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The pharmacokinetics of voriconazole show a nonlinear dose-exposure relationship caused by inhibition of its own CYP3A-dependent metabolism. Because the magnitude of autoinhibition also depends on voriconazole concentrations, infusion rate might modulate voriconazole exposure. The impact of four different infusion rates on voriconazole pharmacokinetics was investigated.Twelve healthy participants received 100 mg voriconazole intravenous over 4 h, 400 mg over 6 h, 4 h, and 2 h in a crossover design. Oral midazolam (3 μg) was given at the end of infusion. Blood and urine samples were collected up to 48 h. Voriconazole and its N-oxide metabolite were quantified using high-performance liquid chromatography coupled to tandem mass spectrometry. Midazolam estimated metabolic clearance (eCLmet) was calculated using a limited sampling strategy. Voriconazole-N-oxide inhibition of cytochrome P450 (CYP) isoforms 2C19 and 3A4 were assessed with the P450-Glo luminescence assay.Area under the concentration-time curve for 400 mg intravenous voriconazole was 16% (90% confidence interval: 12-20%) lower when administered over 6 h compared to 2 h infusion. Dose-corrected area under the concentration-time curve for 100 mg over 4 h was 34% lower compared to 400 mg over 4 h. Midazolam eCLmet was 516 ml minVoriconazole pharmacokinetics is modulated by infusion rate, an autoinhibitory contribution voriconazole metabolism by CYP3A and 2C19 and to a lesser extent its main N-oxide metabolite for CYP2C19. To avoid reduced exposure, the infusion rate should be 2 h.

To investigate the dose and concentration dependency of CYP3A inhibition by ritonavir using the established limited sampling strategy with midazolam for CYP3A activity. An open, fixed-sequence study was carried out in 12 healthy subjects. Single ascending doses of ritonavir (0.1–300 mg) were evaluated for CYP3A inhibition in two cohorts using midazolam as a marker substance. Ritonavir administered as a single oral dose produced a dose-dependent CYP3A inhibition with an ID50 of 3.4 mg. Using the measured ritonavir concentrations an exposure–inhibition effect curve was established with an IC50 of 600 h pmol/L (AUC2–4). Over the ritonavir dose range studied non-linear exposure of ritonavir was observed. Ritonavir shows a dose and concentration effect relationship of CYP3A inhibition. In addition, a proposed auto-inhibition of ritonavir metabolism resulted in a non-linear exposure of ritonavir with sub-proportional concentrations at low doses. A time-dependent CYP3A activity may result when inhibitors of CYP3A with short elimination half-lives are used.

Background : The 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. Objective : To report an assessment of health providers’ computer knowledge, experience, and attitudes prior to the implementation of the QUALMAT electronic CDSS. Design : A 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. Results : A 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

"The Gothic" is a hybrid genre relying on a set of narrative conventions: the setting a dark and crumbling castle, its plots fuelled by motifs of pursuit and flight. With the publication of The Banished Man (1794), which included Avis au Lecteur, her manifesto on realistic writing, Charlotte Smith turned on the genre she had done much to popularize with her early romances. This article examines how Smith harnessed spaces and themes generally classified as "Gothic" to serve her novelistic project of writing the "real"—at a moment in history when authors searched for an appropriate mode to present a credible account of the socio-political horrors perpetrated in the Revolutionary Wars without having recourse to a conventional Gothic discourse and genre, which routinely centred on representations of monstrous humankind.

ObjectiveThis paper investigated the cost-effectiveness of a computer-assisted Clinical Decision Support System (CDSS) in the identification of maternal complications in Ghana.MethodsA cost-effectiveness analysis was performed in a before- and after-intervention study. Analysis was conducted from the provider's perspective. The intervention area was the Kassena- Nankana district where computer-assisted CDSS was used by midwives in maternal care in six selected health centres. Six selected health centers in the Builsa district served as the non-intervention group, where the normal Ghana Health Service activities were being carried out.ResultsComputer-assisted CDSS increased the detection of pregnancy complications during antenatal care (ANC) in the intervention health centres (before-intervention = 9 /1,000 ANC attendance; after-intervention = 12/1,000 ANC attendance; P-value = 0.010). In the intervention health centres, there was a decrease in the number of complications during labour by 1.1%, though the difference was not statistically significant (before-intervention =107/1,000 labour clients; after-intervention = 96/1,000 labour clients; P-value = 0.305). Also, at the intervention health centres, the average cost per pregnancy complication detected during ANC (cost -effectiveness ratio) decreased from US$17,017.58 (before-intervention) to US$15,207.5 (after-intervention). Incremental cost -effectiveness ratio (ICER) was estimated at US$1,142. Considering only additional costs (cost of computer-assisted CDSS), cost per pregnancy complication detected was US$285.ConclusionsComputer -assisted CDSS has the potential to identify complications during pregnancy and marginal reduction in labour complications. Implementing computer-assisted CDSS is more costly but more effective in the detection of pregnancy complications compared to routine maternal care, hence making the decision to implement CDSS very complex. Policy makers should however be guided by whether the additional benefit is worth the additional cost.

Aim: Saliva is an alternative sampling matrix to plasma, offering a noninvasive technique, but requires a highly sensitive bioanalytical method. Materials & methods: An API 3000 triple quadrupole mass spectrometer with an electrospray ionization source operated in the positive ion mode was used for the analysis. Results: A high-throughput LC–MS/MS method using SPE for the quantification of artesunate and dihydroartemisinin in plasma and saliva has been optimized and validated according to US FDA guidelines. For both analytes the LLOQ was determined to 5 ng/ml and the calibration range was 5–1000 ng/ml for artesunate and 5–2000 ng/ml for dihydroartemisinin. Conclusion: For the first time, a bioanalytical method for determination of artesunate and dihydroartemisinin in human saliva has been described, showing possible applicability in clinical saliva samples in addition to plasma samples.

Background : The European Union (EU) supports North–South Partnerships and collaborative research projects through its Framework Programmes and Horizon 2020. There is limited research on how such projects can be harnessed to provide a structured platform for doctoral level studies as a way of strengthening health system research capacity in sub-Saharan Africa (SSA). Objective : The aim of this study was to explore the challenges of, and facilitating factors for, ‘nesting’ doctoral students in North–South collaborative research projects. The term nesting refers to the embedding of the processes of recruiting, supervising, and coordinating doctoral students in the overall research plan and processes. Design : This cross-sectional qualitative study was undertaken by the EU-funded QUALMAT Project. A questionnaire was implemented with doctoral students, supervisors, and country principal investigators (PIs), and content analysis was undertaken. Results : Completed questionnaires were received from nine doctoral students, six supervisors, and three country PIs (86% responses rate). The doctoral students from SSA described high expectations about the input they would receive (administrative support, equipment, training, supervision). This contrasted with the expectations of the supervisors for proactivity and self-management on the part of the students. The rationale for candidate selection, and understandings of the purpose of the doctoral students in the project were areas of considerable divergence. There were some challenges associated with the use of the country PIs as co-supervisors. Doctoral student progress was at times impeded by delays in the release of funding instalments from the EU. The paper provides a checklist of essential requirements and a set of recommendations for effective nesting of doctoral students in joint North–South projects. Conclusion : There are considerable challenges to the effective nesting of doctoral students within major collaborative research projects. However, ways can be found to overcome them. The nesting process ultimately helped the institutions involved in this example to take better advantage of the opportunities that collaborative projects offer to foster North–South partnerships as a contribution to the strengthening of local research capacity. Keywords : collaborative project; doctoral students; health systems research capacity; North–South Partnership (Published: 15 July 2014) Citation : Glob Health Action 2014, 7 : 24070 - http://dx.doi.org/10.3402/gha.v7.24070

The purpose of this study were firstly to characterize the population pharmacokinetics of artesunate (ARS) and its active metabolite dihydroartemisinin (DHA) in patients with metastatic breast cancer during long-term (>3 weeks) daily oral ARS administration and secondly to study the relationship between salivary and plasma concentrations of DHA. Drug concentration-time data from 23 patients, receiving oral ARS (100, 150, or 200 mg OD), was analyzed using nonlinear mixed effects modeling. A combined drug-metabolite population pharmacokinetic model was developed to describe the plasma pharmacokinetics of ARS and DHA in plasma. Saliva drug concentrations were incorporated as being directly proportional to plasma concentrations. A first-order absorption model for ARS linked to a combined two-compartment disposition model for ARS and one-compartment disposition model for DHA provided the best fit to the data. No covariates were identified that could explain between-subject variability. A time-dependent increase in apparent elimination clearance of DHA was observed. Salivary DHA concentrations were proportionally correlated with total DHA plasma concentrations, with an estimated slope factor of 0.116. Population pharmacokinetics of ARS and DHA in patients with breast cancer was well described by a combined drug-metabolite model without any covariates and with an increase in apparent elimination clearance of DHA over time. The estimated DHA saliva/plasma ratio was in good agreement with the reported DHA unbound fraction in human plasma. Saliva ARS concentrations correlated poorly with plasma concentrations. This suggests the use of saliva sampling for therapeutic drug monitoring of DHA. However, further studies are warranted to investigate the robustness of this approach.

The therapeutic activity of tilidine, an opioid analgesic, is mainly related to its active metabolite nortilidine. Nortilidine formation mainly occurs during the high intestinal first-pass metabolism of tilidine by N-demethylation. Elimination of the active nortilidine to the inactive bisnortilidine is also mediated by N-demethylation and is supposed to take place in the liver, probably at a smaller rate. The aim of this study was the investigation of the pre-systemic elimination of tilidine using grapefruit juice (GFJ) as an intestinal CYP3A4 inhibitor and efavirenz (EFV) as a CYP3A4 activator. A randomized, open, placebo-controlled, cross-over study was conducted in 12 healthy volunteers using 100 mg tilidine solution p.o., regular strength GFJ 250 mL (3 times at 12-hr intervals) and EFV 400 mg (12 hr before tilidine administration). Tilidine, nortilidine and bisnortilidine in plasma and urine were quantified by a validated LC/MS/MS analysis. GFJ did not change any pharmacokinetic parameter of tilidine and its metabolites, which suggests that intestinal CYP3A4 does not contribute to the first-pass metabolism of tilidine. No effect of EFV on the pharmacokinetics of the active nortilidine was observed except a significant reduction of the terminal elimination half-life by 15%. Overall elimination (renal and metabolic clearances) was unaffected by every treatment. CYP3A4 does not seem to play a major role in tilidine first-pass and overall metabolism. Other unknown metabolites and their enzymes responsible for their formation have to be investigated as they account for the majority of renally excreted metabolites.

Objective This study analyzed cost of implementing computer-assisted Clinical Decision Support System (CDSS) in selected health care centres in Ghana. Methods A descriptive cross sectional study was conducted in the Kassena-Nankana district (KND). CDSS was deployed in selected health centres in KND as an intervention to manage patients attending antenatal clinics and the labour ward. The CDSS users were mainly nurses who were trained. Activities and associated costs involved in the implementation of CDSS (pre-intervention and intervention) were collected for the period between 2009–2013 from the provider perspective. The ingredients approach was used for the cost analysis. Costs were grouped into personnel, trainings, overheads (recurrent costs) and equipment costs (capital cost). We calculated cost without annualizing capital cost to represent financial cost and cost with annualizing capital costs to represent economic cost. Results Twenty-two trained CDSS users (at least 2 users per health centre) participated in the study. Between April 2012 and March 2013, users managed 5,595 antenatal clients and 872 labour clients using the CDSS. We observed a decrease in the proportion of complications during delivery (pre-intervention 10.74% versus post-intervention 9.64%) and a reduction in the number of maternal deaths (pre-intervention 4 deaths versus post-intervention 1 death). The overall financial cost of CDSS implementation was US$23,316, approximately US$1,060 per CDSS user trained. Of the total cost of implementation, 48% (US$11,272) was pre-intervention cost and intervention cost was 52% (US$12,044). Equipment costs accounted for the largest proportion of financial cost: 34% (US$7,917). When economic cost was considered, total cost of implementation was US$17,128–lower than the financial cost by 26.5%. Conclusions The study provides useful information in the implementation of CDSS at health facilities to enhance health workers' adherence to practice guidelines and taking accurate decisions to improve maternal health care.

Background Despite 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. Methods A 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”. Results The 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. Conclusion The 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 registration http://www.clinicaltrials.gov/NCT01409824.

Background Initiatives to raise the quality of care provided to mothers need to be given priority in Sub Saharan Africa (SSA). The promotion of clinical practice guidelines (CPGs) is a common strategy, but their implementation is often challenging, limiting their potential impact. Through a cross-country perspective, this study explored CPGs for maternal health in Burkina Faso, Ghana, and Tanzania. The objectives were to compare factors related to CPG use including their content compared with World Health Organization (WHO) guidelines, their format, and their development processes. Perceptions of their availability and use in practice were also explored. The overall purpose was to further the understanding of how to increase CPGs' potential to improve quality of care for mothers in SSA. Methods The study was a multiple case study design consisting of cross-country comparisons using document review and key informant interviews. A conceptual framework to aid analysis and discussion of results was developed, including selected domains related to guidelines' implementability and use by health workers in practice in terms of usability, applicability, and adaptability. Results The study revealed few significant differences in content between the national guidelines for maternal health and WHO recommendations. There were, however, marked variations in the format of CPGs between the three countries. Apart from the Ghanaian and one of the Tanzanian CPGs, the levels of both usability and applicability were assessed as low or medium. In all three countries, the use of CPGs by health workers in practice was perceived to be limited. Conclusion Our cross-country study suggests that it is not poor quality of content or lack of evidence base that constitute the major barrier for CPGs to positively impact on quality improvement in maternal care in SSA. It rather emphasises the need to prioritise the format of guidelines to increase their usability and applicability and to consider these attributes together with implementation strategies as integral to their development processes.

We investigated the effect of efavirenz treatment on the results of drug screening tests of urine samples obtained from 100 patients infected with human immunodeficiency virus. Of 50 patients who received efavirenz, 49 tested positive for benzodiazepines inor =1 drug screening test, whereas of 50 patients who did not receive efavirenz, only 1 tested positive for benzodiazepines inor =1 drug screening test. The major metabolite 8-hydroxy-efavirenz is responsible for this cross-reactivity.

Mx proteins have molecular masses between 70 and 80 kDa and their synthesis is tightly regulated by interferons in mammalian and non-mammalian vertebrates. Some Mx proteins function as intracellular mediators of the interferon-induced antiviral state. When suitable cDNA constructs were constitutively expressed in mouse 3T3 cells the mouse nuclear Mx1 protein conferred selective resistance to influenza virus. The human cytoplasmic MxA protein conferred resistance to influenza virus and vesicular stomatitis virus but not to other viruses. Mx1 blocks influenza virus mRNA synthesis within the nucleus of infected cells. Mx1 presumably interacts with the influenza virus polymerase subunit PB2, because overexpression of PB2 titrates out the Mx1 block. MxA does not inhibit mRNA synthesis of influenza virus; it inhibits a subsequent cytoplasmic viral multiplication step. A possible target is the transport of newly synthesized influenza virus polymerase proteins back to the nucleus. Inhibition by MxA of vesicular stomatitis virus, which replicates in the cytoplasm, is at the transcriptional level. Parts of the N-terminal halves of all known Mx proteins are highly conserved. They contain the typical GTP-binding motif and show significant homology to other members of a new family of GTPases that includes rat dynamin, Drosophila Shibire and the yeast proteins Vps1/Spo15 and Mgm1. Purified Mx1 and MxA proteins possess GTPase activity. The GTP/GDP conversion rates are about 40 per min, and Km values about 700 microM. Mx1 and MxA variants with mutations in the GTP-binding sequences that violate the consensus are unable to confer virus resistance in vivo or to hydrolyse GTP in vitro, suggesting that GTPase activity is necessary for antiviral activity of Mx proteins. We hypothesize that the antivirally active Mx proteins (directly or indirectly) bind to polymerase proteins of susceptible viruses, thereby abolishing normal viral polymerase function. Interaction of Mx with viral targets is probably a GTP-dependent process.

Background : The implementation of new technology can interrupt established workflows in health care settings. The Quality of Maternal Care (QUALMAT) project has introduced an electronic clinical decision support system (eCDSS) for antenatal care (ANC) and delivery in rural primary health care facilities in Africa. Objective : This study was carried out to investigate the influence of the QUALMAT eCDSS on the workflow of health care workers in rural primary health care facilities in Ghana and Tanzania. Design : A direct observation, time-and-motion study on ANC processes was conducted using a structured data sheet with predefined major task categories. The duration and sequence of tasks performed during ANC visits were observed, and changes after the implementation of the eCDSS were analyzed. Results : In 24 QUALMAT study sites, 214 observations of ANC visits (144 in Ghana, 70 in Tanzania) were carried out at baseline and 148 observations (104 in Ghana, 44 in Tanzania) after the software was implemented in 12 of those sites. The median time spent combined for all centers in both countries to provide ANC at baseline was 6.5 min [interquartile range (IQR) =4.0–10.6]. Although the time spent on ANC increased in Tanzania and Ghana after the eCDSS implementation as compared to baseline, overall there was no significant increase in time used for ANC activities (0.51 min, p =0.06 in Ghana; and 0.54 min, p =0.26 in Tanzania) as compared to the control sites without the eCDSS. The percentage of medical history taking in women who had subsequent examinations increased after eCDSS implementation from 58.2% (39/67) to 95.3% (61/64) p

Background Poor quality of care is among the causes of high maternal and newborn disease burden in Tanzania. Potential reason for poor quality of care is the existence of a “know-do gap” where by health workers do not perform to the best of their knowledge. An electronic clinical decision support system (CDSS) for maternal health care was piloted in six rural primary health centers of Tanzania to improve performance of health workers by facilitating adherence to World Health Organization (WHO) guidelines and ultimately improve quality of maternal health care. This study aimed at assessing the cost of installing and operating the system in the health centers. Methods This retrospective study was conducted in Lindi, Tanzania. Costs incurred by the project were analyzed using Ingredients approach. These costs broadly included vehicle, computers, furniture, facility, CDSS software, transport, personnel, training, supplies and communication. These were grouped into installation and operation cost; recurrent and capital cost; and fixed and variable cost. We assessed the CDSS in terms of its financial and economic cost implications. We also conducted a sensitivity analysis on the estimations. Results Total financial cost of CDSS intervention amounted to 185,927.78 USD. 77% of these costs were incurred in the installation phase and included all the activities in preparation for the actual operation of the system for client care. Generally, training made the largest share of costs (33% of total cost and more than half of the recurrent cost) followed by CDSS software- 32% of total cost. There was a difference of 31.4% between the economic and financial costs. 92.5% of economic costs were fixed costs consisting of inputs whose costs do not vary with the volume of activity within a given range. Economic cost per CDSS contact was 52.7 USD but sensitive to discount rate, asset useful life and input cost variations. Conclusions Our study presents financial and economic cost estimates of installing and operating an electronic CDSS for maternal health care in six rural health centres. From these findings one can understand exactly what goes into a similar investment and thus determine sorts of input modification needed to fit their context. Electronic supplementary material The online version of this article (doi:10.1186/s12913-015-0780-9) contains supplementary material, which is available to authorized users.