Search

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.

Obesity and type 2 diabetes are strongly associated with adipose tissue dysfunction and impaired adipogenesis. Understanding the molecular underpinnings that control adipogenesis is thus of fundamental importance for the development of novel therapeutics against metabolic disorders. However, translational approaches are hampered as current models do not accurately recapitulate adipogenesis. Here, a scaffold-free versatile 3D adipocyte culture platform with chemically defined conditions is presented in which primary human preadipocytes accurately recapitulate adipogenesis. Following differentiation, multi-omics profiling and functional tests demonstrate that 3D adipocyte cultures feature mature molecular and cellular phenotypes similar to freshly isolated mature adipocytes. Spheroids exhibit physiologically relevant gene expression signatures with 4704 differentially expressed genes compared to conventional 2D cultures (false discovery rate < 0.05), including the concerted expression of factors shaping the adipogenic niche. Furthermore, lipid profiles of >1000 lipid species closely resemble patterns of the corresponding isogenic mature adipocytes in vivo (R2 = 0.97). Integration of multi-omics signatures with analyses of the activity profiles of 503 transcription factors using global promoter motif inference reveals a complex signaling network, involving YAP, Hedgehog, and TGFβ signaling, that links the organotypic microenvironment in 3D culture to the activation and reinforcement of PPARγ and CEBP activity resulting in improved adipogenesis.

Insurance is built on the principle that a group of people contributes to a common pool of money which will be used to cover the costs for individuals who suffer from the insured event. In a competitive market, an insurance company will only be profitable if their pricing reflects the covered risks as good as possible. This thesis investigates the recently proposed Combined Actuarial Neural Network (CANN), a model nesting the traditional Generalised Linear Model (GLM) used in insurance pricing into a Neural Network (NN). The main idea of utilising NNs for insurance pricing is to model interactions between features that the GLM is unable to capture. The CANN model is analysed in a commercial insurance setting with respect to two research questions. The first research question, RQ 1, seeks to answer if the CANN model can outperform the underlying GLM with respect to error metrics and actuarial model evaluation tools. The second research question, RQ 2, seeks to identify existing interpretability methods that can be applied to the CANN model and also showcase how they can be applied. The results for RQ 1 show that CANN models are able to consistently outperform the GLM with respect to chosen model evaluation tools. A literature search is conducted to answer RQ 2, identifying interpretability methods that either are applicable or are possibly applicable to the CANN model. One interpretability method is also proposed in this thesis specifically for the CANN model, using model-fitted averages on two-dimensional segments of the data. Three interpretability methods from the literature search and the one proposed in this thesis are demonstrated, illustrating how these may be applied., Försäkringar bygger på principen att en grupp människor bidrar till en gemensam summa pengar som används för att täcka kostnader för individer som råkar ut för den försäkrade händelsen. I en konkurrensutsatt marknad kommer försäkringsbolag endast vara lönsamma om deras prissättning är så bra som möjligt. Denna uppsats undersöker den nyligen föreslagna Combined Actuarial Neural Network (CANN) modellen som bygger in en Generalised Linear Model (GLM) i ett neuralt nätverk, i en praktiskt och kommersiell försäkringskontext med avseende på två forskningsfrågor. Huvudidén för en CANN modell är att fånga interaktioner mellan variabler, vilket en GLM inte automatiskt kan göra. Forskningsfråga 1 ämnar undersöka huruvida en CANN modell kan prestera bättre än en GLM med avseende på utvalda statistiska prestationsmått och modellutvärderingsverktyg som används av aktuarier. Forskningsfråga 2 ämnar identifiera några tolkningsverktyg som kan appliceras på CANN modellen samt demonstrera hur de kan användas. Resultaten för Forskningsfråga 1 visar att CANN modellen kan prestera bättre än en GLM. En literatursökning genomförs för att svara på Forskningsfråga 2, och ett antal tolkningsverktyg identifieras. Ett tolkningsverktyg föreslås också i denna uppsats specifikt för att tolka CANN modellen. Tre av tolkningsverktygen samt det utvecklade verktyget demonstreras för att visa hur de kan användas för att tolka CANN modellen.

Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event., SCOPUS: ar.j, info:eu-repo/semantics/published

Younger adults with epilepsy have an increased mortality. Some deaths are seizure-related, e.g. sudden unexpected death in epilepsy (SUDEP), while others, e.g. suicide, have multiple causes including adverse effects of the treatment on mood. In this retrospective population-based study of all Danish persons with epilepsy aged 18-49 years during 2007-2009 we evaluated the risk of death from seizures and suicide. SUDEP comprised 82.7% of all seizure-related death. Younger adults with epilepsy had an 8.3-fold increased risk of death from seizure-related causes compared with suicide. This underpins the importance of effective seizure control in preventing premature death.

BACKGROUND: Brugada syndrome (BrS) is associated with mutations in the cardiac sodium channel gene, SCN5A. However, genetic studies of patients with BrS with arrhythmic events have been limited. We sought to compare various clinical, ECG, and electrophysiological parameters according to SCN5A genotype in a large cohort of BrS probands with first arrhythmic event.METHODS: Survey on Arrhythmic Events in Brugada Syndrome is a survey of 10 Western and 4 Asian countries, gathering 678 patients with BrS with first arrhythmic event. Only probands were included, and SCN5A genotype adjudicated. Patients without appropriate genetic data were excluded. Associations of genotype with clinical features were analyzed.RESULTS: The study group comprised 392 probands: 92 (23.5%) SCN5A+(44 pathogenic/likely pathogenic [P/LP] and 48 variants of unknown significance) and 300 (76.5%) SCN5A-. SCN5A missense variants and the patients hosting them were similar regardless of adjudication. A higher proportion of patients with P/LP were pediatric (<16 years) compared with SCN5A- (11.4% versus 3%, P=0.023). The proportion of females was higher among patients with P/LP compared with SCN5A- (18.2% versus 6.3%, P=0.013). P/LP probands were more likely to have a family history of sudden cardiac death compared with SCN5A- (41.9% versus 16.8%, P<0.001). A higher proportion of patients with P/LP were White compared with SCN5A- (87.5% versus 47%, P<0.001). Ethnicity (odds ratio, 5.41 [2.8-11.19], P<0.001) and family history of sudden cardiac death (odds ratio, 2.73 [1.28-5.82], P=0.009) were independent variables associated with P/LP genotype following logistic regression.CONCLUSIONS: The genetic basis of BrS has a complex relationship with gender, ethnicity, and age. Probands hosting a P/LP variant tended to experience their first arrhythmic event at a younger age and to have events triggered by fever compared with patients with SCN5A-. In addition, they were more l

OBJECTIVE: Persons with epilepsy have an increased mortality including a high risk of sudden unexplained death (SUD), also referred to as sudden unexpected death in epilepsy (SUDEP). We aimed to evaluate the risk of SUDEP in comparison to other causes of death and the risk of SUD in persons with and without epilepsy.METHODS: We undertook a retrospective population-based cohort study of all Danish citizens with and without epilepsy aged 1-49 years during 2007-2009. All deaths in the population were evaluated, and all cases of SUD identified. Primary causes of death in persons with epilepsy were evaluated independently by three neurologists and one neuropediatrician, using the unified SUDEP criteria.RESULTS: The three most frequent causes of death in persons with epilepsy were cancer (2.38 per 1000 person-years), SUDEP (1.65 per 1000 person-years), and pneumonia (1.09 per 1000 person-years) compared with cancer (.17 per 1000 person-years), accident-related deaths (.14 per 1000 person-years), and cardiovascular disease (.09 per 1000 person-years) in persons without epilepsy. Considering definite, definite plus, and probable cases, the SUDEP incidence was .27 per 1000 person-years (95% confidence interval [CI] = .11-.64) in children aged 1-17 years and 1.21 per 1000 person-years (95% CI = .96-1.51) in adults aged 18-49 years. Adjusted for age and sex, persons with epilepsy younger than 50 years had a 10.8-fold (95% CI = 9.97-11.64, p < .0001) increased all-cause mortality and a 34.4-fold (95% CI = 23.57-50.28, p < .0001) increased risk of SUD compared with persons without epilepsy. SUDEP accounted for 23.3% of all SUD.SIGNIFICANCE: This nationwide study of all deaths in persons with epilepsy younger than 50 years found a lower SUDEP risk in children compared with adults, and that epilepsy was a major risk factor for SUD in the background population. This underlines the importance of addressing risk factors for SUDEP to prevent premature dea

Background: Remodeling due to myocardial infarction (MI) significantly increases patient arrhythmic risk. Simulations using patient-specific models have shown promise in predicting personalized risk for arrhythmia. However, these are computationally- and time- intensive, hindering translation to clinical practice. Classical machine learning (ML) algorithms (such as K-nearest neighbors, Gaussian support vector machines, and decision trees) as well as neural network techniques, shown to increase prediction accuracy, can be used to predict occurrence of arrhythmia as predicted by simulations based solely on infarct and ventricular geometry. We present an initial combined image-based patient-specific in silico and machine learning methodology to assess risk for dangerous arrhythmia in post-infarct patients. Furthermore, we aim to demonstrate that simulation-supported data augmentation improves prediction models, combining patient data, computational simulation, and advanced statistical modeling, improving overall accuracy for arrhythmia risk assessment. Methods: MRI-based computational models were constructed from 30 patients 5 days post-MI (the “baseline” population). In order to assess the utility biophysical model-supported data augmentation for improving arrhythmia prediction, we augmented the virtual baseline patient population. Each patient ventricular and ischemic geometry in the baseline population was used to create a subfamily of geometric models, resulting in an expanded set of patient models (the “augmented” population). Arrhythmia induction was attempted via programmed stimulation at 17 sites for each virtual patient corresponding to AHA LV segments and simulation outcome, “arrhythmia,” or “no-arrhythmia,” were used as ground truth for subsequent statistical prediction (machine learning, ML) models. For each patient geometric model, we measured and used choice data features: the myocardial volume and ischemic volume, as well as the segment-specific myoca

Lipases comprise one of the major enzyme classes in biotechnology with applications within, e.g., baking, brewing, biocatalysis, and the detergent industry. Understanding the mechanisms of lipase function and regulation is therefore important to facilitate the optimization of their function by protein engineering. Advances in single-molecule studies in model systems have provided deep mechanistic insights on lipase function, such as the existence of functional states, their dependence on regulatory cues, and their correlation to activity. However, it is unclear how these observations translate to enzyme behavior in applied settings. Here, single-molecule tracking of individual Thermomyces lanuginosus lipase (TLL) enzymes in a detergency application system allowed real-time direct observation of spatiotemporal localization, and thus diffusional behavior, of TLL enzymes on a lard substrate. Parallelized imaging of thousands of individual enzymes allowed us to observe directly the existence and quantify the abundance and interconversion kinetics between three diffusional states that we recently provided evidence to correlate with function. We observe redistribution of the enzyme's diffusional pattern at the lipid-water interface as well as variations in binding efficiency in response to surfactants and calcium, demonstrating that detergency effectors can drive the sampling of lipase functional states. Our single-molecule results combined with ensemble activity assays and enzyme surface binding efficiency readouts allowed us to deconvolute how application conditions can significantly alter protein functional dynamics and/or surface binding, both of which underpin enzyme performance. We anticipate that our results will inspire further efforts to decipher and integrate the dynamic nature of lipases, and other enzymes, in the design of new biotechnological solutions.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families.

Objective: Activation of brown adipose tissue is a promising strategy to t reat and prevent obesity and obesity-related disorders. Activation of uncoupling protein 1 (UCP1) leads to u ncoupled respiration and dissipation of stored energy as heat. Induction of UCP1-rich adipocytes in white adipose tis sue, a process known as 'browning', serves as an alternative strategy to increase whole body uncoupling capacity . Here, we aim to assess the association between parathyroid hormone (PTH) receptor expression and UCP1 expression in human adipose tissues and to study PTH effects on human white and brown adipocyte lipolysis and UCP1 expression. Design: A descriptive study of human neck adipose tissue biopsies subst antiated by an interventional study on human neck-derived adipose tissue cell models. Methods: Thermogenic markers and PTH receptor gene expression are assessed in human neck adipose tissue biopsies and are related to individual health records. PTH-init iated lipolysis and thermogenic gene induction are assessed in cultured human white and brown adipocyte cell model s. PTH receptor involvement is investigated by PTH receptor silencing. Results: PTH receptor gene expression correlates with UCP1 gene expression in the deep-neck adipose tissue in humans. In cell models, PTH receptor stimulation increases lipo lysis and stimulates gene transcription of multiple thermogenic markers. Silencing of the PTH receptor attenuates t he effects of PTH indicating a direct PTH effect via this receptor. Conclusion: PTH 1 receptor stimulation by PTH may play a role in human adip ose tissue metabolism by affecting lipolysis and thermogenic capacity.

OBJECTIVE: More knowledge about the development of sudden cardiac death (SCD) in the general population is needed to develop meaningful predictors of SCD. Our aim with this study was to estimate the incidence of SCD in the general population and examine the temporal changes, demographics and clinical characteristics.METHODS: All participants in the Copenhagen City Heart Study were followed from 1993 to 2016. All death certificates, autopsy reports and national registry data were used to identify all cases of SCD.RESULTS: A total of 14 562 subjects were included in this study. There were 8394 deaths with all information available, whereof 1335 were categorised as SCD. The incidence of SCD decreased during the study period by 41% for persons aged 40-90 years, and the standardised incidence rates decreased from 504 per 100 000 person-years (95% CI 447 to 569) to 237 per 100 000 person-years (95% CI 195 to 289). The incidence rate ratio of SCD between men and women ≤75 years was 1.99 (95% CI 1.62 to 2.46). The proportion of SCD of all cardiac deaths decreased during the observation period and decreased with increasing age. Men had more cardiovascular comorbidities (OR 1.34, 95% CI 1.07 to 1.68, p<0. 01), and SCD was the first registered manifestation of cardiac disease in 50% of all cases.CONCLUSION: The incidence of SCD in the general population has declined significantly during the study period but should be further investigated for more recent variations as well as novel risk predictors for persons with low to medium risk of SCD.

BACKGROUND: A large proportion of all deaths are sudden cardiac death (SCD). Reliable estimates of nationwide incidence of SCD, however, are missing.OBJECTIVE: To estimate SCD burden across all ages in Denmark and compare this with other common causes of death.METHODS: All deaths in Denmark (population of 5.5 million) in 2010 were manually reviewed case-by-case. Autopsy reports, death certificates, and information from nationwide health registries were systematically examined to identify all SCD in 2010. According to the level of detail of the available information, all deaths were categorized as either non-SCD, definite SCD, probable SCD, or possible SCD.RESULTS: There were 54,028 deaths in Denmark in 2010, of which 6,867 (13%) were categorized as SCD (591 definite SCD, 1,568 probable SCD, and 4,708 possible SCD). Incidence rate of definite SCD was 11 (95%-CI: 10-12) per 100,000 person-years. Including definite, probable, and possible SCD cases, the highest possible overall SCD incidence rate was 124 (95%-CI: 121-127) per 100,000 person-years. Estimated SCD burden was larger than or similar to all other common causes of death. Of all SCD cases, 49% were not diagnosed with cardiovascular disease prior to death.CONCLUSION: SCD accounted for up to 13% of all deaths. Almost half of all SCD occurred in persons without prior history of cardiovascular disease. Consequently, optimization of risk stratification and prevention of SCD in the general population should be given high priority.

Background Sudden cardiac death (SCD) constitutes a major health problem worldwide. We investigated whether birth weight (BW), small for gestational age (SGA), and large for gestational age are associated with altered risk of SCD among the young (aged 1-36 years). Methods and Results We included all people born in Denmark from 1973 to 2008 utilizing the Danish Medical Birth Register. All SCDs in Denmark in 2000 to 2009 have previously been identified. We defined 5 BW groups, SGA, and large for gestational age as exposure and SCD as the outcome. We estimated the age-specific relative risk of SCD with 95% CI. Additionally, we investigated if SGA and large for gestational age are associated with pathological findings at autopsy. The study population for the BW analyses comprised 2 234 501 people with 389 SCD cases, and the SGA and large for gestational age analyses comprised 1 786 281 people with 193 SCD cases. The relative risk for SCD was 6.69 for people with BW between 1500 and 2499 g (95% CI, 2.38-18.80, P<0.001) and 5.89 for people with BW ≥4500 g (95% CI, 1.81-19.12, P=0.003) at age 5 years. BW 2500 to 3400 g was the reference group. Compared with an appropriate gestational age, the relative risk for SGA was 2.85 (95% CI, 1.35-6.00, P=0.006) at age 10 years. For the autopsied cases, the relative risk of sudden arrhythmic death syndrome at age 5 years was 4.19 for SGA (95% CI, 1.08-16.22, P=0.038). Conclusions We found an association between BW and SCD in the young, with an increased risk among SGA infants. In addition, we found an association between SGA and sudden arrhythmic death syndrome.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased risk of sudden cardiac death.OBJECTIVE: In pigs, we aimed to elucidate changes in ventricular repolarization and electromechanical interaction during obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP). Moreover, we investigated the effect of a reduced repolarization reserve in drug-induced Long-QT (LQT) following INAP induced changes in ventricular repolarization.METHODS: In sedated spontaneously breathing pigs, 75 seconds of INAP were applied by a negative pressure device connected to the endotracheal tube. Ventricular electromechanical coupling was determined by the electromechanical window (EMW) before (Pre-INAP), during (INAP) and after INAP (Post-INAP). Incidence rates of premature ventricular contractions (PVC) were measured respectively. Moreover, a drug-induced LQT was modelled by treating the pigs with the hERG1 blocker dofetilide (DOF).RESULTS: While QT-interval increased during and decreased after INAP (Pre-INAP: 273±5ms; INAP: 281±6ms; Post-INAP: 254±9ms), EMW shortened progressively throughout INAP and Post-INAP periods (Pre-INAP: 81±4ms; Post-INAP: 44±7ms). DOF shortened EMW at baseline. Throughout INAP, EMW decreased in a comparable fashion as prior to DOF (Pre-INAP/+DOF: 61±7ms; Post-INAP/+DOF: 14±9ms), yet resulting in shorter absolute EMW-levels. Short EMW-levels were associated with increased occurrence of PVCs (Pre-INAP 7±2ms vs. Post-INAP 26±6ms; p=0.02), which were potentiated in DOF-pigs (Pre-INAP/+DOF 5±2ms vs. Post-INAP/+DOF 40±8ms; p=0.006). Administration of atenolol prevented Post-INAP EMW-shortening and decreased occurrence of PVCs.CONCLUSION: Transient dissociation of ventricular electromechanical coupling during simulated obstructive respiratory events creates a dynamic ventricular arrhythmogenic substrate, which is sympathetically mediated and aggravated by drug-induced LQT.

Sudden cardiac death (SCD) is a diagnostic challenge in forensic medicine. In a relatively large proportion of the SCDs, the deaths remain unexplained after autopsy. This challenge is likely caused by unknown disease mechanisms. Changes in DNA methylation have been associated with several heart diseases, but the role of DNA methylation in SCD is unknown. In this study, we investigated DNA methylation in two SCD subtypes, sudden unexplained death (SUD) and sudden unexpected death in epilepsy (SUDEP). We assessed DNA methylation of more than 850,000 positions in cardiac tissue from nine SUD and 14 SUDEP cases using the Illumina Infinium MethylationEPIC BeadChip. In total, six differently methylated regions (DMRs) between the SUD and SUDEP cases were identified. The DMRs were located in proximity to or overlapping genes encoding proteins that are a part of the glutathione S-transferase (GST) superfamily. Whole genome sequencing (WGS) showed that the DNA methylation alterations were not caused by genetic changes, while whole transcriptome sequencing (WTS) showed that DNA methylation was associated with expression levels of the GSTT1 gene. In conclusion, our results indicate that cardiac DNA methylation is similar in SUD and SUDEP, but with regional differential methylation in proximity to GST genes.

AIMS: The aim of this study is to compare clinical characteristics and causes of death among witnessed and unwitnessed sudden cardiac death (SCD) cases aged 1-35 years.METHODS AND RESULTS: In this retrospective nationwide study, all deaths in persons aged 1-35 years in Denmark during 2000-09 were included (23.7 million person-years). Using the in-depth descriptive Danish death certificates and Danish nationwide registries, 860 cases of sudden, unexpected death were identified. Through review of autopsy reports and register data, we identified 635 cases of SCD of which 266 (42%) were witnessed and 326 (51%) were unwitnessed. In 43 cases (7%), witnessed status was missing. Clinical characteristics were overall similar between the two groups. We found a male predominance among unwitnessed SCD compared to witnessed SCD (71% and 62%, respectively, P-value 0.012), as well as more psychiatric comorbidity (20% and 13%, respectively, P-value 0.029). Unwitnessed SCD more often occurred during sleep whereas witnessed SCD more often occurred while the individual was awake and relaxed (P-value < 0.001). The autopsy rate among all SCD cases was 70% with no significant difference in autopsy rate between the two groups. Sudden unexplained death, which was the leading autopsy conclusion in both groups, was more frequent among unwitnessed SCD (P-value 0.001).CONCLUSION: Several clinical characteristics and autopsy findings were similar between witnessed and unwitnessed SCD cases. Our data support the inclusion of both witnessed and unwitnessed cases in epidemiological studies of SCD cases aged 1-35 years, although the risk of misclassification is higher among unwitnessed and non-autopsied cases of SCD.

Background - Familial cascade screening is well established in patients with heritable cardiac disease and in cases of Sudden Arrhythmic Death Syndrome (SADS). The clinical benefit of family screening in idiopathic ventricular fibrillation (IVF) is unknown. Methods - Patients with IVF were identified from national and institutional registries. All underwent systematic and comprehensive clinical evaluation to exclude identifiable causes of cardiac arrest with a minimum requirement of ECG, cardiac (echocardiogram and/or MRI) and coronary imaging, exercise ECG and sodium channel blocker (SCB) provocation. Additional investigations including genetic testing were performed at the physician's discretion. First-degree relatives who were assessed with at least a 12-lead ECG were included in the final cohort. Results of additional investigations, performed at the physician's discretion, were also recorded. Results were coded as normal, abnormal or minor findings. Results - We identified 201 first-degree relatives of 96 IVF patients. In addition to a 12 lead ECG, echocardiography was performed in 159 (79%) and ≥ 1 additional investigation in 162 (80%) relatives. An inherited arrhythmia syndrome was diagnosed in 5 (3%) individuals from 4 (4%) families. Two relatives hosted the DPP6 risk haplotype identified in a single proband, one of whom received a primary prevention ICD. In three separate families an asymptomatic parent of the IVF proband developed a type 1 Brugada ECG pattern during SCB provocation. All were managed with lifestyle measures only. The Early Repolarisation ECG pattern (ER) was present in 16% probands and was more common in relatives in those families than those where the proband did not have ER (25% vs. 8%, p=0.04). Conclusions - The yield of family screening in relatives of IVF probands is low when the proband is comprehensively investigated. The significance of J wave syndromes in relatives and the role for systematic SCB provocation are, however, uncert

PURPOSE OF REVIEW: Sports-related sudden cardiac death (Sr-SCD) is a leading natural cause of death in young athletes. To prevent Sr-SCD in athletes, it is important to identify individuals at risk. This review sought to summarize the current knowledge of symptoms prior to Sr-SCD in athletes aged 1-49 years.RECENT FINDINGS: Cardiovascular screening of athletes is a subject of interest. However, the cost of ECG screening in a young population is relatively high compared to potential benefits, and systematic screening of athletes is heavily debated. In the background population, both cardiac and non-specific symptoms are often present prior to SCD. Both cardiac and non-specific symptoms are present in up to 74% prior to Sr-SCD. The main symptoms are syncope, chest pain, palpitations and dizziness. Knowledge of symptoms could potentially be used in combination with non-invasive prediction models to prevent Sr-SCD and treat athletes at risk.

BACKGROUND: Cardiac arrhythmias in horses are diagnosed by auscultation or electrocardiogram (ECG), which results in a low sensitivity for detecting arrhythmias that occur sporadically. Implantable loop recorders (ILRs) are small ECG devices placed subcutaneously, to automatically detect arrhythmias in human patients.OBJECTIVES: To test ILRs ability to detect atrial fibrillation (AF) in horses. Further, we hypothesised that anatomical location of the implant site might influence signal quality. Signal quality was evaluated both during exercise and over time.STUDY DESIGN: Experimental study.METHODS: In five Standardbred mares, eleven ILRs were implanted subcutaneously in up to three different positions (Front: pectoral region, Left-6: sixth left intercostal space, Ventral: xiphoid region) and AF induced. The R and T wave amplitudes were measured in all positions over time during AF. AF burden automatically registered by the ILRs over a 2-month period were compared with selected Holter ECG recordings.RESULTS: All three positions had stable R and T wave amplitudes during the study period and were of sufficient quality to allow AF detection at rest. The position Left-6 showed significantly higher R and T wave amplitudes compared to the other positions. During submaximal exercise only the Left-6 position was able to record ECG signals of diagnostic quality. No position yielded diagnostic signals at maximum exercise due to artefacts.MAIN LIMITATIONS: Few horses and ILRs included and no spontaneous AF episodes were studied.CONCLUSIONS: This preliminary study indicates that ILRs can be used for AF detection in horses, but the anatomical location is important for optimal ECG quality. Despite insufficient quality during exercise, ILRs were suitable for AF detection at rest. Therefore, the ILR may be a valuable diagnostic tool for detecting paroxysmal AF in horses.

Sudden Cardiac Death (SCD) is a leading cause of death among persons in their youth and early middle-age. To prevent SCD it is crucial to identify persons at high-risk of SCD. Knowledge of symptoms and medical contact prior to SCD could potentially aid in the identification of high-risk persons in the general population who would benefit from further investigation. This review aims to summarize the current knowledge of symptoms and healthcare contact preceding SCD in persons aged 1-49 years, and to explore how the symptoms differ according to SCD cause and age of the deceased. There was a high frequency of both cardiac and non-specific symptoms prior to SCD. Additionally, many SCD victims contacted the healthcare system prior to death on the basis of their symptoms and only a few were diagnosed with cardiovascular disease. This information underlines that young persons reporting potential cardiac symptoms should also be thoroughly examined. Furthermore, such symptoms could be used in combination with other easily accessible information in non-invasive prediction models aiming at identifying persons at high risk of SCD that would benefit from further investigation and possibly treatment.

AIMS: Persons with diabetes mellitus have increased all-cause mortality compared with the general population. Nationwide studies on causes of death and mortality among young persons with diabetes mellitus are sparse. The aim of this study was to examine all-cause and cause-specific mortality in children and young adults with and without diabetes.METHODS AND RESULTS: The study population consisted of all persons in Denmark aged 1-35 years in 2000-2009 and 36-49 years in 2007-2009, which equals 27.1 million person-years. All 14,294 deaths in the 10-year period were included and cause of death was established based on information from autopsy reports and death certificates. The Danish Register of Medicinal Product Statistics was used to identify persons with type 1 diabetes and type 2 diabetes. During the study period, which included 153,070 diabetic person-years, 669 (5% of all deceased) persons with diabetes mellitus died, of which 70% had type 1 and 30% had type 2 diabetes. Persons with diabetes mellitus had an all-cause mortality rate (ASMR) of 327 per 100,000 person-years compared with 74 per 100,000 person-years among persons without diabetes mellitus (ASMR ratio 4, p < 0.001). The leading cause of death among persons with diabetes mellitus was cardiac diseases ( n = 230, 34%) with an ASMR ratio of 8 (95% confidence interval 6-9).CONCLUSIONS: Young persons with diabetes mellitus had four-fold increased all-cause mortality and eight-fold increased cardiovascular mortality compared with persons without diabetes mellitus. Focus on cardiovascular risk monitoring and management among young persons with diabetes mellitus is warranted to prevent premature death in diabetes mellitus.