product use remains at a very high frequency in preterm neonates born at less than 30 weeks' gestation. Evolutionary practice changes and relative high tolerance for anemia may be associated with a reduction in RBC usage in recent years in neonates born at at least 26 weeks' gestation. This contrasts with the ongoing higher usage of blood products observed at extremely low gestational ages.
Polymorphisms of ACE2 are associated with blood pressure response to cold pressor test: the GenSalt study.

Increased blood pressure (BP) reactivity to cold pressor test (CPT) is a risk factor for hypertension. Genetic factors may influence the variation of BP response to CPT among individuals. We explored the association of genetic variants in the apelin system genes (APLN, APLNR and ACE2) and BP response to CPT in a Chinese population.



A total of 1,998 Han Chinese participants from the Genetic Epidemiology Network of Salt Sensitivity completed a CPT. The percentage changes of BP right after the end of ice-water immersion were used as the measurement of BP responses to CPT. Twenty-two single nucleotide polymorphisms (SNPs) were selected and genotyped, including both tag and potential functional SNPs of the APLN, APLNR, and ACE2 genes. A mixed-effect linear model was used to assess the association between SNPs and BP responses to CPT.



In women, three SNPs (rs1514283, rs4646176, and rs879922) of the ACE2 gene were significantly associated with the diastolic BP (DBP) response to CPT in the general and recessive genetic models after adjustment for multiple testing (all false discovery rate q < 0.05). There were no significant associations of polymorphisms in APLN and APLNR genes with BP responses to CPT.



Our study identified genetic variants in the ACE2 gene that were significantly associated with DBP responses to cold stress in the Chinese female population. Future studies are warranted to confirm these findings.
Drug-eluting stents compared with thin-strut bare stents for the reduction of restenosis: a prospective, randomized trial.

Drug-eluting stents have considerably reduced restenosis. Their relative merits have been assessed on the basis of comparisons made with control bare stents with thick struts. However, increased strut thickness negatively affects restenosis. No direct comparisons between drug-eluting stents and bare stents with thin struts have been performed. The aim of this study was to evaluate the relative efficacy of sirolimus-eluting stents (Cypher) as compared with that of bare stents with thin struts (BeStent 2).



A total of 500 patients with coronary artery disease were randomly assigned to receive a Cypher stent or BeStent. The primary endpoint was angiographic restenosis defined as a stenosis diameter > or = 50% at 6-month angiographic follow-up. The secondary endpoint was the need for target vessel revascularization (TVR) during the year following the procedure. Follow-up angiography was performed in 81.8% of the patients. Patients treated with Cypher stents had a lower angiographic restenosis rate [8.3 vs. 25.5%, relative risk, 0.33 (95% confidence interval, 0.19-0.56), P<0.001] and a lower incidence of TVR [7.2 vs. 18.8%, relative risk, 0.38 (0.22-0.66), P<0.001]. For smaller vessels (< 2.8 mm), the angiographic restenosis rates were 7.0% with the Cypher stent and 34.2% with the BeStent (P<0.001). For larger vessels (> or = 2.8 mm), angiographic restenosis rates were 10.0% with the Cypher stent and 13.1% with the BeStent (P=0.52).



The drug-eluting stent, Cypher, is associated with a significantly lower risk of restenosis compared with the bare thin-strut BeStent. The advantage of the Cypher stent is vastly reduced in large vessels.