nils-herrmann/clean_scirepeval huggingface dataset:
T cell profiling reveals high CD4+CTLA-4+ T cell frequency as dominant predictor for survival after Prostate GVAX/ipilimumab treatment

Immune checkpoint blockade enhances antitumor responses, but can also lead to severe immune-related adverse events (IRAE). To avoid unnecessary exposure to these potentially hazardous agents, it is important to identify biomarkers that correlate with clinical activity and can be used to select patients that will benefit from immune checkpoint blockade. To understand the consequences of CTLA-4 blockade and identify biomarkers for clinical efficacy and/or survival, an exploratory T cell monitoring study was performed in a phase I/II dose escalation/expansion trial (n = 28) of combined Prostate GVAX/ipilimumab immunotherapy. Phenotypic T cell monitoring in peripheral blood before and after Prostate GVAX/ipilimumab treatment revealed striking differences between patients who benefited from therapy and patients that did not. Treatment-induced rises in absolute lymphocyte counts, CD4+ T cell differentiation, and CD4+ and CD8+ T cell activation were all associated with clinical benefit. Moreover, significantly prolonged overall survival (OS) was observed for patients with high pre-treatment frequencies of CD4+CTLA-4+, CD4+PD-1+, or differentiated (i.e., non-naive) CD8+ T cells or low pre-treatment frequencies of differentiated CD4+ or regulatory T cells. Unsupervised clustering of these immune biomarkers revealed cancer-related expression of CTLA-4+ in CD4+ T cells to be a dominant predictor for survival after Prostate GVAX/ipilimumab therapy and to thus provide a putative and much-needed biomarker for patient selection prior to therapeutic CTLA4 blockade.
Abnormal susceptibility to distracters hinders perception in early stage Parkinson's disease: a controlled study

One of the perceptual abnormalities observed in Parkinson's disease (PD) is a deficit in the suppression of reflexive saccades that are automatically triggered by the onset of a peripheral target. Impairment of substantia nigra function is thought to lead to this reduced ability to suppress reflexive saccades.



The present study examined whether this perceptual deficit is also present in early stage PD when using hardly noticeable task-irrelevant stimuli. Eleven non-demented de novo, untreated PD patients (mean age 57 yr, range 44-70) participated in the study as well as 12 age-matched controls. Performance on an 'oculomotor capture' task, in which in half of the trials an irrelevant stimulus with sudden onset was added to the display, was compared between patients and controls. Analysis of variance (ANOVA) was performed with group (patients/controls) and age (< 61 yrs/> or = 61 yrs) as independent factors and type of trial (control/distracter) as repeated measurements factor. The factor sex was used as covariate.



With respect to Reaction Time (RT), a significant interaction between group and condition was found. RTs increased under the 'irrelevant stimulus' condition in both groups, the patients exhibiting a significantly larger increase in RTs than the control group. Also, a significant interaction effect between group and condition for number of correct responses was found. The number of correct responses was reduced in the onset distracter condition, the reduction being larger in the patients. In the patient group, contrary to the control group, a higher age was associated with fewer correct responses at baseline and in the onset distracter condition, suggesting that perceptual functions in PD are highly susceptible to the effects of ageing. The increased reaction times and larger number of incorrect responses of the PD patients in the onset distracter condition may be related to impairments of substantia nigra function and lower brain stem.



The capture task seems to be a sensitive instrument to detect early perceptual deficits in PD. The magnitude of the observed deficits suggests that perceptual functions in early stage PD are so substantially impaired that this may interfere with daily activities.
A randomized controlled trial of 6-week Chlorella vulgaris supplementation in patients with major depressive disorder.

Major depressive disorder (MDD) is a widespread psychiatric disorder with incapacitating symptoms. Oxidative stress has been identified to play a role in the pathophysiology of MDD.



To evaluate the therapeutic effectiveness of a chemically defined and antioxidant-rich Chlorella vulgaris extract (CVE) as adjunct to standard treatment in patients suffering from MDD.



Subjects with MDD diagnosis according to DSM-IV criteria who were receiving standard antidepressant therapy were assigned to add-on therapy with CVE (1800 mg/day; n=42), or continued standard antidepressant therapy alone (n=50) for a period of 6 weeks. Changes in the frequency of depressive symptoms were assessed using the Hospital Anxiety and Depression Scale (HADS) and Beck Depression Inventory II (BDI-II) scale.



There were significant reductions in total and subscale BDI-II and HADS scores in both CVE and control groups by the end of trial. The magnitude of reductions in total BDI-II score [-4.14 (-5.30 to -2.97)] as well as physical [-2.34 (-2.84 to -1.84)] and cognitive [-1.12 (-1.62 to -0.61)] subscales were significantly greater in the CVE versus control group, however, reduction of the affective symptoms was greater in the control compared with the CVE group [0.95 (0.18-0.72)]. Total HADS [-3.71 (-4.44 to -2.98)] as well as individual subscales of depression [-1.46 (-2.02 to -0.90)] and anxiety [-2.25 (-2.74 to -1.76)] were reduced to a greater degree in the CVE group. CVE was well tolerated and no serious adverse event was reported.



This pilot exploratory trial provides the first clinical evidence on the efficacy and safety of adjunctive therapy with CVE in improving physical and cognitive symptoms of depression as well as anxiety symptoms in patients who are receiving standard antidepressant therapy.
N-acetylcysteine improves arterial vascular reactivity in patients with chronic kidney disease.

Patients with stage 5 chronic kidney disease show increased cardiovascular morbidity and mortality that are partly related to impaired arterial vascular reactivity. We investigated whether intravenous administration of the antioxidant acetylcysteine improves arterial vascular reactivity in these patients.



Arterial vascular reactivity was determined during reactive hyperemia by photoplethysmography of digital pulse waves in a randomized, prospective, placebo-controlled cross-over study of 24 patients with stage 5 chronic kidney disease with and without infusion of acetylcysteine during hemodialysis. Acetylcysteine (5 g in 5% glucose in a final volume of 50 ml) was continuously administered intravenously during one hemodialysis session.



In the absence of acetylcysteine, the reflective index was 38.5 +/- 9.4 (mean +/- SD; n = 24) at baseline and 33.8 +/- 9.9 during reactive hyperemia, immediately after the hemodialysis session; thus there was no significant vasodilatation (p > 0.05), indicating impaired arterial vascular reactivity in these patients. However, when the hemodialysis session in the same patients was performed in the presence of acetylcysteine, the reflective index significantly decreased from 37.9 +/- 8.6 at baseline to 30.2 +/- 10.3 during reactive hyperemia (n = 24; p < 0.01).



The present study shows that intravenous administration of acetylcysteine during hemodialysis significantly improves arterial vascular reactivity during reactive hyperemia.
Improving fatigue and depression in individuals with multiple sclerosis using telephone-administered physical activity counseling.

To evaluate the impact of a physical activity intervention consisting of telephone counseling with home-based monitoring to improve fatigue and depression in individuals with multiple sclerosis (MS).



Single-blind randomized controlled trial. Sixty-four individuals with MS received either telephone counseling (N = 31), or self-directed physical activity education (N = 33). The education condition (EC) consisted of advice to increase physical activity and a DVD with examples of in-home exercises for multiple physical ability levels. The telephone counseling condition (TC) included EC as well as mailed graphic feedback, 6 telephone counseling sessions using principles of motivational interviewing, and telehealth home monitoring to track progress on physical activity goals. Booster sessions were provided when participants indicated they did not meet their goals. Assessment was conducted at baseline, 3-month, and 6-month follow-up.



TC participants reported significantly reduced fatigue (d = -.70), reduced depression (d = -.72) and increased physical activity (d = .92) relative to EC participants. Of individuals receiving TC, 33.3% experienced clinically significant improvement in fatigue (vs. 18.2% in EC) and 53.3% experienced clinically significant improvement in depression (vs. 9.1% in EC). Improvements in physical activity mediated improvements in fatigue with a similar trend for depression. TC was highly feasible (participants completed 99.5% of schedule telephone sessions) and well tolerated (100% rated it highly successful).



Telephone-based counseling with home monitoring is a promising modality to improve physical activity and treat fatigue and depression.
Impact of Obliterative Portal Venopathy Associated With Human Immunodeficiency Virus

HIV-associated obstructive portopathy (HIVOP) is an obstruction of the hepatic microvasculature of unknown origin. The purpose of this study was to describe the clinical and paraclinical presentation of the disease and its impact in terms of morbidity. Twenty-nine HIV1-infected patients (average 12 years of infection, nadir of CD4 210/mm, including 7 patients with a history of opportunistic infection) with a biopsy-proven or likely HIVOP have been followed up for an average of 6.1 years. Modes of revelation of the HIVOP were: cytolysis and/or cholestasis (60%), occult (14%) or symptomatic (37%) portal hypertension (esophageal varices 17%, ascites 10%, cytopenia 10%), or fortuitous (8%). Hypoalbuminemia (≤35 g/L) was present in (31%), thrombocytopenia (<150,000 platelets) in 52% and prothrombin rate <70% in 10%. Esophageal varices were detected in 71%. Thrombophilia was present in 23 patients (80%): in head, protein S deficiency (87%). MRI showed in 82% at least 1 morphological abnormality. The average value of the liver stiffness by Fibroscan was 8.3 kPa. During follow-up, there was no radiological improvement, 15 (52%) patients presented with variceal hemorrhage, 10 patients (34%) ascites, 10 (34%) portal vein thrombosis, 7 (24%) an iron deficiency, and 2 (7%) with a protein-losing enteropathy, including 14 patients (48%) with several events. Four patients (14%) were transplanted, 1 (25%) recurred the HIVOP on the graft, and 1 patient is waiting for a transplant. HIVOP is a severe disease associated with high morbidity related to symptomatic portal hypertension, which occurred in 50% and required liver transplantation in 14%.
Effect of boosted fosamprenavir or lopinavir-based combinations on whole-body insulin sensitivity and lipids in treatment-naive HIV-type-1-positive men.

Antiretroviral therapy is associated with metabolic complications, including dyslipidaemia, body fat changes and insulin resistance. Healthy volunteer studies have demonstrated a decrease in glucose disposal associated with dosing with specific antiretrovirals.



HIV-type-1-positive male participants were randomized to receive tenofovir disoproxil fumarate and lamivudine, with either fosamprenavir (FPV)/ritonavir or lopinavir (LPV)/ritonavir twice daily. A hyperinsulinaemic euglycaemic clamp was performed at baseline and at 2 weeks after commencing treatment. The homeostasis model assessment index for insulin resistance (HOMA-IR) was also calculated at these time points. Changes in lipids and lipoprotein subfractions (by nuclear magnetic resonance spectroscopy) were assessed. A pharmacokinetic assessment was undertaken at week 2.



A total of 27 participants were enrolled. There was no significant change in whole-body insulin sensitivity or HOMA-IR from baseline or between groups. Total cholesterol increased significantly, by 6.6% with FPV and 10.9% with LPV. The changes in lipids and lipoprotein subfractions were similar between groups with increases in triglycerides, very low-density lipoprotein (VLDL) and chylomicrons, and low-density lipoprotein (LDL) particles. Although the total high-density lipoprotein (HDL) particles were not significantly altered, a decrease in small HDL particles was seen. Changes in VLDL and chylomicron particles in both groups and triglycerides and small HDL particles in the LPV group were statistically significant.



In HIV-type-1-positive men initiating antiretroviral therapy with FPV- or LPV-based regimens, there were no significant changes in whole-body insulin sensitivity after 2 weeks. A proatherogenic lipid profile characterized by increases in triglycerides, VLDL and chylomicron particles and LDL particles, and a decrease in small HDL particles, was observed in both groups.
Effects of low dose versus conventional dose thiazide diuretic on insulin action in essential hypertension.

To see whether low dose thiazide diuretics given to patients with essential hypertension might avoid the adverse metabolic consequences seen with conventional doses.



Double blind randomised crossover study of two 12 week treatment periods with either low dose (1.25 mg) or conventional dose (5.0 mg) bendrofluazide given after a six week placebo run in period.



Outpatient clinics serving the greater Belfast area.



16 white non-diabetic patients (9 male) under 65 with essential hypertension recruited from general practices within the greater Belfast area.



Systolic and diastolic blood pressure and peripheral and hepatic insulin action.



One man failed to complete the study. There were no differences between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had substantially less effect on serum potassium concentration than the 5.0 mg dose. There were no intertreatment differences in fasting glucose, insulin, cholesterol, and triglyceride concentrations. Bendrofluazide 5.0 mg significantly increased postabsorptive endogenous glucose production compared with baseline (mean 10.9 (SD 1.2) v 10.0 (0.8) mumol/kg/min), whereas bendrofluazide 1.25 mg did not. Postabsorptive endogenous glucose production was significantly higher with bendrofluazide 5.0 mg compared with 1.25 mg (10.9 (1.2) v 9.9 (0.8) mumol/kg/min) but was suppressed to a similar extent after insulin (bendrofluazide 5.0 mg 2.8 (1.5) mumol/kg/min v bendrofluazide 1.25 mg 2.2 (1.5) mumol/kg/min). Exogenous glucose infusion rates required to maintain euglycaemia were not significantly different between doses and were similar to baseline.



Bendrofluazide 1.25 mg is as effective as conventional doses but has less adverse metabolic effect. In contrast with conventional doses, low dose bendrofluazide has no effect on hepatic insulin action. There is no difference between low and conventional doses of bendrofluazide in their effect on peripheral insulin sensitivity.
Estrogen Treatment Effects on Anticholinergic-Induced Cognitive Dysfunction in Normal Postmenopausal Women

Estrogen has been shown to interact with the cholinergic system and influence cognition in animal models. This study investigated the interaction of estrogen and cholinergic system functioning and the effects of this interaction on cognitive task performance in healthy older women. Fifteen post-menopausal women were randomly and blindly placed on 1 mg of 17-β estradiol or placebo for 3 months after which they participated in five anticholinergic challenge sessions, where they were administered one of two doses of the antimuscarinic drug scopolamine (SCOP) or the antinicotinic drug mecamylamine (MECA) or placebo. After the first challenge phase, they were crossed over to the other hormone treatment for another 3 months and repeated the challenges. Performance in multiple domains of cognition was assessed during anticholinergic drug challenge, including attention and verbal and nonverbal learning and memory. Results showed that estrogen pretreatment attenuated the anticholinergic drug-induced impairments on tests of attention and tasks with speed components. This study is the first to demonstrate the interaction of estrogen and the cholinergic system and the effects on cognitive performance in humans. The results suggest that estrogen status may affect cholinergic system tone and may be important for cholinergic system integrity.
Telephone interviews can be used to collect follow-up data subsequent to no response to postal questionnaires in clinical trials.

Follow-up data were collected using postal questionnaires and if participants did not respond, then data was collected using telephone interviews. The objectives of this study were to examine, for the two methods, how respondents differed in characteristics and whether the observed treatment difference varied.



A large clinical trial of lower back pain.



About 60% (98/163) of the nonresponders to postal questionnaire provided data by telephone, which increased the overall response rate by 14% (from 71% to 85%). A consistent treatment difference was found across the methods for the outcome measures at 12 months, implying that the observed treatment effect had not been modified. There were some differences between the participants: responders of postal questionnaire were older, likely to be female, white (ethnic origin), not working, with less disability of back pain, compared with those who responded by a telephone interview. At 12 months, there was greater improvement in back pain, disability, and general health for those who responded by postal questionnaires.



Researchers should consider the use of more than one method of collecting data as this increases response rate, participant representativeness, and enhances precision of effect estimates.
Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients

To characterize the clinical signature and etiopathogenetic factors of diabetes associated with pancreas disease [type 3 diabetes mellitus (T3cDM)]. To estimate incidence and identify predictors of both diabetes onset and remission after pancreatic surgery. A prospective observational study was conducted. From January 2008 to December 2012, patients (n = 651) with new diagnosis of pancreatic disease admitted to the Pancreatic Surgery Unit of the San Raffaele Scientific Institute were evaluated. Hospital and/or outpatient medical records were reviewed. Blood biochemical values including fasting blood glucose, insulin and/or C-peptide, glycosylated hemoglobin and anti-islet antibodies were determined. Diabetes onset was assessed after surgery and during follow-up. At baseline, the prevalence of diabetes was 38 % (age of onset 64 ± 11 years). In most cases, diabetes occurred within 48 months from pancreatic disease diagnosis. Among different pancreatic diseases, minor differences were observed in diabetes characteristics, with the exception of the prevalence. Diabetes appeared associated with classical risk factors for type 2 diabetes (i.e., age, sex, family history of diabetes and body mass index), and both beta-cell dysfunction and insulin resistance appeared relevant determinants. The prevalence of adult-onset autoimmune diabetes was as previously reported within type 2 diabetes. Within a few days after surgery, either diabetes remission or new-onset diabetes was observed. In patients with pancreatic cancer, no difference in diabetes remission was observed after palliative or resective surgery. Classical risk factors for type 2 diabetes were associated with the onset of diabetes after surgery. T3cDM appeared as a heterogeneous entity strongly overlapped with type 2 diabetes.
The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib.

The third-generation tyrosine kinase inhibitor (TKI) ponatinib shows activity against all common BCR-ABL1 single mutants, including the highly resistant BCR-ABL1-T315I mutant, improving outcome for patients with refractory chronic myeloid leukemia (CML). However, responses are variable, and causal baseline factors have not been well-studied. The type and number of low-level BCR-ABL1 mutations present after imatinib resistance has prognostic significance for subsequent treatment with nilotinib or dasatinib as second-line therapy. We therefore investigated the impact of low-level mutations detected by sensitive mass-spectrometry before ponatinib initiation (baseline) on treatment response in 363 TKI-resistant patients enrolled in the PONATINIB for Chronic Myeloid Leukemia Evaluation and Ph(+)Acute Lymphoblastic Leukemia trial, including 231 patients in chronic phase (CP-CML). Low-level mutations were detected in 53 patients (15%, including low-level T315I in 14 patients); most, however, did not undergo clonal expansion during ponatinib treatment and, moreover, no specific individual mutations were associated with inferior outcome. We demonstrate however, that the number of mutations detectable by mass spectrometry after TKI resistance is associated with response to ponatinib treatment and could be used to refine the therapeutic approach. Although CP-CML patients with T315I (63/231, 27%) had superior responses overall, those with multiple mutations detectable by mass spectrometry (20, 32%) had substantially inferior responses compared with those with T315I as the sole mutation detected (43, 68%). In contrast, for CP-CML patients without T315I, the inferior responses previously observed with nilotinib/dasatinib therapy for imatinib-resistant patients with multiple mutations were not seen with ponatinib treatment, suggesting that ponatinib may prove to be particularly advantageous for patients with multiple mutations detectable by mass spectrometry after TKI resistance.
Terlipressin decreases vascular endothelial growth factor expression and improves oxygenation in patients with acute respiratory distress syndrome and shock.

Recent clinical data suggest that treatment with terlipressin (TP) may be more advantageous for septic shock than catecholamines. However, it is unknown whether TP would be effective for acute respiratory distress syndrome (ARDS) patients with shock.



The aim of this study was to compare the impact of TP vs. dopamine on hemodynamic variables and vascular endothelial growth factor (VEGF) in ARDS patients with shock.



We studied 32 ARDS patients with shock despite fluid loading, who were randomized to receive TP (16 patients) or dopamine (16 patients). TP was administered as a continuous intravenous dose of 1.3 μg/kg/h and dopamine was administered in doses up to 20 μg/kg/min to maintain a mean arterial pressure of 70 ± 5 mm Hg for 48 h. Hemodynamic changes, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO(2)/FiO(2)), and VEGF were recorded prospectively.



There was a significant correlation between the plasma VEGF level and the lung injury score at baseline (r = 0.387, p < 0.01). VEGF concentrations significantly decreased from baseline levels in the TP group (p < 0.05) at 48 h; there was no difference in the dopamine group (p > 0.05) at 48 h vs. baseline. There was no significant difference in the tumor necrosis factor-α concentration between the groups.



TP treatment has the potential to inhibit VEGF and improve oxygenation in patients with shock in the early stage of ARDS.