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.

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.

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.

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.

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.

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.

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.

Development of a Cognitive Training Support Programme for prevention of dementia and cognitive decline in at-risk older adults.

Background: Evidence for the beneficial effects of cognitive training on cognitive function and daily living activities is inconclusive. Variable study quality and design does not allow for robust comparisons/meta-analyses of different cognitive training programmes. Fairly low adherence to extended cognitive training interventions in clinical trials has been reported. Aims: The aim of further developing a Cognitive Training Support Programme (CTSP) is to supplement the Computerised Cognitive Training (CCT) intervention component of the multimodal Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), which is adapted to different cultural, regional and economic settings within the Word-Wide FINGERS (WW-FINGERS) Network. The main objectives are to improve adherence to cognitive training through a behaviour change framework and provide information about cognitive stimulation, social engagement and lifestyle risk factors for dementia. Methods: Six CTSP sessions were re-designed covering topics including (1) CCT instructions and tasks, (2) Cognitive domains: episodic memory, executive function and processing speed, (3) Successful ageing and compensatory strategies, (4) Cognitive stimulation and engagement, (5) Wellbeing factors affecting cognition (e.g., sleep and mood), (6) Sensory factors. Session content will be related to everyday life, with participant reflection and behaviour change techniques incorporated, e.g., strategies, goal-setting, active planning to enhance motivation, and adherence to the CCT and in relevant lifestyle changes. Conclusions: Through interactive presentations promoting brain health, the programme provides for personal reflection that may enhance capability, opportunity and motivation for behaviour change. This will support adherence to the CCT within multidomain intervention trials. Efficacy of the programme will be evaluated through participant feedback and adherence metrics.

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.

Peat formation potential of temperate fens increases with hydrological stability.

Peat formation is the key process responsible for carbon sequestration in peatlands. In rich fens, peat is formed by brown mosses and belowground biomass of vascular plants. However, the impact of ecohydrological settings on the contribution of mosses and belowground biomass to peat formation remains an open question. We established seven transects in well-preserved fens in NE Poland along an ecohydrological gradient from mesotrophic sedge-moss communities with stable water levels, to more eutrophic tall sedge communities with higher water level fluctuations. In each transect, we measured the production of brown mosses (using the plug method), aboveground vascular plant biomass (one year after cutting) and belowground biomass (using ingrowth cores). Decomposition rates of all biomass fractions were assessed using litter bags. The first-year surplus of potentially peat-forming fractions, i.e., mosses and belowground biomass, decreased with increasing water level fluctuations and along a vegetation gradient from sedge-moss to tall sedge communities. Moss production was highest in the sedge-moss fen with a stable water level at the ground surface. We did not detect any difference in belowground biomass production across the gradient but found it to be consistently higher in the upper 0-5 cm than in the deeper layers. The decomposition rate also showed no response to the gradient, but differed between biomass types, with aboveground biomass of vascular plants decomposing 2.5 times faster than belowground biomass and mosses. Pattern of peat formation potential along the ecohydrological gradient in rich fen was strongly driven by brown moss production. Sedge-moss fens with a stable water level at the ground surface have the highest peat formation capacity compared to other vegetation types. In the part of the gradient that is poorer in nutrients, vascular plants invest in belowground production, and mosses dominate the aboveground layer.

Assessment of socio-demographic characteristics and social status of patients with negative symptoms in schizophrenia at different stages of the disease.

OBJECTIVE: Aim: To determine the features of socio-demographic characteristics of patients with negative symptoms of schizophrenia. PATIENTS AND METHODS: Materials and Methods: 252 patients with negative symptoms of schizophrenia took part in the study: 83 patients with the first episode of schizophrenia, 88 patients with schizophrenia in a state of exacerbation, and 81 patients with schizophrenia in a state of remission. During the research, a comprehensive approach was used, which consisted in the use of clinical-psychopathological, clinical-anamnestic and statistical research methods. RESULTS: Results: Socio-demographic characteristics of patients with negative symptoms in schizophrenia were established. Among patients with the first episode of schizophrenia, the majority were of 20-29 years old, mostly with secondary education, unmarried, with a mental labor, with low and average levels of a material well-being, poor and satisfactory living conditions. Among patients with negative symptoms of schizophrenia in an exacerbation state, the majority was of persons of 30-49 years old, with a special secondary education, mostly divorced, with a disability, with a low and extremely low level of material well-being, with poor and very poor living conditions prevailed. Among patients with negative symptoms of schizophrenia in a state of remission, there was a predominance of persons of 30-39 and 50-60 years old, with a special secondary education, divorced, mainly with a physical labor, with a low and average level of material well-being and poor living conditions. CONCLUSION: Conclusions: The obtained data can be used to establish diagnostic criteria for patients with negative symptoms in schizophrenia, depending on the dynamics of the disease.

Methamphetamine-induced adaptation of learning rate dynamics depend on baseline performance.

The ability to calibrate learning according to new information is a fundamental component of an organism's ability to adapt to changing conditions. Yet, the exact neural mechanisms guiding dynamic learning rate adjustments remain unclear. Catecholamines appear to play a critical role in adjusting the degree to which we use new information over time, but individuals vary widely in the manner in which they adjust to changes. Here, we studied the effects of a low dose of methamphetamine (MA), and individual differences in these effects, on probabilistic reversal learning dynamics in a within-subject, double-blind, randomized design. Participants first completed a reversal learning task during a drug-free baseline session to provide a measure of baseline performance. Then they completed the task during two sessions, one with MA (20 mg oral) and one with placebo (PL). First, we showed that, relative to PL, MA modulates the ability to dynamically adjust learning from prediction errors. Second, this effect was more pronounced in participants who performed poorly at baseline. These results present novel evidence for the involvement of catecholaminergic transmission on learning flexibility and highlights that baseline performance modulates the effect of the drug.

An endothelial regulatory module links blood pressure regulation with elite athletic performance.

The control of transcription is crucial for homeostasis in mammals. A previous selective sweep analysis of horse racing performance revealed a 19.6 kb candidate regulatory region 50 kb downstream of the Endothelin3 (EDN3) gene. Here, the region was narrowed to a 5.5 kb span of 14 SNVs, with elite and sub-elite haplotypes analyzed for association to racing performance, blood pressure and plasma levels of EDN3 in Coldblooded trotters and Standardbreds. Comparative analysis of human HiCap data identified the span as an enhancer cluster active in endothelial cells, interacting with genes relevant to blood pressure regulation. Coldblooded trotters with the sub-elite haplotype had significantly higher blood pressure compared to horses with the elite performing haplotype during exercise. Alleles within the elite haplotype were part of the standing variation in pre-domestication horses, and have risen in frequency during the era of breed development and selection. These results advance our understanding of the molecular genetics of athletic performance and vascular traits in both horses and humans.

Event Analysis for Automated Estimation of Absent and Persistent Medication Alerts: Novel Methodology.

Background: Event analysis is a promising approach to estimate the acceptance of medication alerts issued by computerized physician order entry (CPOE) systems with an integrated clinical decision support system (CDSS), particularly when alerts cannot be interactively confirmed in the CPOE-CDSS due to its system architecture. Medication documentation is then reviewed for documented evidence of alert acceptance, which can be a time-consuming process, especially when performed manually. Objective: We present a new automated event analysis approach, which was applied to a large data set generated in a CPOE-CDSS with passive, noninterruptive alerts. Methods: Medication and alert data generated over 3.5 months within the CPOE-CDSS at Heidelberg University Hospital were divided into 24-hour time intervals in which the alert display was correlated with associated prescription changes. Alerts were considered "persistent" if they were displayed in every consecutive 24-hour time interval due to a respective active prescription until patient discharge and were considered "absent" if they were no longer displayed during continuous prescriptions in the subsequent interval. Results: Overall, 1670 patient cases with 11,428 alerts were analyzed. Alerts were displayed for a median of 3 (IQR 1-7) consecutive 24-hour time intervals, with the shortest alerts displayed for drug-allergy interactions and the longest alerts displayed for potentially inappropriate medication for the elderly (PIM). Among the total 11,428 alerts, 56.1% (n=6413) became absent, most commonly among alerts for drug-drug interactions (1915/2366, 80.9%) and least commonly among PIM alerts (199/499, 39.9%). Conclusions: This new approach to estimate alert acceptance based on event analysis can be flexibly adapted to the automated evaluation of passive, noninterruptive alerts. This enables large data sets of longitudinal patient cases to be processed, allows for the derivation of the ratios of persistent and absent alerts, and facilitates the comparison and prospective monitoring of these alerts.

Genetic drivers and cellular selection of female mosaic X chromosome loss.

Mosaic loss of the X chromosome (mLOX) is the most common clonal somatic alteration in leukocytes of female individuals1,2, but little is known about its genetic determinants or phenotypic consequences. Here, to address this, we used data from 883,574 female participants across 8 biobanks; 12% of participants exhibited detectable mLOX in approximately 2% of leukocytes. Female participants with mLOX had an increased risk of myeloid and lymphoid leukaemias. Genetic analyses identified 56 common variants associated with mLOX, implicating genes with roles in chromosomal missegregation, cancer predisposition and autoimmune diseases. Exome-sequence analyses identified rare missense variants in FBXO10 that confer a twofold increased risk of mLOX. Only a small fraction of associations was shared with mosaic Y chromosome loss, suggesting that distinct biological processes drive formation and clonal expansion of sex chromosome missegregation. Allelic shift analyses identified X chromosome alleles that are preferentially retained in mLOX, demonstrating variation at many loci under cellular selection. A polygenic score including 44 allelic shift loci correctly inferred the retained X chromosomes in 80.7% of mLOX cases in the top decile. Our results support a model in which germline variants predispose female individuals to acquiring mLOX, with the allelic content of the X chromosome possibly shaping the magnitude of clonal expansion.

How to treat mixed behavior segments in supervised machine learning of behavioural modes from inertial measurement data.

The application of supervised machine learning methods to identify behavioural modes from inertial measurements of bio-loggers has become a standard tool in behavioural ecology. Several design choices can affect the accuracy of identifying the behavioural modes. One such choice is the inclusion or exclusion of segments consisting of more than a single behaviour (mixed segments) in the machine learning model training data. Currently, the common practice is to ignore such segments during model training. In this paper we tested the hypothesis that including mixed segments in model training will improve accuracy, as the model would perform better in identifying them in the test data. We test this hypothesis using a series of data simulations on four datasets of accelerometer data coupled with behaviour observations, obtained from four study species (Damaraland mole-rats, meerkats, olive baboons, polar bears). Results show that when a substantial proportion of the test data are mixed behaviour segments (above ~ 10%), including mixed segments in machine learning model training improves the accuracy of classification. These results were consistent across the four study species, and robust to changes in segment length, sample size, and degree of mixture within the mixed segments. However, we also find that in some cases (particularly in baboons) models trained with mixed segments show reduced accuracy in classifying test data containing only single behaviour (pure) segments, compared to models trained without mixed segments. Based on these results, we recommend that when the classification model is expected to deal with a substantial proportion of mixed behaviour segments (> 10%), it is beneficial to include them in model training, otherwise, it is unnecessary but also not harmful. The exception is when there is a basis to assume that the training data contains a higher rate of mixed segments than the actual (unobserved) data to be classified-such a situation may occur particularly when training data are collected in captivity and used to classify data from the wild. In this case, excess inclusion of mixed segments in training data should probably be avoided.