Regulatory volume decrease in a renal distal tubular cell line (A6) II. Effect of Na+ transport rate

A6 epithelia, a cell line originating from the distal tubular part of the kidney ofXenopus laevis, were cultured on permeable supports and mounted in an Ussing-type chamber. Cell thickness (T _c), short-circuit current (I _sc) and transepithelial conductance (G _t) were recorded while tissues were bilaterally incubated in NaCl solutions and the transepithelial potential was clamped to zero. Effects of inhibition and stimulation of transepithelial Na⁺ transport on cell volume and on its regulation during a hyposmotic challenge were investigated. Under control conditions a slow spontaneous decrease ofT _c described by a linear baseline was recorded. The reduction of the apical osmolality from 260 to 140 mosmol/kg did not alter cell volume significantly, demonstrating a negligible water permeability of the apical barrier. The inhibition of Na⁺ uptake by replacing apical Na⁺ byN-methyl-d-glucamine (NMDG⁺) did not affect cell volume under isotonic conditions. An increase ofT _c by 12.1% above the control baseline was recorded after blocking active transport with ouabain for 60 min. The activation of Na⁺ transport with insulin or oxytocin, which is known to activate the apical water permeability in other epithelia, did not alter cell volume significantly. The insensitivity of cell volume to alterations in apical Na⁺ uptake or Na⁺ pump rate confirms the close coupling between apical and basolateral transport processes. The blockage of basolateral K⁺ channels by 5 mM Ba²⁺ elicited a significant increase inT _c of 16.3% above control. Quinine, a potent blocker of volume-activated K⁺ channels, did not changeT _c significantly. Basolateral hypotonicity elicited a rapid rise inT _c followed by a regulatory volume decrease (RVD). An RVD was also recorded after blocking apical Na⁺ uptake as well as after stimulating apical Na⁺ uptake with oxytocin or insulin. Inhibition of active transport with ouabain as well as blocking K⁺ efflux at the basolateral side with Ba²⁺ or quinine abolished the RVD. The inhibition of the RVD by ouabain seems to be caused by a depletion of cellular K⁺, whereas the effects of Ba²⁺ and quinine are most likely due to the blockage of the basolateral K⁺ pathway.     

A volume-activated anion conductance in insulin-secreting cells

The whole-cell patch-clamp recording technique was used to measure volume-activated currents in K⁺-free solutions in RINm5F and HIT-T15 insulinoma cells and in dispersed rat islet cells. Cell swelling, induced by intracellular hypertonicity or extracellular hypotonicity, caused activation of an outwardly rectifying conductance which could be subsequently inactivated by hypertonic extracellular solutions. The conductance required adenosine 5-triphosphate (ATP) in the pipette solution but was Ca²⁺ independent. Na⁺ and Cl^– substitution studies suggested that the swelling-activated current is Cl^– selective with a halide permeability sequence of Br > Cl > 1. The conductance was reversibly inhibited by the anion channel inhibitors 4,4-diisothiocyanatostilbene-2,2-disulphonic acid (DIDS) and by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Further evidence for a volume-activated anion conductance was provided by studies of volume regulation in insulin-secreting cells. When RINm5F cells were exposed to a hypotonic medium, the initial cell swelling was followed by a regulatory volume decrease (RVD). This RVD response was also inhibited by DIDS and by NPPB. These data therefore provide evidence for a volume-activated anion conductance in insulin-secreting cells which could be involved in the RVD following osmotic stress. A possible role for the conductance in hypotonically induced insulin release is also discussed.     

GITR: a multifaceted regulator of immunity belonging to the tumor necrosis factor receptor superfamily

Glucocorticoid-induced TNFR-related gene (GITR; TNFRSF18), a receptor belonging to the TNFR superfamily (TNFRSF), is activated by GITRL. GITR is expressed at low levels on resting responder T lymphocytes and is up-regulated in T regulatory cells (Treg cells) and in activated T cells. GITRL is expressed in endothelial and antigen-presenting cells. The cytoplasmic region of GITR has a striking homology with other TNFRSF members (4-1BB, CD27, OX40) and binds TRAF molecules and Siva. Over recent years, the role of GITR in the development and in the pathophysiology of the immune system has been actively explored by several groups. GITR triggering induces both pro- and anti-apoptotic effects, abrogates the suppressive activity of Treg cells and co-stimulates responder T cells, with the latter activities over-stimulating the immune system. In vivo, GITR activation causes development of autoimmune diseases and restores immune responses in a persistent retroviral infection model and in a tumor model. Intriguingly, GITR knockout mice demonstrate lower mortality in an ischemia model. The GITR-GITRL system appears crucial in regulating immunity and warrants further study.     

Reported Challenges in Health Technology Assessment of Complex Health Technologies

ObjectivesWith complex health technologies entering the market, methods for health technology assessment (HTA) may require changes. This study aimed to identify challenges in HTA of complex health technologies.MethodsA survey was sent to European HTA organizations participating in European Network for HTA (EUnetHTA). The survey contained open questions and used predefined potentially complex health technologies and 7 case studies to identify types of complex health technologies and challenges faced during HTA. The survey was validated, tested for reliability by an expert panel, and pilot tested before dissemination.ResultsA total of 22 HTA organizations completed the survey (67%). Advanced therapeutic medicinal products (ATMPs) and histology-independent therapies were considered most challenging based on the predefined complex health technologies and case studies. For the case studies, more than half of the reported challenges were “methodological,” equal in relative effectiveness assessments as in cost-effectiveness assessments. Through the open questions, we found that most of these challenges actually rooted in data unavailability. Data were reported as “absent,” “insufficient,” “immature,” or “low quality” by 18 of 20 organizations (90%), in particular data on quality of life. Policy and organizational challenges and challenges because of societal or political pressure were reported by 8 (40%) and 4 organizations (20%), respectively. Modeling issues were reported least often (n = 2, 4%).ConclusionsMost challenges in HTA of complex health technologies root in data insufficiencies rather than in the complexity of health technologies itself. As the number of complex technologies grows, the urgency for new methods and policies to guide HTA decision making increases.     

Toward Better Data Dashboards for US Drug Value Assessments

ObjectivesTo explore the use of data dashboards to convey information about a drug’s value, and reduce the need to collapse dimensions of value to a single measure.MethodsReview of the literature on US Drug Value Assessment Frameworks, and discussion of the value of data dashboards to improve the manner in which information on value is displayed.ResultsThe incremental cost per quality-adjusted life-year ratio is a useful starting point for conversation about a drug’s value, but it cannot reflect all of the elements of value about which different audiences care deeply. Data dashboards for drug value assessments can draw from other contexts. Decision makers should be presented with well-designed value dashboards containing various metrics, including conventional cost per quality-adjusted life-year ratios as well as measures of a drug’s impact on clinical and patient-centric outcomes, and on budgetary and distributional consequences, to convey a drug’s value along different dimensions.ConclusionsThe advent of US drug value frameworks in health care has forced a concomitant effort to develop appropriate information displays. Researchers should formally test different formats and elements.     

Shared decision making in consultations for hypertension: Qualitative study in general practice

BackgroundHypertension is mainly managed in primary care. Shared decision making is widely recommended as an approach to treatment decision making. However, no studies have investigated; in detail, what happens during primary care consultations for hypertension.AimTo understand patients’ and clinicians’ experience of shared decision making for hypertension in primary care, in order to propose how it might be better supported.DesignLongitudinal qualitative study.SettingFive general practices in south‐west England.MethodInterviews with a purposive sample of patients with hypertension, and with the health‐care practitioners they consulted, along with observations of clinical consultations, for up to 6 appointments. Interviews and consultations were audio‐recorded and observational field notes taken. Data were analysed thematically.ResultsForty‐six interviews and 18 consultations were observed, with 11 patients and nine health‐care practitioners (five GPs, one pharmacist and three nurses). Little shared decision making was described by participants or observed. Often patients’ understanding of their hypertension was limited, and they were not aware there were treatment choices. Consultations provided few opportunities for patients and clinicians to reach a shared understanding of their treatment choices. Opportunities for patients to engage in choices were limited by structured consultations and the distribution of decisions across consultations.ConclusionFor shared decision making to be better supported, consultations need to provide opportunities for patients to learn about their condition, to understand that there are treatment choices, and to discuss these choices with clinicians.Patient or Public ContributionA patient group contributed to the design of this study.     

A Local COVID-19 Support Platform for Nursing Homes: Feedback and Perspectives

The COVID-19 pandemic has had a major impact on nursing homes (NHs), which were not prepared to manage infections among their at-risk patient populations. In order to comply with the French government's guidelines, we rapidly set up a local support platform (LSP) to help NHs manage their cases of COVID-19. The LSP comprised multidisciplinary decision support, a specialist phone hotline, mobile geriatric medicine teams, and videoconferences on COVID-19.We first quantified the LSP's interventions in 63 local NHs since the start of the first wave of COVID-19 (March 2020): 9 instances of multidisciplinary decision support, 275 calls to the specialist phone hotline, 84 interventions by mobile geriatric medicine teams, and 16 videoconferences. The LSP had been used during and between the first and second waves of the epidemic, and all had evolved to meet the NHs' needs.     

层次分析法在确定医疗设备维护优先级中的应用研究

目的:运用层次分析法(AHP)确定医疗设备维护中的优先级,增加医疗设备的可用性并降低维护成本。方法:采用AHP对医疗设备标准、子标准和等级进行评定获取其关键评分,基于多标准决策方法确定医疗设备维护的优先级,对选定设备进行评估,以准分子激光器和视力计为例,根据其标准权重、子标准权重和强度计算其总评分,确定维护优先级。结果:医疗设备维护的优先顺序由医疗设备评分的评估结果决定,医疗设备风险是医学技术人员在确定医疗设备维护优先级时的最重要标准。准分子激光器和视力计的关键评分权重分别为0.877和0.373,准分子激光器相比视力计在设备维护方面具有更高的优先级。结论:医疗设备维护优先级评估模型能确定医疗设备维护优先级,根据优先级规模规划医疗设备维护方案,以使资源更多地集中于具有高和中关键度的医疗设备。     

Social tariffs and democratic choice—Do population‐based health state values reflect the will of the people?

In economic evaluations of health technologies, health outcomes are commonly measured in terms of quality‐adjusted life years (QALYs). QALYs are the product of time and health‐related quality of life. Health‐related quality of life, in turn, is determined by a social tariff, which is supposed to reflect the public's preference over health states. This study argues that, because of the tariff's role in the societal decision‐making process, it should not be understood as merely an operational (statistical) definition of health, but as a major instrument of democratic participation. I outline what implications this might have for both the method used to aggregate individual preferences, and the set of individuals whose preferences should count. Alternative tariff specifications and decision rules are explored, and future research directions are proposed.