bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of recombinant human soluble thrombomodulin in disseminated intravascular coagulation patients with acute renal dysfunction
Authors: Kushimoto Shigeki , Watanabe Eizo , Goto Koji , Suzuki Yasushi , Kotani Toru , Kiguchi Takeyuki , Yatabe Tomoaki , Tagawa Jun , Komatsu Fumiyo , Gando Satoshi , Hayakawa Mineji 
Published: February 2017

SummaryRecombinant human soluble thrombomodulin (ART-123) is a novel anticoagulant for patients with disseminated intravascular coagulation (DIC). It is widely used in clinical settings throughout Japan. Furthermore, a global Phase 3 study is currently being conducted. In healthy subjects, ART-123 is excreted mainly via the kidneys. Therefore, ART-123 dose decrease was recommended in DIC patients with severe renal dysfunction. However, the pharmacokinetics of ART-123 in DIC patients with severe acute renal dysfunction has not been elucidated. In an open-label, multicentre, prospective, clinical pharmacological study, we investigated the pharmacokinetics and safety of ART-123 upon repeated administration to DIC patients. ART-123 was administered to patients at a dose of 130 or 380 U/kg/day for six consecutive days. Plasma concentrations of ART-123 were measured at 21 time points until eight days after the final administration. Urinary excretion rates during the first 24 hours (h) were calculated. Patient renal functions were evaluated by measuring 24-h creatinine clearance (Ccr). Forty-three patients were enrolled in the present study. The urinary excretion rates of ART-123 correlated closely with 24-h Ccr. Total body clearance of ART-123 was also weakly related with 24-h Ccr. However, the plasma concentrations of ART-123 were not considerably different among patients with different renal function. Two patients had subcutaneous haemorrhage as an adverse event related to ART-123. In conclusion, plasma concentrations of ART-123 may not be different among patients with different renal functions. ART-123 was well tolerated in these patients.
Mutation in a highly conserved glycine residue in strand 5B of plasminogen activator inhibitor 1 causes polymerisation
Authors: Nagahashi Kotomi , Takano Katsuhiro , Suzuki-Inoue Katsue , Kanayama Naohiro , Umemura Kazuo , Urano Tetsumei , Iwaki Takayuki 
Published: February 2017

SummarySerpinopathy is characterised as abnormal accumulation of serine protease inhibitors (SERPINs) in cells and results in clinical symptoms owing to lack of SERPIN function or excessive accumulation of abnormal SERPIN. We recently identified a patient with functional deficiency of plasminogen activator inhibitor-1 (PAI-1), a member of the SERPIN superfamily. The patient exhibited life-threatening bleeding tendencies, which have also been observed in patients with a complete deficiency in PAI-1. Sequence analysis revealed a homozygous singlenucleotide substitution from guanine to cytosine at exon 9, which changed amino acid residue 397 from glycine to arginine (c.1189G>C; p.Gly397Arg). This glycine was located in strand 5B and was well conserved in other serpins. The mutant PAI-1 was polymerised in the cells, interfering with PAI-1 secretion. The corresponding mutations in SERPINC1 (anti-thrombin III) at position 456 (Gly456Arg) and SERPINI1 (neuroserpin) at position 392 (Gly392Glu) caused an anti-thrombin deficiency and severe dementia due to intracellular retention of the polymers. Glycine is the smallest amino acid, and these mutated amino acids were larger and charged. To determine which factors were important, further mutagenesis of PAI-1 was performed. Although the G397A, C, I, L, S, T, and V were secreted, the G397D, E, F, H, K, M, N, P, Q, W, and Y were not secreted. The results revealed that the size was likely triggered by the polymerisation of SEPRINs at this position. Structural analyses of this mutated PAI-1 would be useful to develop a novel PAI-1 inhibitor, which may be applicable in the context of several pathological states.
Effect of Aggressive Blood Pressure Control on the Recurrence of Atrial Fibrillation After Catheter Ablation
Authors: Parkash Ratika , Wells George A. , Sapp John L. , Healey Jeffrey S. , Tardif Jean-Claude , Greiss Isabelle , Rivard Lena , Roux Jean-Francois , Gula Lorne , Nault Isabelle , Novak Paul , Birnie David , Ha Andrew , Wilton Stephen B. , Mangat Iqwal , Gray Christopher , Gardner Martin , Tang Anthony S.L. 
Published: February 2017

Background:
Radiofrequency catheter ablation for atrial fibrillation has become an important therapy for AF; however, recurrence rates remain high. We proposed to determine whether aggressive blood pressure (BP) lowering prevents recurrent atrial fibrillation (AF) after catheter ablation in patients with AF and a high symptom burden.

Methods:
We randomly assigned 184 patients with AF and a BP >130/80 mm Hg to aggressive BP (target <120/80 mm Hg) or standard BP (target <140/90 mm Hg) treatment before their scheduled AF catheter ablation. The primary outcome was symptomatic recurrence of AF/atrial tachycardia/atrial flutter lasting >30 seconds, determined 3 months beyond catheter ablation by a blinded end-point evaluation.

Results:

The median follow-up was 14 months. At 6 months, the mean systolic BP was 123.2±13.2 mm Hg in the aggressive BP treatment group versus 135.4±15.7 mm Hg (
P
<0.001) in the standard treatment group. The primary outcome occurred in 106 patients, 54 (61.4%) in the aggressive BP treatment group compared with 52 (61.2%) in the standard treatment group (hazard ratio=0.94; 95% confidence interval, 0.65–1.38;
P
=0.763). In the prespecified subgroup analysis of the influence of age, patients ≥61 years of age had a lower primary outcome event rate with aggressive BP (hazard ratio=0.58; 95% confidence interval, 0.34–0.97;
P
=0.013). There was a higher rate of hypotension requiring medication adjustment in the aggressive BP group (26% versus 0%).

Conclusions:
In this study, this duration of aggressive BP treatment did not reduce atrial arrhythmia recurrence after catheter ablation for AF but resulted in more hypotension.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00438113.
Proof-of-Concept Randomized Trial of the Monoclonal Antibody GSK249320 Versus Placebo in Stroke Patients
Authors: Cramer Steven C. , Enney Lori A. , Russell Colleen K. , Simeoni Monica , Thompson Thomas R. 
Published: February 2017

Background and Purpose—
One class of poststroke restorative therapy focuses on promoting axon outgrowth by blocking myelin-based inhibitory proteins such as myelin-associated glycoprotein. The purpose of the current study was to extend preclinical and clinical findings of GSK249320, a humanized monoclonal antibody to myelin-associated glycoprotein with disabled Fc region, to explore effects on motor outcomes poststroke.

Methods—
In this phase IIb double-blind, randomized, placebo-controlled study, patients at 30 centers with ischemic stroke 24 to 72 hours prior and gait deficits were randomized to 2 IV infusions of GSK249320 or placebo. Primary outcome measure was change in gait velocity from baseline to day 90.

Results—
A total of 134 subjects were randomized between May 2013 and July 2014. The 2 groups were overall well matched at baseline. The study was stopped at the prespecified interim analysis because the treatment difference met the predefined futility criteria cutoff; change in gait velocity to day 90 was 0.55±0.46 (mean±SD) in the GSK249320 group and 0.56±0.50 for placebo. Secondary end points including upper extremity function were concordant. The 2 IV infusions of GSK249320 were well tolerated. No neutralizing antibodies to GSK249320 were detected.

Conclusions—
GSK249320, within 72 hours of stroke, demonstrated no improvement on gait velocity compared with placebo. Possible reasons include challenges translating findings into humans and no direct evidence that the therapy reached the biological target. The antibody was well tolerated and showed low immunogenicity, findings potentially useful to future studies aiming to use a monoclonal antibody to modify activity in specific biological pathways to improve recovery from stroke.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01808261.
Ten-Year Temporal Trends in Medical Complications After Acute Intracerebral Hemorrhage in the United States
Authors: Otite Fadar Oliver , Khandelwal Priyank , Malik Amer M. , Chaturvedi Seemant , Sacco Ralph L. , Romano Jose G. 
Published: February 2017

Background and Purpose—
Data on medical complications after intracerebral hemorrhage (ICH) are sparse. We assessed trends in the prevalence of urinary tract infection, pneumonia, sepsis, deep venous thrombosis (DVT), pulmonary embolism, acute renal failure (ARF), and acute myocardial infarction after ICH in the United States.

Methods—
A total of 575 211 adult ICH cases were identified from the 2004 to 2013 Nationwide Inpatient Sample. Weighted complication risks were computed by sex and mechanical ventilation status. Multivariate models were used to evaluate trends in complications and assess their association with in-hospital mortality, cost, and length of stay.

Results—
Overall risks of urinary tract infection, pneumonia, sepsis, DVT, pulmonary embolism, ARF, and acute myocardial infarction after ICH were 14.8%, 7.8%, 4.1%, 2.7%, 0.7%, 8.2%, and 2.0%, respectively, but risk differed by sex and mechanical ventilation status. From 2004 to 2013, odds of DVT and ARF increased, whereas odds of pneumonia, sepsis, and mortality declined over time. All complications were associated with >2.5-day increase in length of stay and >$8000 increase in cost. ARF and acute myocardial infarction were associated with increased mortality in all patients; sepsis and pneumonia were associated with increased mortality only in nonmechanical ventilation patients, whereas urinary tract infection and DVT were associated with reduced mortality in all patients.

Conclusions—
Despite significant mortality reduction, ARF and DVT risk after ICH have increased, whereas odds of sepsis and pneumonia have declined over the last decade. All complications were associated with increased cost and length of stay, but their associations with mortality were variable, likely due in part to survival bias. Innovative strategies are needed to prevent ICH-associated medical complications.
Enhanced Hazard Analysis and Risk Assessment for Human-in-the-Loop Systems
Authors: Kaber David , Zahabi Maryam 
Published: February 2017

Objective: The objective of this study was to enhance the existing system hazard analysis (SHA) technique by introducing the concepts of human and automation reliability quantification as well as fuzzy classification of system risks. These enhancements led to formulation of a new overall system risk-reliability score. Background: Many system safety analysis methods focus on individual physical component failure. Some human reliability analyses (HRA) consider human-automation interaction in determining system failure rates. There is no system safety analysis technique that quantifies the impact of human and automation reliability on the risk of hazard exposure. Method: Classification of the probability and severity of hazard exposure is typically made in terms of linguistic rather than numerical variables. Fuzzy sets are applicable for transforming linguistic classifications to numerical quantities. We focused on using fuzzy sets to define overlapping bands of system risk exposure with reference to the hazard risk categories defined in MIL-STD 882B. Fuzzy sets were also used for human-automated system reliability classification. Results: Introduction of human and automation reliability assessment in the SHA allows for definition of a system risk-reliability modeling space. The enhanced SHA (E-SHA) technique yields a mishap risk index, which is projected based on a composite assessment of human-automated system reliability at the time of operation. The E-SHA was compared with one of the most advanced HRA techniques. Conclusion: The E-SHA technique supports broader safety control recommendations and provides comparable, if not more detailed, results than prior systems safety and HRA techniques.
A comparison between minimized extracorporeal circuits and conventional extracorporeal circuits in patients undergoing aortic valve surgery: is ‘minimally invasive extracorporeal circulation’ just low prime or closed loop perfusion ?
Authors: Starinieri Pascal , Declercq Peter E. , Robic Boris , Yilmaz Alaaddin , Van Tornout Michiel , Dubois Jasperina , Mees Urbain , Hendrikx Marc 
Published: February 2017

Introduction: Even though results have been encouraging, an unequivocal conclusion on the beneficial effect of minimally invasive extracorporeal circulation (MiECC) in patients undergoing aortic valve surgery cannot be derived from previous publications. Long-term outcomes are rarely reported and a significant decrease in operative mortality has not been shown. Most studies have a limited number of patients and are underpowered. They merely report on short-term results of a heterogeneous intraoperative group using different types of ECC system in aortic valve surgery. The aim of the present study was to determine whether MiECC systems are more beneficial than conventional extracorporeal systems (CECC) with regard to mortality, hospital stay and inflammation and with only haemodilution and blood-air interface as differences. Methods: We retrospectively analysed data regarding mortality, hospital stay and inflammation in patients undergoing isolated aortic valve surgery. Forty patients were divided into two groups based on the type of extracorporeal system used; conventional (n=20) or MiECC (n=20). Results: Perioperative blood product requirements were significantly lower in the MiECC group (MiECC: 0.2±0.5 units vs CECC: 0.9±1.2 units, p=0.004). No differences were seen postoperatively regarding mortality (5% vs 5%, p=0.99), total length of hospital stay (10.6±7.2 days (MiECC) vs 12.1±5.9 days (CECC), p=0.39) or inflammation markers (CRP: MiECC: 7.09±13.62 mg/L vs CECC: 3.4±3.2 mg/L, p=0.89). Conclusion: MiECC provides circulatory support that is equally safe and feasible as conventional extracorporeal circuits. No differences in mortality, hospital stay or inflammation markers were observed.
Ovarian cystectomy in the treatment of apparent early-stage immature teratoma
Authors: Zhao Ting , Liu Yan , Wang Xiao , Zhang Hao , Lu Yuan 
Published: February 2017

Objective To investigate the role of ovarian cystectomy in patients with early-stage immature teratoma. Methods A retrospective review was undertaken on patients diagnosed pathologically with immature teratoma and with malignant lesions confined to the ovary. Patients were included if they had been treated between January 1997 and December 2015 at the Obstetrics and Gynaecology Hospital of Fudan University, Shanghai, China. Relevant demographic and clinical data were retrieved from the medical records. Results Forty-three patients were included in the study; 14 underwent ovarian cystectomy (group 1) and 29 underwent unilateral salpingo-oophorectomy (USO; group 2). Three of the patients who underwent USO relapsed and required a second surgical intervention. The 5-year disease-free survival rates were 100% and 88%for groups 1 and 2, respectively. There were no significant differences between the two groups in terms of survival or postoperative fertility outcomes. Univariate and multivariate analysis further revealed that ovarian cystectomy was not a poor prognostic indicator for disease-free survival. Conclusion These current data suggest that ovarian cystectomy can be considered for patients with apparent early-stage immature teratoma as it preserves fertility as much as possible without adversely impacting upon survival.
Serum ionic dysequilibria in clinical opioid dependence: Cross-sectional and longitudinal studies
Authors: Reece AS , Norman A , Hulse GK 
Published: February 2017

Introduction: Despite an increasing awareness that the activity of excitable membranes is determined by the underlying ionic gradients across them, and their importance in drug dependency, we were not able to identify any reports of comparing the electrolyte composition of opioid-dependent and non-addicted controls. Methods: Linear regression was used to compare clinical pathology blood results taken from 2699 opioid-dependent patients (ODP) and 5307 medical control (MC) patients on a total of 21,734 occasions for the period 1995–2015. The presence of a hepatitis C antibody test was used to separate OPD and MC patients. Results: The mean age among ODP and MC was 33.51 ± 0.16 and 37.99 ± 0.23 years, respectively ( p < 0.0001). The groups were 71.5% and 54.2% male ( p < 0.0001). Drug use in this cohort has been reported previously. Analysis of sodium, haemoglobin and albumin were used to exclude marked effects of haemodilution/haemoconcentration. Repeated measures linear regression against age and time showed depressed levels of bicarbonate ( p < 0.0001) and potassium ( p < 0.05) and elevated levels of chloride ( p < 0.025) and anions ( p < 0.01) in ODP in both sexes. Multiple regression in mixed-effects models showed that these effects were all worse in females ( p = 0.0001). Conclusion: This data shows that opioid dependence is associated with significant changes in chloride, potassium, bicarbonate and anions in both sexes, and worse in females. This likely has implications for the electrophysiological properties of excitable membranes. It is consistent with the reported impairment of potassium-chloride exchangers in opioid dependence. Explication of the mechanisms responsible must await further studies.
Knowledge, attitudes and practices related to tetanus toxoid vaccination in women of childbearing age: A cross-sectional study in peri-urban settlements of Karachi, Pakistan
Authors: Shafiq Yasir , Khowaja Asif Raza , Yousafzai Mohammad Tahir , Ali Syed Asad , Zaidi Anita , Saleem Ali Faisal 
Published: February 2017

Backgound: A higher incidence of neonatal tetanus implies failure of the vaccination program in Pakistan. Objectives: The objective of this study was to assess knowledge, attitudes and practices related to tetanus toxoid (TT) vaccine in women of childbearing age. Methods: We performed a cross-sectional survey in peri-urban Karachi, Pakistan, among women of childbearing age, stratified into three mutually exclusive groups as: married pregnant; married non-pregnant; and unmarried. Descriptive and inferential analyses were performed to estimate vaccine coverage and knowledge attributes. Results: A total of 450 women participated, of which the largest proportion were married and non-pregnant (n = 185/450, 41%). Over 50% of women (n = 258/450) had not received TT vaccine. Most unmarried women (n = 139, 97%) were unvaccinated. Non-vaccination predictors included: women aged <25 years without any formal education (adjusted odds ratio [OR], 2.1; 95% confidence interval [CI], 1.0–4.4), lack of knowledge about free vaccination (adjusted OR, 4.0; 95% CI, 1.64–10.20), poor knowledge of tetanus disease/vaccination (adjusted OR, 4.6; 95%, 2.2–9.6), living with extended family (adjusted OR, 2.0; 95% CI, 1.04–3.96); family non-supporting vaccination (adjusted OR, 5.7; 95% CI, 2.3–13.9); and husband/other family member deciding upon issues related to women’s health (adjusted OR, 2.9; 95% CI, 1.3–6.6). Conclusion: Low coverage of TT vaccine is largely influenced by poor knowledge, family structure and family decision-making in the local communities of Pakistan.
Network Unbundling, Ownership Structure and Oligopolies: A Case Study for the Belgian Electricity Market
Authors: Pepermans Guido , Willems Bert 
Published: February 2017

This paper studies how different types of unbundling – accounting, management, legal and ownership unbundling – influence the electricity wholesale market. Starting from the current market situation as observed in many countries, with imperfect competition in generation and imperfect regulation of the network operator, it is not obvious that any kind of unbundling will result in a better outcome in terms of efficiency and welfare. With the imperfections just mentioned, unbundling can create better incentives for entry in the generation market, but it can also create a double marginalisation problem. We study the effect of unbundling in a numerical model that captures two kinds of ownership interactions between the generation and the transmission sector. Passive ownership – or legal unbundling – where the generation firm simply cashes its share of the transmission firm's profit without having a direct impact on its decision process, and active ownership – or management unbundling – where the generator still has a direct influence on the transmission firm's decision process. Simulations, calibrated on Belgian electricity market data, show that the fastest road towards a more efficient electricity market is a road that implies a welfare reduction at an intermediate stage. The results also strongly suggest that the current European electricity directive, imposing legal unbundling, is not sufficient. European legislation should move further and impose ownership unbundling if a level playing field and a competitive electricity market is the objective.
Approximation of National Laws on the Allocation of Radio Frequencies for Broadcasting and Mobile Telecommunications Services in the EU
Authors: Koenig Christian , Bache Volker , Trias Ana 
Published: February 2017

The question addressed is whether the EC has competence under Article 95 EC Treaty1 (EC) on the approximation of laws to allocate the frequencies to be released by the switchover from analogue to digital at the European level, or if the exercise of this legislative power is reserved to the Member States in an exclusive competence on the financing of public broadcasting. Due to the length and scope of this paper, the topic will be treated with a specific focus on the European telecommunications market. Methodologically, the EC competence in question will be studied under the criteria developed by the European Court of Justice (EC]) case law through case Germany v European Parliament and Council (Case 376/98) [2002], hereafter the “Tobacco Advertising Case”. This choice is based on two different sets of reasons: On the one hand, this ruling clarifies the scope of a domaine réservé of Member States under EC Law through the example of health policy and balances it with the requirements of the internal market, and on the other hand, it sets the strictest prerequisites for an EC harmonization competence to be exercised within the aforesaid scope. Therefore, if said conditions are met, there can be no doubt that Article 95 EC is applicable to the case at hand. Within this context, we shall argue that the EC has competence under Article 95 EC to allocate the frequencies to be released, since: First, there is a future likely disparity in national laws. Second, such disparity will create obstacles to the exercise of the free movement of services and goods, as well as of the freedom of establishment. Moreover, it will result in appreciable distortions of competition. Third, a harmonization measure will actually contribute to improve the functioning of the internal market and it would not interfere with the guarantee of existence and development of public broadcasting nor with the subsidiarity principle, provided that they applied.