Quantification of Efavirenz Hydroxymetabolites in Human Plasma Using LC-HRMS/MS.

BACKGROUND: Efavirenz (EFV) is a drug used to treat HIV. Low plasma concentrations of EFV result in suboptimal viral suppression, whereas high concentrations can cause adverse neuropsychiatric side reactions. Some studies have identified a correlation between the plasma concentrations of EFV metabolites and neurotoxicity. To our knowledge, no studies have investigated the metabolism of EFV in young children and its effect on treatment outcomes. Therefore, the aim of this study was to develop and validate a method for quantifying EFV and its metabolites in human plasma derived from children. METHODS: Sample preparation was performed using protein precipitation of 100 µL plasma. Thereafter, an aliquot of the supernatant was used to quantify EFV, 7-hydroxyefavirenz (7-OH-EFV), 8-hydroxyefavirenz (8-OH-EFV), and a newly discovered metabolite ("EFAdeg") associated with 8-OH-EFV. A second aliquot of the supernatant was hydrolyzed using ß-glucuronidase/arylsulfatase and used with the first aliquot to quantify phase II metabolites. The analyses were performed using a Dionex Ultimate 3000RS LC-system coupled with a Q Exactive Orbitrap mass spectrometer. RESULTS: The method has a measuring range of 100-50,000 ng/mL (EFV, 8-OH-EFV), 125-25,000 ng/mL (7-OH-EFV), and 200-10,000 ng/mL ("EFAdeg"). All criteria of the European Medicines Agency guidelines regarding precision, accuracy, and selectivity were met. Of note, carryover must be considered for 8-OH-EFV. Overall, the validated method was successfully applied to plasma samples obtained from children and confirmed the presence of the newly discovered metabolite, "EFAdeg." CONCLUSIONS: An LC-HRMS/MS method for the quantification of EFV and its phase I and II metabolites was developed and validated. This method is suitable for analyzing plasma samples from children. Furthermore, studies using this method identified an additional metabolite that may influence the concentration of 8-OH-EFV in patient samples.

Proud but Powerless: A Qualitative Study of Homecare Workers´ Work Experiences and Their Suggestions for How Care for Homebound Older Adults Can Be Improved.

Many older adults with complex care needs live at home due to ageing-in-place policies. This study explored homecare workers' experiences and suggestions for improvements of care. Twelve semi-structured interviews were analyzed thematically, and revealed pride, capability, and satisfaction in their work, yet they feel undervalued and lack support. They advocate for integrated care models, recognition of their competence, flexible work approaches, and committed leadership. This would enhance patient care and address their own working conditions, addressing concerns from being relegated to the bottom of the hierarchy. They emphasize the need for comprehensive approaches, spanning from housekeeping to end-of-life palliative care.

Homecare workers - an untapped resource in preventing emergency department visits among older individuals? A qualitative interview study from Sweden.

BACKGROUND: Older individuals with functional decline and homecare are frequent visitors to emergency departments (ED). Homecare workers (HCWs) interact regularly with their clients and may play a crucial role in their well-being. Therefore, this study explores if and how HCWs perceive they may contribute to the prevention of ED visits among their clients. METHODS: In this qualitative study, 12 semi-structured interviews were conducted with HCWs from Sweden between July and November 2022. Inductive thematic analysis was used to identify barriers and facilitators to prevent ED visits in older home-dwelling individuals. RESULTS: HCWs want to actively contribute to the prevention of ED visits among clients but observe many barriers that hinder them from doing so. Barriers refer to care organisation such as availability to primary care staff and information transfer; perceived attitudes towards HCWs as co-workers; and client-related factors. Participants suggest that improved communication and collaboration with primary care and discharge information from the ED to homecare services could overcome barriers. Furthermore, they ask for support and geriatric education from primary care nurses which may result in increased respect towards them as competent staff members. CONCLUSIONS: HCWs feel that they have an important role in the health management of older individuals living at home. Still, they feel as an untapped resource in the prevention of ED visits. They deem that improved coordination and communication between primary care, ED, and homecare organisations as well as proactive care would enable them to add significantly to the prevention of ED visits.

Strengthening Global Health Research.

Global Health is a young discipline with equity of health and services as its core value. The discipline has a tradition of close links between practice and research in line with the 'Health for All' declaration launched by the World Health Organization (WHO) in 1978. The multitude of existential health crises facing mankind require a research agenda in line with Global Health Research core values and methods, such as transdisciplinary collaboration, long time series of population-based observations and multifaceted interventions. Knowledge gaps cover climate effects on health and mechanisms for global spread and control of antibiotic resistance across species. Such health threats are preferably studied at Health and Demographic Surveillance Sites, a scientific infrastructure for Global Health Research in Africa and Asia, that gains to expand and monitor climate parameters and include sites in the northern hemisphere. Global Health Scientists together with science societies can ensure long-term funding of a global network of population-based health-climate sites. Global Health Scientists and scientific journals should jointly provide data and evidence on global health to governance bodies on regional, national and global levels, in particular to WHO and United Nations in charge of the programme with Sustainable Development Goals.

How much are we worth? Experiences of nursing assistants in Swedish nursing homes during the first wave of COVID-19.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION AND IMPLICATION FOR PRACTICE: 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.

An Adverse Drug Reaction Database for Clinical Use - Potential of and Difficulties with the Summary of Product Characteristics.

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.

Experiences of patients receiving Home Care and living with polypharmacy: a qualitative interview study.

BACKGROUND: In 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. AIM: To investigate HC patients' experiences and perceptions regarding polypharmacy. DESIGN & SETTING: Semi-structured interviews with 17 patients with HC in Stockholm, Sweden. METHOD: The 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. RESULTS: The 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. CONCLUSION: The 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.

Potential approaches for the pricing of cancer medicines across Europe to enhance the sustainability of healthcare systems and the implications.

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.

ADR databases for on-site clinical use: Potentials of summary of products characteristics.

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.

Guiding principles for the use of knowledge bases and real-world data in clinical decision support systems: report by an international expert workshop at Karolinska Institutet.

INTRODUCTION: Technical and logical breakthroughs have provided new opportunities in medicine to use knowledge bases and large-scale clinical data (real-world) at point-of-care as part of a learning healthcare system to diminish the knowledge-practice gap. AREAS COVERED: The article is based on presentations, discussions and recommendations from an international scientific workshop. Value, research needs and funding avenues of knowledge bases and access to real-world data as well as transparency and incorporation of patient perspectives are discussed. EXPERT OPINION: Evidence-based, publicly funded, well-structured and curated knowledge bases are of global importance. They ought to be considered as a public responsibility requiring transparency and handling of conflicts of interest. Information has to be made accessible for clinical decision support systems (CDSS) for healthcare staff and patients. Access to rich and real-world data is essential for a learning health care ecosystem and can be augmented by data on patient-reported outcomes and preferences. This field can progress by the establishment of an international policy group for developing a best practice guideline on the development, maintenance, governance, evaluation principles and financing of open-source knowledge bases and handling of real-world data.

Pretreatment HIV drug resistance predicts accumulation of new mutations in ART-naïve Ugandan children.

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-naïve 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 < 40 copies/mL and a total of 23 children had DRMs. Children with PDR accumulated new DRMs with a mean number (SD) of 1.4 (2.35) new mutations compared to 0.26 (0.98) in 67 children with wild-type virus (P = .003). High pretreatment VL and PDR (number of baseline DRMs) predicted viremia (P = .003; P = .023) as well as acquired drug resistance (P = .02; P = .04). CONCLUSION: Pretreatment drug resistance to NNRTI/NRTI was common among ART-naïve Ugandan children and predicted viremia and new resistance mutations after only 24 weeks of efavirenz-based therapy. PDR may compromise long-term ART outcomes-especially when access to resistance testing and VL monitoring is poor. The long-term importance of PDR for non-NNRTI-based regimens needs further evaluation.

Parents' perspectives on dried blood spot self-sampling from children with epilepsy: A mixed-method study.

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.

Reported needs of information resources, research tools, connectivity and infrastructure among African Pharmacological Scientists to improve future patient care and health.

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 seek 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 modeling 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 the further provision of resources on the e-infrastructure and potentially enhance research capacity within the continent.

Dried Blood Spot Self-Sampling by Guardians of Children With Epilepsy Is Feasible: Comparison With Plasma for Multiple Antiepileptic Drugs.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Drug and therapeutics committees in Nigeria: evaluation of scope and functionality.

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.

MAGDALENA: study protocol of a randomised, placebo-controlled trial on cognitive development at 2 years of age in children exposed to SSRI in utero.

INTRODUCTION: Ten 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 ANALYSIS: MAGDALENA 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 DISSEMINATION: This 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 NUMBER: EudraCT2013-004444-31; Pre-results.

Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(-) Ketamine Concentrations.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The 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. METHODS: S(+) 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. RESULTS: A 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, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01. CONCLUSIONS: Arterial 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.

Patients' knowledge and attitudes to the Wise List - a drug formulary from the Stockholm Drug and Therapeutic committee.

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.