Hepatic effects of repeated oral administration of diclofenac to hepatic cytochrome P450 reductase null (HRN™) and wild-type mice

Hepatic NADPH-cytochrome P450 oxidoreductase null (HRN?) mice exhibit normal hepatic and extrahepatic biotransformation enzyme activities when compared to wild-type (WT) mice, but express no functional hepatic cytochrome P450 activities. When incubated in vitro with [¹⁴C]-diclofenac, liver microsomes from WT mice exhibited extensive biotransformation to oxidative and glucuronide metabolites and covalent binding to proteins was also observed. In contrast, whereas glucuronide conjugates and a quinone-imine metabolite were formed when [¹⁴C]-diclofenac was incubated with HRN? mouse liver, only small quantities of P450-derived oxidative metabolites were produced in these samples and covalent binding to proteins was not observed. Livers from vehicle-treated HRN? mice exhibited enhanced lipid accumulation, bile duct proliferation, hepatocellular degeneration and necrosis and inflammatory cell infiltration, which were not present in livers from WT mice. Elevated liver-derived alanine aminotransferase, glutamate dehydrogenase and alkaline phosphatase activities were also observed in plasma from HRN? mice. When treated orally with diclofenac for 7 days, at 30 mg/kg/day, the severities of the abnormal liver histopathology and plasma liver enzyme findings in HRN? mice were reduced markedly. Oral diclofenac administration did not alter the liver histopathology or elevate plasma enzyme activities of WT mice. These findings indicate that HRN? mice are valuable for exploration of the role played by hepatic P450s in drug biotransformation, but poorly suited to investigations of drug-induced liver toxicity. Nevertheless, studies in HRN? mice could provide novel insights into the role played by inflammation in liver injury and may aid the evaluation of new strategies for its treatment.     

How physiotherapists perceive,interpret, and respond to the ethical dimensions of practice: A qualitative study

The profile and reach of physiotherapy has expanded in areas of extended scope of practice, and broader engagement with population needs beyond the individual treatment encounter. These changes raise increasingly complex ethical challenges evidenced by growth in physiotherapy-based ethics studies and discussions. This paper examines how a broad cross section of Australian physiotherapists perceive, interpret, and respond to ethical challenges in their work contexts and how professional codes of conduct are used in their practice. Using an interpretive qualitative methodology, purposive sampling of 88 members of national clinical special interest groups were recruited for focus group discussions. Narrative-based and thematic data analysis identified ethical challenges as emerging from specific clinical contexts, and influenced by health organizations, funding policies, workplace relationships, and individually held perspectives. Five themes were developed to represent these findings: (1) the working environment, (2) balancing diverse needs and expectation, (3) defining ethics, (4) striving to act ethically, and (5) talking about ethics. The results portray a diverse and complex ethical landscape where therapists encounter and grapple with ethical questions emerging from the impact of funding models and policies affecting clinical work, expanding boundaries and scope of practice and changing professional roles and relationships. Codes of conduct were described as foundational ethical knowledge but not always helpful for “in the moment” ethical decision-making. Based on this research, we suggest how codes of conduct, educators, and professional associations could cultivate and nurture ethics capability in physiotherapy practitioners for these contemporary challenges.     

美国的听力师教育

随着婴儿潮、人口老龄化及新技术的广泛应用，人们对听力保健的需求显著增加。在美国，听力保健服务由助听设备专员、耳鼻喉科医生和听力师3类人员提供，其中听力师提供除医疗、手术外宽泛的听力保健服务。美国的听力保健服务体系及听力师教育体系经历了一个渐进的过程：20年前对从业人员的学历要求是听力学硕士，随着对服务质量要求的提高和服务范围的扩大，美国听力师逐渐要求专业博士学位（Au.D），毕业后还需3～4年的专门教育才能成为一名听力师。听力师教育有统一的标准，大学课程要通过听力教育认证委员会（the Accreditation Commission for Audiology Education， ACAE）或学术认证委员会（the Council on Academic Accreditation，CAA）的多程序严格的认证才能被承认。美国听力师需求存在巨大缺口，但是各国听力学教育标准不统一及听力师收入与教育投资不匹配，阻碍了更多的人进入这一领域。美国试图通过改变教育模式，降低教育成本及革新教学方法等改善听力师教育状况，但是听力师教育体系远未完善。     

Tranexamic acid through intravenous,intramuscular and oral routes: an individual participant data meta‐analysis of pharmacokinetic studies in healthy volunteers

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post‐partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta‐analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J‐STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two‐compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well‐designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.