nils-herrmann/clean_scirepeval huggingface dataset:
Novel Role of ADAMTS-5 Protein in Proteoglycan Turnover and Lipoprotein Retention in Atherosclerosis*

Atherosclerosis is initiated by the retention of lipoproteins on proteoglycans in the arterial intima. However, the mechanisms leading to proteoglycan accumulation and lipoprotein retention are poorly understood. In this study, we set out to investigate the role of ADAMTS-5 (a disintegrin and metalloprotease with thrombospondin motifs-5) in the vasculature. ADAMTS-5 was markedly reduced in atherosclerotic aortas of apolipoprotein E-null (apoE(-/-)) mice. The reduction of ADAMTS-5 was accompanied by accumulation of biglycan and versican, the major lipoprotein-binding proteoglycans, in atherosclerosis. ADAMTS-5 activity induced the release of ADAMTS-specific versican (DPEAAE(441)) and aggrecan ((374)ALGS) fragments as well as biglycan and link protein from the aortic wall. Fibroblast growth factor 2 (FGF-2) inhibited ADAMTS-5 expression in isolated aortic smooth muscle cells and blocked the spontaneous release of ADAMTS-generated versican and aggrecan fragments from aortic explants. In aortas of ADAMTS-5-deficient mice, DPEAAE(441) versican neoepitopes were not detectable. Instead, biglycan levels were increased, highlighting the role of ADAMTS-5 in the catabolism of vascular proteoglycans. Importantly, ADAMTS-5 proteolytic activity reduced the LDL binding ability of biglycan and released LDL from human aortic lesions. This study provides the first evidence implicating ADAMTS-5 in the regulation of proteoglycan turnover and lipoprotein retention in atherosclerosis.
A randomized controlled study comparing room air with carbon dioxide for abdominal pain, distention, and recovery time in patients undergoing colonoscopy.

Colonoscopy remains the gold standard for colorectal cancer screening. Many barriers to the procedure exist including the possibility of abdominal discomfort that may occur with insufflation. Carbon dioxide (CO2), which is rapidly absorbed in the blood stream, is an alternate method used to distend the lumen during colonoscopy. The goal of this study was to compare patient discomfort, abdominal girth, and recovery time in 2 groups of patients randomized to CO2 versus room air insufflation during colonoscopy. Using a Wong-Baker score, we found statistical difference in postprocedural discomfort levels (CO2 Group: 1.15 ± 2.0 vs. room air: 0.41 ± 0.31, p = .015) and a significantly greater increase in abdominal girth over CO2 immediately postprocedure (room air: 1.06 ± 1.29 inches vs. CO2: 0.56 ± 0.73 inches, p = .054) girth immediately postprocedure; however, recovery time was similar between the 2 study arms (CO2: 9.1 ± 16.2 minutes vs. room air: 10.2 ± 18.6 minutes, p = .713). Further studies are needed to determine whether CO2 is cost-effective and improves patient satisfaction with colonoscopy.
Acute Serotonin and Dopamine Depletion Improves Attentional Control: Findings from the Stroop Task

Schizophrenia is associated with impairments of attentional control on classic experimental paradigms such as the Stroop task. However, at a basic level the neurochemical mechanisms that may be responsible for such impairments are poorly understood. In this study, we sought to investigate the influence of brain monoamine function on Stroop task performance in healthy participants using the established methods of acute dietary serotonin, dopamine, and combined monoamine depletion. The study was a double-blind placebo controlled design in which 12 healthy male participants completed the Stroop task under four acute treatment conditions: (a) balanced/placebo control, (b) acute tryptophan depletion, (c) acute tyrosine/phenylalanine depletion, and (d) acute tyrosine/phenylalanine/tryptophan depletion (combined monoamine depletion). Decreased Stroop interference indicating improved attentional control was observed after both tryptophan depletion and tyrosine/phenylalanine depletion, while there was no significant change in interference after combined monoamine depletion. Findings suggest that reduced tonic dopamine or serotonin activity within specific neural circuits (such as the striatum, anterior cingulate, or prefrontal cortex) may play a critical role in attentional control, possibly by improving gating of information via reducing noise in monoaminergic systems. These findings enhance our understanding of the neurochemical basis of attentional control and the possible cause of attentional control deficits in schizophrenia.
Risk, predictors, and mortality associated with non-AIDS events in newly diagnosed HIV-infected patients: role of antiretroviral therapy.

We aimed to characterize non-AIDS events (NAEs) occurring in newly diagnosed HIV-infected patients in a contemporary cohort.



The Cohort of the AIDS Research Network (CoRIS) is a prospective, multicenter cohort of HIV-infected adults antiretroviral naive at entry, established in 2004. We evaluated the incidence of and the mortality due to NAEs and AIDS events through October 2010. Poisson regression was used to investigate factors associated with a higher incidence of NAEs.



Overall, 5185 patients (13.306 person-years of follow-up), median age (interquartile range) 36 (29-43) years, participated in the study. A total of 86.5% patients had been diagnosed in 2004 or later. The incidence rate of NAEs was 28.93 per 1000 person-years [95% confidence interval (CI) 26.15-32.07], and of AIDS-defining events 25.23 per 1000 person-years (95% CI 22.60-28.16). The most common NAEs were psychiatric, hepatic, malignant, renal, and cardiovascular related. After adjustment, age, higher HIV-viral load, and lower CD4 cell count at cohort entry were associated with the occurrence of NAEs, whereas likelihood significantly decreased with sexual transmission and higher educational level. Additionally, antiretroviral therapy was inversely associated with the development of some NAEs, specifically of psychiatric [incidence rate ratio (95% CI) 0.54 (0.30-0.96)] and renal-related [incidence rate ratio (95% CI) 0.31 (0.13-0.72)] events. One hundred and seventy-three (3.33%) patients died during the study period. NAEs contributed to 28.9% of all deaths, with an incidence rate (95% CI) of 3.75 (2.84-4.94) per 1000 person-years.



In patients newly diagnosed with HIV infection, NAEs are a significant cause of morbidity and mortality. Our results suggest a protective effect of antiretroviral therapy in the occurrence of NAEs, in particular of psychiatric and renal-related events.
Influence of smoking and plasma factors on patency of femoropopliteal vein grafts.

To determine the effects of smoking, plasma lipids, lipoproteins, apolipoproteins, and fibrinogen on the patency of saphenous vein femoropopliteal bypass grafts at one year.



Prospective study of patients with saphenous vein femoropopliteal bypass grafts entered into a multicentre trial.



Surgical wards, outpatient clinics, and home visits coordinated by two tertiary referral centres in London and Birmingham.



157 Patients (mean age 66.6 (SD 8.2) years), 113 with patent grafts and 44 with occluded grafts one year after bypass.



Cumulative percentage patency at one year.



Markers for smoking (blood carboxyhaemoglobin concentration (p less than 0.05) and plasma thiocyanate concentration (p less than 0.01) and plasma concentrations of fibrinogen (p less than 0.001) and apolipoproteins AI (p less than 0.04) and (a) (p less than 0.05) were significantly higher in patients with occluded grafts. Serum cholesterol concentrations were significantly higher in patients with grafts that remained patent one year after bypass (p less than 0.005). Analysis of the smoking markers indicated that a quarter of patients (40) were untruthful in their claims to have stopped smoking. Based on smoking markers, patency of grafts in smokers was significantly lower at one year by life table analysis than in non-smokers (63% v 84%, p less than 0.02). Patency was significantly higher by life table analysis in patients with a plasma fibrinogen concentration below the median than in those with a concentration above (90% v 57%, p less than 0.0002). Surprisingly, increased plasma low density lipoprotein cholesterol concentration was significantly associated with improved patency at one year (85%) at values above the median compared with patency (only 68%) at values in the lower half of the range (p less than 0.02).



Plasma fibrinogen concentration was the most important variable predicting graft occlusion, followed by smoking markers. A more forceful approach is needed to stop patients smoking; therapeutic measures to improve patency of vein grafts should focus on decreasing plasma fibrinogen concentration rather than serum cholesterol concentration.
On an Application of Dynamic Programming to the Synthesis of Logical Systems

In this paper we wish to initiate the study of the application of dynamic programming to the domain of problems arising in the synthesis of logical systems.
In a number of fields one encounters the problem of converting a system in one state into another state in a most efficient fashion—in mathematical economics, in the theory of control processes, in network theory, and in trajectory processes. Here we wish to consider a type of question which arises in the design of computers and switching circuits.
We shall first treat the problem in general terms, and then consider a special example to illustrate the methods.
Multicenter Analysis of the SLC6A3/DAT1 VNTR Haplotype in Persistent ADHD Suggests Differential Involvement of the Gene in Childhood and Persistent ADHD

Attention deficit/hyperactivity disorder (ADHD) is one of the most common neuropsychiatric disorders with a worldwide prevalence around 4–5% in children and 1–4% in adults. Although ADHD is highly heritable and familial risk may contribute most strongly to the persistent form of the disorder, there are few studies on the genetics of ADHD in adults. In this paper, we present the first results of the International Multicentre Persistent ADHD Genetics CollaboraTion (IMpACT) that has been set up with the goal of performing research into the genetics of persistent ADHD. In this study, we carried out a combined analysis as well as a meta-analysis of the association of the SLC6A3/DAT1 gene with persistent ADHD in 1440 patients and 1769 controls from IMpACT and an earlier report. DAT1, encoding the dopamine transporter, is one of the most frequently studied genes in ADHD, though results have been inconsistent. A variable number tandem repeat polymorphism (VNTR) in the 3′-untranslated region (UTR) of the gene and, more recently, a haplotype of this VNTR with another VNTR in intron 8 have been the target of most studies. Although the 10/10 genotype of the 3′-UTR VNTR and the 10-6 haplotype of the two VNTRs are thought to be risk factors for ADHD in children, we found the 9/9 genotype and the 9-6 haplotype associated with persistent ADHD. In conclusion, a differential association of DAT1 with ADHD in children and in adults might help explain the inconsistencies observed in earlier association studies. However, the data might also imply that DAT1 has a modulatory rather than causative role in ADHD.
Pharmacokinetics of sodium valproate in epileptic patients: Prediction of maintenance dosage by single-dose study

Pharmacokinetic analysis of the plasma valproic acid concentration-time course, following a single oral dose (600 mg) of sodium valproate, was performed in 20 epileptic patients as an aid to the prediction of a proper chronic dosage regimen. A simple one-compartment model was found inadequate to describe the drug concentration-time course in 15 of the 20 patients studied. The average elimination (β phase) half-life of 9 h was shorter than that previously reported in healthy subjects. The latter observation and the wide variation in plasma valproic acid clearance observed between patients (0.09–0.53 ml/kg/min) may have been related to its altered disposition by concomitant anticonvulsant therapy. Sodium valproate maintenance therapy, determined by single-dose pharmacokinetic prediction of steady-state plasma valproic acid levels, did not require dosage adjustment because of unwanted effects. However, the occurrence of drug-related adverse events led to dosage reduction in 4 of 9 patients whose chronic therapy was not pharmacokinetically predicted. Moreover, the pharmacokinetic variability demonstrated for sodium valproate by patients on multiple therapy, whose chronic sodium valproate therapy was pharmacokinetically predicted, indicates the value of monitoring plasma valproic acid levels for the regulation of anticonvulsant therapy.
Sinonasal characteristics and quality of life by SNOT-22 in adult patients with cystic fibrosis

The prevalence of chronic sinus disease in cystic fibrosis (CF) has gradually increased. Sinonasal involvement may have influence on pulmonary exacerbations and can have a negative impact on the quality of life. To evaluate nasal characteristics and quality of life in adult patients with CF; to establish an association and determine the predictors in SNOT-22 questionnaire. Cross- sectional study with prospective data collection was performed to evaluate adult CF patients. Patients underwent clinical evaluation, lung function tests, nasal endoscopy, and paranasal sinuses CT scan. All the patients answered the SNOT-22 questionnaire.  A total of 91 patients were allocated, of which, 45.1% were male. Patients were divided into three groups by SNOT-22. A high average age, late age of diagnosis, rhinitis symptoms, and clinical criteria for rhinosinusitis were observed more frequently in patients with high SNOT-22 scores (p < 0.05). Overall, 84.6% patients had abnormal CT findings, with aplasia/hypoplasia of the sphenoid sinus being the most common finding. In multiple regression model, age, female gender, and Pseudomonas aeruginosa in the sputum were associated with high SNOT-22 scores in the nasal domain. Hyposmia and lack of medial bulging of lateral nasal wall were variables associated with high SNOT-22 scores in the quality of life domain. In total score, there was a positive association with age and the presence of P. aeruginosa in sputum. Despite high prevalence of abnormal tomographic findings, patients reported mild intensity of sinonasal symptoms. Advanced age and the presence of P. aeruginosa were associated with higher SNOT-22 scores.
Interleukin-25 Mediates Transcriptional Control of PD-L1 via STAT3 in Multipotent Human Mesenchymal Stromal Cells (hMSCs) to Suppress Th17 Responses

Multipotent human mesenchymal stromal cells (hMSCs) harbor immunomodulatory properties that are therapeutically relevant. One of the most clinically important populations of leukocytes is the interleukin-17A (IL-17A)-secreting T (Th17) lymphocytes. However, mechanisms of hMSC and Th17 cell interactions are incompletely resolved. We found that, along with Th1 responses, hMSCs strongly suppressed Th17 responses and this required both IL-25--also known as IL--17E-as well as programmed death ligand-1 (PD-L1), a potent cell surface ligand for tolerance induction. Knockdown of IL-25 expression in hMSCs abrogated Th17 suppression in vitro and in vivo. However, IL-25 alone was insufficient to significantly suppress Th17 responses, which also required surface PD-L1 expression. Critically, IL-25 upregulated PD-L1 surface expression through the signaling pathways of JNK and STAT3, with STAT3 found to constitutively occupy the proximal region of the PD-L1 promoter. Our findings demonstrate the complexities of hMSC-mediated Th17 suppression, and highlight the IL-25/STAT3/PD-L1 axis as a candidate therapeutic target.
Locoregional cellular immunotherapy for patients with advanced esophageal cancer.

The objectives of the present study were to determine the safety of locoregional administration of autologous lymphocytes stimulated with autologous tumor cells and interleukin (IL) 2 in vitro and to find laboratory markers to predict either clinical toxicity or clinical response. Eleven patients with advanced (n = 4) or recurrent (n = 7) esophageal cancers received the locoregional administration of these activated lymphocytes every 2 weeks for two to nine times (mean, 5.6 times), and mean numbers of the administered cells were 0.8 x 10(9) cells per treatment. The activated lymphocytes that were pretested for their surface markers and CTL activity were endoscopically injected into primary tumor sites (n = 4) or directly injected into metastatic lymph nodes (n = 2), pleural (n = 4) or ascitic (n = 1) regions. Grade 3 hypotension, grade 2 diarrhea, and grade 1 fever were observed in 1, 1, and 6 patients, respectively, and there was no adverse effect in the remaining three patients. The clinical outcome was as follows: one, complete response (CR); three, partial response (PR); two, stable response (SR); and five, progressive disease (PD). CTL activity in the administered cells was observed in 5 of the 11 patients (1 CR, 3 PR, and 1 PD) and was not observed in the remaining 6 patients (2 SR and 4 PD). Percentages of CD16+ cells in the peripheral blood of the responder group (CR+PR) significantly increased when compared with those before treatment or with those of the nonresponder group before as well as after treatment. Because the clinical toxicity was moderate and tolerable, this new method of locoregional immunotherapy will be applicable for use in treatment of patients with advanced and recurrent esophageal cancers. Both CTL activity in the administered cells and the percentages of CD16+ cells in the peripheral blood may be useful laboratory markers for predicting of clinical response.
Causes of death in patients ≥75 years of age with non-ST-segment elevation acute coronary syndrome.

The causes of death within 1 year of hospital admission in patients with non-ST-segment elevation acute coronary syndromes are ill defined, particularly in patients aged ≥75 years. From January 2008 through May 2010, we enrolled 645 patients aged ≥75 years with non-ST-segment elevation acute coronary syndromes: 313 in a randomized trial comparing an early aggressive versus an initially conservative approach, and 332, excluded from the trial for specific reasons, in a parallel registry. Each death occurring during 1 year of follow-up was adjudicated by an independent committee. The mean age was 82 years in both study cohorts, and 53% were men. By the end of the follow-up period (median 369 days, interquartile range 345 to 391), 120 patients (18.6%) had died. The mortality was significantly greater in the registry (23.8% vs 13.1%, p = 0.001). The deaths were classified as cardiac in 94% of the cases during the index admission and 68% of the cases during the follow-up period. Eighty-six percent of the cardiac deaths were of ischemic origin. In a multivariate logistic regression model that included the variables present on admission in the whole study population, the ejection fraction (hazard ratio 0.95, 95% confidence interval 0.94 to 0.97; p <0.001), hemoglobin level (hazard ratio 0.85, 95% confidence interval 0.76 to 0.94; p = 0.001), older age (hazard ratio 1.05, 95% confidence interval 1.01 to 1.10, p = 0.010), and creatinine clearance (hazard ratio 0.99, 95% confidence interval 0.97 to 0.99; p = 0.030) were the independent predictors of all-cause death at 1 year. In conclusion, within 1 year after admission for non-ST-segment elevation acute coronary syndromes, most deaths in patients aged ≥75 years have a cardiac origin, mostly owing to myocardial ischemia.
Survival Paradox Between Stage IIB/C (T4N0) and Stage IIIA (T1-2N1) Colon Cancer

The survival paradox between stage IIB/C (T4N0) and stage IIIA (T1-2N1) colon cancer remains in the 7th edition of the American Joint Committee on Cancer staging system. This multicenter study aimed to compare the oncologic outcomes of T4N0 and T1-2N1 colon cancers and to investigate the presumptive prognostic factors that might influence the survival paradox. Patients who underwent curative surgery for pT4N0 (n = 224) and pT1-2N1 (n = 135) primary colon cancer between January 1999 and December 2010 at five tertiary referral cancer centers were included for analysis. The clinicopathologic, treatment-related factors, and oncologic outcomes in terms of the 5-year overall survival (5-OS) and 5-year disease-free survival (5-DFS) were compared. The T4N0 group had significantly worse 5-OS and 5-DFS rates than the T1-2N1 group (5-OS: 84.0 vs. 92.3 %, p = 0.012; 5-DFS: 73.6 vs. 88.0 %, p = 0.001). T4N0 cancers more frequently showed elevated preoperative carcinoembryonic antigen, lower grade of differentiation, larger tumor size, and higher proportions of perineural invasion, microsatellite instability, obstruction, and perforation than T1-2N1 cancers. Peritoneal seeding and liver metastasis were the predominant recurrence pattern in the T4N0 and T1-2N1 groups, respectively (p = 0.042). The T4N0 group showed inferior survival to the T1-2N1 group in postoperative adjuvant chemotherapy (5-OS: 87.1 vs. 93.2 %, p = 0.045; 5-DFS: 76.1 vs. 89.0 %, p = 0.001). T4N0 colon cancer had significantly worse oncologic outcomes than T1-2N1 cancer regardless of adjuvant chemotherapy. The survival paradox may result from the biologic aggressiveness of T4N0 colon carcinomas.
The study protocol of a cluster-randomised controlled trial of family-mediated personalised activities for nursing home residents with dementia

Following admission to a nursing home, the feelings of depression and burden that family carers may experience do not necessarily diminish. Additionally, they may experience feelings of guilt and grief for the loss of a previously close relationship. At the same time, individuals with dementia may develop symptoms of depression and agitation (BPSD) that may be related to changes in family relationships, social interaction and stimulation. Until now, interventions to alleviate carer stress and BPSD have treated carers and relatives separately rather than focusing on maintaining or enhancing their relationships. One-to-one structured activities have been shown to reduce BPSD and also improve the caring experience, but barriers such as a lack of resources impede the implementation of activities in aged care facilities. The current study will investigate the effect of individualised activities based on the Montessori methodology administered by family carers in residential care.



We will conduct a cluster-randomised trial to train family carers in conducting personalised one-to-one activities based on the Montessori methodology with their relatives. Montessori activities derive from the principles espoused by Maria Montessori and subsequent educational theorists to promote engagement in learning, namely task breakdown, guided repetition, progression in difficulty from simple to complex, and the careful matching of demands to levels of competence. Persons with dementia living in aged care facilities and frequently visiting family carers will be included in the study. Consented, willing participants will be randomly assigned by facility to a treatment condition using the Montessori approach or a control waiting list condition. We hypothesise that family carers conducting Montessori-based activities will experience improvements in quality of visits and overall relationship with the resident as well as higher self-rated mastery, fewer depressive symptoms, and a better quality of life than carers in the waiting list condition.



We hypothesise that training family carers to deliver personalised activities to their relatives in a residential setting will make visits more satisfying and may consequently improve the quality of life for carers and their relatives. These beneficial effects might also reduce nursing staff burden and thus impact positively on residential facilities.