Prevalence of strong anticholinergic use in residents with and without cognitive impairment and frailty: Analysis from 106 nursing homes in 12 Asia-Pacific and European countries.

PURPOSE: There is a need to balance the benefits and risks associated with strong anticholinergic medications in older adults, particularly among those with frailty and cognitive impairment. This study explored the international prevalence of strong anticholinergic medication use in residents of nursing homes with and without cognitive impairment and frailty. METHODS: Secondary, cross-sectional analyses of data from 5,800 residents of 106 nursing homes in Australia, China, Czech Republic, England, Finland, France, Germany, Israel, Italy, Japan, Netherlands, and Spain were conducted. Strong anticholinergic medications were defined as medications with a score of 2 or 3 on the Anticholinergic Cognitive Burden scale. Dementia or cognitive impairment was defined as a documented diagnosis or using a validated scale. Frailty was defined using the FRAIL-NH scale as 0-2 (non-frail), 3-6 (frail) and 7-14 (most-frail). Data were analyzed using descriptive statistics. RESULTS: Overall, 17.4 % (n = 1010) residents used ≥1 strong anticholinergic medication, ranging from 1.3 % (n = 2) in China to 27.1 % (n = 147) in Italy. The most prevalent strong anticholinergics were quetiapine (n = 290, 5.0 % of all residents), olanzapine (132, 2.3 %), carbamazepine (102, 1.8 %), paroxetine (88, 1.5 %) and amitriptyline (87, 1.5 %). Prevalence was higher among residents with cognitive impairment (n = 602, 17.9 %) compared to those without (n = 408, 16.8 %), and among residents who were most frail (n = 553, 17.9 %) compared to those who were frail (n = 286, 16.5 %) or non-frail (n = 171, 17.5 %). CONCLUSIONS: One in six residents who were most frail and living with cognitive impairment used a strong anticholinergic. However, there was a 20-fold variation in prevalence across the 12 countries. Targeted deprescribing interventions may reduce potentially avoidable medication-harm.

Visualizing Active Sites in Electrospun Photoactive Membranes via Fluorescence Lifetime Imaging.

Interest in antibacterial nanomaterials has surged in recent years, driven by the rise in antibiotic resistance among microbes. However, their practical application remains limited because many crucial properties have yet to be thoroughly investigated. In this study, we have developed novel nanofibrous membranes based on hydrophilic polyacrylonitrile (PAN) or hydrophobic polycaprolactone (PCL) with embedded hydrophilic or hydrophobic zinc(II)phthalocyanines (ZnPcs) as photosensitizers and investigated their water disinfection properties. Several key characteristics were evaluated to link the activity of the material and composition/structure. As demonstrated by reflectance UV-vis spectroscopy, the aggregation states of dyes within the polymer support vary significantly. We have proposed and validated the use of fluorescence lifetime imaging (FLIM) for visualizing "active sites" in the membranes. The results of this study provide useful insights for the engineering of photoactive nanomaterials with tailor-made properties and highlight the crucial role of the nature of polymeric support in modulating the material's activity.

Proposal for a new study design and endpoint in research on medication history taking.

Introduction: Medication history errors at hospital admission are common and effective strategies to improve the quality of medication histories are still being researched. However, studies on new approaches regarding medication history taking are often time-consuming and resource-intensive. The gold standard when evaluating the quality of medication histories is the comparison of a Best Possible Medication History to the original. However, this double collection requires significant resources, disrupts clinical procedures, and places an additional burden on patients. Therefore, more efficient study designs need to be explored. We aimed to develop a design for future studies on medication history taking that uses fewer research resources and places less strain on patients and staff. Discussion: We first identified shortcomings of the established study designs on medication history taking and subsequently defined requirements for a new design. A pragmatic study with an alternative endpoint was identified in a previous literature search. It served as the starting point from which we developed a new study design to assess the quality of approaches to medication history taking. Instead of taking a second medication history, a patient's pre-existing medication document can be used as comparator to determine the quality of the medication history. Furthermore, we defined a new primary endpoint, i.e. the number of updates per patient. Updates are differences between the newly acquired medication history and the comparator. They include discontinued, initiated, and changed medications. To enhance our proposed design, we recommend a preparatory phase to identify a suitable comparator document, and a baseline phase to assess the current process. Conclusion: We propose a more resource-efficient study design with a new endpoint. We plan to test its feasibility and evaluate whether it could enhance the efficacy of research on medication history taking in a pilot project.

Connecting the dots: Network structures of internalizing and functional symptoms in a population-based cohort.

OBJECTIVE: Comorbidities between internalizing disorders (IDs) and functional disorders (FDs) are well-documented, indicating shared pathways. However, their symptom-level relationships have been largely unexplored. This exploratory study employs a network approach to investigate symptoms of major depressive disorder (MDD), generalized anxiety disorder (GAD), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), and irritable bowel syndrome (IBS) to identify bridge symptoms explaining comorbidity between the two domains. METHODS: We used cross-sectional data on 72,919 adult subjects from the Lifelines Cohort Study, a Dutch general population sample. A total of 38 symptoms representing diagnostic criteria of IDs and FDs were assessed with validated questionnaires. Network models were estimated using eLasso, based on the Ising model, to identify bridge symptoms. The Network Comparison Test (NCT) was used to test whether there were differences in network structure and strength across sex and age. RESULTS: Symptoms were moderately connected, with a network density of 52.7%. ID and FD symptoms clustered in their respective domains, but were connected through the bridge symptoms, fatigue, difficulty concentrating, trouble sleeping, and unrefreshing sleep. Fatigue and difficulty concentrating had the most connections, associated with 86.6% and 78.9% of the other symptoms, respectively. NCTs indicated no differences in network connectivity between females versus males or younger versus older adults (>50 years). CONCLUSIONS: ID and FD symptoms are moderately interconnected. Bridge symptoms displaying strong connections to multiple disorders may play a central role in the mechanisms underpinning the comorbidity between IDs and FDs.

Broad Adaptability of Coronavirus Adhesion Revealed from the Complementary Surface Affinity of Membrane and Spikes.

Coronavirus stands for a large family of viruses characterized by protruding spikes surrounding a lipidic membrane adorned with proteins. The present study explores the adhesion of transmissible gastroenteritis coronavirus (TGEV) particles on a variety of reference solid surfaces that emulate typical virus-surface interactions. Atomic force microscopy informs about trapping effectivity and the shape of the virus envelope on each surface, revealing that the deformation of TGEV particles spans from 20% to 50% in diameter. Given this large deformation range, experimental Langmuir isotherms convey an unexpectedly moderate variation in the adsorption-free energy, indicating a viral adhesion adaptability which goes beyond the membrane. The combination of an extended Helfrich theory and coarse-grained simulations reveals that, in fact, the envelope and the spikes present complementary adsorption affinities. While strong membrane-surface interaction lead to highly deformed TGEV particles, surfaces with strong spike attraction yield smaller deformations with similar or even larger adsorption-free energies.

FGFR­related phenotypic and functional profile of CAFs in prognostication of breast cancer (Review).

While preclinical studies consistently implicate FGFR­signalling in breast cancer (BC) progression, clinical evidence fails to support these findings. It may be that the clinical significance of FGFR ought to be analysed in the context of the stroma, activating or repressing its function. The present review aimed to provide such a context by summarizing the existing data on the prognostic and/or predictive value of selected cancer­associated fibroblasts (CAFs)­related factors, that either directly or indirectly may affect FGFR­signalling. PubMed (https://pubmed.ncbi.nlm.nih.gov/) and Medline (https://www.nlm.nih.gov/medline/medline_home.html) databases were searched for the relevant literature related to the prognostic and/or predictive significance of: CAFs phenotypic markers (αSMA, S100A4/FSP­1, PDGFR, PDPN and FAP), CAFs­derived cognate FGFR ligands (FGF2, FGF5 and FGF17) or inducers of CAFs' paracrine activity (TGF­ß1, HDGF, PDGF, CXCL8, CCL5, CCL2, IL­6, HH and EGF) both expressed in the tumour and circulating in the blood. A total of 68 articles were selected and thoroughly analysed. The findings consistently identified upregulation of αSMA, S100A4/FSP­1, PDGFR, PDPN, HDGF, PDGF, CXCL8, CCL5, CCL2, IL­6, HH and EGF as poor prognostic markers in BC, while evaluation of the prognostic value of the remaining markers varied between the studies. The data confirm an association of CAFs­specific features with BC prognosis, suggesting that both quantitative and qualitative profiling of the stroma might be required for an assessment of the true FGFR's clinical value.

Advancements in Assays for Micro- and Nanoplastic Detection: Paving the Way for Biomonitoring and Exposomics Studies.

Although plastic pollution and exposure to plastic-related compounds have received worldwide attention, health risks associated with micro- and nanoplastics (MNPs) are largely unknown. Emerging evidence suggests MNPs are present in human biofluids and tissue, including blood, breast milk, stool, lung tissue, and placenta; however, exposure assessment is limited and the extent of human exposure to MNPs is not well known. While there is a critical need to establish robust and scalable biomonitoring strategies to assess human exposure to MNPs and plastic-related chemicals, over 10,000 chemicals have been linked to plastic manufacturing with no existing standardized approaches to account for even a fraction of these exposures. This review provides an overview of the status of methods for measuring MNPs and associated plastic-related chemicals in humans, with a focus on approaches that could be adapted for population-wide biomonitoring and integration with biological response measures to develop hypotheses on potential health effects of plastic exposures. We also examine the exposure risks associated with the widespread use of chemical additives in plastics. Despite advancements in analytical techniques, there remains a pressing need for standardized measurement protocols and untargeted, high-throughput analysis methods to enable comprehensive MNP biomonitoring to identify key MNP exposures in human populations. This review aims to merge insights into the toxicological effects of MNPs and plastic additives with an evaluation of analytical challenges, advocating for enhanced research methods to fully assess, understand, and mitigate the public health implications of MNPs.

Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.

Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.

Kupffer cells dictate hepatic responses to the atherogenic dyslipidemic insult.

Apolipoprotein-B (APOB)-containing lipoproteins cause atherosclerosis. Whether the vasculature is the initially responding site or if atherogenic dyslipidemia affects other organs simultaneously is unknown. Here we show that the liver responds to a dyslipidemic insult based on inducible models of familial hypercholesterolemia and APOB tracing. An acute transition to atherogenic APOB lipoprotein levels resulted in uptake by Kupffer cells and rapid accumulation of triglycerides and cholesterol in the liver. Bulk and single-cell RNA sequencing revealed a Kupffer-cell-specific transcriptional program that was not activated by a high-fat diet alone or detected in standard liver function or pathological assays, even in the presence of fulminant atherosclerosis. Depletion of Kupffer cells altered the dynamic of plasma and liver lipid concentrations, indicating that these liver macrophages help restrain and buffer atherogenic lipoproteins while simultaneously secreting atherosclerosis-modulating factors into plasma. Our results place Kupffer cells as key sentinels in organizing systemic responses to lipoproteins at the initiation of atherosclerosis.

Continuity of medication information transfer and continuous medication supply during hospital-to-home transitions - nationwide surveys in hospital and community pharmacies after implementing new legal requirements in Germany.

BACKGROUND: While successful information transfer and seamless medication supply are fundamental to medication safety during hospital-to-home transitions, disruptions are frequently reported. In Germany, new legal requirements came into force in 2017, strengthening medication lists and discharge summaries as preferred means of information transfer. In addition to previous regulations - such as dispensing medication at discharge by hospital pharmacies - hospital physicians were now allowed to issue discharge prescriptions to be supplied by community pharmacies. The aim of this survey study was to gain first nationwide insights into how these requirements are implemented and how they impact the continuity of medication information transfer and continuous medication supply. METHODS: Two nationwide self-administered online surveys of all hospital and community pharmacies across Germany were developed and conducted from April 17th to June 30th, 2023. RESULTS: Overall, 31.0% (n = 111) of all German hospital pharmacies and 4.5% (n = 811) of all community pharmacies participated. The majority of those hospital pharmacies reported that patients who were discharged were typically provided with discharge summaries (89.2%), medication lists (59.5%) and if needed, discharge prescriptions (67.6%) and/or required medication (67.6%). About every second community pharmacy (49.0%) indicated that up to half of the recently discharged patients who came to their pharmacy typically presented medication lists. 34.0% of the community pharmacies stated that they typically received a discharge summary from recently discharged patients at least once per week. About three in four community pharmacies (73.3%) indicated that most discharge prescriptions were dispensed in time. However, one-third (31.0%) estimated that half and more of the patients experienced gaps in medication supply. Community pharmacies reported challenges with the legal requirements - such as patients´ poor comprehensibility of medication lists, medication discrepancies, unmet formal requirements of discharge prescriptions, and poor accessibility of hospital staff in case of queries. In comparison, hospital pharmacies named technical issues, time/personnel resources, and deficits in patient knowledge of medication as difficulties. CONCLUSION: According to the pharmacies´ perceptions, it can be assumed that discontinuation in medication information transfer and lack of medication supply still occur today during hospital-to-home transitions, despite the new legal requirements. Further research is necessary to supplement these results by the perspectives of other healthcare professionals and patients in order to identify efficient strategies.

Ability of Nicotinamide Riboside to Prevent Muscle Fatigue of Barrows Subjected to a Performance Test.

The objective of this study was to determine the daily dietary nicotinamide riboside (NR) dose required to maximize the delay of subjective muscle fatigue onset. Barrows (N = 100) were assigned to one of five treatments: a conventional swine finishing diet containing 0 (CON), 15 (15NR), 30 (30NR), 45 (45NR) mg·kg body weight-1·d-1 NR, or CON supplemented with 45 mg·kg body weight-1·d-1 NR by drench or cookie dough (DRE). All treatments were administered for the final 11 days of feeding. On supplementation d 10, barrows individually experienced a performance test at 1.09 m/s until they were subjectively exhausted. Wireless electromyography (EMG) sensors were affixed to the biceps femoris (BF), tensor fascia latae (TFL), and semitendinosus (ST) to measure real-time muscle activity. There were no treatment effects for barrow speed (p = 0.57), a tendency for a treatment effect (p = 0.07) for distance, and a treatment effect (p = 0.04) on time to exhaustion. Barrows of the 15NR and DRE treatments had greater (p = 0.05) distances to exhaustion than CON barrows but did not differ from other NR barrows (p > 0.11). Barrows in the 45NR treatment did not differ (p = 0.11) in distance from 30NR barrows but tended to have a greater (p = 0.07) distance compared to CON barrows. All other treatment comparisons did not differ (p > 0.27). Barrows in the DRE treatment moved for longer (p < 0.01) than CON barrows, but all other treatments did not differ from each other (p > 0.15). There was no treatment × period interaction for all muscles' root mean square (RMS) values (p > 0.16), but there were Period effects for all muscles (p < 0.01) and a Treatment effect (p = 0.04) in the TFL. For all muscles, period 4 had greater RMS values than all other periods (p < 0.01), who did not differ from each other (p > 0.29). In the TFL, CON barrows had greater RMS values during the performance test compared to all NR treatments (p < 0.02), who did not differ from each other (p > 0.18). Overall, NR demonstrates potential in being a useful tool in fatigue prevention, but efficient administration of the compound needs further investigation.

Haplotype Analysis Reveals Pleiotropic Disease Associations in the HLA Region.

The human leukocyte antigen (HLA) region plays an important role in human health through involvement in immune cell recognition and maturation. While genetic variation in the HLA region is associated with many diseases, the pleiotropic patterns of these associations have not been systematically investigated. Here, we developed a haplotype approach to investigate disease associations phenome-wide for 412,181 Finnish individuals and 2,459 traits. Across the 1,035 diseases with a GWAS association, we found a 17-fold average per-SNP enrichment of hits in the HLA region. Altogether, we identified 7,649 HLA associations across 647 traits, including 1,750 associations uncovered by haplotype analysis. We find some haplotypes show trade-offs between diseases, while others consistently increase risk across traits, indicating a complex pleiotropic landscape involving a range of diseases. This study highlights the extensive impact of HLA variation on disease risk, and underscores the importance of classical and non-classical genes, as well as non-coding variation.

Hepatitis B serology testing and vaccination for Gambian healthcare workers: A pilot study.

Background: Hepatitis B infection is a significant global health threat contributing to healthcare worker (HCW) harm, threatening already precarious health systems. Aim: To document self-reported hepatitis B vaccination history and serology results. Setting: A select group of high-risk HCWs in a tertiary care hospital in Banjul, the Gambia. Methods: This was a cross-sectional pilot study conducted from 12 June 2023 to 16 June 2023. Participants were HCWs at high risk for blood exposure who completed a health history interview prior to serology testing for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (anti-HBs) and vaccination. Results: The pilot study enrolled 70 HCWs who were primarily female (n = 44; 62.9%). The majority of the participants, 43 (61.4%) reported having received at least one dose of the hepatitis B vaccine in the past. The overall prevalence of HBsAg positivity in this study was 4.3% (95% confidence interval [CI]: 1.5-11.9), all in older participants. Importantly, 60.0% (95% CI: 48.3-70.7) of participants had no anti-HBs detected. Conclusion: This pilot study documents a higher prevalence of hepatitis B infection among older workers and the lack of anti-HBs across the majority of participants. This suggests a serious vulnerability for the individual health worker and indicates the need for a wider screening and vaccination campaign to assess the risk across the Gambian health workforce. Contribution: This pilot study provides the first evidence to support a wider assessment of hepatitis B serology status of Gambian health workers to gauge the need for a broader vaccine campaign.

CFTR Modulators Therapy Efficacy in Reducing Cystic Fibrosis (CF) Exacerbation and Improving Selected Spirometry Parameters: A Real-Life Study in a Single-Centre Polish Population.

Background/Objectives: Cystic fibrosis is a genetically determined disease that significantly influences and shortens life. Treatment with CFTR modulators (CFTR-T) is a new hope for patients. It can change the predictive values of a poor prognosis (e.g., exacerbation rate and FEV1 value). The aim of the study was to analyse exacerbation incidence and spirometry data before and after one year (+/- 2 weeks) of CFTR-T in 85 CF patients at the CF Centre in Poznan. To our knowledge, this is the first analysis of CFTR-T efficiency in the Central-Eastern Europe population. Methods: We retrospectively analysed the spirometry and exacerbation data of 85 CF adult patients (both men and women), who in the middle of 2022 began treatment with CFTR modulators. Results: The one-year ratio of hospitalisation caused by severe exacerbations lowered from 1.25 to 0.21 per patient per year. We also saw a 66% decline in ambulatory exacerbations. The median FEV1% increased by 9.60% in absolute values and by 460 mL. Even in the group with very severe obstruction (FEV1 < 35%), there was an increase in median FEV1% of 5.9 in absolute values. We also proved the increase in FVC% (median 17.10% in absolute value and 600 mL) in the study group. Conclusions: After one year of treatment, an impressive improvement was observed in two important predictive values of poor prognosis: exacerbation rate and FEV1 values. Further observation is needed to determine how long the improvement will be present and its influence on quality of life and life expectancy.

Study Protocol for the Opioid and Pain Treatment in Indigenous Communities Trial: A Systems Level Intervention for Enhanced Screening and Brief Intervention and Referral for Co-Occurring Chronic Pain and Opioid Use Disorder.

American Indian/Alaska Native (AI/AN) individuals have the highest rates of opioid overdose mortality and chronic pain (CP) compared to other racial/ethnic groups in the United States. These individuals also report higher rates of pain anxiety and pain catastrophizing, which are both associated with poorer outcomes and risk for opioid misuse (OM) and opioid use disorder (OUD) among individuals with CP. Yet, no prior studies have examined rates of comorbid pain and OUD among AI/AN adults. This commentary describes an implementation research partnership of 3 AI/AN-serving clinics and a university team that utilizes an implementation hybrid type III design to examine the impact of implementation strategies on adoption and sustainability of evidence-based screening and brief intervention for CP and OM/OUD among AI/AN clients. As part of our community-engaged approach, we embrace both AI/AN models and Western models, and a collaborative board of 10 individuals guided the research throughout. We hypothesize that our culturally centered approach will increase rates of screening and brief intervention and improve identification of and outcomes among AI/AN clients with CP and OUD who receive treatment at participating sites. Each site convenes a workgroup to evaluate and set goals to culturally center screening and brief interventions for CP and OM/OUD. Data collected include deidentified electronic health records to track screening and brief interventions and rates of CP and OUD; provider and staff surveys beginning prior to implementation and every 6 months for 2 years; and a subset of clients will be recruited (N = 225) and assessed at baseline, 6, and 12 months to examine biopsychosocial and spiritual factors and their experiences with culturally centered screening and brief intervention. Cultural adaptations to the measures and screening and brief intervention as well as barriers and facilitators will be addressed. Recommendations for successful Tribal health clinic-university partnerships are offered.

Genetic variants affect diurnal glucose levels throughout the day.

Circadian rhythms not only coordinate the timing of wake and sleep but also regulate homeostasis within the body, including glucose metabolism. However, the genetic variants that contribute to temporal control of glucose levels have not been previously examined. Using data from 420,000 individuals from the UK Biobank and replicating our findings in 100,000 individuals from the Estonian Biobank, we show that diurnal serum glucose is under genetic control. We discover a robust temporal association of glucose levels at the Melatonin receptor 1B (MTNR1B) (rs10830963, P = 1e-22) and a canonical circadian pacemaker gene Cryptochrome 2 (CRY2) loci (rs12419690, P = 1e-16). Furthermore, we show that sleep modulates serum glucose levels and the genetic variants have a separate mechanism of diurnal control. Finally, we show that these variants independently modulate risk of type 2 diabetes. Our findings, together with earlier genetic and epidemiological evidence, show a clear connection between sleep and metabolism and highlight variation at MTNR1B and CRY2 as temporal regulators for glucose levels.

Inline Raman Spectroscopy Provides Versatile Molecular Monitoring for Platelet Extracellular Vesicle Purification with Anion-Exchange Chromatography.

Extracellular vesicles (EVs) are relatively recently discovered biological nanoparticles that mediate intercellular communication. The development of new methods for the isolation and characterization of EVs is crucial to support further studies on these small and structurally heterogenous vesicles. New scalable production methods are also needed to meet the needs of future therapeutic applications. A reliable inline detection method for the EV manufacturing process is needed to ensure reproducibility and to identify any possible variations in real time. Here, we demonstrate the use of an inline Raman detector in conjunction with anion exchange chromatography for the isolation of EVs from human platelets. Anion-exchange chromatography can be easily coupled with multiple inline detectors and provides an alternative to size-based methods for separating EVs from similar-sized impurities, such as lipoprotein particles. Raman spectroscopy enabled us to identify functional groups in EV samples and trace EVs and impurities in different stages of the process. Our results show a notable separation of impurities from the EVs during anion-exchange chromatography and demonstrate the power of inline Raman spectroscopy. Compared to conventional EV analysis methods, the inline Raman approach does not require hands-on work and can provide detailed, real-time information about the sample and the purification process.

Real-World Application of a Quantitative Systems Pharmacology (QSP) Model to Predict Potassium Concentrations from Electronic Health Records: A Pilot Case towards Prescribing Monitoring of Spironolactone.

Quantitative systems pharmacology (QSP) models are rarely applied prospectively for decision-making in clinical practice. We therefore aimed to operationalize a QSP model for potas-sium homeostasis to predict potassium trajectories based on spironolactone administrations. For this purpose, we proposed a general workflow that was applied to electronic health records (EHR) from patients treated in a German tertiary care hospital. The workflow steps included model exploration, local and global sensitivity analyses (SA), identifiability analysis (IA) of model parameters, and specification of their inter-individual variability (IIV). Patient covariates, selected parameters, and IIV then defined prior information for the Bayesian a posteriori prediction of individual potassium trajectories of the following day. Following these steps, the successfully operationalized QSP model was interactively explored via a Shiny app. SA and IA yielded five influential and estimable parameters (extracellular fluid volume, hyperaldosteronism, mineral corticoid receptor abundance, potassium intake, sodium intake) for Bayesian prediction. The operationalized model was validated in nine pilot patients and showed satisfactory performance based on the (absolute) average fold error. This provides proof-of-principle for a Prescribing Monitoring of potassium concentrations in a hospital system, which could suggest preemptive clinical measures and therefore potentially avoid dangerous hyperkalemia or hypokalemia.

A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.

BACKGROUND AIMS: Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD. APPROACH RESULTS: We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD. CONCLUSIONS: Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.

Comorbidity and sex differences in functional disorders and internalizing disorders.

OBJECTIVE: In the current exploratory study we estimate comorbidity rates between FDs [fibromyalgia (FM), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and irritable bowel syndrome (IBS)]-and IDs-[major depressive disorder (MDD) and generalized anxiety disorder (GAD)] by using self-reported diagnostic criteria. METHOD: We analyzed data from 107,849 participants (mean age = 49.3 (SD = 13.0), 58.6% women) of the Lifelines Cohort Study. Lifelines is a prospective population-based cohort study in the northeast of the Netherlands. Current IDs were assessed using the Mini-International Neuropsychiatric Interview. Current FM, ME/CFS, and IBS were assessed according to the 2010 American College of Rheumatology criteria, the 1994 Centers for Disease Control and Prevention criteria and the ROME IV criteria, respectively. We estimated tetrachoric correlations between diagnoses and tested for sex differences. Additionally, we estimated the ratio of observed-to-expected frequency for combinations of diagnoses. RESULTS: FDs and IDs are highly comorbid (odds ratios: 3.2-12.6) with associations stronger among men. Participants with at least three disorders/diagnoses were more prevalent than expected by chance. CONCLUSION: Studies that aim to explain sex differences and the comorbidity of specific combinations of IDs and FDs will be an important contribution to understanding the etiology of these conditions.