Association Between Vegetation Size and Outcome in the Partial Oral Antibiotic Endocarditis Treatment Trial.

Step-down oral antibiotic therapy is associated with a non-inferior long-term outcome compared with continued intravenous antibiotic therapy in the treatment of left-sided infective endocarditis. We aimed to analyze whether step-down oral therapy compared with continued intravenous antibiotic therapy is also associated with a non-inferior outcome in patients with large vegetations (vegetation length ≥ 10 mm) or among patients who underwent surgery before step-down oral therapy. We included patients without presence of aortic root abscess at diagnosis from the POET (Partial Oral Antibiotic Endocarditis Treatment) study. Multivariable Cox regression analyses were used to find associations between large vegetation, cardiac surgery, step-down oral therapy, and the primary end point (composite of all-cause mortality, unplanned cardiac surgery, embolic event, or relapse of positive blood cultures during follow-up). A total of 368 patients (age 68 ± 12, 77% men) were included. Patients with large vegetations (n = 124) were more likely to undergo surgery compared with patients with small vegetations (n = 244) (65% vs 20%, p <0.001). During a median 1,406 days of follow-up, 146 patients reached the primary end point. Large vegetations were not associated with the primary end point (hazard ratio 0.74, 95% confidence interval 0.47 to 1.18, p = 0.21). Step-down oral therapy was non-inferior to continued intravenous antibiotic in all subgroups when stratified by the presence of a large vegetation at baseline and early cardiac surgery. Step-down oral therapy is safe in the presence of a large vegetation at diagnosis and among patients who underwent early cardiac surgery.

Single-cell ionic current phenotyping elucidates non-canonical features and predictive potential of cardiomyocytes during automated drug experiments.

All new drugs must go through preclinical screening tests to determine their proarrhythmic potential. While these assays effectively filter out dangerous drugs, they are too conservative, often misclassifying safe compounds as proarrhythmic. In this study, we attempt to address this shortcoming with a novel, medium-throughput drug-screening approach: we use an automated patch-clamp system to acquire optimized voltage clamp (VC) and action potential (AP) data from human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) at several drug concentrations (baseline, 3×, 10× and 20× the effective free plasma concentrations). With our novel method, we show correlations between INa block and upstroke slowing after treatment with flecainide or quinine. Additionally, after quinine treatment, we identify significant reductions in current during voltage steps designed to isolate If and IKs. However, we do not detect any IKr block by either drug, and upon further investigation, do not see any IKr present in the iPSC-CMs when prepared for automated patch experiments (i.e. in suspension) - this is in contrast to similar experiments we have conducted with these cells using the manual patch setup. In this study, we: (1) present a proof-of-concept demonstration of a single-cell medium-throughput drug study, and (2) characterize the non-canonical electrophysiology of iPSC-CMs when prepared for experiments in a medium-throughput setting. KEY POINTS: Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model to study the proarrhythmic potential of drugs, but insights from these cells are often limited by the low throughput of manual patch-clamp. In this study, we use a medium-throughput automated patch-clamp system to acquire action potential (AP) and complex voltage clamp (VC) data from single iPSC-CMs at multiple drug concentrations. A correlation between AP upstroke and INa transients was identified and drug-induced changes in ionic currents found. We also characterize the substantially altered physiology of iPSC-CMs when patched in an automated system, suggesting the need to investigate differences between manual and automated patch experiments.

Stem cell-derived cardiomyocyte heterogeneity confounds electrophysiological insights.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer potential as an in vitro model for studying drug cardiotoxicity and patient-specific cardiovascular disease. The inherent electrophysiological heterogeneity of these cells limits the depth of insights that can be drawn from well-designed experiments. In this review, we provide our perspective on some sources and the consequences of iPSC-CM heterogeneity. We demonstrate the extent of heterogeneity in the literature and explain how such heterogeneity is exacerbated by patch-clamp experimental artifacts in the manual and automated set-up. Finally, we discuss how this heterogeneity, caused by both intrinsic and extrinsic factors, limits our ability to build digital twins of patient-derived cardiomyocytes.

Mobile device screen time is associated with poorer language development among toddlers: results from a large-scale survey.

BACKGROUND: Despite young children's widespread use of mobile devices, little research exists on this use and its association with children's language development. The aim of this study was to examine the associations between mobile device screen time and language comprehension and expressive language skills. An additional aim was to examine whether three factors related to the domestic learning environment modify the associations. METHODS: The study uses data from the Danish large-scale survey TRACES among two- and three-year-old children (n = 31,125). Mobile device screen time was measured as time spent on mobile devices on a normal day. Measurement of language comprehension and expressive language skills was based on subscales from the Five to Fifteen Toddlers questionnaire. Multivariable linear regression was used to examine the association between child mobile device screen time and language development and logistic regression to examine the risk of experiencing significant language difficulties. Joint exposure analyses were used to examine the association between child mobile device screen time and language development difficulties in combination with three other factors related to the domestic learning environment: parental education, reading to the child and child TV/PC screen time. RESULTS: High mobile device screen time of one hour or more per day was significantly associated with poorer language development scores and higher odds for both language comprehension difficulties (1-2 h: AOR = 1.30; ≥ 2 h: AOR = 1.42) and expressive language skills difficulties (1-2 h: AOR = 1.19; ≥ 2 h: AOR = 1.46). The results suggest that reading frequently to the child partly buffers the negative effect of high mobile device screen time on language comprehension difficulties but not on expressive language skills difficulties. No modifying effect of parental education and time spent by the child on TV/PC was found. CONCLUSIONS: Mobile device screen time of one hour or more per day is associated with poorer language development among toddlers. Reading frequently to the child may have a buffering effect on language comprehension difficulties but not on expressive language skills difficulties.

A systematic review and meta-analysis of the child-level effects of family-based interventions for the prevention of type 2 diabetes mellitus.

AIMS: The purpose of this systematic review and meta-analysis was to investigate the effects of family-based health promotion interventions on child-level risk factors for type 2 diabetes in vulnerable families. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for systematic reviews formed the methodological framework. CINAHL, Embase, MEDLINE, PsycINFO, and Web of Science were searched on January 12, 2024. The NTP-OHAT Risk of Bias Assessment Tool was used to assess the risk of bias in the individual studies, and meta-analyses were performed. RESULTS: The 4723 studies were identified, and 55 studies met the inclusion criteria. Results showed significant effects on children's body mass index (mean difference [MD], -0.18, 95% CI [-0.33 to -0.03], p = 0.02), body fat percentage (MD, -2.00, 95% CI [-3.31 to -0.69], p = 0.003), daily activity (standardized mean difference [SMD], 0.23, 95% CI [0.01; 0.44], p = 0.04), physical activity self-efficacy (SMD, 0.73, 95% CI [0.36 to 1.10], p < 0.01), intake of snacks (MD, -0.10, 95% CI [-0.17 to -0.04], p = 0.002), and sugar-sweetened beverages (SMD, -0.21, 95% CI [-0.42 to -0.01], p = 0.04). Subgroup analyses suggested that interventions aiming to change child and parent behavior simultaneously have larger effect on fasting glucose and nutrition consumption, and that interventions longer than 26 weeks have larger effects on body composition and physical activity behavior than shorter interventions.

The Danish Aging and Cognition (DanACo) cohort.

BACKGROUND: With aging populations worldwide, identification of predictors of age-related cognitive decline is becoming increasingly important. The Danish Aging and Cognition Cohort (DanACo) including more than 5000 Danish men was established to investigate predictors of age-related cognitive decline from young adulthood to late mid-life. CONSTRUCTION AND CONTENT: The DanACo cohort was established through two separate data collections with identical designs involving a follow-up examination in late mid-life of men for whom intelligence test scores were available from their mandatory conscription board examination. The cohort consists of 5,183 men born from 1949 through 1961, with a mean age of 20.4 years at baseline and a mean age of 64.4 years at follow-up. The baseline measures consisted of height, weight, intelligence test score and educational level collected at the conscription board examination. The follow-up assessment consisted of a re-administration of the same intelligence test and a comprehensive questionnaire covering socio-demographic factors, lifestyle, and health-related factors. The data were collected in test sessions with up to 24 participants per session. Using the unique personal identification number assigned to all Danes, the cohort has been linked to data from national administrative and health registers for prospectively collected data on socioeconomic and health-related factors. UTILITY AND DISCUSSION: The DanACo cohort has some major strengths compared to existing cognitive aging cohorts such as a large sample size (n = 5,183 men), a validated global measure of cognitive ability, a long retest interval (mean 44.0 years) and the availability of prospectively collected data from registries as well as comprehensive questionnaire data. The main weakness is the low participation rate (14.3%) and that the cohort consists of men only. CONCLUSION: Cognitive decline is a result of a summary of factors across the life-course. The DanACo cohort is characterized by a long retest interval and contains data on a wealth of factors across adult life which is essential to establish evidence on predictors of cognitive decline. Moreover, the size of the cohort ensures sufficient statistical power to identify even relatively weak predictors of cognitive decline.

Lifetime exposure to air pollution and academic achievement: A nationwide cohort study in Denmark.

Recent research suggests a link between air pollution and cognitive development in children, and studies on air pollution and academic achievement are emerging. We conducted a nationwide cohort study in Denmark to explore the associations between lifetime exposure to air pollution and academic performance in 9th grade. The study encompassed 785,312 children born in Denmark between 1989 and 2005, all of whom completed 9th-grade exit examinations. Using linear mixed models with a random intercept for each school, we assessed the relationship between 16 years of exposure to PM2.5, PM10, and gaseous pollutants and Grade Point Averages (GPA) in exit examinations, covering subjects such as Danish literature, Danish writing, English, mathematics, and natural sciences. The study revealed that a 5 µg/m3 increase in PM2.5 and PM10 was associated with a decrease of 0.99 (95 % Confidence Intervals: -1.05, -0.92) and 0.46 (-0.50, -0.41) in GPA, respectively. Notably, these negative associations were more pronounced in mathematics and natural sciences compared to language-related subjects. Additionally, girls and children with non-Danish mothers were found to be particularly susceptible to the adverse effects of air pollution exposure. These results underscore the potential long-term consequences of air pollution on academic achievement, emphasizing the significance of interventions that foster healthier environments for children's cognitive development.

Single-cell ionic current phenotyping explains stem cell-derived cardiomyocyte action potential morphology.

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) are a promising tool to study arrhythmia-related factors, but the variability of action potential (AP) recordings from these cells limits their use as an in vitro model. In this study, we use recently published brief (10 s), dynamic voltage-clamp (VC) data to provide mechanistic insights into the ionic currents contributing to AP heterogeneity; we call this approach rapid ionic current phenotyping (RICP). Features of this VC data were correlated to AP recordings from the same cells, and we used computational models to generate mechanistic insights into cellular heterogeneity. This analysis uncovered several interesting links between AP morphology and ionic current density: both L-type calcium and sodium currents contribute to upstroke velocity, rapid delayed rectifier K+ current is the main determinant of the maximal diastolic potential, and an outward current in the activation range of slow delayed rectifier K+ is the main determinant of AP duration. Our analysis also identified an outward current in several cells at 6 mV that is not reproduced by iPSC-CM mathematical models but contributes to determining AP duration. RICP can be used to explain how cell-to-cell variability in ionic currents gives rise to AP heterogeneity. Because of its brief duration (10 s) and ease of data interpretation, we recommend the use of RICP for single-cell patch-clamp experiments that include the acquisition of APs.NEW & NOTEWORTHY We present rapid ionic current phenotyping (RICP), a current quantification approach based on an optimized voltage-clamp protocol. The method captures a rich snapshot of the ionic current dynamics, providing quantitative information about multiple currents (e.g., ICa,L, IKr) in the same cell. The protocol helped to identify key ionic determinants of cellular action potential heterogeneity in iPSC-CMs. This included unexpected results, such as the critical role of IKr in establishing the maximum diastolic potential.

Pulmonary arteriovenous malformations in patients with previous brain abscess: a cross-sectional population-based study.

BACKGROUND AND PURPOSE: Pulmonary arteriovenous malformations (PAVMs) may cause recurrent brain abscess. The primary aim was to determine the prevalence of PAVM amongst survivors of brain abscess. The proportion with cardiac right-to-left shunts was also assessed post hoc. METHODS: This was a cross-sectional population-based study of adult (≥18 years) survivors of cryptogenic bacterial brain abscess in Denmark from 2007 through 2016. Patients were invited for bubble-echocardiography to detect vascular right-to-left shunting and, if abnormal, subsequent computed tomography thorax for diagnosis of PAVM. Data are presented as n/N (%) or median with interquartile range (IQR). RESULTS: Study participation was accepted by 47/157 (30%) eligible patients amongst whom two did not appear for scheduled bubble-echocardiography. The median age of participants was 54 years (IQR 45-62) and 19/57 (33%) were females compared with 59 years (IQR 48-68, p = 0.05) and 41/85 females (48%, p = 0.22) in non-participants. Bubble-echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting. The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06-11.8) amongst all examined participants. Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population. CONCLUSIONS: Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients. The prevalence of cardiac right-to-left shunts amongst brain abscess patients corresponds to the prevalence in the general population.

Optimization of a cardiomyocyte model illuminates role of increased INa,L in repolarization reserve.

Cardiac ion currents may compensate for each other when one is compromised by a congenital or drug-induced defect. Such redundancy contributes to a robust repolarization reserve that can prevent the development of lethal arrhythmias. Most efforts made to describe this phenomenon have quantified contributions by individual ion currents. However, it is important to understand the interplay between all major ion-channel conductances, as repolarization reserve is dependent on the balance between all ion currents in a cardiomyocyte. Here, a genetic algorithm was designed to derive profiles of nine ion-channel conductances that optimize repolarization reserve in a mathematical cardiomyocyte model. Repolarization reserve was quantified using a previously defined metric, repolarization reserve current, i.e., the minimum constant current to prevent normal action potential repolarization in a cell. The optimization improved repolarization reserve current up to 84% compared to baseline in a human adult ventricular myocyte model and increased resistance to arrhythmogenic insult. The optimized conductance profiles were not only characterized by increased repolarizing current conductances but also uncovered a previously unreported behavior by the late sodium current. Simulations demonstrated that upregulated late sodium increased action potential duration, without compromising repolarization reserve current. The finding was generalized to multiple models. Ultimately, this computational approach, in which multiple currents were studied simultaneously, illuminated mechanistic insights into how the metric's magnitude could be increased and allowed for the unexpected role of late sodium to be elucidated.NEW & NOTEWORTHY Genetic algorithms are typically used to fit models or extract desired parameters from data. Here, we use the tool to produce a ventricular cardiomyocyte model with increased repolarization reserve. Since arrhythmia mitigation is dependent on multiple cardiac ion-channel conductances, study using a comprehensive, unbiased, and systems-level approach is important. The use of this optimization strategy allowed us to find robust profiles that illuminated unexpected mechanistic determinants of key ion-channel conductances in repolarization reserve.

The effect of the SAFE intervention on post-discharge suicidal behavior: a quasi-experimental study using propensity score matching.

OBJECTIVES: The risk of suicidal behavior after discharge from psychiatric admission is high. The aim of this study was to examine whether the SAFE intervention, an implementation of a systematic safer discharge procedure, was associated with a reduction in suicidal behavior after discharge. METHODS: The SAFE intervention was implemented at Mental Health Center Copenhagen in March 2018 and consisted of three systematic discharge procedures: (1) A face-to-face meeting between patient and outpatient staff prior to discharge, (2) A face-to-face meeting within the first week after discharge, and (3) Involvement of relatives. Risk of suicide attempt at six-month post-discharge among patients discharged from the SAFE intervention was compared with patients discharged from comparison mental health centers using propensity score matching. RESULTS: 7604 discharges took place at the intervention site, which were 1:1 matched with discharges from comparison sites. During the six months of follow-up, a total of 570 suicide attempts and 25 suicides occurred. The rate of suicide attempt was 11,652 per 100,000 person-years at the SAFE site, while it was 10,530 at comparisons sites. No observable difference in suicide attempt 1.10 (95% CI: 0.89-1.35) or death by suicide (OR = 1.27; 95% CI:0.58-2.81) was found between sites at 6-month follow-up. CONCLUSION: No difference in suicidal behavior between the sites was found in this pragmatic study. High rates of suicidal behavior were found during the 6-months discharge period, which could suggest that a preventive intervention should include support over a longer post-discharge period than the one-week follow-up offered in the SAFE intervention.

Prediction models of suicide and non-fatal suicide attempt after discharge from a psychiatric inpatient stay: A machine learning approach on nationwide Danish registers.

INTRODUCTION: To develop machine learning models capable of predicting suicide and non-fatal suicide attempt as separate outcomes in the first 30 days after discharge from a psychiatric inpatient stay. METHODS: Prospective cohort study using nationwide Danish registry data. We included individuals who were 18 years or older, and all discharges from psychiatric hospitalizations in Denmark from 1995 to 2018. We trained predictive models using 10-fold cross validation on 80% of the data and did testing on the remaining 20%. RESULTS: The best model for predicting non-fatal suicide attempt was an ensemble of predictions from gradient boosting (XGBoost) and categorical boosting (catBoost). The ROC-AUC for predicting suicide attempt was 0.85 (95% CI: 0.84-0.85). At a risk threshold of 4.36%, positive predictive value (PPV) was 11.0% and sensitivity was 47.2%. The best model for predicting suicide was an ensemble of predictions from random forest, XGBoost and catBoost. For suicide, the ROC-AUC was 0.71 (95% CI: 0.70-0.73). At a risk threshold of 0.15%, PPV was 0.34% and sensitivity was 56.0%. The most contributing predictors differed when predicting suicide and suicide attempt, indicating that separate models are needed. The ensemble model was fair across sex and age, and more so than the penalized logistic regression model. CONCLUSIONS: We achieved good performance for predicting suicide attempts and demonstrated a clinical application of ensemble models. Our results indicate a difference in predictive performance for models predicting suicide and suicide attempt, respectively. Thus, we recommend that suicide and suicide attempt are treated as two separate endpoints, in particular for clinical application. We demonstrated that the ensemble model is fairer across sex and age compared with a penalized logistic regression, and therefore we recommend the use of well-tested ensembles despite a more complex explainability.

Patients With Hypertrophic Cardiomyopathy and Normal Genetic Investigations Have Few Affected Relatives.

BACKGROUND: Current guidelines recommend that relatives of index patients with hypertrophic cardiomyopathy (HCM) are offered clinical investigations to identify individuals at risk of adverse disease complications and sudden cardiac death. However, the value of family screening in relatives of index patients with a normal genetic investigation of recognized HCM genes is largely unknown. OBJECTIVES: The purpose of this study was to perform family screening among relatives of HCM index patients with a normal genetic investigation to establish the frequency of familial disease and the clinical characteristics of affected individuals. METHODS: Clinical and genetic investigations were performed in consecutive and unrelated HCM index patients. Relatives of index patients who did not carry pathogenic/likely pathogenic variants in recognized HCM genes were invited for clinical investigations. RESULTS: In total, 60% (270 of 453) of HCM index patients had a normal genetic investigation. A total of 80% of their relatives (751 of 938, median age 44 years) participated in the study. Of these, 5% (34 of 751) were diagnosed with HCM at baseline, whereas 0.3% (2 of 717 [751-34]) developed the condition during 5 years of follow-up. Their median age at diagnosis was 57 years (IQR: 51-70 years). Two-thirds (22 of 36) were diagnosed following family screening, whereas one-third (14 of 36) had been diagnosed previously because of cardiac symptoms, a murmur, or an abnormal electrocardiogram. None of the affected relatives experienced adverse disease complications. The risk of SCD was low. CONCLUSIONS: Systematic family screening of index patients with HCM and normal genetic investigations was associated with a low frequency of affected relatives who appeared to have a favorable prognosis.

Situation Analysis of Suicide and Self-Harm in the WHO Eastern Mediterranean Region.

OBJECTIVE: An estimated 41,000 lives are lost to suicide each year in World Health Organization Eastern Mediterranean Region Office (WHO EMRO) countries. The objective of this study was to conduct a situation analysis for suicide and self-harm in the WHO EMRO region. METHODS: Data on suicide were obtained from the WHO Global Health Estimates for the years 2000-2019. Information on risk groups efforts to prevent self-harm and suicide in the EMRO region were retrieved through scientific studies, grey literature, and public websites. RESULTS: During 2000-2019, the age-standardized suicide rate was 6.7 per 100,000 inhabitants, albeit there are concerns regarding data quality. Self-harm and suicide remain criminal acts in more than half of the countries. Few countries have a national plan for prevention of suicide. Toxic agents, such as pesticides and black henna, are easily available and frequently used for suicide in some areas, as are firearms and self-immolation. Successful prevention measures include means restriction and psychosocial interventions after self-harm. CONCLUSION: Many WHO EMRO countries remain underserved in terms of mental health care. Decriminalization of suicide and means restriction might be further promoted. Online-based tools for mental health literacy and psychosocial therapy are other options to explore.

Suicidal behavior remains a criminal act in more than half of the WHO EMRO countries.Easily available toxic agents, such as pesticides and black henna, and firearms are common methods used for suicidal behavior in the WHO EMRO countries.Access to mental health care is limited in many of the WHO EMRO countries.Online-based psychoeducation and psychosocial intervention programs might be further explored as preventive efforts.

20-year trajectories of positive and negative symptoms after the first psychotic episode in patients with schizophrenia spectrum disorder: results from the OPUS study.

This study aimed to identify the 20-year trajectories of positive and negative symptoms after the first psychotic episode in a sample of patients with an ICD-10 diagnosis of schizophrenia spectrum disorder, and to investigate the baseline characteristics and long-term outcomes associated with these trajectories. A total of 373 participants in the OPUS trial were included in the study. Symptoms were assessed at baseline and after 1, 2, 5, 10 and 20 years using the Scales for the Assessment of Positive and Negative Symptoms. We used latent class growth mixture modelling to identify trajectories, and multinominal regression analyses to investigate predictors of membership to identified trajectories. Five trajectories of positive symptoms were identified: early continuous remission (50.9% of the sample), stable improvement (18.0%), intermittent symptoms (10.2%), relapse with moderate symptoms (11.9%), and continuous severe symptoms (9.1%). Substance use disorder (odds ratio, OR: 2.83, 95% CI: 1.09-7.38, p=0.033), longer duration of untreated psychosis (OR: 1.02, 95% CI: 1.00-1.03, p=0.007) and higher level of negative symptoms (OR: 1.60, 95% CI: 1.07-2.39, p=0.021) were predictors of the relapse with moderate symptoms trajectory, while only longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.030) predicted membership to the continuous severe symptoms trajectory. Two trajectories of negative symptoms were identified: symptom remission (51.0%) and continuous symptoms (49.0%). Predictors of the continuous symptoms trajectory were male sex (OR: 3.03, 95% CI: 1.48-6.02, p=0.002) and longer duration of untreated psychosis (OR: 1.01, 95% CI: 1.00-1.02, p=0.034). Trajectories displaying continuous positive and negative symptoms were linked to lower neurocognition, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) (z-score: -0.78, CI: -1.39 to -0.17, for continuous positive symptoms; z-score: -0.33, CI: -0.53 to -0.13, for continuous negative symptoms). The same trajectories were also linked to higher use of antipsychotic medication at 20-year follow-up (continuous positive symptoms: 78%; continuous negative symptoms: 67%). These findings suggest that the majority of patients with first-episode schizophrenia spectrum disorder have a trajectory with early stable remission of positive symptoms. Long duration of untreated psychosis and comorbid substance abuse are modifiable predictors of poor trajectories for positive symptoms in these patients. In about half of patients, negative symptoms do not improve over time. These symptoms, in addition to being associated with poor social and neurocognitive functioning, may prevent patients from seeking help.

Rapid ionic current phenotyping (RICP) identifies mechanistic underpinnings of iPSC-CM AP heterogeneity.

As a renewable, easily accessible, human-derived in vitro model, human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) are a promising tool for studying arrhythmia-related factors, including cardiotoxicity and congenital proarrhythmia risks. An oft-mentioned limitation of iPSC-CMs is the abundant cell-to-cell variability in recordings of their electrical activity. Here, we develop a new method, rapid ionic current phenotyping (RICP), that utilizes a short (10 s) voltage clamp protocol to quantify cell-to-cell heterogeneity in key ionic currents. We correlate these ionic current dynamics to action potential recordings from the same cells and produce mechanistic insights into cellular heterogeneity. We present evidence that the L-type calcium current is the main determinant of upstroke velocity, rapid delayed rectifier K+ current is the main determinant of the maximal diastolic potential, and an outward current in the excitable range of slow delayed rectifier K+ is the main determinant of action potential duration. We measure an unidentified outward current in several cells at 6 mV that is not recapitulated by iPSC-CM mathematical models but contributes to determining action potential duration. In this way, our study both quantifies cell-to-cell variability in membrane potential and ionic currents, and demonstrates how the ionic current variability gives rise to action potential heterogeneity. Based on these results, we argue that iPSC-CM heterogeneity should not be viewed simply as a problem to be solved but as a model system to understand the mechanistic underpinnings of cellular variability.

Leak current, even with gigaohm seals, can cause misinterpretation of stem cell-derived cardiomyocyte action potential recordings.

AIMS: Human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have become an essential tool to study arrhythmia mechanisms. Much of the foundational work on these cells, as well as the computational models built from the resultant data, has overlooked the contribution of seal-leak current on the immature and heterogeneous phenotype that has come to define these cells. The aim of this study is to understand the effect of seal-leak current on recordings of action potential (AP) morphology. METHODS AND RESULTS: Action potentials were recorded in human iPSC-CMs using patch clamp and simulated using previously published mathematical models. Our in silico and in vitro studies demonstrate how seal-leak current depolarizes APs, substantially affecting their morphology, even with seal resistances (Rseal) above 1 GΩ. We show that compensation of this leak current is difficult due to challenges with obtaining accurate measures of Rseal during an experiment. Using simulation, we show that Rseal measures (i) change during an experiment, invalidating the use of pre-rupture values, and (ii) are polluted by the presence of transmembrane currents at every voltage. Finally, we posit that the background sodium current in baseline iPSC-CM models imitates the effects of seal-leak current and is increased to a level that masks the effects of seal-leak current on iPSC-CMs. CONCLUSION: Based on these findings, we make recommendations to improve iPSC-CM AP data acquisition, interpretation, and model-building. Taking these recommendations into account will improve our understanding of iPSC-CM physiology and the descriptive ability of models built from such data.

Association between substance-induced psychosis and suicide attempt: A Danish nation-wide register-based study.

BACKGROUND AND AIMS: Substance-induced psychosis has previously been linked to an excess risk of suicide; however, the association between substance-induced psychosis and suicide attempt has hitherto not been investigated. We investigated whether substance-induced psychosis was associated with a higher risk of subsequent suicide attempt. DESIGN: Nation-wide prospective register-based cohort study. SETTING: Denmark. PARTICIPANTS: All people living in Denmark aged 13 years or more during 1995 to 2017. MEASUREMENTS: Substance-induced psychosis and suicide attempts were identified through hospital records as ICD-10 codes. FINDINGS: A total of 8900 (78.8% males) individuals were diagnosed with a substance-induced psychosis, and 740 of these had a suicide attempt during follow-up. People with a substance-induced psychosis had a higher risk of a subsequent suicide attempt [hazard ratio (HR) = 13.4, 95% confidence interval (CI) = 12.4-14.4] when compared with the general population. The highest hazard ratios were found for psychosis induced by opioids (HR = 26.4, 95% CI = 18.2-38.2); alcohol (HR = 17.7, 95% CI = 15.2-20.6); sedatives (HR = 17.2, 95% CI = 8.9-33.0); and cocaine (HR = 15.6, 95% CI = 10.7-22.8), while cannabis-induced psychosis was linked to an HR of 8.9 (95% CI = 7.7-10.3). Approximately 15% of patients with substance-induced psychosis had had a suicide attempt within 20 years of their substance-induced psychosis diagnosis. CONCLUSIONS: In Denmark, substance-induced psychosis appears to be strongly associated with subsequent suicide attempt, underscoring the importance of attention and better follow-up for this patient group.

Early Motor Developmental Milestones and Personality Traits in Midlife: A 50-Year Follow-Up Study.

Background The purpose of this study was to investigate if infants' age at attaining motor developmental milestones is associated with the big five personality traits 50 years later. Methods Mothers of 8395 infants from the Copenhagen Perinatal Cohort recorded a total of 12 motor developmental milestones during the first year of their infant's life. Information on at least one milestone was available for 1307 singletons with adult follow-up scores on the NEO-Five-Factor Inventory. The mean age at personality testing was 50.1 years. Results Slower attainment of motor milestones was associated with increased neuroticism and lower conscientiousness in midlife. All 12 motor developmental milestones explained a total of 2.4% of the variance in neuroticism, while they explained 3.2% of the variance in conscientiousness. These results remained significant after adjustment for the included family and perinatal covariates, as well as adult intelligence. Discussion The personality trait of neuroticism is a general risk factor for psychopathology and has in young adulthood been found to be associated with early motor development. However, evidence on associations of motor developmental milestones with other personality traits has been non-existent. These findings suggest that delays in early motor development may not only characterise individuals with later psychopathology, including schizophrenia, but may also be associated with personality traits such as neuroticism and conscientiousness through the life course.