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NHs have been severely exposed during the COVID-19 pandemic. Little is known about how staff who provide practical daily care of older residents experienced work during the pandemic. The aim of this study was to understand how nursing assistants (NAs) experienced their work at nursing homes (NHs) for older people during the first wave of the COVID-19 pandemic.We conducted a qualitative study of focus group discussions with in total 20 participants from four NHs in Stockholm, Sweden. Discussions were held in November 2020. Transcripts were analyzed using inductive thematic analysis.We identified three major themes: 1) We felt abandoned, scared and disrespected, 2) We made sure we made it through, and 3) We can do good work with appropriate resources. NAs felt disregarded as they were often left alone without adequate support from managers, registered nurses and the municipalities. NAs felt distressed and guilty and developed their own strategies to cope and manage their work.During the first wave of the COVID-19 pandemic NAs felt abandoned and burdened due to lack of leadership. Organizational improvements are required to protect the wellbeing of NAs and to ensure sustainability of patient safety. NAs are crucial in the care for vulnerable older people and their experiences should constitute a keystone for development of future policy and practice in NHs.

Purpose Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. Method Pregnant women with moderate untreated depression were recruited in 2016–2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. Results Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers’, measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. Conclusion Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. Trial registration The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.

Adverse drug reactions (ADRs) for all drugs in Europe are described in the legally approved Summary of Product Characteristics (SmPC). An overview of all ADRs of the patients' drug list can support healthcare staff to link patient symptoms to possible ADRs. We review the possibilities and challenges to extract ADR information from SmPCs and present the development of our semi-automated procedure for extraction of ADRs from the tabulated section of the SmPCs to create a database, named Bikt, which is regularly updated and used at point of care in Sweden. The existence of five major table formats for ADRs used in the SmPCs required the development of different parsing scripts. Manual checks for correctness for all content has to be performed. The quality of extraction was investigated for all SmPCs by measuring precision, recall and F1 scores (i.e. the weighted harmonic mean of precision and recall) and compared with other methods published. We conclude that it is possible to semi-automatically extract ADR information from SmPCs. However, clear technical and content guidelines and standards for ADR tables and terms from drug registration authorities would lead to improved extraction and usability of ADR information at point of care.

AIM To assess the prevalence of pretreatment drug resistance (PDR) and its association with virologic outcomes after 24 weeks of antiretroviral therapy (ART), within an urban cohort of Ugandan children. METHODS Prospective observational study. Baseline and 24-week assessments of viral load (VL) and genotypic drug resistance to nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI) were performed. RESULTS Ninety-nine ART-naive children (3-12 years) initiated efavirenz-based ART 2015-2016 and 18/90 (20%) had baseline NRTI/NNRTI associated drug resistance mutations (DRMs). By 24 weeks, 72/93 (77%) children had VL

Aim Children with epilepsy often have concomitant diagnoses. Dried blood spot samples for drug monitoring can be collected by parents at home as an alternative to traditional sampling. This mixed-method study aimed to understand the parents' perspectives on blood self-sampling from their children and to identify factors contributing to successful sampling. Method Parents who had collected a sample from their child during a visit to the neuropediatric clinic were asked to fill in a questionnaire. To get in-depth information and individual perspectives, parents and nurses participated in semi-structured interviews and analysed with thematic analysis. Results The results from questionnaires (n = 64) and interviews (n = 9) were interpreted together. Watching an instruction video and practical training contributed to successful sampling. 97% of the parents managed to collect a sample, 72% thought it was easy to perform, and 80% found self-sampling at home desirable. Factors for success were as follows: high motivation, prepared parents with pre-understanding, a pragmatic attitude, flexible education, effective communication and willingness to take on the role as a performer. Risk factors were as follows: conflict, fear, unprepared parents, confused or worried children. Conclusion Voluntary self-sampling at home for parents of children with epilepsy is feasible and can reduce stress factors in everyday life.

In this editorial we attempt to define additional rationales for SHAJ, the Somali Health Action Journal, further to those presented in our inaugural editorial. We recognize the health information divide as one of the three health gaps characterizing the global health inequality landscape. The SHAJ venture emerged from a joint Somali-Swedish initiative to revive a former collaborative research programme also recognizing the need for a Somali-based platform for research communication. The members of the SHAJ Editorial team decided to join forces in designing and carrying out an empirical bibliometric study to assess the state of the art of the published literature on Somali health issues over a 75-year period covering major societal development eras in Somali academic history. This editorial is basically presented in the form of a report from this study, concluding with a statement on the policy implications for SHAJ and Somali based research for health. The study raises concerns about the scarcity of research publications on Somali public health issues. This points to the need for research capacity strengthening in general and with special attention to the important role of the newly established Somali universities. We note a lack of balance regarding the topics and public health relevance of published papers in relation to the burden of prevailing health problems which calls for efforts to set research priorities in tune with the broad needs of the communities. Another observation is that the papers reviewed indicate a heavy dependence of the research agenda on external organisations and funders, which calls for active attention to research ownership issues in terms of Somali leadership and authorship. There is a lack of dissemination channels for Somali based health research and limited possibilities for young Somali scientists to publish their studies. As a Somali-owned journal, we envisage that SHAJ can play a catalytic role in the promotion and dissemination of "Essential Somali Health Research".

INTRODUCTION:The potentials of Africa for growth and economic transformation through science remains challenging because of existing gaps in knowledge and infrastructure. The Africa Pharmacological Science Gateway project and the Medicines Utilization Research in Africa Group seeks to meet the research needs of African pharmacologists. This study aimed at identifying priority needs that might be met by access to information and tools through e-infrastructure. METHODS:A web-based cross-sectional study among 472 members of pharmacological societies in Africa to obtain information on their research interests and skills, available resources, needs and knowledge gaps. Descriptive analyses were done. RESULTS:A total of 118 responses from 13 countries were received, mostly from Nigeria (48.3%) and South Africa (21.3%). Respondents had wide ranges of research interests predominantly in drug utilization research.The desired resources included drug utilization research training and tools, pharmacokinetics and pharmacometrics modelling training and tools, drug-drug interaction and medicine prices resources, statistical analysis resources, access to journals, training in specific laboratory techniques, equipment and funding for research-related activities. CONCLUSIONS:Key areas of needs not currently provided by the African Pharmacological Science Gateway e-infrastructure were identified to guide further provision of resources on the e-infrastructure and potentially enhance research capacity within the continent.

Adverse drug reactions (ADRs) for all drugs in Europe are described in the legally approved Summary of Product Characteristics (SmPC). An overview of all ADRs of the patients' drug list can support healthcare staff to link patient symptoms to possible ADRs. We review the possibilities and challenges to extract ADR information from SmPCs or American Structured Product Labels and present the development of our semi-automated procedure for extraction of ADRs from the tabulated section in the SmPCs to create a database, named Bikt, which is regularly updated and used at point of care in Sweden. The existence of five major table formats for ADRs used in the SmPCs required the development of different parsing scripts. Manual checks for correctness for all content have to be performed. The quality of extraction was investigated for all SmPCs by measuring precision, recall and F1 scores and compared with other methods published. We conclude that it is possible to semi-automatically extract ADR information from SmPCs. However, clear technical and content guidelines and standards for ADR tables and terms from drug registration authorities would lead to improved extraction and usability of ADR information at point of care.

Introduction: There are growing concerns among European health authorities regarding increasing prices for new cancer medicines, prices not necessarily linked to health gain and the implications for the sustainability of their healthcare systems. Areas covered: Narrative discussion principally among payers and their advisers regarding potential approaches to the pricing of new cancer medicines. Expert opinion: A number of potential pricing approaches are discussed including minimum effectiveness levels for new cancer medicines, managed entry agreements, multicriteria decision analyses (MCDAs), differential/tiered pricing, fair pricing models, amortization models as well as de-linkage models. We are likely to see a growth in alternative pricing deliberations in view of ongoing challenges. These include the considerable number of new oncology medicines in development including new gene therapies, new oncology medicines being launched with uncertainty regarding their value, and continued high prices coupled with the extent of confidential discounts for reimbursement. However, balanced against the need for new cancer medicines. This will lead to greater scrutiny over the prices of patent oncology medicines as more standard medicines lose their patent, calls for greater transparency as well as new models including amortization models. We will be monitoring these developments., peer-reviewed

BackgroundIn Sweden, patients receiving Home Care (HC) are older people with frailty and multimorbidity, and are often treated with many medicines. Their perspectives on polypharmacy have been sparsely explored.AimTo investigate HC patients’ experiences and perceptions regarding polypharmacy.Design & settingSemi-structured interviews with 17 patients with HC in Stockholm, Sweden.MethodThe interview questions were open and aimed to encourage participants to speak freely about their personal experiences of living with polypharmacy. Data were analysed using an inductive thematic analysis.ResultsThe participants’ median age was 83.5 years (range 74–97 years) and the median number of prescribed medicines was 11 (range 5–30). The following two themes were identified: (1) experiences from daily life with polypharmacy; and (2) dependency on the relationship to healthcare professionals. The first theme contains the main finding, which was the diversity in how older people experienced polypharmacy and how they coped with polypharmacy in everyday life. While some were satisfied despite having multiple medicines, others experienced such psychological unease owing to polypharmacy that it led to reduced quality of life. The second theme reflects the importance of the relationship between the older person and healthcare professionals for medicine-related ideas and attitudes.ConclusionThe individual variation in experiences regarding polypharmacy points to the value of interprofessional teamwork with the patient as an active partner. Therefore, healthcare professionals need to adapt a more person-centred approach where the patient’s perspectives are respected and considered in medicine-related decisionmaking.

What We Already Know about This TopicWhat This Article Tells Us That Is NewBackgroundThe pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(–) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations.MethodsS(+) or R(–) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses.ResultsA three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(–) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(–) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min–1, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01.ConclusionsArterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

Aim This study evaluated whether maternal mood disorders (MMD), particularly bipolar disorder, and lithium treatment during pregnancy influenced the neonatal health and cognition of children born from 2006 to 2010. Methods Our study at Karolinska University Hospital, Stockholm, Sweden, focused on women with and without mood disorders and their children. Information on pharmacotherapy, mental health, delivery and neonatal complications was retrospectively collected from electronic patient records. Children were tested in a blinded manner at four to five years of age with the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition. Maternal health, child health and social situations were evaluated. Results Of the 39 children, 20 were exposed to lithium and MMD during pregnancy, eight were exposed to MMD but not lithium and 11 were not exposed to MMD or lithium. The children's full scale intelligence quotient (IQ), performance IQ and verbal IQ results did not differ significantly between the groups. The processing speed quotient was significantly lower in children exposed to mood disorders, but there was a high level of missing data for this subtest. Conclusion This small, clinical cohort showed no significant association between mothers' prenatal exposure to lithium or mood disorders and their offspring's IQ.

Objectives To investigate if dried blood spots could be used for therapeutic drug monitoring of the antiepileptic drugs, carbamazepine, lamotrigine and valproic acid in children with epilepsy. Methods Fingerprick blood samples from 46 children at a neuropediatric outpatient clinic was collected on filterpaper at the same time as capillary plasma sampling. A validated dried blood spot liquid chromatography tandem mass spectrometry method for carbamazepine, lamotrigine and valproic acid was compared with the routine plasma laboratory methods. Method agreement was evaluated and plasma concentrations were estimated by different conversion approaches. Results Strong correlation was shown between dried blood spot and plasma concentrations for all three drugs, with R2 values > 0.89. Regression analysis showed a proportional bias with 35% lower dried blood spot concentrations for valproic acid (n = 33) and concentrations were 18% higher for carbamazepine (n = 17). A ratio approach was used to make a conversion from dried blood spots to estimated plasma for these two drugs. Dried blood spot concentrations were directly comparable with plasma for lamotrigine (n = 20). Conclusions This study supports that dried blood spot concentrations can be used as an alternative to plasma in a children population for three commonly used antiepileptic drugs with the possibility to expand by adding other antiepileptic drugs. Clinical decisions can be made based on converted (carbamazepine, valproic acid) or unconverted (lamotrigine) dried blood spot concentrations. Dried blood spot sampling, in the future taken at home, will simplify an effective therapeutic drug monitoring for this group of patients who often have concomitant disorders and also reduce costs for society.

Dried blood spot (DBS) is an attractive matrix alternative to plasma for the measurement of antiepileptic drug concentrations with the possibility of self-sampling at home. The aim of this study was to evaluate whether DBS concentrations from a children population could be used as an alternative to plasma concentrations in a clinical routine laboratory.Children with epilepsy using carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproic acid (VPA) had capillary blood collected for routine plasma analysis. DBS samples were collected by guardians or nurses, and the quality of sampling was compared between the groups. DBS samples were analyzed with liquid chromatography-tandem mass spectrometry methods and plasma samples with immunochemical methods. In the comparison between DBS and plasma concentrations, previously analyzed sample data were pooled with data in this study and resulted in 190 comparison pairs. A bioanalytical cross-validation according to European Medicines Agency was performed. Clinicians evaluated the results to understand if a DBS concentration was linked to a different clinical dose recommendation for the patient in comparison with plasma concentrations.Comparison of DBS sample quality showed that 2.3% of the capillary DBS collected by guardians were rejected and 8.0% of the capillary DBS collected by nurses. For DBS, a conversion factor of 0.85 for CBZ and 1.65 for VPA was applied for the comparison with plasma. LTG and LEV results were directly comparable. In the cross-validation, 88% of CBZ, 75% of LTG, 74% of LEV, and 94% of VPA comparisons were within 20% of the difference of the mean, although LEV had a few major differences (+31% to -40%). In 4 of the 190 comparisons, the clinical evaluation indicated a risk of conflicting decisions regarding the need for dose adjustment when using DBS concentrations. However, the risk of negative patient outcomes was considered negligible.Our study demonstrates that a combination of bioanalytical cross-validation and clinical evaluation is an effective way to describe the applicability of DBS as an alternative to plasma, taking into account how therapeutic drug monitoring is used in specific patient groups. For LTG, converted CBZ and VPA, DBS is a feasible alternative for self-sampling at home. DBS for LEV can only be recommended for nonadherence queries due to the high variability of the plasma/DBS concentration ratios.

Background Artemisinin-based combination therapy (ACT) is the first-line treatment of Plasmodium falciparum malaria. Since the introduction of artemether-lumefantrine (AL) for treatment of uncomplicated malaria in Sweden, treatment failures have been reported in adults. Methods A retrospective comparative analysis of treatment regimen for P. falciparum malaria in adults in Stockholm during 2000-2015 was performed to evaluate the effectiveness of AL. Parasite genotyping and drug concentrations were investigated in the AL treatment failures. Results Among the total 397 P. falciparum episodes, 310 were treated with oral regimen only (95 AL, 162 mefloquine, 36 atovaquone-proguanil [AP], and 17 others), and 87 were administered initial intravenous therapy (38 artesunate and 49 quinine) followed by oral treatments. Five late treatment failures were detected after AL and one slow response to AP. The effectiveness of AL alone was 94.7% (95% confidence interval [CI], 88.1%-98.3%), compared with 99.5% for other oral regimens (P = .003). All AL failures occurred in European men and the effectiveness in this group was only 73.7% (95% CI, 48.8%-90.0%). Genotyping confirmed recrudescence of the initial parasite populations and drug resistance markers revealed no clinically significant resistance patterns. Lumefantrine concentrations suggested subtherapeutic concentrations in at least 2 cases. Conclusions Our findings indicate a high rate of symptomatic late treatment failures after 6-dose AL regime in nonimmune adults, especially in men. Our report warrants the need to establish optimal dosing of AL in adults and to alert clinicians about the importance of informing patients regarding the risk of parasites reappearing weeks after AL treatment.

Aim: To assess genotype effect on efavirenz (EFV) pharmacokinetics, treatment outcomes and provide genotype-based EFV doses recommendations during for tuberculosis (TB)-HIV-1 cotreatment. Materials & methods: EFV concentrations from 158 HIV-TB co-infected patients treated with EFV/lamivudine/zidovidine and rifampicin were analyzed. Genotype and CD4 and viral load data were analyzed using a population PK model. Results: Simulated AUCs for 600 mg EFV dose were 1.2- and 2.4-times greater than the product label for Ugandans in general and CYP2B6*6/*6 genotypes respectively. EFV daily doses of 450 and 250 mg for Ugandans and CYP2B6*6/*6 genotypes, respectively, yielded simulated exposures comparable to the product label. Conclusions: Around 450 and 250 mg daily doses might meet EFV dosing needs of HIV-TB infected Ugandans in general and CYP2B6*6/*6 genotypes, respectively.

Introduction: Inappropriate use of medicines remains a problem, with consequences including increasing adverse drug reactions (ADRs) and prolonged hospitalizations. The Essential Medicines List and Drug and Therapeutics Committees (DTCs) are accepted initiatives to promote the rational use of medicines. However, little is known about DTC activities in Nigeria, the most populous African country. Areas covered: A cross-sectional questionnaire-based study was conducted among senior pharmacists, consultant physicians, and clinical pharmacologists in 12 leading tertiary health-care facilities across Nigeria. Expert commentary: Six (50%, 6/12) health-care facilities had existing DTCs with three (50%) having a subcommittee on antimicrobials. Seventy-five percent had infection control committees, with presence even in centers without DTCs. Chairpersons and secretaries of the DTCs were predominantly physicians (83.3%) and pharmacists (100%), respectively. Hospital formularies were available in five facilities with DTCs, while one facility without a DTC had an Essential Medicines Committee responsible for developing and updating the hospital formulary. The evaluation of ADRs was undertaken by pharmacovigilance units in nine facilities. Overall, DTCs were present in only half of the surveyed facilities and most were performing their statutory functions sub-optimally. The functioning of DTCs can be improved through government directives and mechanisms for continuous evaluation of activities.

IntroductionTen per cent of all pregnant women are depressed. Standard therapy of pregnant women with moderate depression is selective serotonin reuptakeinhibitors (SSRI). Observational studies on neurodevelopment after fetal SSRI exposure show conflicting results. Our primary objective is to compare the cognitive development in children exposed to sertraline and maternal depression with those exposed to maternal depression and placebo in utero. We hypothesise that there is a significant neurodevelopmental difference between the groups. As a secondary objective, we study the add-on effect of sertraline to internet-based cognitive behavioural therapy (ICBT) to treat moderate depression during pregnancy.Methods and analysisMAGDALENA is a randomised, placebo-controlled, double-blinded trial in Stockholm Healthcare Region with 2.3 million inhabitants. The women are recruited in weeks 9–21 of pregnancy either through Antenatal Health Clinics or through social media. They are to be diagnosed with moderate depression without ongoing antidepressive therapy or any serious comorbidity. The women in the intervention arm receive sertraline combined with a 12-week period of ICBT; the control arm is treated with placebo and ICBT. We assess the cognitive development in the offspring at the age of 2 years using Bayley Scales of Infant and Toddler Development, third edition (BSID-III). We aim at recruiting 200 women, 100 women in each treatment arm, to ensure statistical power to detect a clinically relevant difference between the groups.Ethics and disseminationThis randomised trial will provide long-sought evidence about the effects of SSRI and maternal depression during pregnancy on the neurodevelopment in the offspring. The study is approved by the Regional Ethical Review Board at Karolinska Institutet in Stockholm and the Swedish Medical Products Agency. It is registered with the European Clinical Trials Database (EudraCT), Number: 2013-004444-31. Results will be disseminated at scientific conferences, published in peer-reviewed journals and made available to the public.Trial registration numberEudraCT2013-004444-31; Pre-results.

The burden of human immunodeficiency virus (HIV) is mainly concentrated to resources-limited countries where the response to available antiretroviral therapy is often limited by the occurrence of toxicity or by the emergence of HIV drug resistance. Efavirenz and nevirapine are the antiretroviral drugs most prescribed in resources-limited countries as part of antiretroviral combination therapy. Their metabolism and conjugation are largely influenced by enzymatic genetic polymorphisms. The genetic variability of their metabolism could be associated to different metabolic phenotypes causing reduced patients' adherence because of toxicity or drug-drug interactions with concomitant therapies. The purpose of this review is to summarize published evidence on pharmacogenetic and pharmacokinetic aspects related to efavirenz and nevirapine, the influence of concomitant anti-tubercular, anti-malarial or contraceptive treatments, and the impact of human genetic variation and drug-drug interaction on the virologic and immunologic response to antiretroviral therapy in resources-limited countries.

Brazil has had a National Essential Medicines List (EML) since 1964. From 2000 to 2010, five consecutive evidence-based editions were produced, building on the essential medicine concept. In 2012, the government changed course to establish a new paradigm, introducing adoption of new medicines as the main aim within the recommendation process. The objective of the article was to report efforts to develop Brazil's national EML, policy changes from 2000 to 2014, discussing results, challenges and perspectives. Brazilian EML history and development process were collected from legislation, minutes, reports and legal ordinances, from 2000 to 2014. The Brazilian EML and the WHO Model Lists were compared using the Anatomical Therapeutic Chemical system. Overlap between lists was verified, and linear trends were produced. Type of membership, inclusion criteria, procedures, flow and listed medicines varied greatly between the selection committees acting before and after 2012. Paradigm-changing legislation aiming at linking list compliance to public financing in 2012 produced (i) greater importance given to political and administrative stakeholders, (ii) increasing trends in number of medicines over the years, (iii) decrease in use of WHO Model List as a reference and (iv) substitution of an essential medicines list review and update process by an adoption decision output. Other issues remained unchanged. Insufficient efforts for list implementation, such as lack of physician education, presented consequences to the health system. Substantial efforts were made to produce and update the list from 2000 to 2014. However, continuous and intense health litigation disproves process outcome effectiveness.

Objective: Maternal and neonatal mortality is high in sub-Saharan Africa. To support Healthcare Workers (HCWs), a computerized decision support system (CDSS) was piloted at six rural maternal care units in Burkina Faso. During the two years of the study period, it was apparent from reports that the CDSS was not used regularly in clinical practice. This study aimed to explore the reasons why HCWs failed to use the CDSS.Methods: A workshop, organised as group discussions and a plenary session, was performed with 13 participants to understand their experience with the CDSS and suggest improvements if pertinent. Workshop transcripts were analysed thematically. Socio-demographic and usage patterns of the CDSS were examined by a questionnaire and analysed descriptively.Results: The participants reported that the contextual basic conditions for using the CDSS were not fulfilled. These included unreliable power supply, none user-friendly partograph, the CDSS was not integrated with workflow and staff lacked motivational incentives. Despite these limitations, the HCWs reported learning benefits from guidance and alerts in the CDSS. Using the CDSS enabled them to discover problems earlier as they learned to focus on symptoms to prevent harmful situations.Conclusion: The CDSS was not tailored to the needs and context of the users. The HCWs, defined their needs and suggested how the CDSS should be re-designed. This suggests that the successful and regular usage of any CDSS in rural settings requires the involvement of users throughout the construction and pilot-testing phases and not only during the early prototype design period.

Monitoring of antiepileptic drugs in children with epilepsy require multiple visits at a clinic for blood collection. Dried blood spot sampling is an alternative way of collection, performed at home by self-collection and can save time and costs for patients and family members. The aim was to develop and validate an LC-MS/MS dried blood spot method for carbamazepine, lamotrigine, levetiracetam and valproic acid with the requirements of using standard equipment and material in a routine laboratory setting. Whatman-903 filter paper was utilized, and discs were punched into a 96 well plate with an automated puncher and barcode reading. Extraction with methanol/water solution including internal standards on an orbital shaker was followed by a vacuum centrifuge step and reconstitution in mobile phase. Bioanalytical validation was performed according to guidelines from European Medicines Agency and additional dried blood spot specific validation. Calibration curves of the four included drugs had R2 values ≥0.994. Therapeutic relevant concentrations were well within measuring ranges. Within and -between run precision had %CV:s of 2.9-10.5%. Accuracy (%bias) was between -16.5% (lower limit of quantification) to +7.4%. Blood spots in a volume range of 15-50μL with hematocrit in expected ranges for this patient group were within precision and accuracy limits. To test the method, concentrations from dried blood spot venous and capillary patient samples (n=50) were compared with plasma concentrations. Good correlations for all four drugs with R2 of >0.92 was shown. In summary, a fast method for dried blood spots based on a 96 well format was developed for four commonly prescribed antiepileptic drugs. This validated method with traceability in sample preparation by bar code reading makes it suitable for the clinical laboratory.

Purpose Inappropriate use of medicines causes increased morbidity, mortality, adverse drug reactions, therapeutic failures and drug resistance as well as wastes valuable resources. Evidence-based cost-effective treatment recommendations of essential medicines are a way of avoiding these. We assessed primary care prescribers’ knowledge about and perceptions of an essential medicines formulary, as well as the reasons for adhering to the recommendations. Methods We conducted a web based questionnaire survey targeting all physicians working in the primary healthcare of the Stockholm healthcare region (2.3 million inhabitants), regarding the knowledge of, attitudes to and usefulness of the essential medicines formulary of the Stockholm Drug and Therapeutics Committee, the so-called Wise List. Results Of the 1862 physicians reached by our e-mail invitations, 526 (28%) participated in the survey. All but one respondent knew of the formulary, and 72% used it at least once a week when prescribing. The main reason for using the formulary was evidence-based prescribing; 97% trusted the guidelines, and almost all (98%) found the content easy to understand. At the same time, many prescribers thought that the annual changes of some recommendations were too frequent, and some felt that a national formulary would increase its trustworthiness. Conclusions We found that the essential medicines formulary was widely used and trusted by the prescribers. The high uptake of the treatment recommendations could be due to the Stockholm Drug and Therapeutics Committee’s transparent process for developing recommendations involving respected experts and clinicians using strict criteria for handling potential conflicts of interest, feedback to prescribers, continuous medical education and minor financial incentives. Electronic supplementary material The online version of this article (10.1007/s00228-017-2354-8) contains supplementary material, which is available to authorized users.

Objectives To present the ‘Wise List’ (a formulary of essential medicines for primary and specialised care in Stockholm Healthcare Region) and assess adherence to the recommendations over a 15-year period. Design Retrospective analysis of all prescription data in the Stockholm Healthcare Region between 2000 and 2015 in relation to the Wise List recommendations during the same time period. Setting All outpatient care in the Stockholm Healthcare Region. Participants All prescribers in the Stockholm Healthcare Region. Main outcome measures The number of core and complementary substances included in the Wise List, the adherence to recommendations by Anatomic Therapeutic Chemical (ATC) 1st level using defined daily doses (DDDs) adjusted to the DDD for 2015, adherence to recommendations over time measured by dispensed prescriptions yearly between 2002 and 2015. Results The number of recommended core substances was stable (175–212). Overall adherence to the recommendations for core medicines for all prescribers increased from 75% to 84% (2000 to 2015). The adherence to recommendations in primary care for core medicines increased from 80% to 90% (2005 to 2015) with decreasing range in practice variation (32% to 13%). Hospital prescriber adherence to core medicine recommendations was stable but increased for the combination core and complementary medicines from 77% to 88% (2007 to 2015). Adherence varied between the 4 therapeutic areas studied. Conclusions High and increasing adherence to the Wise List recommendations was seen for all prescriber categories. The transparent process for developing recommendations involving respected experts and clinicians using strict criteria for handling potential conflicts of interests, feedback to prescribers, continuous medical education and financial incentives are possible contributing factors. High-quality evidence-based recommendations to prescribers, such as the Wise List, disseminated through a multifaceted approach, will become increasingly important and should be developed further to include recommendations and introduction protocols for new expensive medicines.

Background Involving patients in decisions about their pharmacotherapy is crucial for a satisfactory treatment outcome. Information and opinions about medicines are available from a variety of sources. The Wise List is the drug formulary of recommended essential medicines for the Stockholm healthcare region and is issued by the Drug and Therapeutics Committee (DTC). To inform the public about treatment for common diseases and the concept of recommended medicines, a patient edition of the Wise List was developed. The aim of this study was to explore patients’ knowledge, needs and attitudes to the Wise List, DTC and information about medicines in general. Methods To examine patient knowledge about recommended medicines a survey (n = 312) was carried out at four large primary healthcare centres in Stockholm, Sweden. To further elucidate the patients’ needs of the information on recommended medicines and medicines in general, three focus group discussions (FGDs) were performed. Results Of the respondents 57% did not recognise the Wise List, 26% recognised but did not use it and 17% used it. A total of 63% reported that they search for information about medicines. The most common information source was “asking their doctor” (36%) followed by searching the internet (31%). The FGDs revealed that the patients were not interested in medicines in general, only in the medicines they use themselves. They did not understand the aim of the Wise List or how they could benefit from information about recommended medicines. The patients expressed a wish to access all information they need about their own care as well as public healthcare information at one location. Conclusion The intended aim of the DTC with providing information to the public was not achieved as the patients have difficulties to understand the information and how they should use it. The patients were not interested in medicines in general, they wanted information tailored to their specific needs. The findings highlight the importance of creating tools for patients in collaboration with them and evaluate the concept continuously.

Therapeutic drug monitoring (TDM) of the antiepileptic drug valproic acid (VPA) is recommended in patients with multiple drug therapy or with concomitant disabilities to ensure treatment efficacy and avoid adverse reactions in both adults and children. The use of sampling techniques compatible with home sampling, such as dried blood spot sampling could potentially facilitate this for patients. AIM. To assess the usefulness of a bioanalytical method for quantification of VPA in dried blood spots.Quantification was based on liquid chromatography-mass spectrometry (LC-MS), both for the DBS method and the plasma-based reference method.The method was validated in the range 10-1200 μmol/L. Total imprecision ranged from 4.9-8.9 (%CV) and accuracy was within ± 14%.The validated method has potential for evaluation in therapeutic drug monitoring in combination with home sampling of DBS. The impact of spot size can be controlled through acceptance criteria and hematocrit in the range 30-60% can be accepted in sampling. Comparison of VPA levels between plasma and whole blood cannot be done without considering the blood-plasma ratio.

University teaching hospitals usually provide tertiary care and are subject to early adoption of new technologies, which may compromise healthcare systems when uncritically adopted. Knowledge on the decision-making process - drug selection by drug selection committees or DTCs - is crucial to improve the quality of care. There are no models for studying the selection of drugs in Brazilian healthcare services. This study aims to discuss DTC structure and the processes regarding adoption of medicines in tertiary university hospitals in Brazil and to propose an analytical structure for providing direction for the future. State of the art content regarding drug selection processes and DTC procedures was reviewed in three databases. Information on the medicine selection process in a Brazilian gold standard teaching hospital was collected through observations and a review of existing procedures. A structured discussion on medicine selection and DTC procedures in tertiary hospitals ensued. This discussion resulted in findings that were organized in three dimensions, composing an analytical framework for the application in tertiary Brazilian hospitals (i) motivations for the adoption of drugs; (ii) necessary structural and organizational aspects for decision-making; and (iii) criteria and methods employed by the decision-making process. We believe that the suggested framework is compatible with tertiary Brazilian hospitals, because a gold standard in the country was able to conduct all its procedures in the light of WHO and international recommendations. We hope to contribute in producing knowledge which may hopefully be adopted in tertiary hospitals across Brazil.

This paper outlines some of the key political and socio-economic drivers to instability in Somalia and the challenges faced in delivering healthcare in a country where neither economic support nor stability of the healthcare workforce can be assured. We will describe the scope of international assistance and explore key priorities for healthcare system strengthening in the future.

Background In 2010, 245,000 women died due to pregnancy-related causes in sub-Saharan Africa and southern Asia. Our study is nested into the QUALMAT project and seeks to improve the quality of maternal care services through the introduction of a computerized clinical decision support system (CDSS) to help healthcare workers in rural areas. Healthcare information technology applications in low-income countries may improve healthcare provision but recent studies demonstrate unintended consequences with underuse or resistance to CDSS and that the fit between the system and the clinical needs does present challenges. Aims To explore and describe perceived needs and attitudes among healthcare workers to access WHO guidelines using CDSS in maternal and neonatal care in rural Burkina Faso. Methods Data were collected with semi-structured interviews in two rural districts in Burkina Faso with 45 informants. Descriptive statistics were used for the analysis of the quantitative part of the interview corresponding to informants’ background. Qualitative data were analyzed using manifest content analysis. Results Four main findings emerged: (a) an appreciable willingness among healthcare workers for and a great interest to adapt and use modern technologies like computers to learn more in the workplace, (b) a positive attitude to easy access of guidelines and implementation of decision-support using computers in the workplace, (c) a fear that the CDSS would require more working time and lead to double-work, and (d) that the CDSS is complicated and requires substantial computer training and extensive instructions to fully implement. Conclusions The findings can be divided into aspects of motivators and barriers in relation to how the CDSS is perceived and to be used. These aspects are closely connected to each other as the motivating aspects can easily be turned into barriers if not taken care of properly in the final design, during implementation and maintenance of the CDSS at point of care.

BackgroundThere has been an appreciable increase in the prescribing efficiency of proton pump inhibitors, statins, and renin-angiotensin inhibitor drugs in Sweden in recent years. This has been achieved through multiple reforms encouraging the prescription of generics at low prices versus patented drugs in the same class. Generic venlafaxine also presents an opportunity to save costs given the prevalence of depression. However, depression is more complex to treat, with physicians reluctant to change prescriptions if patients are responding to a particular antidepressant.ObjectivesWe assessed (a) changes in the utilization pattern of venlafaxine versus other newer antidepressants before and after the availability of generic venlafaxine and before and after the initiation of prescription restrictions for duloxetine limiting its prescription to refractory patients, (b) utilization of generic versus original venlafaxine after its availability, and (c) price reductions for generic venlafaxine and the subsequent influence on total expenditure on newer antidepressants over time.MethodologyWe performed interrupted time series analysis of changes in monthly reimbursed prescriptions using defined daily doses (DDDs) of patients dispensed at least one newer antidepressant from January 2007 to August 2011. DDDs was defined as the average maintenance dose of a drug when used in its major indication in adults. This included 19 months after the availability of generic venlafaxine and before initiation of prescription restrictions for duloxetine to 13 months after prescription restrictions. Total expenditure and expenditure/DDD for venlafaxine were measured over time.ResultsNo appreciable change in the utilization pattern for venlafaxine was observed after generic availability when no appreciable demand-side activities by the regions (counties) were implemented to encourage its use. The utilization of venlafaxine significantly increased after prescription restrictions for duloxetine. Generic venlafaxine was dispensed once available, reaching 99.6 % of total venlafaxine (DDD basis) by August 2011. There was an appreciable fall in expenditure for newer antidepressants in Sweden after generic venlafaxine despite increased utilization, helped by a 90 % reduction in expenditure/DDD for venlafaxine by the end of the study versus prepatent loss prices.ConclusionMultiple demand-side measures are needed to change physician prescribing habits. Authorities should not rely on a spillover effect between drug classes to effect change. Limited influence of prescription restrictions on the subsequent utilization of duloxetine reflects the complexity of this disease area. This is exacerbated by heterogeneous indications for duloxetine.

Information must be collected, evaluated and utilized to support every qualified activity. Medicine, with a written scientific tradition stretching back more than 2,000 years, is no exception. Here, we discuss a number of important items associated with the establishment of a drug information centre run by clinical pharmacologists and information pharmacists, serving a broad demand, mainly among clinical specialists. The working methods include a professional literature search, critical evaluation of the material, writing a structured answer, quality control, feedback to the inquirer and storage in a database which is publicly available. One can foresee even more complex systems wherein a number of active and specialized databases communicate to provide relevant advice and support at the point of care, supplying information on drug recommendations, reimbursement, environmental aspects, antimicrobial resistance, pharmacogenetics and adverse effects, and linked to a list of prescribed drugs for the individual patient. This will be possible in both rich and poor countries through the application of modern and developing information technology. However, research on the best and safest methods of such decision support systems will be needed to ensure that they really do improve the quality of drug prescribing and use.

In recent years the use of the opioid oxycodone has increased markedly and replacing morphine as the first-line choice of opioid in several countries. There are formulations for oral immediate, oral extended release and intravenous use. The bioavailability is higher than for morphine and less variable. Oxycodone is primarily metabolized in the liver by the cytochrome P450 (CYP) enzymes with CYP3A as the major metabolic pathway and CYP2D6 as the minor metabolic pathway to noroxycodone, oxymorphone and noroxymorphone. Oxycodone exerts its analgesic effect via the µ-opioid receptor. The metabolism of CYP2D6 substrates varies to a large degree between individuals as a result of allele functionality. Poor metabolizers (PM) have two non-functional alleles, extensive metabolizers (EM) are homozygous with two functional alleles or heterozygous with one functional allele and ultrarapid metabolizers (UM) have more than two functional alleles. There are pronounced interethnic differences in the allele distribution. On the basis of studies performed thus far, oxycodone concentrations in comparison with EM are similar in PM and reduced in UM. The pharmacokinetics in UM are insufficiently investigated. Simultaneous inhibition of both CYP3A and CYP2D6 results in increased oxycodone concentrations and such a combination should be avoided. A similar effect is to be expected with use of a CYP3A inhibitor in CYP2D6 PM. Concomitant use of enzyme inducers such as rifampicin, St John's wort and carbamazepine should be avoided because of the risk of subtherapeutic concentrations of oxycodone. When the dosage of morphine may result in unpredictable bioavailability, like in patients with severe hepatic cirrhosis, oxycodone might be beneficial because it has higher and less variability in bioavailability between patients than morphine.

Interindividual variability in patients' responses to medicines, including the likelihood of toxicity, is commonly due to differences in their genetics.1 Both problems present adverse care and resource issues, with non-response rates as high as 30–60%.2 Resource issues include the cost of adverse reactions which increase the number of emergency hospital admission at an estimated cost of GB£2 billion per annum.3 Such resource issues are an increasing concern among health authorities with pharmaceutical expenditure growing faster than other components of ambulatory care, driven by ageing populations, rising patient expectations and the continued launch of new expensive drugs.4 New premium-priced medicines are being launched at over US$300,000 per year, often with only limited health gain versus current standards.4,5 Targeting valuable resources through personalization is empirically an attractive proposition for health authorities or health insurers as it reduces the numbers needed to treat (NNT) and increases the numbers needed to harm (NNH), thereby improving the health gain for patients within available resources. It claims to deliver the right treatment to the right patient at the right time.6 However, there are barriers that need to be addressed before personalized medicine becomes a reality. This article aims to stimulate this ongoing debate and provide guidance for the future. Personalized medicine is not new. For instance, GPs in the UK do not prescribe non-steroidal antiinflammatory drugs (NSAIDs) to patients with asthma as a matter of course. The guidelines for antihypertensives are predicated on knowledge of a patient's race, age and co-morbidities. When there are a few examples, physicians can memorize and integrate these into routine practice. However, as we dissect diseases beyond such phenotypic stratification, we find increasing examples of genetic differences in therapeutic responses, some of which are already being exploited.1,7–9 This is resulting in a more heterogeneous spectrum of disease referred to by the recently coined ‘precision medicine’.6 Ultimately, full personalization of medicines will require a better understanding of the systems of genetic pathways rather than just single gene association, as demonstrated by the disappointing predictive yield of genome-wide association studies (GWAS). New technologies for whole genome sequencing and new approaches for combining information from a panel of biological variables will have a profound impact on the way in which drugs and diagnostic tests are being and will be developed, as well as the way physicians will practise medicine in the future.2 As this field of systems biology evolves with greater clinical utility in personalizing therapy, the funding and policy environment must also evolve to facilitate the expediency with such therapies that are introduced, used and evaluated in routine care.2 Currently, there are only relatively few clinical examples of personalized medicine being integrated into routine care, a phenomenon that has not been helped by the current controversies surrounding the testing of patients prescribed clopidogrel or warfarin.7–9 However, this is changing with recent research suggesting that 50% of the variability in the dosing of anticoagulant therapy can be explained by genetic factors.10 Overall, greater integration of personalized medicine into routine care will require new clinical trial structures, and innovative funding strategies that make it easier to fund new diagnostic drugs and any additional facilities along with potentially ‘valued’ drug therapy. Patient education will also be needed as the range of therapeutic options increases and becomes more complicated to navigate.

Background Approximately 2.6 million children live with HIV globally, and efavirenz (EFV) is one of the most widely used antiretroviral agents for HIV treatment in children and adults. There are concerns about the appropriateness of current EFV dosing and it has been discussed whether EFV dosing should be adapted according to genotype in children as suggested for adults. Aim To investigate if pediatric EFV dosing should be guided by genetic variation in drug metabolizing enzymes rather than by body weight. Method EFV plasma concentrations measured for clinical purposes from all children less than 18 years old at Karolinska University Hospital, Stockholm, Sweden, treated with EFV were collected retrospectively. They were genotyped for eleven polymorphisms in genes coding for drug-metabolizing enzymes and P-glycoprotein, of potential importance for EFV disposition. Data on country of origin, sex, age, weight, HIV RNA, viral resistance patterns, CD4 cells, adherence to treatment, subjective health status and adverse events were collected from their medical records. Results Thirty-six patients and 182 (mean 5 samples/patient) EFV plasma concentration measurements from children of African, Asian and Latin American origin were included. EFV plasma concentration varied 21-fold between measurements (n = 182) (0.85–19.3 mg/L) and 9-fold measured as mean EFV plasma concentration across the subjects (1.55–13.4 mg/L). A multivariate mixed-effects restricted maximum likelihood regression model, including multiple gene polymorphisms, identified CYP2B6*6 T/T (p < 0.0005), CYP2B6*11 G/G (p < 0.0005), CYP2A6*9 A/C (p = 0.001) genotypes, age at treatment initiation (p = 0.002) and time from treatment initiation (p < 0.0005) as independent factors significantly related to loge concentration/(dose/weight). The contribution of the model to the intra- and interindividual variation were 6 and 75%, respectively (Bryk/Raudenbush R-squared level). Conclusion Genetic polymorphisms in CYP2B6 and CYP2A6 explained a significant proportion of variability in EFV plasma concentration in HIV-infected children in a multi-ethnic outpatient clinic. Knowledge about individual variants in key drug metabolizing enzyme genes could improve clinical safety and genotype directed dosing could achieve more predictable EFV plasma concentrations in HIV-infected children.

Artemether-lumefantrine (AL) is a first-line treatment for uncomplicated malaria. Absorption of lumefantrine (LUM) is fat dependent, and in children, intake is recommended with milk. We investigated whether oil-fortified maize porridge can be an alternative when milk is not available. In an open-label pharmacokinetic study, Ugandan children 15 kg] with milk (A) or maize porridge plus oil (B). Parametric two-sample t-test was used to compare relative oral LUM bioavailability. The primary end-point was LUM exposure till 8 hr after the first dose (AUC0-8 hr ). Secondary outcome included day 7 concentrations (d7LUM ), LUM exposure between days 7 and 28 (AUCd7-28 ) and day 28 PCR-adjusted parasitological response. Evaluable children (n = 33) included 16 in arm A and 17 in arm B. The AUC0-8 hr was comparable between A and B [geometric mean (95% CI): 6.01 (3.26-11.1) versus 6.26 (4.5-8.43) hr*μg/mL, p = 0.9]. Less interindividual variability in AUC0-8 hr was observed in B (p = 0.01), but d7LUM and AUCd7-28 were comparable. Children receiving two tablets had significantly higher exposure than those receiving one tablet [median d7LUM (505 versus 289 ng/mL, p = 0.02) and AUCd7-28 (108 versus 41 hr*μg/mL, p = 0.006)]. One parasitological failure (d28 recrudescence) was observed. Our findings suggest that oil-fortified maize porridge can be an alternative to milk in augmenting absorption of LUM. The lower LUM exposure observed in children dosed with one AL tablet needs further attention.