nils-herrmann/clean_scirepeval huggingface dataset:
A path-analytical approach to differentiate between direct and indirect drug effects on negative symptoms in schizophrenic patients

The hypothesis that differences in drug effects of risperidone and haloperidol on negative symptoms in schizophrenia are secondary to effects on positive, extrapyramidal, and depressive symptoms was investigated by means of an analysis of the data from the USA-Canada risperidone double-blind randomized clinical trial of 523 chronic schizophrenic patients. Regression analyses in the total sample and within treatment groups confirmed a strong relationship between changes in negative symptoms and the other variables studied (R2=0.50−0.51,p<0.001). Only depressive symptoms did not contribute significantly to these results (p>0.10). Path analysis showed that the greater mean change (p<0.05) of negative symptoms with risperidone compared to haloperidol could not be fully explained by correlations with favourable effects on positive and extrapyramidal symptoms. The relationship between shift in extrapyramidal symptoms and shift in negative symptoms failed to reach statistical significance; however, there was a clear tendency in the expected direction in both treatment groups.
Prognostic value of total atrial conduction time measured with tissue Doppler imaging to predict the maintenance of sinus rhythm after external electrical cardioversion of persistent atrial fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia, with a high recurrence rate, especially during the first months after cardioversion (CV). Few parameters have been evaluated as predictors for the maintenance of sinus rhythm (SR), with limited results. Recently total atrial conduction time (TACT) has been proposed as independent predictor of AF recurrence. The aim of this study was to investigate the prognostic value of TACT, measured using PA-TDI duration, to predict 1-year maintenance of restored SR after electrical CV.



In a population of 104 patients (58 male, aged 70 ± 9) with persistent AF, submitted to external electrical CV, we performed a complete echocardiogram after restoring SR. The TACT was estimated by measuring the time delay between the onset of the P-wave in lead II of the surface electrocardiogram and the peak A'-wave on the tissue Doppler imaging (TDI) tracing of the left atrial lateral wall (so-called PA-TDI duration). After a mean follow-up of 14 ± 2 months, 34 (33%) patients had recurrent AF, whereas 70 (67%) patients maintained SR. At multivariate analysis only PA-TDI was identified as independent predictor of AF recurrence (HR 1.04; 95% CI 1.03-1.06; P < 0.001). Receiver operator characteristics curve analyses demonstrated a high degree of discrimination (area under the curve 0.923); with a cut point of 152 msec, we obtain a good diagnostic accuracy (sensitivity 91%, specificity 87%).



The TACT using TDI is an independent predictor of AF recurrence and can be used to predict the maintenance of SR after external electrical CV.
Primary central nervous system lymphoma treated with high-dose methotrexate, high-dose busulfan/thiotepa, autologous stem-cell transplantation and response-adapted whole-brain radiotherapy: results of the multicenter Ostdeutsche Studiengruppe Hamato-Onkologie OSHO-53 phase II study.

We investigated the efficacy and safety of tandem high-dose methotrexate (HD-MTX) induction followed by high-dose busulfan/thiotepa (HD-BuTT) with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiation therapy (WBRT) in patients with newly diagnosed primary central nervous system lymphoma.



Twenty-three patients were treated with HD-MTX on days 1 and 10. In case of at least a partial remission (PR), HD-BuTT followed by aPBSCT was given. Patients without response to induction or without complete remission (CR) after HD-BuTT received WBRT.



Sixteen patients received HD-MTX and HD-BuTT achieving a CR/PR rate of 69%/13%. CR/PR rates for all patients (n = 23) were 70%/13%. There were three deaths during therapy. With longer follow-up three neurotoxic deaths occurred in irradiated patients (n = 9), while no persistent neurotoxicity was seen after HD-BuTT without subsequent WBRT. At a median follow-up of 15 months (range 1-69) median event-free survival (EFS) and overall survival (OS) for all patients were 17 and 20 months (Kaplan-Meier), after HD-BuTT 27 months and "not reached", respectively. Estimated 2-year EFS and OS were 45% and 48% for all patients versus 56% and 61% for the HD-BuTT group, respectively.



MTX induction followed by HD-BuTT is an effective and very short time-on-treatment regimen. Median survival for patients treated with high-dose chemotherapy is not reached yet. The induction regimen needs optimisation. In this study WBRT was associated with a high incidence of severe neurotoxicity.
Migraine history, nonsteroidal anti-inflammatory drug use, and risk of postmenopausal endometrial cancer.

Endometrial cancer is primarily a hormonally mediated disease. As such, factors that mediate or reflect exposure to estrogens, or that mediate response to such exposure, may plausibly be associated with endometrial cancer risk. History of migraines, another hormonally mediated condition, has recently been associated with a reduced risk of hormone receptor-positive breast cancer; however, the relationship between migraines and endometrial cancer has not previously been explored. We evaluated the relationship between migraine history and endometrial cancer risk in postmenopausal women, considering also the potential impact of nonsteroidal anti-inflammatory drug (NSAID) use, given the relationship of NSAIDs to hormones and to migraine history. We identified 93,384 women participating in the Women's Health Initiative prospective cohort who had an intact uterus at the time of study entry. Using Cox proportional hazards regression, we assessed risk of endometrial cancer during study follow-up according to history of migraines and according to current NSAID use at the time of study entry, adjusting for age, study arm, race, and hormone therapy use. We also evaluated interaction in these associations by body mass index. Having a history of migraines was not associated with endometrial cancer risk [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.75-1.11], regardless of body mass index (BMI) or NSAID use status. Similarly, current NSAID use was not associated with endometrial cancer risk (HR = 1.01, 95% CI = 0.88-1.16), regardless of BMI. Migraine history and NSAID use do not appear to be associated with risk of endometrial cancer.
Novel LHRH-receptor-targeted cytolytic peptide, EP-100: first-in-human phase I study in patients with advanced LHRH-receptor-expressing solid tumors

To conduct a phase I study determining the safety, pharmacokinetics and preliminary efficacy of EP-100, a novel anticancer drug consisting of natural luteinizing-hormone-releasing hormone (LHRH) ligand linked to a cationic membrane-disrupting peptide. Patients with advanced, solid tumors, positive for LHRH receptor by immunohistochemistry (IHC), received EP-100 weekly or twice weekly for 3 of 4 weeks in a 28 day cycle. A modified Fibonacci 3 + 3 dose-escalation schema was used. Initial cohorts received EP-100 once weekly (cohorts 1–7, 0.6–7.8 mg/m2, n = 21). Later cohorts received doses twice weekly (cohorts 7–11, 7.8–40 mg/m2, n = 16). LHRH-receptor expression was confirmed by IHC in 52 of 89 consented patients; 37 patients received at least 1 dose. Cohorts receiving doses of 5.2 mg/m2 and above achieved therapeutic levels from in vitro studies Clearance was rapid (mean half-life 7.1 ± 3.8 to 15.9 ± 3.6 min). The maximum-tolerated dose was not reached at the highest dose evaluated (40 mg/m2 twice weekly). Grade 2 increase in alanine aminotransferase/serum aspartate aminotransferase in one patient resolved, did not recur upon re-treatment, and was not observed in other patients. The only drug-related adverse event was transient infusion-related dermatologic reactions (10 patients). No complete or partial tumor responses were observed; seven patients had stable disease of 16 weeks. EP-100 was well tolerated in patients with advanced, LHRH-receptor-expressing solid tumors. The recommended phase 2 dose is 40 mg/m2 twice weekly for 3 of 4 weeks per cycle.
Evaluation of stabilized blood cell products as candidate preparations for quality assessment programs for CD4 T-cell counting.

Exceptionally robust cell preparations are needed for quality assessment programs (QAPs) such as the International Program for Quality Assessment and Standardization for Immunological Measures (QASI) relevant to HIV/AIDS. A suitable product must withstand environmental stress related to transportation for a minimum of 6 days. The two objectives of this study are (1) to evaluate the performance of various commercial preparations with multicenter participation and (2) to evaluate the robustness of stabilized blood cell products.



Phase 1: The performance of stabilized blood cell products was evaluated in a multicenter QAP utilizing various staining procedures and flow cytometers. Absolute cell enumeration was achieved using single-platform T-cell subset methodology. Phase 2: The robustness of stabilized blood cell products was evaluated by monitoring T-cell subset values from samples stored at 4 degrees C, 22 degrees C, and 37 degrees C for up to 10 days.



The largest interlaboratory variation in both absolute and relative T-cell values was 16% in samples with CD4 levels > or =400 cells per microliter and 21% in samples with CD4 levels <400 cells per microliter. Six preparations retained their phenotypic expression for 7 days at 4 degrees C and 22 degrees C. However, only two preparations remained stable for 4 days at 37 degrees C.



Some stabilized cell preparations are more robust and therefore more suitable for quality assessment purposes.
Effect of a low-fat fish oil diet on proinflammatory eicosanoids and cell-cycle progression score in men undergoing radical prostatectomy.

We previously reported that a 4- to 6-week low-fat fish oil (LFFO) diet did not affect serum insulin-like growth factor (IGF)-1 levels (primary outcome) but resulted in lower omega-6 to omega-3 fatty acid ratios in prostate tissue and lower prostate cancer proliferation (Ki67) as compared with a Western diet. In this post hoc analysis, the effect of the LFFO intervention on serum pro-inflammatory eicosanoids, leukotriene B4 (LTB4) and 15-S-hydroxyeicosatetraenoic acid [15(S)-HETE], and the cell-cycle progression (CCP) score were investigated. Serum fatty acids and eicosanoids were measured by gas chromatography and ELISA. CCP score was determined by quantitative real-time reverse transcriptase PCR (RT-PCR). Associations between serum eicosanoids, Ki67, and CCP score were evaluated using partial correlation analyses. BLT1 (LTB4 receptor) expression was determined in prostate cancer cell lines and prostatectomy specimens. Serum omega-6 fatty acids and 15(S)-HETE levels were significantly reduced, and serum omega-3 levels were increased in the LFFO group relative to the Western diet group, whereas there was no change in LTB4 levels. The CCP score was significantly lower in the LFFO compared with the Western diet group. The 15(S)-HETE change correlated with tissue Ki67 (R = 0.48; P < 0.01) but not with CCP score. The LTB4 change correlated with the CCP score (r = 0.4; P = 0.02) but not with Ki67. The LTB4 receptor BLT1 was detected in prostate cancer cell lines and human prostate cancer specimens. In conclusion, an LFFO diet resulted in decreased 15(S)-HETE levels and lower CCP score relative to a Western diet. Further studies are warranted to determine whether the LFFO diet antiproliferative effects are mediated through the LTB4/BLT1 and 15(S)-HETE pathways.
Do metronomes improve the quality of life in people with Parkinson's disease? A pragmatic, single-blind, randomized cross-over trial.

To evaluate the effect of acoustic cueing using metronomes on the quality of life of people with moderate to severe Parkinson's disease.



Pragmatic, single-blind, randomized cross-over trial.



Forty-two people aged 50-85 years, in Hoehn and Yahr stage II-IV and on stable medication. Eight were lost to follow-up.



Participants were randomized using concealed allocation to either an early group (n = 21) to receive an electronic metronome without therapy but limited support (5-10 minutes instruction and on-demand telephone assistance) for four weeks, or a late group (n = 21) to receive the same intervention at 10 weeks. In both groups the beat frequency was initially set to be comfortable for walking.



Primary and secondary outcomes were measured at baseline, 4, 10 and 14 weeks using the Parkinson's Disease Questionnaire 39 (PDQ-39), the Short Form 36 version 2 (SF-36 version 2) and a falls diary.



There were positive effects in six domains of the SF-36 version 2 and eight domains of the PDQ-39, although only one mean difference was clinically important: the role limitation (emotional) domain of SF-36 version 2 (a mean difference of 3.77, 95% confidence interval (CI), -2.68 to 10.22), a secondary outcome. None of these changes were statistically significant. There were no statistically significant differences in falls rates over the study period. Ten participants (24%) wanted to continue with their metronomes at the end of the study.



To demonstrate metronomes are beneficial on the role limitation domain of the SF-36 version 2 in people with moderate to severe Parkinson's disease a sample size of 600 would be required.
Double-blind comparison of cimetidine and placebo in the maintenance of healing of chronic duodenal ulceration.

Patients suffering from chronic duodenal ulceration were allocated at random to treatment with either cimetidine (400 mg twice daily) or matching placebo for six months. Before entry to the trial all patients were shown to have healed ulcers on endoscopy. Most of the patients had participated in a one-month trial of cimetidine during which their ulcers healed. The trial showed that four of 29 patients relapsed on maintenance treatment with cimetidine, which therefore did not confer complete immunity from relapse. However, cimetidine treatment was very much better than placebo treatment, on which 18 of 31 patients relapsed. Of the 22 patients who relapsed clinically, 20 were submitted to endoscopy and 19 of these were shown to have ulcerated again. Endoscopy at the end of the trial showed that ulcers had also redeveloped in five of 28 asymptomatic patients. Length of previous dyspeptic history had no bearing on the results of the trial but there was evidence that relapse on placebo was less likely if the ulcer had originally healed on a high dose of cimetidine. Clinical relapse was associated with worsening duodenitis. Symptoms, clinical observation, and laboratory tests showed no important abnormalities in the patients.
The comparative effectiveness of a team-based versus group-based physical activity intervention for cancer survivors

Physical activity benefits cancer survivors, but the comparative effectiveness of a team-based delivery approach remains unexplored. The hypothesis tested was that a team-based physical activity intervention delivery approach has added physical and psychological benefits compared to a group-based approach. A team-based sport accessible to survivors is dragon boating, which requires no previous experience and allows for diverse skill levels. In a non-randomized trial, cancer survivors chose between two similarly structured 8-week programs, a dragon boat paddling team (n = 68) or group-based walking program (n = 52). Three separate intervention rounds were carried out in 2007–2008. Pre–post testing measured physical and psychosocial outcomes. Compared to walkers, paddlers had significantly greater (all p < 0.01) team cohesion, program adherence/attendance, and increased upper-body strength. For quality-of-life outcomes, both interventions were associated with pre–post improvements, but with no clear-cut pattern of between-intervention differences. These hypothesis-generating findings suggest that a short-term, team-based physical activity program (dragon boat paddling) was associated with increased cohesion and adherence/attendance. Improvements in physical fitness and psychosocial benefits were comparable to a traditional, group-based walking program. Compared to a group-based intervention delivery format, the team-based intervention delivery format holds promise for promoting physical activity program adherence/attendance in cancer survivors.
Early prediction of therapy responses and outcomes in breast cancer patients using quantitative ultrasound spectral texture

Early alterations in textural characteristics of quantitative ultrasound spectral parametric maps, in conjunction with changes in their mean values, are demonstrated here, for the first time, to be capable of predicting ultimate clinical/pathologic responses of breast cancer patients to chemotherapy. Mechanisms of cell death, induced by chemotherapy within tumor, introduce morphological alterations in cancerous cells, resulting in measurable changes in tissue echogenicity. We have demonstrated that the development of such changes is reflected in early alterations in textural characteristics of quantitative ultrasound spectral parametric maps, followed by consequent changes in their mean values. The spectral/textural biomarkers derived on this basis have been demonstrated as non-invasive surrogates of breast cancer chemotherapy response. Particularly, spectral biomarkers sensitive to the size and concentration of acoustic scatterers could predict treatment response of patients with up to 80% of sensitivity and specificity (p=0.050), after one week within 3-4 months of chemotherapy. However, textural biomarkers characterizing heterogeneities in distribution of acoustic scatterers, could differentiate between treatment responding and non-responding patients with up to 100% sensitivity and 93% specificity (p=0.002). Such early prediction permits offering effective alternatives to standard treatment, or switching to a salvage therapy, for refractory patients.
Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.

Dolutegravir (S/GSK1349572), a once-daily, unboosted integrase inhibitor, was recently approved in the United States for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in combination with other antiretroviral agents. Dolutegravir, in combination with abacavir-lamivudine, may provide a simplified regimen.



We conducted a randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily (DTG-ABC-3TC group) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily (EFV-TDF-FTC group). The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance.



A total of 833 participants received at least one dose of study drug. At week 48, the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (88% vs. 81%, P=0.003), thus meeting the criterion for superiority. The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group (28 vs. 84 days, P<0.001), as well as greater increases in CD4+ T-cell count (267 vs. 208 per cubic millimeter, P<0.001). The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group (2% vs. 10%); rash and neuropsychiatric events (including abnormal dreams, anxiety, dizziness, and somnolence) were significantly more common in the EFV-TDF-FTC group, whereas insomnia was reported more frequently in the DTG-ABC-3TC group. No participants in the DTG-ABC-3TC group had detectable antiviral resistance; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group.



Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine. (Funded by ViiV Healthcare; SINGLE ClinicalTrials.gov number, NCT01263015 .).
Ribavirin improves the IFN-γ response of natural killer cells to IFN-based therapy of hepatitis C virus infection.

Ribavirin (RBV) is an important component of interferon (IFN)-based and direct antiviral treatment regimens for hepatitis C virus (HCV) infection. Immunomodulation, in particular improvement of the host IFN response, has been proposed as RBV's mechanism of action. Natural killer (NK) cells are sensitive biomarkers for IFN-α/β receptor signaling, as NK cell cytotoxicity and IFN-γ production are regulated by signal transducer and activator of transcription (STAT)1- and STAT4-phosphorylation, respectively. Specifically, pSTAT1-dependent NK cell cytotoxicity increases and pSTAT4-dependent IFN-γ production decreases in response to endogenous, virus-induced IFN-α and during IFN-α-based therapy. To assess whether RBV has a direct effect on NK cells and/or improves the IFN-γ response of NK cells in the presence of IFN-α, we prospectively studied 22 HCV patients with and 32 patients without 4 weeks of RBV pretreatment, who all received subsequent pegylated (Peg)IFN/ribavirin combination therapy. During RBV pretreatment, both the frequency of CD56(dim) NK cells with cytotoxic effector functions and the frequency of CD56(bright) NK cells with the capacity to produce IFN-γ decreased (P = 0.049 and P = 0.001, respectively). In vitro or in vivo exposure of NK cells to RBV improved the pSTAT4 (P < 0.01) but not pSTAT1 response of NK cells to subsequent stimulation with IFN-α. This was associated with an increase in IFN-γ production but not cytotoxicity of NK cells during subsequent IFN-α-based therapy. The frequency of IFN-γ-producing NK cells was greater in fast second-phase virological responders than in slow responders.



RBV enhances the pSTAT4 and IFN-γ response of NK cells to IFN-α-stimulation.
Calculation of fractions of lung cancer incidence attributable to occupational exposure to asbestos and combustion products in Stockholm, Sweden

In a population-based case–referent study of lung cancer we wanted to estimate the over-all influence on the lung cancer incidence from several occupational exposures. Standard methods to do this are based on addition of separately estimated attributable fractions (AFs) by rather complex formulas. Although a simple and valid method for direct estimation of summary effects was published in 1990, it is not well known and has rarely been used. We here describe the method and apply it to the data from the case–referent study. The AF for withdrawal of occupational exposure to both asbestos and combustion products were nearly identical regardless of if it was calculated by an algorithm for summation of AF for the exposure factors separately (6.90%), by a bootstrap method (6.89%, 95% confidence interval, CI: 3.69, 10.04), or by the simple ‘dichotomization’-method (6.88%, 95%CI: 3.81, 9.84). The method is very easy to apply to population-based case–referent studies analyzed by logistic regression.
Long-term TENS treatment improves tactile sensitivity in MS patients

Long-lasting increases in tactile sensitivity were achieved by repetitive stimulation of sensory afferents with TENS in MS patients but not in healthy subjects. This increased sensitivity was not only restricted to the median nerve area but also expanded to the ulnar nerve area. Remarkably, MS patients reached the same level of sensitivity as healthy subjects immediately after the intervention, and longterm effects were reported 3 weeks later.