nils-herrmann/clean_scirepeval huggingface dataset:
Geographic distribution and origin of CFTR mutations in Germany

The geographic distribution and origin of CFTR mutations in Germany was evaluated in 658 three-generation families with cystic fibrosis (CF). Fifty different mutations were detected on 1305 parental CF chromosomes from 22 European countries and overseas. The major mutation ΔF508 was identified on 71.5% of all CF chromosomes, followed by R553X (1.8%), N1303K (1.3%), G542X (1.1%), G551D (0.8%) and R347P (0.8%). According to the grandparents' birthplace, 74% of CF chromosomes had their origin in Germany; the ΔF508 percentage was 77%, 75%, 70% and 62% in northern, southern, western and eastern Germany, respectively. Ten or more mutant alleles in the investigated CF gene pool originated from Austria, the Czech Republic, Poland, Russia, Turkey and the Ukraine. This widespread geographic origin of CFTR mutations in today's Germany reflects the many demographic changes and migrations in Central Europe during the 20th century.
Early cure rates with narrow-margin slow-Mohs surgery for periocular malignant melanoma.

Staged excision with rush-processed paraffin-embedded tissue sections (Slow-Mohs) is an effective treatment for periocular melanoma. Although there is no consensus on initial margins of excision, narrower margins in the eyelids have the functionally and cosmetically important consequence of smaller postoperative wounds.



To report early cure rates for periocular melanoma using Slow-Mohs surgery with en-face margin sectioning.



Retrospective, multicenter, noncomparative case series. Slow-Mohs surgery in 14 patients with periocular melanoma from 2000 to 2006.



Fourteen patients underwent 14 Slow-Mohs procedures for eight lentigo maligna, one nodular, and one superficial spreading melanoma, and four lentigo maligna, 12 primary, and two recurrent tumors. The most common site was the lower eyelid (8/14, 57.1%). Breslow thickness ranged from 0.27 to 1.70 mm, with four cases less than 0.76 mm and one case greater than 1.5 mm. Five cases were a Clark level II or greater. Complete excision was achieved with one level (6 cases) or two or three levels (8 cases), with 2- to 3-mm margins at each level in all but one case. With median follow-up of 36 months, there were two local recurrences (2/14, 14.3%).



Slow-Mohs with en-face sections achieves similar early cure rates to previously published margin-controlled excision techniques. Narrow margins of excision can optimize tissue preservation without compromising outcome.
Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901.

Although often investigated in locally advanced esophageal cancer (EC), the impact of neoadjuvant chemoradiotherapy (NCRT) in early stages is unknown. The aim of this multicenter randomized phase III trial was to assess whether NCRT improves outcomes for patients with stage I or II EC.



The primary end point was overall survival. Secondary end points were disease-free survival, postoperative morbidity, in-hospital mortality, R0 resection rate, and prognostic factor identification. From June 2000 to June 2009, 195 patients in 30 centers were randomly assigned to surgery alone (group S; n = 97) or NCRT followed by surgery (group CRT; n = 98). CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m(2) and cisplatin 75 mg/m(2). We report the long-term results of the final analysis, after a median follow-up of 93.6 months.



Pretreatment disease was stage I in 19.0%, IIA in 53.3%, and IIB in 27.7% of patients. For group CRT compared with group S, R0 resection rate was 93.8% versus 92.1% (P = .749), with 3-year overall survival rate of 47.5% versus 53.0% (hazard ratio [HR], 0.99; 95% CI, 0.69 to 1.40; P = .94) and postoperative mortality rate of 11.1% versus 3.4% (P = .049), respectively. Because interim analysis of the primary end point revealed an improbability of demonstrating the superiority of either treatment arm (HR, 1.09; 95% CI, 0.75 to 1.59; P = .66), the trial was stopped for anticipated futility.



Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC.
Comparative effectiveness of antihypertensive treatment for older children with primary hypertension: study protocol for a series of n-of-1 randomized trials

Children are increasingly being diagnosed with primary hypertension. The absence of comparative effectiveness research of antihypertensive medications in children has contributed to considerable differences in prescribing practices among physicians treating children with primary hypertension. Even if parallel-group trials had established a best overall choice for most of these children, the best medication for an individual may differ from the best overall medication.



This project consists of a series of systematically administered n-of-1 trials among older children to verify the need for ongoing antihypertensive treatment and, if so, to identify the preferred single drug therapy from among the three major classes of drugs commonly used for primary hypertension (angiotensin-converting enzyme inhibitors, calcium channel blockers, and diuretics). We will determine whether one of these is the preferred therapy for the great majority of patients. The "preferred" therapy is the drug which produces normal ambulatory blood pressure, with the greatest reduction in blood pressure without unacceptable side effects. We will recruit 50 patients from the Houston Pediatric and Adolescent Hypertension Program clinic. For each patient, the three drugs will be prescribed in random order and each drug will be taken for 2 weeks. The effectiveness of each therapy will be measured with 24-h ambulatory blood pressure monitoring, and tolerability will be assessed using a side effect questionnaire. Participants will rotate through treatment periods, repeating drugs and adjusting doses until the preferred therapy is identified. In assessing whether one of the medications is most effective for the majority of subjects, the primary outcome will be the percentage of participants for whom each drug is selected as the preferred therapy. We hypothesize that no drug will be selected for the great majority of the subjects, a finding that would support consideration of clinical use of n-of-1 trials. Secondary analyses will explore whether patient characteristics predict which medication will be selected as a preferred drug.



This study will help optimize care of participating patients and provide evidence regarding the usefulness of n-of-1 trials in identifying appropriate treatment for children with hypertension and potentially other disorders.
Spot urine sodium excretion as prognostic marker in acutely decompensated heart failure: the spironolactone effect

Loop diuretic resistance characterized by inefficient sodium excretion complicates many patients with acutely decompensated heart failure (ADHF). Mineralocorticoid receptor antagonists (MRAs) in natriuretic doses may improve spot urine sodium excretion and outcomes. Our primary aim was to assess the association of high-dose spironolactone with short-term spot urine sodium excretion, and our secondary aim was to determine if this higher short-term spot urine sodium excretion is associated with reduction in the composite clinical outcome (of cardiovascular mortality and/or ADHF hospitalization) event rate at 180 days. Single-centre, non-randomized, open-label study enrolling 100 patients with ADHF. Patients were treated with standard ADHF therapy alone (n = 50) or oral spironolactone 100 mg/day plus standard ADHF therapy (n = 50). Spot urine samples were collected at day 1 and day 3 of hospitalization. Spironolactone group had significantly higher spot urine sodium levels compared to standard care group at day 3 (84.13 ± 28.71 mmol/L vs 70.74 ± 34.43 mmol/L, p = 0.04). The proportion of patients with spot urinary sodium <60 mmol/L was lower in spironolactone group at day 3 (18.8 vs 45.7, p = 0.01). In multivariate analysis, spironolactone was independently associated with increased spot urinary sodium and urinary sodium/potassium ratio of >2 at day 3 (both, p < 0.05). Higher spot urine sodium levels were associated with a lower event rate [HR for urinary sodium >100 mmol/L = 0.16 (0.06–0.42), p < 0.01, compared to <60], and provided a significant prognostic gain measured by net reclassification indexes. Spot urinary sodium levels >60 mmol/L and urinary sodium/potassium ratio >2 measured at day 3 of hospitalization for ADHF are associated with improved mid-term outcomes. Spironolactone is associated with increased spot urinary sodium and sodium/potassium ratio >2.
[Supported own initiative of rehabilitation patients ("new credo") - longterm effects of the nonrandomized trial].

Our project is closely related to the previous study "Rehabilitation aftercare - a new credo for rehabilitation clinics"; the intensified aftercare-strategy was developed by an interdisciplinary group of health professionals and scientists for patients with chronic back pain. Main objective is the resumption and maintenance of regular physical activity in everyday life of pa-tients undergoing rehabilitation. The aim of our present study was to evaluate the long-term (24-month-follow-up) efficacy of the "New Credo" (inpatient medical rehabilitation+intensified aftercare=IG) as compared with usual care (inpatient medical rehabilitation=CG).



We conducted a prospective controlled multicentre trial (IG: 3 clinics vs. CG: 3 clinics) with 4 points of measurement (T0: before and T1: after rehabilitation as well as T3: 12 and T4: 24 month after discharge). We enrolled rehabilitants with a primary diagnosis of chronic back pain (ICD-10: M51-54) who had given their consent. Exclusion criteria were mental and/or psychological impairments as well as surgery in the past 6 months. Primary Outcomes included restriction of social participation (IMET) and functional capacity (FFbH-R). Treatment effects were evaluated using analyses of variance and adjusting for differences between baseline -values; furthermore we calculated effect sizes (SMDInter, SMDIntra, ORs).



Complete data were available for 123 IG-rehabilitants and 299 CG-participants (Completer-Analysis, response: 52%). Regarding restriction in functional capacity in everyday life (FFbH-R) multivariate analysis confirmed a treatment*time interaction, the appropriate effect-sizes showed no significant effects (SMDInter and SMDIntra). With respect to long-term effects 24 months after discharge no significant effects were found for social participation, however. With respect to secondary outcomes there are no significant differences between the groups (SMDInter, ORs); in fact rehabilitants of both groups showed similar effects (SMDIntra) in most cases.



In summary our results doesn't confirm that the intensified aftercare-programme is able to improve longer-term effectiveness of inpatient orthopaedic rehabilitation up to 24 month.
Atherosclerotic plaque vulnerability as an explanation for the increased risk of stroke in elderly undergoing carotid artery stenting.

Recent randomized trials showed an increased periprocedural risk for stroke with increasing age in patients undergoing carotid artery stenting. Manipulation of atherosclerotic plaques during carotid artery stenting can result in plaque rupture with subsequent superimposed thrombus formation, embolization, and cerebrovascular events. We hypothesized that atherosclerotic plaques become more unstable with increasing age and thereby might provide insight into the age-related increased risk of cerebrovascular events during carotid artery stenting.



Carotid atherosclerotic plaques were harvested from 1385 consecutive patients undergoing carotid endarterectomy between 2002 and 2010. Carotid plaques were quantitatively analyzed for macrophages, smooth muscle cells, and microvessels; and semiquantitatively analyzed for collagen, calcifications lipid cores, and intraplaque hemorrhages. Patients were divided in 4 groups by age: <60, 60 to 69, 70 to 79, and ≥80 years. Measures of association between age as a continuous variable and histological characteristics were also calculated.



Increasing age was associated with a decrease in the amount of smooth muscle cells in the carotid plaque. More plaques with large atheroma and heavy plaque calcifications were observed among elderly patients. After correction for baseline differences, risk factors, and medication use, age was independently associated with a more vulnerable carotid plaque composition.



Plaque stability decreases gradually with age. Older patients with carotid stenosis have relatively unstable plaques with low smooth muscle cell content, a high amount of large lipid cores, and more calcified plaques as compared with younger patients. The underlying vulnerable plaque composition in the elderly might be an important contributing factor to the increased risk of stroke for older patients undergoing carotid artery stenting.
Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells.

Chronic myeloid leukemia (CML) stem and progenitor cells overexpress BcrAbl and are insensitive to imatinib mesylate (IM). We therefore investigated whether these cells were efficiently targeted by nilotinib. In K562, the inhibitory concentration (IC50) of nilotinib was 30 nM versus 600 nM for IM, consistent with its reported 20-fold-higher potency. However, in primary CD34(+) CML cells, nilotinib and IM were equipotent for inhibition of BcrAbl activity, producing equivalent but incomplete reduction in CrkL phosphorylation at 5 microM. CML CD34(+) cells were still able to expand over 72 hours with 5 microM of either drug, although there was a concentration-dependent restriction of amplification. As for IM, the most primitive cells (CFSE(max)) persisted and accumulated over 72 hours with nilotinib and remained caspase-3 negative. Furthermore, nilotinib with IM led to further accumulation of this population, suggesting at least additive antiproliferative effects. These results confirmed that, like IM, the predominant effect of nilotinib is antiproliferative rather than proapoptotic.
Endo-laparoscopic approach versus conventional open surgery in the treatment of obstructing left-sided colon cancer: long-term follow-up of a randomized trial.

We previously conducted a randomized trial comparing the endo-laparoscopic approach (i.e. placing self-expanding metallic stents followed by laparoscopic resection) and conventional open surgery in the treatment of obstructing left-sided colon cancer. This study is a follow-up of the previous randomized trial and aims to report the long-term outcomes of the two groups.



Forty-eight patients from the randomized trial were followed up in an outpatient clinic with regular monitoring. Patients were compared for clinicopathological variables, disease recurrence and survival rates.



Clinicopathological details were comparable between the two groups. During the median follow-up periods of 32 months for the open group and 65 months endo-laparoscopic group, no statistically significant difference was observed between the groups in disease recurrence rate, 5-year overall survival (27% vs 48%, P = 0.076) and 5-year disease-free survival rates (48% vs 52%, P = 0.63).



Besides being a safe bridge to subsequent elective laparoscopic surgery, preoperative self-expanding metallic stents insertion does not adversely affect oncological outcomes and patient survival. Based on our data, the endo-laparoscopic approach is the treatment of choice for patients presenting with malignant left-sided colonic obstruction.
BDNF Levels and Genotype are Associated with Antipsychotic-Induced Weight Gain in Patients with Chronic Schizophrenia

Recent evidence suggests that centrally released brain-derived neurotrophic factor (BDNF) modulates eating behavior and metabolism that is responsible for body weight fluctuation. BDNF also may play an important role in the therapeutic action of antipsychotic medications. We investigated whether the Val66Met polymorphism of the BDNF gene affected weight gain after long-term antipsychotic treatment in schizophrenia. The polymorphism was genotyped in 196 Chinese patients with schizophrenia on long-term antipsychotic medication. Serum BDNF was measured in all patients and 50 normal controls. Mean body mass index (BMI) change was evaluated retrospectively by means of clinical records. The results showed that there was a significant relationship between the three BDNF Val/Met genotypes and mean BMI gain, with genotype having a strong effect on BMI gain in male but not female patients. BDNF levels were significantly lower in patients than normal controls, and negatively correlated with BMI gain in female but not male patients. Our results suggest that variation in the BDNF gene may be a risk factor for weight gain in male patients with schizophrenia on long-term antipsychotic treatment, and decreased BDNF levels may be associated with weight gain in females.
Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).

In adult Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), minimal residual disease (MRD) after stem cell transplantation (SCT) is associated with a relapse probability exceeding 90%. Starting imatinib in the setting of MRD may decrease this high relapse rate. In this prospective multicenter study, 27 Ph+ ALL patients received imatinib upon detection of MRD after SCT. Bcr-abl transcripts became undetectable in 14 (52%) of 27 patients, after a median of 1.5 months (0.9-3.7 months) ((early)CR(mol)). All patients who achieved an (early)CR(mol) remained in remission for the duration of imatinib treatment; 3 patients relapsed after imatinib was discontinued. Failure to achieve polymerase chain reaction (PCR) negativity shortly after starting imatinib predicted relapse, which occurred in 12 (92%) of 13 patients after a median of 3 months. Disease-free survival (DFS) in (early)CR(mol) patients is 91% +/- 9% and 54% +/- 21% after 12 and 24 months, respectively, compared with 8% +/- 7% after 12 months in patients remaining MRD+ (P < .001). In conclusion, approximately half of patients with Ph+ ALL receiving imatinib for MRD positivity after SCT experience prolonged DFS, which can be anticipated by the rapid achievement of a molecular complete remission (CR). Continued detection of bcr-abl transcripts after 2 to 3 months on imatinib identifies patients who will ultimately experience relapse and in whom additional or alternative antileukemic treatment should be initiated.
Impact of certolizumab pegol on patient-reported outcomes in rheumatoid arthritis and correlation with clinical measures of disease activity

The effect of certolizumab pegol (CZP) on patient-reported outcomes (PROs) was investigated in 1063 patients with rheumatoid arthritis (RA) from the REALISTIC trial (double-blind, placebo-controlled to week 12, open-label to week 28; randomized 4:1 [CZP:placebo]). Correlations between PROs and RA signs and symptoms, and the relative efficacy of these measures, were examined.



Adults with RA and an inadequate response to at least one disease-modifying antirheumatic drug were enrolled. PROs assessed included physical function (using the Health Assessment Questionnaire-Disability Index), pain, fatigue, sleep disturbance, Patient Global Assessment of Disease Activity (PtGA), Routine Assessment of Patient Index Data 3 (RAPID3), and Rheumatoid Arthritis Disease Activity Index (RADAI).



Early significant and clinically meaningful improvements in all PROs were observed to week 12 with CZP vs. placebo and were maintained to the end of the trial (week 28). At week 12, up to one-third more CZP patients showed improvements compared with placebo that were greater than or equal to the minimal clinically important difference (MCID) in fatigue, sleep problems, pain, PtGA, RADAI, and RAPID3. The changes in PROs were correlated with clinical measures of disease activity, including the Disease Activity Score in 28 joints using C-reactive protein as well as tender and swollen joint counts.



Rapid improvements in PROs were seen in patients with RA treated with CZP. The magnitude of improvement exceeded the MCID in multiple domains and demonstrated that CZP improves aspects of health-related quality of life that are meaningful to patients and superior to placebo. PROs provide information complementary to clinical outcomes in assessment of treatment benefits.
Phase 1 and pharmacokinetic study of intravenous irinotecan in refractory solid tumor patients with hepatic dysfunction.

To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule.



Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 x institutional upper limit of normal (IULN) and ALT/AST <or=5.0 x IULN; Group 2 (n = 7): total bilirubin 3.1 to 5.0 x IULN and ALT/AST <or=5.0 x IULN; Group 3 (n = 6): total bilirubin <or=1.5 x IULN and ALT/AST 5.1 to 20.0 x IULN; Group 4 (n = 10): total bilirubin 1.5 to 3.0 x IULN and ALT/AST 5.1 to 20.0 x IULN. Irinotecan was given as a 90-minute i.v. infusion weekly for the first 4 weeks in each 6-week cycle at starting doses which escalated from 40 to as much as 75 mg/m(2). After the first treatment, doses were adjusted based on individual patient toxicities. Starting doses for patients with hepatic dysfunction were derived from the maximum tolerated doses noted in the four hepatic dysfunction groups.



Forty-two patients were treated. Among the most frequent adverse events were neutropenia (41%, grades 3/4), diarrhea (15%, grades 3/4), nausea (10%, grade 3), and vomiting (5%, grades 3/4). Two patients died from drug-induced neutropenic sepsis. Two patients had objective tumor responses (complete response, liver metastases from unknown primary; partial response, colon cancer). Hepatic dysfunction reduced irinotecan clearance while increasing relative exposure to the active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38 exposures in patients receiving doses of 40 to 75 mg/m(2) were comparable to exposures in patients with normal liver function treated with a starting dose of 125 mg/m(2).



Irinotecan starting doses that seem to be safe for hepatically impaired patients treated with the weekly schedule are 60, 50, 60, and 40 mg/m(2) for groups 1 to 4, respectively. At these starting doses, exposure to SN-38 and the adverse event profile are similar to that observed in patients with normal liver function and antitumor activity can be observed.