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.

Profiling chronic diseases and hospitalizations in older home care recipients: a nationwide cohort study in Sweden.

BACKGROUND: Older adults with home care (HC) often have complex disease patterns and use healthcare extensively. Increased understanding is necessary to tailor their care. To our knowledge, this is the first study to describe patterns of morbidity and hospitalizations among community-dwelling older HC recipients nationwide and in subgroups defined by age, sex, and amount of HC, and to compare patterns to community-dwelling older adults without HC. METHODS: Nationwide register-based cohort study in community-dwelling adults aged 70 and older receiving publicly funded HC in Sweden on January 1st 2019 and an age-and-sex matched comparison group ("non-HC recipients"). Using register data from inpatient and specialized outpatient care, we assessed the prevalence of sixty chronic diseases, frailty, multimorbidity and hospitalizations, calculated incidence rates and explored reasons for hospitalizations during two years of follow-up. RESULTS: We identified 138,113 HC recipients (mean age 85, 66% women, 57% ≥5 chronic diseases). The most prevalent diseases were hypertension (55%) and eye conditions (48%). Compared to non-HC recipients, HC recipients had a higher prevalence of almost all diseases, with an overrepresentation of neurological (26.1 vs. 9.5%) disease and dementia (9.3 vs. 1.5%). 61% of HC recipients were hospitalized at least once during two years, which was 1.6 times as often as non-HC recipients. One third of HC recipients´ hospitalizations (37.4%) were due to injuries, infections, and heart failure. Hospitalizations for chronic obstructive pulmonary disease, confusion, infections, and breathing difficulties were 3-5 times higher among HC recipients compared to non-HC recipients. CONCLUSION: Compared to non-HC recipients, HC recipients more often live alone, have higher degrees of frailty, suffer from more chronic diseases, especially neurological disease, and are hospitalized almost twice as often. The results provide a thorough description of HC recipients, which might be useful for targeted healthcare interventions including closer collaboration between primary care, neurologists, and rehabilitation.

Pulmonary nitric oxide in astronauts before and during long-term spaceflight.

Introduction: During exploratory space flights astronauts risk exposure to toxic planetary dust. Exhaled nitric oxide partial pressure (PENO) is a simple method to monitor lung health by detecting airway inflammation after dust inhalation. The turnover of NO in the lungs is dependent on several factors which will be altered during planetary exploration such as gravity (G) and gas density. To investigate the impacts of these factors on normal PENO, we took measurements before and during a stay at the International Space Station, at both normal and reduced atmospheric pressures. We expected stable PENO levels during the preflight and inflight periods, with lower values inflight. With reduced pressure we expected no net changes of PENO. Material and methods: Ten astronauts were studied during the pre-flight (1 G) and inflight (µG) periods at normal pressure [1.0 ata (atmospheres absolute)], with six of them also monitored at reduced (0.7 ata) pressure and gas density. The average observation period was from 191 days before launch until 105 days after launch. PENO was measured together with estimates of alveolar NO and the airway contribution to the exhaled NO flux. Results: The levels of PENO at 50 mL/s (PENO50) were not stable during the preflight and inflight periods respectively but decreased with time (p = 0.0284) at a rate of 0.55 (0.24) [mean (SD)] mPa per 180 days throughout the observation period, so that there was a significant difference (p < 0.01, N = 10) between gravity conditions. Thus, PENO50 averaged 2.28 (0.70) mPa at 1 G and 1.65 (0.51) mPa during µG (-27%). Reduced atmospheric pressure had no net impact on PENO50 but increased the airway contribution to exhaled NO. Discussion: The time courses of PENO50 suggest an initial airway inflammation, which gradually subsided. Our previous hypothesis of an increased uptake of NO to the blood by means of an expanded gas-blood interface in µG leading to decreased PENO50 is neither supported nor contradicted by the present findings. Baseline PENO50 values for lung health monitoring in astronauts should be obtained not only on ground but also during the relevant gravity conditions and before the possibility of inhaling toxic planetary dust.

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.

Age- and trait-dependent breeding responses to environmental variation in a short-lived songbird.

Breeding responses of organisms to environmental changes may profoundly depend on an individual's age, as an age-environment interaction may be expected to affect the expression of reproductive traits. However, little is known about how this interaction affects short-lived species that experience various environmental conditions in adulthood. Here, we used a 32-year dataset from the collared flycatcher, Ficedula albicollis, population to test whether and how the environment interacts with age to shape female age-specific reproduction. To characterise environmental variation, we applied the remotely sensed normalised difference vegetation index (NDVI), estimating vegetation productivity, and used it as a surrogate for habitat quality. Then, we analysed how within-individual age and NDVI determine patterns in laying date, clutch size, offspring production, and recruitment. We found that young and old females, but not middle-aged females, breeding under low NDVI started to lay eggs later and produced smaller clutches than females of the same age breeding under higher NDVI. No such effects were observed for offspring production or recruitment. Our study provides evidence that both an individual's age and the environmental variation experienced during adulthood may be crucial for shaping reproductive patterns in short-lived avian species, as has been found in long-lived birds.

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.

[Pharmacological knowledge bases in Sweden: successes and future in a time of information overflow]. / Låt Sil bli kärnan i framtidens kunskaps- och beslutsstöd.

Skewed information about medicines in social media influence the healthcare-patient contact. Healthcare staff need situation adapted evidence that can be linked to patient data. For 20 years Sweden has provided praised Pharmacological Knowledge Bases (PKB). They include ¼Janusmed drug-drug interactions«, ¼Janusmed drugs and birth defects« and ¼e-Ped (electronic pediatric) instructions and drug dosage control«. PKBs need to be better integrated into digital tools adhering to a national guide for optimal interface presentation of information. They should be produced by medical editors and delivered through a national digital highway. Experts need to adhere to a policy for handling conflicts of interest and evaluate that information is appreciated and used. PKBs should be accessible as a public good for healthcare staff, students and the public to support personalized medical care.

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.

Genetic variance in fitness indicates rapid contemporary adaptive evolution in wild animals.

The rate of adaptive evolution, the contribution of selection to genetic changes that increase mean fitness, is determined by the additive genetic variance in individual relative fitness. To date, there are few robust estimates of this parameter for natural populations, and it is therefore unclear whether adaptive evolution can play a meaningful role in short-term population dynamics. We developed and applied quantitative genetic methods to long-term datasets from 19 wild bird and mammal populations and found that, while estimates vary between populations, additive genetic variance in relative fitness is often substantial and, on average, twice that of previous estimates. We show that these rates of contemporary adaptive evolution can affect population dynamics and hence that natural selection has the potential to partly mitigate effects of current environmental change.

The interactive effect of ambient temperature and brood size manipulation on nestling body mass in blue tits: an exploratory analysis of a long-term study.

BACKGROUND: Relatively few studies have examined the interactive effects of ecological factors on physiological responses in wild animals. Nearly all of them have been short-term investigations that did not include experimental manipulations, limiting our ability to understand how climate change will affect natural populations. Using a 10-year brood size manipulation experiment in wild blue tits (Cyanistes caeruleus), we quantified the impact of weather conditions and brood competition on the body mass and structural size (tarsus length) of nestlings just prior to leaving the nest. RESULTS: We found that variation in nestling body mass on day 14 after hatching was explained by an interactive effect between average ambient temperature experienced during nestling period and brood size treatment. Specifically, in control broods nestling body mass was correlated with temperature in a non-linear manner (concave) with the vertex point (maximum body mass) at ca. 13 °C. In contrast, in enlarged broods nestling body mass permanently increased (also non-linearly) as temperature advanced. CONCLUSIONS: Our results highlight the importance of considering the effects of brood rearing conditions alongside other environmental factors experienced during growth while investigating early-life environmental effects on body condition.

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.

Differential effects of steroid hormones on levels of broad-sense heritability in a wild bird: possible mechanism of environment × genetic variance interaction?

Genetic variation is one of the key concepts in evolutionary biology and an important prerequisite of evolutionary change. However, we know very little about processes that modulate its levels in wild populations. In particular, we still are to understand why genetic variances often depend on environmental conditions. One of possible environment-sensitive modulators of observed levels of genetic variance are maternal effects. In this study we attempt to experimentally test the hypothesis that maternally transmitted agents (e.g. hormones) may influence the expression of genetic variance in quantitative traits in the offspring. We manipulated the levels of steroid hormones (testosterone and corticosterone) in eggs laid by blue tits in a wild population. Our experimental setup allowed for full crossing of genetic and rearing effects with the experimental manipulation. We observed that birds treated with corticosterone exhibited a significant decrease in broad-sense genetic variance of tarsus length, and an increase in this component in body mass on the 2nd day post-hatching. Our study indicates, that maternally transmitted substances such as hormones may have measurable impact on the levels of genetic variance and hence, on the evolutionary potential of quantitative traits.

Sexual dichromatism, size dimorphism, and microscale anatomy of white wing stripe in blue tits.

Achromatic patches are a common element of plumage patterns in many bird species and there is growing body of evidence that in many avian taxa they can play a signaling role in mate choice. Although the blue tit Cyanistes caeruleus is a well-established model species in the studies on coloration, its white wing patch has never been examined in the context of sex-specific trait expression. In this exploratory study, we examined sexual size dimorphism and dichromatism of greater covert's dots creating white wing patch and analyzed its correlations with current body condition and crown coloration-a trait with established role in sexual selection. Further, we qualitatively analyzed microstructural barb morphology underlying covert's coloration. We found significant sexual dimorphism in the dot size independent of covert size and sexual dichromatism in both white dot and blue outer covert's vane spectral characteristics. Internal structure of covert barbs within the white dot was similar to the one found in barbs from the blue part that is, with a medullary area consisting of dead keratinocytes containing channel-type ß-keratin spongy nanostructure and centrally located air cavities. However, it lacked melanosomes which was the main observed difference. Importantly, UV chroma of covert's blue vane was positively correlated with crown UV chroma and current condition (the latter only in males), which should be a premise for further research on the signal function of the wing stripe.

Machine learning for prediction of diabetes risk in middle-aged Swedish people.

AIMS: To study if machine learning methodology can be used to detect persons with increased type 2 diabetes or prediabetes risk among people without known abnormal glucose regulation. METHODS: Machine learning and interpretable machine learning models were applied on research data from Stockholm Diabetes Preventive Program, including more than 8000 people initially with normal glucose tolerance or prediabetes to determine high and low risk features for further impairment in glucose tolerance at follow-up 10 and 20 years later. RESULTS: The features with the highest importance on the outcome were body mass index, waist-hip ratio, age, systolic and diastolic blood pressure, and diabetes heredity. High values of these features as well as diabetes heredity conferred increased risk of type 2 diabetes. . The machine learning model was used to generate individual, comprehensible risk profiles, where the diabetes risk was obtained for each person in the data set. Features with the largest increasing or decreasing effects on the risk were determined. CONCLUSIONS: The primary application of this machine learning model is to predict individual type 2 diabetes risk in people without diagnosed diabetes, and to which features the risk relates. However, since most features affecting diabetes risk also play a role for metabolic control in diabetes, e.g. body mass index, diet composition, tobacco use, and stress, the tool can possibly also be used in diabetes care to develop more individualized, easily accessible health care plans to be utilized when encountering the patients.

Genomic inference of contemporary effective population size in a large island population of collared flycatchers (Ficedula albicollis).

Due to its central importance to many aspects of evolutionary biology and population genetics, the long-term effective population size (Ne ) has been estimated for numerous species and populations. However, estimating contemporary Ne is difficult and in practice this parameter is often unknown. In principle, contemporary Ne can be estimated using either analyses of temporal changes in allele frequencies, or the extent of linkage disequilibrium (LD) between unlinked markers. We applied these approaches to estimate contemporary Ne of a relatively recently founded island population of collared flycatchers (Ficedula albicollis). We sequenced the genomes of 85 birds sampled in 1993 and 2015, and applied several temporal methods to estimate Ne at a few thousand (4000-7000). The approach based on LD provided higher estimates of Ne (20,000-32,000) and was associated with high variance, often resulting in infinite Ne . We conclude that whole-genome sequencing data offers new possibilities to estimate high (>1000) contemporary Ne , but also note that such estimates remain challenging, in particular for LD-based methods for contemporary Ne estimation.

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.

Density-Dependent Adaptive Topography in a Small Passerine Bird, the Collared Flycatcher.

AbstractAdaptive topography is a central concept in evolutionary biology, describing how the mean fitness of a population changes with gene frequencies or mean phenotypes. We use expected population size as a quantity to be maximized by natural selection to show that selection on pairwise combinations of reproductive traits of collared flycatchers caused by fluctuations in population size generated an adaptive topography with distinct peaks often located at intermediate phenotypes. This occurred because r- and K-selection made phenotypes favored at small densities different from those with higher fitness at population sizes close to the carrying capacity K. Fitness decreased rapidly with a delay in the timing of egg laying, with a density-dependent effect especially occurring among early-laying females. The number of fledglings maximizing fitness was larger at small population sizes than when close to K. Finally, there was directional selection for large fledglings independent of population size. We suggest that these patterns can be explained by increased competition for some limiting resources or access to favorable nest sites at high population densities. Thus, r- and K-selection based on expected population size as an evolutionary maximization criterion may influence life-history evolution and constrain the selective responses to changes in the environment.