bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical risk management in hospitals: strategy, central coordination and dialogue as key enablers
Authors: Briner Matthias , Manser Tanja , Kessler Oliver 
Published: March 2012

AbstractObjective  The study aims to identify key enablers fostering clinical risk management (CRM) in hospitals to guide health care in this vital area of patient safety.Method  A cross‐sectional survey was conducted at the national level in 324 Swiss hospitals in 2007–2008 to assess the relationship between key elements and systematic CRM. Therefore, a comprehensive monitoring instrument for CRM was used for the first time. Organizational factors (e.g. strategy, coordination, resources) and structural conditions (e.g. hospital size) were tested as key elements. CRM was assessed by evaluating its maturity (i.e. the level of CRM development) by 12 theoretically derived indices joining together essential aspects of CRM at the hospital level and the service level. Chi‐square measures were used to analyse the relationships between organizational factors or structural conditions and maturity of CRM.Results  Participation in this voluntary survey was good, with CRM experts of 138 out of 324 hospitals responding (response rate 43%). Three key enablers for CRM were identified: implementing a function for central CRM coordination, assuring dialogue with and between the different hospital services, and developing strategic CRM objectives.Conclusions  This study offers, for the first time, an assessment of the maturity of hospitals' CRM and identifies key enablers related to CRM. This is a feasible first step in guiding hospitals to shape their CRM and presents a basis for future studies, for example, linking CRM to outcome data.
Considerations for extrapolating in vivo bioequivalence data across species and routes
Authors: MODRIC S. , BERMINGHAM E. , HEIT M. , LAINESSE C. , THOMPSON C. 
Published: March 2012

Modric, S., Bermingham, E., Heit, M., Lainesse, C., Thompson, C. Considerations for extrapolating in vivo bioequivalence data across species and routes. J. vet. Pharmacol. Therap.35 (Suppl. 1), 45–52.The purpose of this article is to discuss the numerous species‐specific and route‐specific factors that can influence the peak and extent of exposure of an active pharmaceutical ingredient as they relate to the demonstration of bioequivalence between veterinary drug products (test and reference formulations). Evaluation of potential circumstances when species‐to‐species or route‐to‐route extrapolations of bioequivalence data could be considered is provided, together with suggestions for alternative statistical analysis. It is concluded that further research is much needed in this area to establish an appropriate scientific basis for across‐species and across‐route comparisons.
Demonstrating bioequivalence using clinical endpoint studies
Authors: BERMINGHAM E. , Del CASTILLO J. R. E. , LAINESSE C. , PASLOSKE K. , RADECKI S. 
Published: March 2012

Bermingham, E., del Castillo, J. R. E., Lainesse, C., Pasloske, K., Radecki, S. Demonstrating bioequivalence using clinical endpoint studies. J. vet. Pharmacol. Therap.35 (Suppl. 1), 31–37.For drug products not amenable to blood level studies, clinical endpoint studies have been used as an indirect measure of formulation difference in bioavailability between test and reference products. However, clinical endpoint studies are not as sensitive in detecting formulation differences as blood level studies and offer numerous challenges to both regulatory authorities and sponsors. The objective of this article is not to suggest new regulatory policies, but to explore new methodologies and alternative solutions to clinical endpoint bioequivalence (BE) studies, which are used when a blood level study is not considered to be appropriate. To achieve this objective, this article identifies situations where a clinical endpoint study might be appropriate, lists the advantages and disadvantages of this type of study design, and discusses possible alternative solutions. It is concluded that future evidence‐based research is needed to explore new methodologies such as clinical trial simulations of various study designs, new statistical methods, and new in vitro methods to demonstrate BE.
Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination
Authors: LEES P. , HUNTER R. P. , REEVES P. T. , TOUTAIN P. L. 
Published: March 2012

Lees, P., Hunter, R. P., Reeves, P. T., Toutain, P. L. Pharmacokinetics and pharmacodynamics of stereoisomeric drugs with particular reference to bioequivalence determination.J. vet. Pharmacol. Therap.35(Suppl. 1), 17–29.Drugs containing one or more chiral centres exist in stereoisomeric molecular forms. Most commonly, drugs containing a single asymmetric carbon atom exist in two enantiomeric forms, designated as eutomer (the more potent) and distomer (the less potent). As well as differences in potency and other pharmacodynamic properties, most members of enantiomeric pairs commonly differ also in their pharmacokinetic profiles. This article reviews factors underlying differences in pharmacological properties of enantiomers. The relevance of such differences for studies designed to evaluate the bioequivalence of products containing chiral drugs is also reviewed.
Introduction to the bioequivalence theme issue
Authors: MARTINEZ M. N. , HUNTER R. P. 
Published: March 2012

Martinez, M. N., Hunter, R. P. Introduction to the bioequivalence theme issue. J. vet. Pharmacol. Therap. 35 (Suppl. 1), 1–2.This introduction provides an overview of the veterinary bioequivalence initiative and of the foundational goals and objectives of this theme issue.
Assessing product bioequivalence for extended‐release formulations and drugs with long half‐lives
Authors: GEHRING R. , MARTINEZ M. 
Published: March 2012

Gehring, R., Martinez, M. Assessing product bioequivalence for extended‐release formulations and drugs with long half‐lives. J. vet. Pharmacol. Therap.35 (Suppl. 1), 3–9.When a drug product remains in the body for a duration of hours or days, estimating the extent of drug exposure is relatively straightforward. For immediate release (IR) dosage forms, the peak drug concentration (Cmax) and time to peak concentrations (Tmax) are typically adequate for comparing product rates of drug absorption. However, unique complexities need to be addressed when a drug remains in the system for a duration of months or years. Specifically, if the long duration of exposure is attributable to formulation effects, Cmax and Tmax may not be adequate to compare the rate of drug absorption, especially when there are multiphasic absorption processes. In this case, it may be appropriate to use partial (segmented areas) for comparing product profiles. However, the decision of how the curves are segmented is not straightforward. Points to consider are discussed in this manuscript. Alternatively, if the long half‐life is due to the pharmacokinetics (PK) of the active pharmaceutical ingredient and not to formulation effects, Cmax and Tmax may be appropriate metrics for the rate of absorption but decisions regarding the duration of blood sampling needed to capture the AUC should be based upon an assessment of the inherent variability in drug absorption and elimination. Furthermore, it is important to be confident that the absorption phase is complete. In this manuscript, we explore some of the difficulties associated with determining optimal metrics for comparing the rate and extent of product release for long half life drugs when the long duration of exposure is attributable to either the inherent drug PK or to formulation effects.
Challenges associated with the demonstration of bioequivalence of intramammary products in ruminants
Authors: LAINESSE C. , GEHRING R. , PASLOSKE K. , SMITH G. , SOBACK S. , WAGNER S. , WHITTEM T. 
Published: March 2012

Lainesse, C., Gehring, R., Pasloske, K., Smith, G., Soback, S., Wagner, S., Whittem, T. Challenges associated with the demonstration of bioequivalence of intramammary products in ruminants. J. vet. Pharmacol. Therap. 35 (Suppl. 1), 65–79.This article explores the numerous challenges encountered when the goal is to demonstrate bioequivalence (BE) between test and reference intramammary (IMM) products in ruminants. Numerous pathophysiological factors of mastitis and physicochemical properties of IMM formulations are implicated in the difficulties in confirming BE for this dosage form. Advantages and disadvantages of current BE study designs are discussed, and alternative perspectives are outlined. Ongoing and future research increasing our knowledge of the pharmacokinetics and pharmacodynamics of antimicrobial drugs delivered through this route is crucial to better understanding the implications of clinically significant formulation differences in the demonstration of BE and may also help in developing more effective IMM formulations for ruminants.
Estimating product bioequivalence for highly variable veterinary drugs
Authors: CLAXTON R. , COOK J. , ENDRENYI L. , LUCAS A. , MARTINEZ M. N. , SUTTON S. C. 
Published: March 2012

Claxton, R., Cook, J., Endrenyi, L., Lucas, A., Martinez, M. N., Sutton, S. C. Estimating product bioequivalence for highly variable veterinary drugs. J. vet. Pharmacol. Therap.35 (Suppl. 1), 11–16.The occurrence of drugs and drug formulations associated with large intrasubject pharmacokinetic (PK) variability has been well described in humans and is likewise encountered in veterinary medicine. The scaled average bioequivalence (SABE) approach adopted by CDER of the FDA for the determination of bioequivalence (BE) of highly variable drugs (HVD) needs to be considered when applied to veterinary dosage forms. However, because of some of the unique challenges that are encountered within the framework of veterinary medicine, variations of CDER’s approach are presented. The present manuscript discusses HVD and highly variable veterinary drugs (HVVD) from the perspective of possible alternative approaches to support the assessment of product BE in veterinary medicine. Limitations in the use of 3‐ and 4‐way crossover study designs are enumerated. In addition to a need for a statistical analysis of HVVD when using a parallel study design, the use of the secondary criteria (test‐to‐reference ratio), definition of σ0, and average BE with expanding limits are raised. A number of the details need to be finalized, from the selection of a regulatory constant to the determination of ‘highly variable’ in a veterinary drug product. Academicians, industrial scientists, and regulators should continue this discussion and resolve these details.
Cardiolipin synthase is required for Streptomyces coelicolor morphogenesis
Authors: Jyothikumar Vinod , Klanbut Khanungkan , Tiong John , Roxburgh James S. , Hunter Iain S. , Smith Terry K. , Herron Paul R. 
Published: March 2012

SummaryThe fluid mosaic model has recently been amended to account for the existence of membrane domains enriched in certain phospholipids. In rod‐shaped bacteria, the anionic phospholipid cardiolipin is enriched at the cell poles but its role in the morphogenesis of the filamentous bacterium Streptomyces coelicolor is unknown. It was impossible to delete clsA (cardiolipin synthase; SCO1389) unless complemented by a second copy of clsA elsewhere in the chromosome. When placed under the control of an inducible promoter, clsA expression, phospholipid profile and morphogenesis became inducer dependent. TLC analysis of phospholipid showed altered profiles upon depletion of clsA expression. Analysis of cardiolipin by mass spectrometry showed two distinct cardiolipin envelopes that reflected differences in acyl chain length; the level of the larger cardiolipin envelope was reduced in concert with clsA expression. ClsA‐EGFP did not localize to specific locations, but cardiolipin itself showed enrichment at hyphal tips, branch points and anucleate regions. Quantitative analysis of hyphal dimensions showed that the mycelial architecture and the erection of aerial hyphae were affected by the expression of clsA. Overexpression of clsA resulted in weakened hyphal tips, misshaped aerial hyphae and anucleate spores and demonstrates that cardiolipin synthesis is a requirement for morphogenesis in Streptomyces.
Portal hypertension after combined liver and intestinal transplantation, a diagnostic and therapeutic challenge?
Authors: Monbaliu Diethard , Vandersmissen Jo , De Hertogh Gert , Van Assche Gert , Hoffman Ilse , Knops Noël , Debbaut Charlotte , Heye Sam , Pirenne Jacques , Maleux Geert 
Published: March 2012

Monbaliu D, Vandersmissen J, De Hertogh G, Van Assche G, Hoffman I, Knops N, Debbaut C, Heye S, Pirenne J, Maleux G. Portal hypertension after combined liver and intestinal transplantation, a diagnostic and therapeutic challenge?  Pediatr Transplantation 2012: 00: 000–000. © 2012 John Wiley & Sons A/S.Abstract:  A widely accepted technique to transplant the liver‐bowel bloc is first to perform a piggyback anastomosis of the donor suprahepatic vena cava to the recipient vena cava; second to restore the arterial blood supply through an aortic interposition graft; and third to ensure venous drainage of the native foregut. The venous drainage of the native foregut can be restored through an end‐to‐end portocaval anastomosis between the donor infrahepatic vena cava and the recipient portal vein. Stenosis of this anastomosis can lead to portal hypertension presenting with upper GI congestion, bleeding, and hypersplenism. We report the successful treatment of this complication using an e‐PTFE‐covered stent inserted following balloon angioplasty.
Effects of dietary supplementation of fermented garlic powder on growth performance, apparent total tract digestibility, blood characteristics and faecal microbial concentration in weanling pigs
Authors: Yan L. , Kim I. H. 
Published: March 2012

SummaryA total of 144 weanling pigs (5.5 ± 0.42 kg) were used in a 5‐week trial to evaluate the effect of fermented garlic powder (FGP) supplementation in weaning pigs. Pigs were randomly allocated to the following four dietary treatments: (i) control (CON; basal diet), (ii) FGP0.5 (CON + 0.5 g/kg FGP), (iii) FGP1 (CON + 1 g/kg FGP), (iv) FGP2 (CON + 2 g/kg FGP). There were six replications with six pigs (three barrows and three gilts) per pen. Pigs fed FGP0.5 treatments increased (p < 0.05) average daily gain (ADG) and average daily feed intake (ADFI) during 3–5 and 0–5 week. No difference was observed on gain/ feed (G/F) ratio in this study. The inclusion of FGP1 and FGP2 treatments increased DM (p < 0.05) digestibility compared with the CON treatment throughout the experiment. The apparent total tract digestibility of N was (p < 0.05) increased by the dietary FGP throughout the experiment. Pigs fed FGP1 and FGP2 treatments increased the lymphocyte concentration (p < 0.05) and RBC concentration compared with the CON group. Dietary FGP decreased the blood total cholesterol (p < 0.05) in comparison with the CON group. The triglyceride (p < 0.05) concentration was decreased in FGP1 and FGP2 treatments compared with those in the CON treatment at the end of the experiment. Pigs fed FGP1 and FGP2 treatments had a lower number of Escherichia coli in faeces on 21 (p < 0.05) and 35 days (p = 0.05) than those in the CON treatment. In conclusion, dietary fermented garlic powder (0.5 g/kg) can improve ADG and ADFI in weanling pigs, but not at higher levels (1 and 2 g/kg). Dietary fermented garlic powder can also increase the nutrient digestibility, lymphocytes and RBC concentrations, but decrease the faecal E. coli concentration in weaning pigs.
KCNQ1 gene polymorphisms are associated with the therapeutic efficacy of repaglinide in Chinese Type 2 diabetic patients
Authors: Dai Xing‐Ping , Huang Qiong , Yin Ji‐Ye , Guo Yu , Gong Zhi‐Cheng , Lei Min‐Xiang , Jiang Tie‐Jian , Zhou Hong‐Hao , Liu Zhao‐Qian 
Published: March 2012

Summary
The present study evaluated the effects of KCNQ1 rs2237892 and rs2237895 polymorphisms on repaglinide efficacy in Chinese patients with Type 2 diabetes mellitus (T2DM).
In all, 367 T2DM patients and 214 controls were genotyped. Forty of the T2DM patients were randomly selected to undergo 8 weeks repaglinide treatment.
The frequency of the rs2237892 allele was lower in the T2DM patients than in the control group (P < 0.05). The frequency of the rs2237895 C allele was higher in T2DM patients than in healthy control subjects (P < 0.05). Diabetic patients with the rs2237892 risk C allele had lower fasting insulin levels (P < 0.01) and homeostasis model assessment of insulin resistance (HOMA‐IR; P < 0.01) values than carriers of the T allele. Diabetic patients with the rs2237895 risk C allele had higher fasting plasma glucose (P < 0.01), postprandial plasma glucose (PPG) levels (P < 0.01) and HOMA‐IR values (P < 0.01) than those with the A allele.
Following repaglinide treatment, those T2DM patients with the rs2237892 T allele and rs2237895 C allele were more likely to have a positive response to repaglinide in terms of PPG levels (P < 0.05) than T2DM patients with the rs2237892 CC and rs2237895 AA genotypes.
In conclusion, KCNQ1 rs2237892 and rs2237895 polymorphisms were found to be associated with the therapeutic efficacy of repaglinide in Chinese T2DM patients.
Pathogenesis and management of pruritus in cholestatic liver disease
Authors: Imam Mohamad H , Gossard Andrea A , Sinakos Emmanouil , Lindor Keith D 
Published: March 2012

AbstractPatients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.
Prevalence and associated factors with esophageal varices in early primary biliary cirrhosis
Authors: Ikeda Fusao , Okamoto Ryoichi , Baba Nobuyuki , Fujioka Shin‐ichi , Shoji Bon , Yabushita Kazuhisa , Ando Masaharu , Matsumura Shuji , Kubota Junichi , Yasunaka Tetsuya , Miyake Yasuhiro , Iwasaki Yoshiaki , Kobashi Haruhiko , Okada Hiroyuki , Yamamoto Kazuhide 
Published: March 2012

AbstractBackground and Aims:  Recent routine testing for anti‐mitochondrial antibodies has increased the number of patients with early primary biliary cirrhosis (PBC). The prevalence and clinical significance of esophageal varices in those patients remains obscure.Methods:  A systematic cohort analysis of 256 PBC patients was performed to clarify the prevalence, characteristics, and prognosis of the patients with early PBC and esophageal varices.Results:  Twenty‐two patients had esophageal varices at the time of diagnosis: 5.5% (12/217) with early disease of histological stage 1 or 2, and 25.6% (10/39) with advanced disease of stage 3 or 4. Immediate treatments were required for two patients with early PBC: one for bleeding varices, and the other for large varices. The overall survival of the patients with early PBC and esophageal varices at diagnosis did not significantly differ from that of patients without esophageal varices (P = 0.66). High alkaline phosphatase (ALP) ratios (odds ratio = 2.3) and low platelet counts (odds ratio = 0.77) were significantly associated with the presence of esophageal varices in the patients with early PBC. Significant associations of these two factors with the development of esophageal varices during follow‐up were also revealed (odds ratio = 1.4 and 0.88, respectively). The patients with early PBC and high ALP ratios ≥ 1.9 had significantly high risks of developing esophageal varices during follow‐up (P = 0.022).Conclusions:  High ALP ratios and low platelet counts at diagnosis and decreased platelet counts during follow‐up are useful predictors of esophageal varices in patients with early PBC.
Current status and future perspectives of leukocytapheresis for inflammatory bowel disease
Authors: Fukunaga Ken , Matsumoto Takayuki 
Published: March 2012

AbstractUlcerative colitis (UC) and Crohn's disease (CD) comprise the idiopathic inflammatory bowel diseases (IBD) of the gut. The etiology of IBD is poorly understood, but an autoimmune disturbance has been suggested to play an important role in this incurable disease. Extracorporeal leukocytapheresis (CAP) is an additional adjunct for IBD patients refractory to other conventional therapies, including steroids. The primary aim of CAP should be to suppress such unwanted immunological response by removing circulating inflammatory cells from the blood stream. The first decade has been passed since CAP was approved by Japanese social health insurance policy. It is therefore now an appropriate opportunity to upgrade and summarize our current understandings and/or future perspectives of this unique non‐pharmacological and non‐surgical strategy for IBD patients. According to several clinical and basic research reports, an early introduction of CAP should produce higher efficacy as compared with CAP applied sometime after a clinical relapse. Likewise, CAP therapy adjusted to patients' body‐weight as well as two treatment sessions per week (intensive regimen) should benefit the efficacy rate. The etiology of IBD is not fully elucidated yet. As a result, the major therapeutic strategies in the Western world have been immunosuppressive therapy, including biologics. CAP is an unusual treatment modality for IBD because it seems to have both effectiveness and safety, which should generally be balanced in this type of illness. We now have to develop future strategies with and without combining biologics to improve the quality of life of IBD patients.
Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity
Authors: Adams Leon A , Marsh Julie A , Ayonrinde Oyekoya T , Olynyk John K , Ang Wei Q , Beilin Lawrence J , Mori Trevor , Palmer Lyle J , Oddy Wendy W , Lye Steven J , Pennell Craig E 
Published: March 2012

AbstractBackground and Aim:  Environmental factors including excessive caloric intake lead to disordered lipid metabolism and fatty liver disease (FLD). However, FLD demonstrates heritability suggesting genetic factors are also important. We aimed to use a candidate gene approach to examine the association between FLD and single nucleotide polymorphisms (SNPs) in lipid metabolism genes in the adolescent population‐based Western Australian Pregnancy (Raine) Cohort.Methods:  A total 951 seventeen year‐olds underwent hepatic ultrasound, anthropometric and biochemical characterization, DNA extraction and genotyping for 57 SNPs in seven lipid metabolism genes (ApoB100, ATGL, ABHD5, MTTP, CETP, SREBP‐1c, PPARα). Associations were adjusted for metabolic factors and Bonferroni corrected.Results:  The prevalence of FLD was 16.2% (11.4% male vs 21.2% female, P = 0.001). Multivariate analysis of metabolic factors found suprailiac skinfold thickness (SST) to be the major predictor of FLD in females and males (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.08‐1.15, P = 1.7 × 10−10 and OR 1.17, 95%CI 1.13–1.22, P = 2.4 × 10−11, respectively). In females, two SNPs in linkage disequilibrium from the CETP gene were associated with FLD: rs12447924 (OR 2.16, 95%CI 1.42–3.32, P = 0.0003) and rs12597002 (OR = 2.22, 95%CI 1.46–3.41 P = 0.0002). In lean homozygotes, the probability of FLD was over 30%, compared with 10–15% in lean heterozygotes and 3–5% in lean wild‐types. However, these associations were modified by SST, such that for obese individuals, the probability of FLD was over 30% in all genotype groups.Conclusions:  Cholesteryl ester transfer protein gene polymorphisms are associated with an increased risk of FLD in adolescent females. The effect is independent of adiposity in homozygotes, thereby placing lean individuals at a significant risk of FLD.