nils-herrmann/clean_scirepeval huggingface dataset:
Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.

The inhibition of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor.



This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation.



We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice daily (grade 3 mood alteration and fatigue) and two of five patients receiving 600 mg twice daily (grade 4 thrombocytopenia and grade 3 somnolence). This led us to enroll another cohort, consisting only of carriers of a BRCA1 or BRCA2 mutation, to receive olaparib at a dose of 200 mg twice daily. Other adverse effects included mild gastrointestinal symptoms. There was no obvious increase in adverse effects seen in the mutation carriers. Pharmacokinetic data indicated rapid absorption and elimination; pharmacodynamic studies confirmed PARP inhibition in surrogate samples (of peripheral-blood mononuclear cells and plucked eyebrow-hair follicles) and tumor tissue. Objective antitumor activity was reported only in mutation carriers, all of whom had ovarian, breast, or prostate cancer and had received multiple treatment regimens.



Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCA2 mutation.
Lung nodules: improved detection with software that suppresses the rib and clavicle on chest radiographs.

To demonstrate possible superiority in the performance of a radiologist who is tasked with detecting actionable nodules and aided by the bone suppression and soft-tissue visualization algorithm of a new software program that produces a modified image by suppressing the ribs and clavicles, filtering noise, and equalizing the contrast in the area of the lungs.



The study and use of anonymized and deidentified data received approval from the MedStar-Georgetown University Oncology Institutional Review Board. Informed consent was obtained from 15 study radiologists. The study radiologists participated as observers in a reader study of 368 patients in an approximately 2:1 cancer-free-to-cancer ratio. The localized receiver operating characteristic (LROC) method was used for analyses. Images were rerandomized for each radiologist. Each patient image was sequentially read, first with the standard radiograph and then with the software-aided image. Normal studies were confirmed with computed tomography (CT), follow-up, and/or panel consensus.



Each reader and the combined scores of the 15 readers showed improvement. The area under the combined LROC curve increased significantly from 0.460 unaided to 0.558 aided by visualization software (P = .0001). When measured according to the reader's indication that a case should be sent or not sent for CT or biopsy, sensitivity for cancer detection increased from 49.5% unaided to 66.3% aided by software (P < .0001); specificity decreased from 96.1% to 91.8% (P = .004). Seventy-four percent of the aided detections occurred in cancers with 70% or greater overlap of the bone and the nodule.



The radiologists using visualization software significantly increased their detection of lung cancers and benign nodules.
Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia.

To evaluate efficacy and safety of ramelteon (MT1/MT2-receptor [corrected] agonist) in subjects with chronic primary insomnia.



Randomized, multicenter, double-blind, placebo-controlled trial of nightly ramelteon treatment (8 mg or 16 mg) in adults (N=405) with primary chronic insomnia (DSM-IV-TR). Latency to persistent sleep (LPS), TST, sleep efficiency, wake time after sleep onset, and number of awakenings were measured by polysomnography. Subject-reported measures were also assessed.



LPS at Week 1 (primary measure) was significantly shorter with ramelteon 8 mg (32.2 min) or 16 mg (28.9 min) vs placebo (47.9 min; p <0.001). Significant improvements in LPS were maintained at Weeks 3 and 5. TST was significantly longer with both doses of ramelteon at Week 1 (p <0.001) vs placebo. Subject-reported sleep latency was significantly shorter with ramelteon 8 mg at Weeks 1, 3, and 5 (p <0.001) and ramelteon 16 mg at Weeks 1 and 3 (p < or =0.050) vs placebo. Wake time after sleep onset and number of awakenings were not significantly different with ramelteon 8 mg or 16 mg treatment vs placebo. Subjective TST was significantly longer with ramelteon 8 mg at Weeks 1, 3, and 5 (p < or =0.050) and ramelteon 16 mg at Week 1 (p = 0.003) vs placebo. Ramelteon had no clinically meaningful effect on sleep architecture, next-morning psychomotor tasks, alertness, or ability to concentrate. No withdrawal or rebound effects were observed.



Ramelteon reduced LPS over 5 weeks of treatment in subjects with chronic insomnia, with no clinically meaningful sleep architecture alterations, next-morning residual pharmacologic effects, and no evidence of rebound insomnia or withdrawal. No numerical differences were observed between the 2 doses of ramelteon.
Spinal manipulative therapy has an immediate effect on thermal pain sensitivity in people with low back pain: a randomized controlled trial.

Current evidence suggests that spinal manipulative therapy (SMT) is effective in the treatment of people with low back pain (LBP); however, the corresponding mechanisms are unknown. Hypoalgesia is associated with SMT and is suggestive of specific mechanisms.



The primary purpose of this study was to assess the immediate effects of SMT on thermal pain perception in people with LBP. A secondary purpose was to determine whether the resulting hypoalgesia was a local effect and whether psychological influences were associated with changes in pain perception.



This study was a randomized controlled trial.



A sample of convenience was recruited from community and outpatient clinics.



Thirty-six people (10 men, 26 women) currently experiencing LBP participated in the study. The average age of the participants was 32.39 (SD=12.63) years, and the average duration of LBP was 221.79 (SD=365.37) weeks.



Baseline demographic and psychological measurements were obtained, followed by quantitative sensory testing to assess temporal summation and Adelta fiber-mediated pain perception. Next, participants were randomly assigned to ride a stationary bicycle, perform low back extension exercises, or receive SMT. Finally, the same quantitative sensory testing protocol was reassessed to determine the immediate effects of each intervention on thermal pain sensitivity.



Hypoalgesia to Adelta fiber-mediated pain perception was not observed. Group-dependent hypoalgesia of temporal summation specific to the lumbar innervated region was observed. Pair-wise comparisons indicated significant hypoalgesia in participants who received SMT, but not in those who rode a stationary bicycle or performed low back extension exercises. Psychological factors did not significantly correlate with changes in temporal summation in participants who received SMT.



Only immediate effects of SMT were measured, so the authors are unable to comment on whether the inhibition of temporal summation is a lasting effect. Furthermore, the authors are unable to comment on the relationship between their findings and changes in clinical pain.



Inhibition of Adelta fiber-mediated pain perception was similar for all groups. However, inhibition of temporal summation was observed only in participants receiving SMT, suggesting a modulation of dorsal horn excitability that was observed primarily in the lumbar innervated area.
Estimating variability in outcomes attributable to therapists: a naturalistic study of outcomes in managed care.

To estimate the variability in outcomes attributable to therapists in clinical practice, the authors analyzed the outcomes of 6,146 patients seen by approximately 581 therapists in the context of managed care. For this analysis, the authors used multilevel statistical procedures, in which therapists were treated as a random factor. When the initial level of severity was taken into account, about 5% of the variation in outcomes was due to therapists. Patient age, gender, and diagnosis as well as therapist age, gender, experience, and professional degree accounted for little of the variability in outcomes among therapists. Whether or not patients were receiving psychotropic medication concurrently with psychotherapy did affect therapist variability. However, the patients of the more effective therapists received more benefit from medication than did the patients of less effective therapists.
Quality of life in patients with pancreatic cancer.

Pancreatic cancer is a rapidly fatal disease with palliation often serving as the main goal of treatment. The end of life is often marked by severe symptoms and poor quality of life (QoL). Several studies presented at the 2012 ASCO Gastrointestinal Cancers Symposium addressed the importance of symptom identification and management for patients with pancreatic cancer: 1) a study evaluating the correlation between patient-reported symptoms, disease burden and treatment duration in patients with advanced pancreatic cancer undergoing gemcitabine-based chemotherapy (; 2) a Japanese study found that patients without worsening of pain or sleep symptoms at one month of chemotherapy had higher frequency of disease control ( and 3) a study showed that fear of cancer recurrence is a substantial problem following resection and should be targeted (. The authors summarize the findings and discuss the importance of QoL in these patients. The results of these studies may facilitate in identifying symptom changes as predictive markers, and improving care and QoL for patients with this devastating disease.
Stage 2 of the Wellcome Trust UK–Irish bipolar affective disorder sibling-pair genome screen: evidence for linkage on chromosomes 6q16–q21, 4q12–q21, 9p21, 10p14–p12 and 18q22

Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16-q21 (MLS=2.61) and 4q12-q21 (MLS=2.38). 6q16-q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male-male pairs. Our scan also provides support for linkage (MLS> or =1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14-p12 and 18q22.
Clinoptilolite for Treatment of Dyslipidemia: Preliminary Efficacy Study.

A tribomechanically activated clinoptilolite (natural aluminosilicate mineral) has been used to increase growth in meat-producing animals, as an adjuvant in cancer therapy, and a heavy metal remover in humans. Because of its unique cation exchanging and chelating properties, we hypothesized that clinoptilolite may be beneficial for the treatment of dyslipidemia in the manner similar to bile acid sequestrants. Thus, specific aims of this pilot study were to orally administer clinoptilolite in different doses and granule size combinations to determine magnitude and time profile of changes in blood lipids.



A phase I/IIa prospective, open-label, uncontrolled, dose/granule size-ranging study (treatment phase 8 weeks, follow-up 6 weeks). Blood lipids were examined every 2 weeks.



Outpatient clinic of a university-affiliated hospital.



Forty-one subjects (all white, mean age 57.6 ± 6.8 years, 17 women) with blood lipids above the normative limits divided into three groups.



A tribomechanically activated clinoptilolite was administered in three dose/grind combinations: 6 g/day of fine grind (6gF), 6 g/day of coarse grind (6gC), and 9 g/day of coarse grind (9gC).



Blood concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc), and triglycerides (TG).



For the 3 groups combined, all lipid fractions significantly improved after 8 weeks of treatment (20-25%, p < 0.001), which reversed to baseline after 6 weeks of clinoptilolite withdrawal. Early (week 2) and the most pronounced decrease in TC and LDLc was observed in the 6gF group (19% and 23% in week 8, respectively), with no difference in HDLc and TG between the three dose/grind groups. No side effects were reported.



These pilot results suggest that oral administration of clinoptilolite may improve lipid profile in individuals with dyslipidemia, which warrants further investigations.
Influence of LDL-receptor mutation type on age at first cardiovascular event in patients with familial hypercholesterolaemia.

To investigate the influence of different LDL-receptor (LDLR) gene mutations on age at first cardiovascular event in familial hypercholesterolaemia (FH) patients.



Dutch FH patients (n = 862) with known LDLR mutations from a retrospective cohort study were included. A gamma frailty Cox model was used. An event was defined as the first cardiovascular event. Gender, hypertension, smoking, diabetes, HDL cholesterol, LDL cholesterol (LDL-C), or triglycerides were included as covariates. Furthermore, the effect of LDLR mutation type on LDL and HDL cholesterol levels was investigated using mixed effects models, including gender, smoking, body mass index, and age at time of lipid measurement as covariates. A total of 86 different LDLR mutations were present in this cohort. Twenty-two percent of patients experienced an event (median age: 47.1 year; range: 25.6-85.8 years). The effect of LDLR mutation type on event-free survival is only significant in the models without LDL-C levels. Also, LDLR mutation type was significantly associated with LDL-C levels (P = 0.007), but not with HDL cholesterol levels (P = 0.12).



In the present study, LDL-C levels are a more important risk factor of event-free survival than the type of LDLR mutation.
The combination of hypointense and hyperintense signal changes on T2-weighted magnetic resonance imaging sequences: a specific marker of multiple system atrophy?

To compare the frequency and specificity of hypointense magnetic resonance imaging (MRI) signal changes alone with the frequency and specificity of a pathological MRI pattern consisting of a hyperintense lateral rim and a dorsolateral signal attenuation on T2-weighted MRIs in patients with parkinsonism of various origins.



Ninety patients with Parkinson disease (PD) (n = 65), progressive supranuclear palsy (PSP) (n = 10), and multiple system atrophy (MSA) of the striatonigral degeneration type (n = 15) underwent MRI.



University medical center.



Nine of the 15 patients with MSA showed the pattern with hyperintense lateral rim and a dorsolateral hypointense signal attenuation on T2-weighted images within the putamen. This pattern was not found in the 65 patients with PD, nor in the 10 patients with PSP. Only hypointense changes in the putamen were found in 6 patients (9%) with PD, 4 patients (40%) with PSP, and 5 patients (36%) with MSA.



Our data suggest that the pattern consisting of hypointense and hyperintense T2 changes within the putamen is a highly specific MRI sign of MSA, while hypointensity alone remains a sensitive, but nonspecific MRI sign of MSA. In clinically doubtful cases, the appearance of a hypointense and hyperintense signal pattern on MRI makes the diagnosis of PD very unlikely, while hypointense signal changes alone do not exclude idiopathic PD.
Evaluation of ischaemia in obese patients: feasibility and accuracy of a low-dose protocol with a cadmium-zinc telluride camera

Obesity is a significant and independent risk factor for cardiovascular disease, and assessing ischaemia in obese patients is clinically important but sometimes difficult because of imaging artefacts. The aim of this study was to evaluate the feasibility and diagnostic accuracy of stress/rest imaging with a cadmium-zinc telluride (CZT) camera using a low-dose protocol in a series of consecutive obese patients referred for the evaluation of coronary artery disease. We considered 148 consecutive obese patients (mean BMI 39 ± 7 kg/m2) with known or suspected coronary artery disease referred to our laboratory for stress/rest myocardial perfusion imaging. A subgroup of 103 of the 148 patients underwent invasive coronary angiography for clinical reasons. All patients underwent a single-day stress/rest low-dose ultrafast protocol. Patients were injected with 99mTc-tetrofosmin at a dose in the range 185–222 MBq during bicycle exercise or dipyridamole stress, and underwent the first scan with an acquisition time of 7 min starting 15 min after the end of the stress. The rest scan with an acquisition time of 6 min was started from 30 to 45 min after 99mTc-tetrofosmin injection at a dose in the range 370–444 MBq. Images were visually inspected, and the summed stress score (SSS) and summed rest score (SRS) were obtained. Image quality was graded very good or excellent in all patients. Of the 103 patients who underwent coronary angiography, 12 (12 %), 26 (25 %) and 56 (54 %) showed one-, two- and three-vessel disease, and 9 showed normal coronary vessels. In the 103 patients submitted to coronary angiography, the mean SSS and SRS were 7±6 and 2±3, respectively. Semiquantitative regional and global SSS was a good discriminant of coronary artery disease and the area under the overall ROC curve was 0.848 (95 % CI 0.723–0.975). In obese patients, a single-day stress/rest low-dose ultrafast protocol with a CZT camera is clinically feasible and provides high image quality.
Self-awareness of foot health status in patients with Type 2 diabetes: the Fremantle Diabetes Study Phase II.

To determine self-awareness of diabetes-related foot problems and its associates in a community-based cohort of people with Type 2 diabetes.



A survey concerning diabetic foot problems was administered to 358 consecutive patients with Type 2 diabetes [mean ± SD age 67.4 ± 10.8 years, 56.1% males, median (interquartile range) diabetes duration 9.0 (3.9-16.8) years] attending for detailed clinical, biochemical and questionnaire assessment as part of the longitudinal observational Fremantle Diabetes Study Phase II.



Compared with the 213 patients (59.5%) who considered their feet to be normal, the 145 (40.5%) who considered their feet to be abnormal were older, had longer diabetes duration and were more likely to have sensory neuropathic symptoms and self-reported poor circulation (P < 0.001). In those who considered their feet to be normal, 67.9% had peripheral sensory neuropathy (score >2/8 on the Michigan Neuropathy Screening Instrument clinical portion), 9.9% had an ankle-brachial index < 0.9, 6.1% had both peripheral sensory neuropathy and an ankle-brachial index < 0.90, and 86.9% had one or more features on inspection, such as deformity, dry skin, callus and fissures that could facilitate more serious complications, despite the majority having had at least one foot examination by a healthcare professional in the previous year.



Self-assessment of diabetes-related foot problems by patients in the Fremantle Diabetes Study Phase II was unreliable. The present data suggest that self-perceived foot health should be assessed together with foot examination findings. Intensive education and monitoring may be necessary in those who consider their feet to be normal but who have neurovascular, structural and/or other precursors of serious foot pathology.
Early effects of Communities That Care on targeted risks and initiation of delinquent behavior and substance use.

Communities That Care (CTC) is a prevention system designed to reduce levels of adolescent delinquency and substance use through the selection and use of effective preventive interventions tailored to a community's specific profile of risk and protection. This article describes early findings from the first group-randomized trial of CTC.



A panel of 4407 fifth-grade students was surveyed annually through seventh grade. Analyses were conducted to assess the effects of CTC on reducing levels of targeted risk factors and reducing initiation of delinquent behavior and substance use in seventh grade, 1.67 years after implementing preventive interventions selected through the CTC process.



Mean levels of targeted risks for students in seventh grade were significantly lower in CTC communities compared with controls. Significantly fewer students in CTC communities than in control communities initiated delinquent behavior between grades 5 and 7. No significant intervention effect on substance use initiation by spring of seventh grade was observed.



CTC's theory of change hypothesizes that it takes from 2 to 5 years to observe community-level effects on risk factors and 5 or more years to observe effects on adolescent delinquency or substance use. The early findings indicating hypothesized effects of CTC on targeted risk factors and initiation of delinquent behavior are promising.