nils-herrmann/clean_scirepeval huggingface dataset:
Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA Working Party on Chronic Myeloid Leukemia.

ABL kinase domain mutations have been implicated in the resistance to the BCR-ABL inhibitor imatinib mesylate of Philadelphia-positive (Ph+) leukemia patients.



Using denaturing high-performance liquid chromatography and sequencing, we screened for ABL kinase domain mutations in 370 Ph+ patients with evidence of hematologic or cytogenetic resistance to imatinib.



Mutations were found in 127 of 297 (43%) evaluable patients. Mutations were found in 27% of chronic-phase patients (14% treated with imatinib frontline; 31% treated with imatinib post-IFN failure), 52% of accelerated-phase patients, 75% of myeloid blast crisis patients, and 83% of lymphoid blast crisis/Ph+ acute lymphoblastic leukemia (ALL) patients. Mutations were associated in 30% of patients with primary resistance (44% hematologic and 28% cytogenetic) and in 57% of patients with acquired resistance (23% patients who lost cytogenetic response; 55% patients who lost hematologic response; and 87% patients who progressed to accelerated phase/blast crisis). P-loop and T315I mutations were particularly frequent in advanced-phase chronic myeloid leukemia and Ph+ ALL patients, and often accompanied progression from chronic phase to accelerated phase/blast crisis.



We conclude that (a) amino acid substitutions at seven residues (M244V, G250E, Y253F/H, E255K/V, T315I, M351T, and F359V) account for 85% of all resistance-associated mutations; (b) the search for mutations is important both in case of imatinib failure and in case of loss of response at the hematologic or cytogenetic level; (c) advanced-phase chronic myeloid leukemia and Ph+ ALL patients have a higher likelihood of developing imatinib-resistant mutations; and (d) the presence of either P-loop or T315I mutations in imatinib-treated patients should warn the clinician to reconsider the therapeutic strategy.
Cerebral oxygenation in mechanically ventilated early cardiac arrest survivors: The impact of hypercapnia.

Optimal cerebral oxygenation is considered fundamental to cerebral protection in cardiac arrest (CA) patients. Hypercapnia increases cerebral blood flow and may also improve cerebral oxygenation. It is uncertain, however, whether this effect occurs in mechanically ventilated early survivors of CA.



We enrolled mechanically ventilated resuscitated patients within 36h of their cardiac arrest. We performed a prospective double cross-over physiological study comparing the impact of normocapnia (PaCO2 35-45mmHg) vs. mild hypercapnia (PaCO2 45-55mmHg) on regional cerebral tissue oxygen saturation (SctO2) assessed by near infrared spectroscopy (NIRS).



We studied seven adult CA patients with a median time to return of spontaneous circulation of 28min at a median of 26h and 30min after CA. During normocapnia (median EtCO2 of 32mmHg [30-41mmHg] and PaCO2 of 37mmHg [32-45mmHg]) the median NIRS-derived left frontal SctO2 was 61% [52-65%] and the right frontal SctO2 was 61% [54-68%]. However, during mild hypercapnia (median EtCO2 of 49mmHg [40-57mmHg] and PaCO2 of 52mmHg [43-55mmHg) the median left frontal SctO2 increased to 69% [59-78%] and the right frontal SctO2 increased to 73% [61-76%])(p=0.001, for all comparisons).



During the early post-resuscitation period, in mechanically ventilated CA patients, mild hypercapnia increases cerebral oxygenation as assessed by NIRS. Further investigations of the effect of prolonged mild hypercapnia on cerebral oxygenation and patient outcomes appear justified.
Evaluation of Multiparametric Magnetic Resonance Imaging in Detection and Prediction of Prostate Cancer

Although European Society of Urogenital Radiology proposed the potential of multiparametric magnetic resonance imaging (MP-MRI) as a tool in the diagnostic pathway for prostate cancer (PCa) and published a unified scoring system named Prostate Imaging Reporting and Data System (PI-RADS version 1), these still need to be validated by real-life studies.



To evaluate the role of MP-MRI in detection and prediction of PCa.



Patients with clinical suspicion of PCa who underwent prebiopsy MP-MRI from 2002 to 2009 were recruited. MP-MRI results were retrospectively assigned as overall scores using PI-RADS by two radiologists. Patients were followed and the end point was the diagnosis of PCa. Receiver operating characteristics (ROC) curve was performed to test diagnostic efficacy of MP-MRI, under results of biopsy within three months. The cox proportional hazards model was used to identify independent variables for the detection of PCa.



Finally, 1113 of the 1806 enrolled patients were included for analysis. The median follow-up was 56.0 months (1-137 mo). For 582 patients biopsied within three months, area under the curve for the detection of PCa with MP-MRI was 0.88 (95% confidence interval [CI], 0.75-1.00) in group of baseline prostate specific antigen (PSA) 0.01-4.00 ng/ml (n = 31), 0.90 (95% CI, 0.84-0.95) in PSA 4.01-10.00 ng/ml (n = 142), and 0.91 (95% CI, 0.87-0.94) in PSA >10.00 ng/ml (n = 409), respectively. In the cox model adjusted for age and baseline PSA level, for the detection rate of PCa, compared with PI-RADS 1-2 (reference), the hazard ratio was 6.43 (95% CI, 4.29-9.65) for PI-RADS 3, 18.58 (95% CI, 13.36-25.84) for PI-RADS 4-5 (p < 0.001).



Prebiopsy MP-MRI with PI-RADS is demonstrated as a valuable diagnostic and predictive tool for PCa.
Social anhedonia as a predictor of the development of schizophrenia-spectrum disorders.

College undergraduates (n = 34) identified by deviant scores (at least 1.96 SD above the mean) on the Revised Social Anhedonia (SocAnh) Scale (M. Eckblad, L. J. Chapman, J. P. Chapman, & M. Mishlove, 1982) were compared with control participants (n = 139) at an initial assessment and at a 10-year follow-up evaluation. Twenty-four percent of the SocAnh group were diagnosed with schizophrenia-spectrum disorders at the follow-up compared with only 1% of the control group, despite the fact that there had been no such difference between the groups at the initial assessment 10 years earlier. The SocAnh group exceeded the control group on severity of psychotic-like experiences and had poorer overall adjustment at the follow-up but not at the initial assessment. The groups did not differ on mood symptoms or substance-use disorders. Thus, the SocAnh Scale, unlike the Perceptual Aberration and Magical Ideation Scales, appears to identify individuals at specific risk for future development of schizophrenia-spectrum disorders.
G-protein receptor kinase 4 polymorphism and response to antihypertensive therapy.

G-protein receptor kinase 4 polymorphism influences blood pressure regulation via modulation of dopamine receptor D1 in renal proximal tubular cells. We investigated the role of G-protein receptor kinase 4 polymorphism in the response to hypertensive therapy in patients with essential hypertension.



In a prospective study, we assessed the G-protein receptor kinase 4 polymorphisms R65L, A142V, and A486V in 100 hypertensive patients. We analyzed the association of the 3 gene variants on blood pressure control and response to antihypertensive therapy with single-locus analysis, haplotype analysis, and regression analysis.



Hypertensive individuals with a homozygous double variant of 65 L and 142 V needed significantly more antihypertensive treatment (number of antihypertensives 2.59 vs 1.95, P = 0.043) and especially diuretic therapy (0.82 vs 0.49, P = 0.029) to reach the same mean arterial blood pressure than did homozygous carriers of only 1 variant or heterozygous/wild-type carriers of R65L, A142V, and A486V alleles.



G-protein receptor kinase 4 polymorphism is associated with antihypertensive treatment response in patients with essential hypertension. Determination of G-protein receptor kinase 4 polymorphism may improve individual antihypertensive blood pressure control in patients with essential hypertension.
Pre-hospital cooling of patients following cardiac arrest is effective using even low volumes of cold saline

Pre-hospital induction of therapeutic mild hypothermia (TH) may reduce post-cardiac arrest brain injury in patients resuscitated from out-of-hospital cardiac arrest. Most often, it is induced by a rapid intravenous administration of as much as 30 ml/kg of cold crystalloids. We decided to assess the pre-hospital cooling effectivity of this approach by using a target dose of 15-20 ml/kg of 4°C cold normal saline in the setting of the physician-staffed Emergency Medical Service. The safety and impact on the clinical outcome have also been analyzed.



We performed a prospective observational study with a retrospective control group. A total of 40 patients were cooled by an intravenous administration of 15-20 ml/kg of 4°C cold normal saline during transport to the hospital (TH group). The pre-hospital decrease of tympanic temperature (TT) was analyzed as the primary endpoint. Patients in the control group did not undergo any pre-hospital cooling.



In the TH group, administration of 12.6 ± 6.4 ml/kg of 4°C cold normal saline was followed by a pre-hospital decrease of TT of 1.4 ± 0.8°C in 42.8 ± 19.6 min (p < 0.001). The most effective cooling was associated with a transport time duration of 38-60 min and with an infusion of 17 ml/kg of cold saline. In the TH group, a trend toward a reduced need for catecholamines during transport was detected (35.0 vs. 52.5%, p = 0.115). There were no differences in demographic variables, comorbidities, parameters of the cardiopulmonary resuscitation and in other post-resuscitation characteristics. The coupling of pre-hospital cooling with subsequent in-hospital TH predicted a favorable neurological outcome at hospital discharge (OR 4.1, CI95% 1.1-18.2, p = 0.046).



Pre-hospital induction of TH by the rapid intravenous administration of cold normal saline has been shown to be efficient even with a lower dose of coolant than reported in previous studies. This dose can be associated with a favorable impact on circulatory stability early after the return of spontaneous circulation and, when coupled with in-hospital continuation of cooling, can potentially improve the prognosis of patients.
T cell-depleted autologous hematopoietic stem cell transplantation for multiple sclerosis: report on the first three patients

Multiple sclerosis (MS) is a disease of the central nervous system characterized by immune-mediated destruction of myelin. In patients with progressive deterioration, we have intensified immunosuppression to the point of myeloablation. Subsequently, a new hematopoietic and immune system is generated by infusion of CD34-positive hematopoietic stem cells (HSC). Three patients with clinical MS and a decline of their Kurtzke extended disability status scale (EDSS) by 1.5 points over the 12 months preceding enrollment and a Kurtzke EDSS of 8.0 at the time of enrollment were treated with hematopoietic stem cell (HSC) transplantation using a myeloablative conditioning regimen of cyclophosphamide (120 mg/kg), methylprednisolone (4 g) and total body irradiation (1200 cGy). Reconstitution of hematopoiesis was achieved with CD34-enriched stem cells. The average time of follow-up is 8 months (range 6–10 months). Despite withdrawal of all immunosuppressive medications, functional improvements have occurred in all three patients. We conclude that T cell-depleted hematopoietic stem cell transplantation can be performed safely in patients with severe and debilitating multiple sclerosis. Stem cell transplantation has resulted in modest neurologic improvements for the first time since onset of progressive disease although no significant changes in EDSS or NRS scales are evident at this time.
The role of nebulised budesonide in the treatment of exacerbations of COPD.

The present study was designed to evaluate the hypothesis that nebulised budesonide (NB) might be an alternative to systemic corticosteroids (SC) in the treatment of patients with exacerbations of chronic obstructive pulmonary disease (ECOPD). Patients hospitalised with ECOPD (n = 159) were randomised into three groups. Group 1 received only standard bronchodilator treatment (SBDT), group 2 received SC (40 mg prednisolone) plus SBDT, and group 3 received NB (1,500 microg q.i.d.) plus SBDT. Improvement during 10-day hospitalisation was compared with exacerbation and rehospitalisation rates after discharge. While mean+/-sd age was 64.1+/-8.9 yrs (female/male = 0.1), mean forced expiratory volume in one second (FEV(1)) at admission was found to be 37.2+/-12.2% predicted. Arterial blood gases and spirograms recovered faster in groups 2 and 3. While improvements in arterial oxygen tension (P(a,O(2))) and forced vital capacity (FVC) in group 2, and improvements in P(a,O(2)), FVC and FEV(1) in group 3, became significant at 24-h control, the first significant improvement in group 1 appeared in arterial oxygen saturation at 72-h control. The mean improvement of P(a,O(2)) after 10 days was 1.20 and 1.06 kPa (9 and 8 mmHg) higher in group 2 and 3, respectively, than in group 1. Blood glucose exhibited an upward trend only in group 2. The study demonstrates that nebulised budesonide may be an effective and safe alternative to systemic corticosteroids in the treatment of exacerbations of chronic obstructive pulmonary disease.
Association of serum markers with improvement in clinical response measures after treatment with golimumab in patients with active rheumatoid arthritis despite receiving methotrexate: results from the GO-FORWARD study

The goal of this study was to identify serum markers that are modulated by treatment with golimumab with or without methotrexate (MTX) and are associated with clinical response.



Sera were collected at weeks 0 and 4 from a total of 336 patients (training dataset, n = 100; test dataset, n = 236) from the GO-FORWARD study of patients with active rheumatoid arthritis despite MTX. Patients were randomly assigned to receive placebo plus MTX; golimumab, 100 mg plus placebo; golimumab, 50 mg plus MTX; or golimumab, 100 mg plus MTX. Subcutaneous injections were administered every 4 weeks. Samples were tested for select inflammatory, bone, and cartilage markers and for protein profiling using multianalyte profiles.



Treatment with golimumab with or without MTX resulted in significant decreases in a variety of serum proteins at week 4 as compared with placebo plus MTX. The American College of Rheumatology (ACR) 20, ACR 50, and Disease Activity Score (DAS) 28 responders showed a distinct biomarker profile compared with nonresponding patients.



ACR 20 and ACR 50 responders among the golimumab/golimumab + MTX-treated patients had a distinct change from baseline to week 4 in serum protein profile as compared with nonresponders. Some of these changed markers were also associated with multiple clinical response measures and improvement in outcome measures in golimumab/golimumab + MTX-treated patients. Although the positive and negative predictive values of the panel of markers were modest, they were stronger than C-reactive protein alone in predicting clinical response to golimumab.



http://ClinicalTrials.gov identification number: NCT00264550.
Response to aerosol salbutamol, SCH 1000, and placebo in cystic fibrosis.

The responses of 20 patients with cystic fribrosis to a B2 agonist, salbutamol, to an anticholinergic agent, SCH 1000, and to a placebo containing difluorodichloroethane and soya lecithin delivered by metered aerosol were compared. Flow rates decreased significantly after placebo (p < 0.05). FEV1 increased significantly after salbutamol (p < 0.05), but the degree of these changes was small. There was a small but significant increase in FVC but no change in flow rates after SCH 1000. Specific conductance increased significantly (p < 0.01) after both salbutamol and SCH 1000. Thoracic gas volume remained unchanged with both drugs and placebo. Four of 20 patients had a clinically significant increase in flow rates with SCH 1000 and three with salbutamol. The consistent increases in sGaw coupled with minimal changes in flow rates, suggest that the physiological effects of both agents is to increase the compressibility of the airway. The results after placebo demonstrate the increased airway reactivity to irritants in cystic fibrosis. In view of this, attention should be paid to the possible irritant effects of inhaled medications.
Antihypertensive Treatment of Acute Intracerebral Hemorrhage by Intravenous Nicardipine Hydrochloride: Prospective Multi-Center Study

The authors performed a multicenter prospective study to evaluate the feasibility and safety of intravenous nicardipine hydrochloride for acute hypertension in patients with intracerebral hemorrhage (ICH). This study included 88 patients (mean age: 58.3 yr, range 26-87 yr) with ICH and acute hypertension in 5 medical centers between August 2008 and November 2010, who were treated using intravenous nicardipine. Administration of nicardipine resulted in a decrease from mean systolic blood pressure (BP) (175.4 ± 33.7 mmHg) and diastolic BP (100.8 ± 22 mmHg) at admission to mean systolic BP (127.4 ± 16.7 mmHg) and diastolic BP (67.2 ± 12.9 mmHg) in 6 hr after infusion (P < 0.001, mixed-effect linear models). Among patients who underwent follow-up by computed tomography, hematoma expansion at 24 hr (more than 33% increase in hematoma size at 24 hr) was observed in 3 (3.4%) of 88 patients. Neurological deterioration (defined as a decrease in initial Glasgow coma scale ≥ 2) was observed in 2 (2.2%) of 88 patients during the treatment. Aggressive nicardipine treatment of acute hypertension in patients with ICH can be safe and effective with a low rate of neurological deterioration and hematoma expansion.
Role of plasmalogens in the enhanced resistance of LDL to copper-induced oxidation after LDL apheresis.

Extracorporeal reduction of plasma low density lipoproteins (LDLs) by LDL apheresis was shown to attenuate the proatherogenic influences of LDL, such as impairment of vasodilation and increased monocyte adhesion to the endothelium. In 16 patients with familial hypercholesterolemia, we analyzed whether LDL apheresis by the heparin precipitation procedure affected the oxidative resistance of LDL. Plasma LDL cholesterol concentrations were reduced by 65% after the apheresis. The lag time of copper-mediated LDL oxidation was increased from 103 to 117 minutes (P<0.0005). The LDL contents of alpha-tocopherol and beta-carotene, as well as the ratio of monounsaturated to polyunsaturated fatty acids in LDL, were not altered. However, the LDL apheresis induced a 15% increase in the LDL contents of plasmalogen phospholipids (P<0.0005), a class of ether phospholipids that were recently shown to prevent lipid oxidation. The phosphatidylcholine (PC) to lysoPC ratio was elevated by 16% after the apheresis (P<0.0005). The percent increase in LDL plasmalogen phospholipids showed a close association with the increased lag time after apheresis (P<0.0005). The LDL plasmalogen contents of the blood samples from patients and from normolipidemic donors were also positively related to the lag time (P<0.005). In vitro loading of LDL with plasmalogen phospholipids resulted in a prolongation of the lag time and an increase in the PC/lysoPC ratio. In conclusion, the rapid rise in LDL contents of plasmalogen phospholipids most probably causes the increase in lag time after LDL apheresis. Plasmalogens appear to play an important role in the oxidation resistance of LDL in vivo.
Regional variations of low-density lipoprotein oxidizability in hemodialysis patients may explain discrepancies in interventional therapy on oxidative profile.

This study aimed at evaluating oxidative stress (OS) markers (i) in a cross-sectional study of hemodialysis (HD) patients to investigate potential regional effects of these markers and (ii) in a prospective crossover study to evaluate vitamin E-coated membrane (VE) effects.



At baseline, OS parameters including low-density lipoprotein (LDL) oxidizability were measured in HD patients from five dialysis facilities. Patients were then randomly assigned to two treatment groups: group I patients (n = 33) switching to VE, and group II patients (n = 29) still using reference polysulfone (PS) membrane. After 3 months, patients were switched from VE to PS and vice versa for 6 months. The same OS parameters were measured after each period.



At baseline, the cross-sectional analysis of LDL oxidizability showed a regional effect. By contrast, the crossover study did not show beneficial effects of VE on this parameter.



Regional variations of LDL oxidizability in HD patients exist and may explain discrepancies in interventional therapy on OS.
Dosage effects of diabetes self-management education for Mexican Americans: the Starr County Border Health Initiative.

The objective of this study was to compare two diabetes self-management interventions designed for Mexican Americans: "extended" (24 h of education, 28 h of support groups) and "compressed" (16 h of education, 6 h of support groups). Both interventions were culturally competent regarding language, diet, social emphasis, family participation, and incorporating cultural beliefs.



We recruited 216 persons between 35 and 70 years of age diagnosed with type 2 diabetes >/=1 year. Intervention groups of eight participants and eight support persons were randomly assigned to the compressed or extended conditions. The interventions differed in total number of contact hours over the year-long intervention period, with the major difference being the number of support group sessions held. The same information provided in the educational sessions of the extended intervention was compressed into fewer sessions, thus providing more information during each group meeting.



The interventions were not statistically different in reducing HbA(1c); however, both were effective. A "dosage effect" of attendance was detected with the largest HbA(1c) reductions achieved by those who attended more of the extended intervention. For individuals who attended >/=50% of the intervention, baseline to 12-month HbA(1c) change was -0.6 percentage points for the compressed group and -1.7 percentage points for the extended group.



Both culturally competent diabetes self-management education interventions were effective in promoting improved metabolic control and diabetes knowledge. A dosage effect was evident; attending more sessions resulted in greater improvements in metabolic control.