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The Na+‐taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild‐type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1‐transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno‐associated virus–mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α‐hydroxylase Cyp7a1 expression was strongly down‐regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B–treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte‐models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. Conclusion: NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631–1643).

BackgroundThe QUALMAT (Quality of Maternal and Prenatal Care: Bridging the Know-do Gap) project has introduced an electronic clinical decision support system (CDSS) for pre-natal and maternal care services in rural primary health facilities in Burkina Faso, Ghana, and Tanzania.ObjectiveTo report an assessment of health providers’ computer knowledge, experience, and attitudes prior to the implementation of the QUALMAT electronic CDSS.DesignA cross-sectional study was conducted with providers in 24 QUALMAT project sites. Information was collected using structured questionnaires. Chi-squared tests and one-way ANOVA describe the association between computer knowledge, attitudes, and other factors. Semi-structured interviews and focus groups were conducted to gain further insights.ResultsA total of 108 providers responded, 63% were from Tanzania and 37% from Ghana. The mean age was 37.6 years, and 79% were female. Only 40% had ever used computers, and 29% had prior computer training. About 80% were computer illiterate or beginners. Educational level, age, and years of work experience were significantly associated with computer knowledge (p<0.01). Most (95.3%) had positive attitudes towards computers – average score (±SD) of 37.2 (±4.9). Females had significantly lower scores than males. Interviews and group discussions showed that although most were lacking computer knowledge and experience, they were optimistic about overcoming challenges associated with the introduction of computers in their workplace.ConclusionsGiven the low levels of computer knowledge among rural health workers in Africa, it is important to provide adequate training and support to ensure the successful uptake of electronic CDSSs in these settings. The positive attitudes to computers found in this study underscore that also rural care providers are ready to use such technology.

Myrcludex B acts as a hepatitis B and D virus entry inhibitor blocking the sodium taurocholate cotransporting polypeptide (SLC10A1). We investigated the effects of myrcludex B on plasma bile acid disposition, tenofovir pharmacokinetics, and perpetrator characteristics on cytochrome P450 (CYP) 3A. Twelve healthy volunteers received 300 mg tenofovir disoproxil fumarate orally and 10 mg subcutaneous myrcludex B. Myrcludex B increased total plasma bile acid exposure 19.2-fold without signs of cholestasis. The rise in conjugated bile acids was up to 124-fold (taurocholic acid). Coadministration of tenofovir with myrcludex B revealed no relevant changes in tenofovir pharmacokinetics. CYP3A activity slightly but significantly decreased by 29% during combination therapy. Myrcludex B caused an asymptomatic but distinct rise in plasma bile acid concentrations and had no relevant impact on tenofovir pharmacokinetics. Changes in CYP3A activity might be due to alterations in bile acid signaling. Long-term effects of elevated bile acids will require critical evaluation.

BackgroundDespite strong efforts to improve maternal care, its quality remains deficient in many countries of Sub-Saharan Africa as persistently high maternal mortality rates testify. The QUALMAT study seeks to improve the performance and motivation of rural health workers and ultimately quality of primary maternal health care services in three African countries Burkina Faso, Ghana, and Tanzania. One major intervention is the introduction of a computerized Clinical Decision Support System (CDSS) for rural primary health care centers to be used by health care workers of different educational levels.MethodsA stand-alone, java-based software, able to run on any standard hardware, was developed based on assessment of the health care situation in the involved countries. The software scope was defined and the final software was programmed under consideration of test experiences. Knowledge for the decision support derived from the World Health Organization (WHO) guideline “Pregnancy, Childbirth, Postpartum and Newborn Care; A Guide for Essential Practice”.ResultsThe QUALMAT CDSS provides computerized guidance and clinical decision support for antenatal care, and care during delivery and up to 24 hours post delivery. The decision support is based on WHO guidelines and designed using three principles: (1) Guidance through routine actions in maternal and perinatal care, (2) integration of clinical data to detect situations of concern by algorithms, and (3) electronic tracking of peri- and postnatal activities. In addition, the tool facilitates patient management and is a source of training material. The implementation of the software, which is embedded in a set of interventions comprising the QUALMAT study, is subject to various research projects assessing and quantifying the impact of the CDSS on quality of care, the motivation of health care staff (users) and its health economic aspects. The software will also be assessed for its usability and acceptance, as well as for its influence on workflows in the rural setting of primary health care in the three countries involved.ConclusionThe development and implementation of a CDSS in rural primary health care centres presents challenges, which may be overcome with careful planning and involvement of future users at an early stage. A tailored software with stable functionality should offer perspectives to improve maternal care in resource-poor settings.Trial registrationhttp://www.clinicaltrials.gov/NCT01409824.