nils-herrmann/clean_scirepeval huggingface dataset:
Echocardiography of Right Ventriculoarterial Coupling Combined With Cardiopulmonary Exercise Testing to Predict Outcome in Heart Failure.

Pulmonary hypertension, which is related to right ventricular (RV) failure, indicates a poor prognosis in heart failure (HF). Increased ventilatory response and exercise oscillatory ventilation (EOV) also have a negative impact. We hypothesized that the severity classification of HF and risk prediction could be improved by combining functional capacity with cardiopulmonary exercise testing (CPET) and RV-pulmonary circulation coupling, as evaluated by the tricuspid annular plane systolic excursion (TAPSE)-pulmonary artery systolic pressure (PASP) relationship.



Four hundred fifty-nine patients with HF were assessed with Doppler echocardiography and CPET and were tracked for outcome. The subjects were followed for major cardiac events (cardiac mortality, left ventricular assist device implant, or heart transplant). Cox regression and Kaplan-Meier analyses were performed with TAPSE and PASP as individual measures that were then combined into a ratio form.



The TAPSE/PASP ratio (TAPSE/PASP) was the strongest predictor, whereas the New York Heart Association classification and EOV added predictive value. A four-quadrant group prediction risk was created based on TAPSE (< 16 mm or ≥ 16 mm) vs PASP (< 40 mm Hg or ≥ 40 mm Hg) thresholds and the CPET variables distribution as follows: group A (TAPSE > 16 mm and PASP < 40 mm Hg) presented the lowest risk (hazard ratio, 0.17) and best ventilation; group B exhibited a low risk (hazard ratio, 0.88) with depressed TAPSE (< 16 mm) and normal PASP, a preserved peak oxygen consumption (V.o2), but high ventilation. Group C had an increased risk (hazard ratio, 1.3; TAPSE ≥ 16 mm, PASP ≥ 40 mm Hg), a reduced peak V.o2, and a high EOV prevalence. Group D had the highest risk (hazard ratio, 5.6), the worse RV-pulmonary pressure coupling (TAPSE < 16 and PASP ≥ 40 mm Hg), the lowest peak V.o2, and the highest EOV rate.



TAPSE/PASP, combined with exercise ventilation, provides relevant clinical and prognostic insights into HF. A low TAPSE/PASP with EOV identifies patients at a particularly high risk of cardiac events.
Considerable delay in diagnosis and acute management of subarachnoid haemorrhage.

Rebleeding from subarachnoid haemorrhage (SAH) usually occurs within the first six hours after the initial bleeding. Rebleeding can be prevented effectively with tranexamic acid (TXA). Although a broad consensus has evolved that SAH should be treated as an emergency, it is likely that delays do exist in the diagnosis and treatment of SAH patients. The aim of this study was to prospectively assess the interval between symptom onset, emergency room (ER) admission, initial diagnosis and treatment, and final closure of the aneurysm.



We prospectively studied the time course from the initial bleeding to ER admission, computed tomography (CT), TXA treatment, referral to the neurosurgical department, and to the final closure of the aneurysm.



A total of 133 patients with SAH due to ruptured intracranial aneurysms were admitted to two neurosurgical units in Copenhagen, Denmark, during a one-year period. The median time to admission was 60 min. The median delay from admission to CT scan was 55 min. Long pre-hospital delay (p = 0.03) and high Glasgow Coma Scale score on arrival (p = 0.0006) were associated with a longer time to CT scan. The median time from CT scan to initiation of TXA treatment was 50 min. The median time from initial insult to final closure of the aneurysm was 30 hours.



The present study demonstrates that considerable diagnostic delays exist in connection with CT and TXA treatment after patients' arrival to the ER.
Probiotic supplementation prevents high-fat, overfeeding-induced insulin resistance in human subjects.

The purpose of the present study was to determine whether probiotic supplementation (Lactobacillus casei Shirota (LcS)) prevents diet-induced insulin resistance in human subjects. A total of seventeen healthy subjects were randomised to either a probiotic (n 8) or a control (n 9) group. The probiotic group consumed a LcS-fermented milk drink twice daily for 4 weeks, whereas the control group received no supplementation. Subjects maintained their normal diet for the first 3 weeks of the study, after which they consumed a high-fat (65 % of energy), high-energy (50 % increase in energy intake) diet for 7 d. Whole-body insulin sensitivity was assessed by an oral glucose tolerance test conducted before and after overfeeding. Body mass increased by 0·6 (SE 0·2) kg in the control group (P< 0·05) and by 0·3 (SE 0·2) kg in the probiotic group (P>0·05). Fasting plasma glucose concentrations increased following 7 d of overeating (control group: 5·3 (SE 0·1) v. 5·6 (SE 0·2) mmol/l before and after overfeeding, respectively, P< 0·05), whereas fasting serum insulin concentrations were maintained in both groups. Glucose AUC values increased by 10 % (from 817 (SE 45) to 899 (SE 39) mmol/l per 120 min, P< 0·05) and whole-body insulin sensitivity decreased by 27 % (from 5·3 (SE 1·4) to 3·9 (SE 0·9), P< 0·05) in the control group, whereas normal insulin sensitivity was maintained in the probiotic group (4·4 (SE 0·8) and 4·5 (SE 0·9) before and after overeating, respectively (P>0·05). These results suggest that probiotic supplementation may be useful in the prevention of diet-induced metabolic diseases such as type 2 diabetes.
Serum adipocyte fatty acid-binding protein levels in patients with critical illness are associated with insulin resistance and predict mortality

Hyperglycemia and insulin resistance are commonplace in critical illness, especially in patients with sepsis. Recently, several hormones secreted by adipose tissue have been determined to be involved in overall insulin sensitivity in metabolic syndrome-related conditions, including adipocyte fatty-acid binding protein (A-FABP). However, little is known about their roles in critical illness. On the other hand, there is evidence that several adipose tissue gene expressions change in critically ill patients.



A total of 120 patients (72 with sepsis, 48 without sepsis) were studied prospectively on admission to a medical ICU and compared with 45 healthy volunteers as controls. Various laboratory parameters and metabolic and inflammatory profiles were assessed within 48 hours after admission. Clinical data were collected from medical records.



Compared with healthy controls, serum A-FABP concentrations were higher in all critically ill patients, and there was a trend of higher A-FABP in patients with sepsis. In multivariate correlation analysis in all critically ill patients, the serum A-FABP concentrations were independently related to serum creatinine, fasting plasma glucose, total cholesterol, TNF-alpha, albumin, and the Acute Physiology and Chronic Health Evaluation II scores. In survival analysis, higher A-FABP levels (> 40 ng/ml) were associated with an unfavorable overall survival outcome, especially in sepsis patients.



Critically ill patients have higher serum A-FABP concentrations. Moreover, A-FABP may potentially serve as a prognostic biomarker in critically ill patients with sepsis.
Complex folding and misfolding effects of deer-specific amino acid substitutions in the β2-α2 loop of murine prion protein

The β2-α2 loop of PrP(C) is a key modulator of disease-associated prion protein misfolding. Amino acids that differentiate mouse (Ser169, Asn173) and deer (Asn169, Thr173) PrP(C) appear to confer dramatically different structural properties in this region and it has been suggested that amino acid sequences associated with structural rigidity of the loop also confer susceptibility to prion disease. Using mouse recombinant PrP, we show that mutating residue 173 from Asn to Thr alters protein stability and misfolding only subtly, whilst changing Ser to Asn at codon 169 causes instability in the protein, promotes oligomer formation and dramatically potentiates fibril formation. The doubly mutated protein exhibits more complex folding and misfolding behaviour than either single mutant, suggestive of differential effects of the β2-α2 loop sequence on both protein stability and on specific misfolding pathways. Molecular dynamics simulation of protein structure suggests a key role for the solvent accessibility of Tyr168 in promoting molecular interactions that may lead to prion protein misfolding. Thus, we conclude that 'rigidity' in the β2-α2 loop region of the normal conformer of PrP has less effect on misfolding than other sequence-related effects in this region.
Outpatient percutaneous endoscopic gastrostomy in selected head and neck cancer patients

Percutaneous endoscopic gastrostomy (PEG) is a relatively simple and safe method of providing access for enteral feeding. The procedure is usually performed in hospitalized patients. The feasibility of PEG as an outpatient procedure has not been well estabilished in the medical literature. The main objective of this study was to investigate the feasibility and safety of PEG as an outpatient procedure in a selected group of head and neck cancer patients. In this prospective cohort study, head and neck cancer subjects in good clinical condition were selected and enrolled in a close follow-up protocol of outpatient PEG. The clinical and demographic variables evaluated were age, gender, early complications, and timing of PEG. Of a total of 136 PEG patients, 129 (94.8%) were discharged 3 h after the procedure. Three were excluded from the study and four were hospitalized because of moderate abdominal pain. The rate of minor complications was 17.6% (local pain, 7.4%; wound infection, 6.6%; abdominal pain, 2.9%; hematoma, 0.7%). Major complications occurred in 2.2% of the procedures (buried bumper syndrome, 1.5%; early tube displacement, 0.7%). There was no mortality. Ambulatory placement of gastrostomy tubes is viable and safe in head and neck cancer patients in good clinical condition. The early complication rates are similar to those described for hospitalized patients. Unnecessary admissions are avoided and costs of hospitalization are reduced.
Concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: treatment outcomes of a prospective, multicentric clinical study.

To evaluate long-term outcome in locoregionally advanced nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy.



Between January 2006 and August 2008, 249 patients with stage III-IVb NPC were treated by IMRT plus concurrent chemotherapy in this multicenter prospective study.



With a mean follow-up of 54.1 months, the 5-year actuarial rates of overall survival (OS), local recurrence-free survival (LRFS), regional recurrence-free survival (RRFS), and distant metastasis-free survival (DMFS) were 78.4%, 86.8%, 88.4%, 78.0%, respectively. There were 29 local recurrences, 25 regional recurrences and 52 distant metastases, respectively. Distant metastasis is the main cause of treatment failure. N-stage was an independent prognostic factor for LRFS, RRFS, DMFS and OS. Acute toxicity ⩾grade III mainly consisted of mucositis (34.9%), neutropenia (11.2%), xerostomia (5.6%), and dermatitis (5.2%). The main documented late toxicity was xerostomia, and the severity of xerostomia decreased over time. At 24 months after treatment, 13.2% of patients had grade 2 xerostomia, and none had grade 3 or 4 xerostomia.



IMRT with concurrent cisplatin chemotherapy resulted in encouraging rates of local and distant control and overall survival with acceptable rates of acute and limited rates of late toxicity in patients with locoregionally advanced NPC. Distant metastasis remained the main cause of failure. More effective systemic therapy should be explored for patients with advanced N-stage.
Circulating anti-citrullinated peptide antibodies, cytokines and genotype as biomarkers of response to disease-modifying antirheumatic drug therapy in early rheumatoid arthritis

To measure circulating anti-citrullinated peptide antibodies (ACPA) and cytokines pre- and 6 months post-therapy as a strategy to predict and optimize responses to traditional disease-modifying antirheumatic drugs (DMARDs) in early RA, which is an unmet need in developing countries.



A cohort of 140 predominantly (88.5 %) black female South African patients with early RA was treated with synthetic DMARDs, mostly methotrexate (MTX) alone, or in combination with low-dose oral corticosteroids (CS). Circulating ACPA and a panel of circulating cytokines/chemokines/growth factors were measured at baseline and after 6 months of therapy in relation to disease activity and Shared Epitope (SE).



Following 6 months of therapy, the median simplified disease activity index (SDAI) declined from a baseline of 41.4 to 16.0 (p = 0.0001) for the entire cohort, which was paralleled by significant falls in median serum ACPA levels (516.6 vs. 255.7 units/ml, p = <0.0001) and several of the circulating cytokines (IL-4, IL-7, IL-8, G-CSF, VEGF; p < 0.0010 - p < 0.0001) which were most evident in the subgroup of patients treated with a combination of MTX and CS. Although biomarker concentrations decreased most notably in the low-disease activity group post-therapy, no significant correlations between these biomarkers and disease activity were observed, Baseline ACPA levels, but not SDAI or cytokines, were significantly higher in the subgroup of risk allele-positive patients (561.1 vs. 331.9 units/ml, p < 0.05), while no associations with ACPA and a smoking history were evident.



The use of DMARDs in RA is associated with significant decreases in ACPA and cytokines which did not correlate with changes in SDAI, precluding the utility of serial measurement of these biomarkers to monitor early responses to therapy, but may have prognostic value.
A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme)

Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80 % statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [18F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response.
Adaptive Estimation of Personalized Maximum Tolerated Dose in Cancer Phase I Clinical Trials Based on All Toxicities and Individual Genomic Profile

Many biomarkers have been shown to be associated with the efficacy of cancer therapy. Estimation of personalized maximum tolerated doses (pMTDs) is a critical step toward personalized medicine, which aims to maximize the therapeutic effect of a treatment for individual patients. In this study, we have established a Bayesian adaptive Phase I design which can estimate pMTDs by utilizing patient biomarkers that can predict susceptibility to specific adverse events and response as covariates.



Based on a cutting-edge cancer Phase I clinical trial design called escalation with overdose control using normalized equivalent toxicity score (EWOC-NETS), which fully utilizes all toxicities, we propose new models to incorporate patient biomarker information in the estimation of pMTDs for novel cancer therapeutic agents. The methodology is fully elaborated and the design operating characteristics are evaluated with extensive simulations.



Simulation studies demonstrate that the utilization of biomarkers in EWOC-NETS can estimate pMTDs while maintaining the original merits of this Phase I trial design, such as ethical constraint of overdose control and full utilization of all toxicity information, to improve the accuracy and efficiency of the pMTD estimation.



Our novel cancer Phase I designs with inclusion of covariate(s) in the EWOC-NETS model are useful to estimate a personalized MTD and have substantial potential to improve the therapeutic effect of drug treatment.
Effect of inhaled fluticasone on bronchial responsiveness to neurokinin A in asthma.

Neurokinin (NK) A causes airway narrowing in patients with asthma through direct and indirect mechanisms. The effects of the inhaled glucocorticosteroid fluticasone propionate (FP) on the bronchial responsiveness to NKA and methacholine were studied. Patients (n=11) with mild asthma participated in a randomized, double-blind, placebo-controlled crossover trial. FP (500 microg b.i.d.) or matched placebo was administered via Diskhaler for 14 days. Bronchial challenges were performed on days 1 and 13 (methacholine) and 0 and 14 (NKA) for each treatment period. At the active treatment period, the mean log2 provocative concentration causing a 20% fall in the forced expiratory volume in one second (PC20)+/-SEM for NKA was -12.72+/-0.63 at the beginning and -9.77+/-0.49 at the end of the period (p<0.0001), while under placebo, it was -12.16+/-0.82 and -12.19+/-0.51 respectively (NS). At the active treatment period, the mean log2 PC20 for methacholine was -5.25+/-0.40 at the beginning and -4.22+/-0.31 at the end of the period (p=0.012), while under placebo, it was -5.47+/-0.47 and -5.24+/-0.42 respectively (NS). The reduction in response to NKA was significantly larger than that for methacholine. A 2-week course of an inhaled steroid reduces bronchial responsiveness to neurokinin A, an effect more pronounced than the reduction in bronchial responsiveness to methacholine.
Prevention of early postmenopausal bone loss using low doses of conjugated estrogens and the non-hormonal, bone-active drug ipriflavone

Hormone replacement therapy is the optimal therapeutic choice for postmenopausal syndrome. While low doses of estrogens (0.3 mg/day of conjugated estrogens) can counteract neurovegetative menopausal symptoms, higher doses (0.625 mg/day of conjugated estrogens) are required to prevent bone loss in postmenopausal women. Experimental and clinical studies have shown that ipriflavone, a non-hormonal isoflavone derivative, is effective in the prevention and treatment of postmenopausal osteoporosis. The aim of the present investigation was to evaluate the efficacy and toler-ability of ipriflavone and very low doses of equine conjugated estrogens on bone loss in early postmenopausal women. Eighty-three healthy postmenopausal women (50.3±0.7 years) were enrolled for this 1-year multicenter study. All subjects were randomly allocated to receive: double placebo (n=24; group A), placebo plus conjugated equine estrogens 0.30 mg/day (n=31; group B) or conjugated equine estrogens 0.30 mg/day plus oral ipriflavone 200 mg tris in die at meals (n=28; group C), according to a double-masked design. Among women who completed the treatment period (valid completers), those of group A showed a progressive decrease in forearm bone density (FBD; measured by dual photon absorptiometry) that reached 1.7% after 12 months. The women in group B maintained their FBD in the first 6 months of treatment but, at the end of the study, showed a bone loss of 1.4% compared with basal values. By contrast, women in group C showed a significant increase in FBD after 1 year of treatment (+5.6%;p<0.01). Bothvalid completers andintention to treat analyses revealed a significant difference (p<0.05) between group A and group C over the study period. None of the treatments produced significant changes of biochemical markers of bone turnover, while hot flushes and other climacteric symptoms were significantly reduced after the sixth month of treatment in women receiving estrogens. Adverse events were generally mild, and did not differ among the groups. The results of this study suggest that low doses of estrogens combined with ipriflavone could represent a new therapeutic approach to the treatment of the postmenopausal syndrome.
Should we abstain from Gleason score 2–4 in the diagnosis of prostate cancer? Results of a German multicentre study

The present study analysed the loss of prognostic information related to the abandonment of Gleason score (GS) 2–4 by the International Society of Urological Pathology (ISUP-2005). Within a 10-year period prior to the modification of GS, 856 patients (mean age 64.2 years) underwent radical prostatectomy (RP). The grade of agreement between GS in biopsy and definitive histology was calculated by Kappa statistics (κ). Univariable and multivariable influence of different preoperatively available parameters on disease-free survival (DFS) were assessed. The mean follow-up period was 39 months. Concordance between GS in biopsy versus RP samples was 58% (κ-value 0.354) and was improved by an increased number of biopsy cores. Undergrading in biopsy was present in 38% and not significantly enhanced by an extended time-period between biopsy and RP (threshold 90d). PSA level, clinical tumour stage, fraction of positive cores (dichotomized at 34%), cases of RP per year and institution (dichotomized at 75), and GS independently influenced DFS. An upgrading to GS ≥ 7 was found in only 5.7% of patients presenting with GS 2–4 in the biopsy. Independent from definitive histology, patients with GS 2–4 had a significantly better prognosis compared to patients with a higher GS. The present study shows an independent prognostic impact of GS in biopsy samples classified according to the previous classification. The elimination of GS 2–4 by the ISUP 2005 results in a considerable loss of pretherapeutic prognostic information and therefore should be questioned in particular with regard to the increasing demand for active surveillance regimens.