Sudden arrhythmic death and cardiomyopathy are important causes of sudden cardiac death in the UK: results from a national coronial autopsy database.

AIMS: Sudden cardiac death (SCD) is defined as natural unexpected death in witnessed cases occurring < 1 h and in unwitnessed cases as last seen alive < 24 h. SCD due to ischaemic heart disease (IHD) is frequent in older age groups; in younger people genetic cardiac causes, including channelopathies and cardiomyopathies, are more frequent. This study aimed to present the causes of SCD from a large specialist pathology registry. METHODS AND RESULTS: Cases were examined macroscopically and microscopically by two expert cardiac pathologists. The hearts from 7214 SCD cases were examined between 1994 and 2021. Sudden arrhythmic death syndrome (SADS), a morphologically normal heart, which can be underlaid by cardiac channelopathies, is most common (3821, 53%) followed by the cardiomyopathies (1558, 22%), then IHD (670, 9%), valve disease (225, 3%), congenital heart disease (213, 3%) and myocarditis/sarcoidosis (206, 3%). Hypertensive heart disease (185, 3%), aortic disease (129, 2%), vascular disease (97, 1%) and conduction disease (40, 1%) occur in smaller proportions. DISCUSSION: To our knowledge, this is the largest SCD cohort with autopsy findings ever reported from one country. SADS and cardiomyopathies predominate. This study highlights the importance of the autopsy in SCD, which is a significant public health concern in all age groups. Knowing the true incidence in our population will improve risk stratification and develop preventative strategies for family members. There is now a national pilot study integrating molecular autopsy and family screening into the assessment of SCD victims.

Dug: a semantic search engine leveraging peer-reviewed knowledge to query biomedical data repositories.

MOTIVATION: As the number of public data resources continues to proliferate, identifying relevant datasets across heterogenous repositories is becoming critical to answering scientific questions. To help researchers navigate this data landscape, we developed Dug: a semantic search tool for biomedical datasets utilizing evidence-based relationships from curated knowledge graphs to find relevant datasets and explain why those results are returned. RESULTS: Developed through the National Heart, Lung and Blood Institute's (NHLBI) BioData Catalyst ecosystem, Dug has indexed more than 15 911 study variables from public datasets. On a manually curated search dataset, Dug's total recall (total relevant results/total results) of 0.79 outperformed default Elasticsearch's total recall of 0.76. When using synonyms or related concepts as search queries, Dug (0.36) far outperformed Elasticsearch (0.14) in terms of total recall with no significant loss in the precision of its top results. AVAILABILITY AND IMPLEMENTATION: Dug is freely available at https://github.com/helxplatform/dug. An example Dug deployment is also available for use at https://search.biodatacatalyst.renci.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A novel approach for exposing and sharing clinical data: the Translator Integrated Clinical and Environmental Exposures Service.

OBJECTIVE: This study aimed to develop a novel, regulatory-compliant approach for openly exposing integrated clinical and environmental exposures data: the Integrated Clinical and Environmental Exposures Service (ICEES). MATERIALS AND METHODS: The driving clinical use case for research and development of ICEES was asthma, which is a common disease influenced by hundreds of genes and a plethora of environmental exposures, including exposures to airborne pollutants. We developed a pipeline for integrating clinical data on patients with asthma-like conditions with data on environmental exposures derived from multiple public data sources. The data were integrated at the patient and visit level and used to create de-identified, binned, "integrated feature tables," which were then placed behind an OpenAPI. RESULTS: Our preliminary evaluation results demonstrate a relationship between exposure to high levels of particulate matter ≤2.5 µm in diameter (PM2.5) and the frequency of emergency department or inpatient visits for respiratory issues. For example, 16.73% of patients with average daily exposure to PM2.5 >9.62 µg/m3 experienced 2 or more emergency department or inpatient visits for respiratory issues in year 2010 compared with 7.93% of patients with lower exposures (n = 23 093). DISCUSSION: The results validated our overall approach for openly exposing and sharing integrated clinical and environmental exposures data. We plan to iteratively refine and expand ICEES by including additional years of data, feature variables, and disease cohorts. CONCLUSIONS: We believe that ICEES will serve as a regulatory-compliant model and approach for promoting open access to and sharing of integrated clinical and environmental exposures data.

Influenza Virus Infectivity Is Retained in Aerosols and Droplets Independent of Relative Humidity.

Pandemic and seasonal influenza viruses can be transmitted through aerosols and droplets, in which viruses must remain stable and infectious across a wide range of environmental conditions. Using humidity-controlled chambers, we studied the impact of relative humidity on the stability of 2009 pandemic influenza A(H1N1) virus in suspended aerosols and stationary droplets. Contrary to the prevailing paradigm that humidity modulates the stability of respiratory viruses in aerosols, we found that viruses supplemented with material from the apical surface of differentiated primary human airway epithelial cells remained equally infectious for 1 hour at all relative humidities tested. This sustained infectivity was observed in both fine aerosols and stationary droplets. Our data suggest, for the first time, that influenza viruses remain highly stable and infectious in aerosols across a wide range of relative humidities. These results have significant implications for understanding the mechanisms of transmission of influenza and its seasonality.

Patients electing medical vs surgical treatment: emotional domain of the Rhinosinusitis Disability Index associates with treatment selection.

BACKGROUND: The Rhinosinusitis Disability Index (RSDI) consists of multiple subdomains shown to be useful in studying chronic rhinosinusitis (CRS). The objective of this study was to determine if RSDI subdomain scores are associated with selection of treatment modality (endoscopic sinus surgery [ESS] or continued medical management [CMM]) in subjects with CRS. METHODS: Patients with CRS were prospectively enrolled into a multi-institutional cohort study. Following an initial period of medical management, patients elected to undergo treatment with either ESS or CMM. Baseline RSDI total and subdomain scores were compared between patients electing different treatment modalities. RESULTS: A total of 684 subjects were enrolled with 122 (17.8%) electing CMM and 562 (82.2%) electing ESS. When compared to patients undergoing CMM, patients electing ESS exhibited significantly higher mean baseline RSDI total scores (mean ± standard deviation [SD]: 48.1 ± 24.9 vs 40.1 ± 24.1; p = 0.001) and subdomain scores (emotional: 13.2 ± 9.1 vs 10.4 ± 8.3; p = 0.001; functional: 15.3 ± 8.9 vs 12.6 ± 8.4; p = 0.002; and physical: 19.6 ± 9.3 vs 17.1 ± 9.6; p = 0.007). Emotional subdomain scores were found to be the most associated with choice of treatment modality. CONCLUSION: Patients with CRS electing ESS had worse baseline RSDI total and subdomain scores compared to those electing CMM. Although both rhinologic and nonrhinologic symptoms contributed to the selection of treatment modality, emotional symptoms appeared to exhibit the greatest influence on patient-centered treatment decisions.

The importance of specialist cardiac histopathological examination in the investigation of young sudden cardiac deaths.

AIMS: Post-mortem examination of the heart in young sudden cardiac death (SCD) is vital as the underlying aetiology is often an inherited cardiac disease with implications for surviving relatives. Our aim is to demonstrate the improvement in diagnostic quality offered by a specialist cardiac pathology service established to investigate SCD with fast-track reporting on hearts sent by pathologists in cases of SCD. METHODS AND RESULTS: A tertiary centre prospective observational study was conducted. Detailed histopathological examination was performed in a tertiary centre specialized in the investigation of cardiac pathology in SCD. Hearts from 720 consecutive cases of SCD referred by coroners and pathologists from 2007 to 2009 were included. A comparison was drawn with diagnoses from referring pathologists. Most SCDs occurred in males (66%), with the median age being 32 years. The majority (57%) of deaths occurred at home. The main diagnoses were a morphologically normal heart (n = 321; 45%), cardiomyopathy (n = 207, 29%), and coronary artery pathology (n = 71; 10%). In 158 out of a sample of 200 consecutive cases, a cardiac examination was also performed by the referring pathologist with a disparity in diagnosis in 41% of the cases (κ = 0.48). Referring pathologists were more inclined to diagnose cardiomyopathy than normality with only 50 out of 80 (63%) normal hearts being described correctly. CONCLUSION: Expert cardiac pathology improves the accuracy of coronial post-mortem diagnoses in young SCD. This is important as the majority of cases may be due to inherited cardiac diseases and the autopsy guides the appropriate cardiological evaluation of blood relatives for their risk of sudden death.

The magnitude of sudden cardiac death in the young: a death certificate-based review in England and Wales.

AIMS: In the UK, the true impact of cardiac and sudden death in the young (

Fibrin as a delivery vehicle for active macrophage activator lipoprotein-2 peptide: in vitro studies.

Fibrin sealants have been used in hemostasis and tissue sealing for over 25 years and recent studies have shown them to be an ideal delivery vehicle for cells and bioactive substances. We examined the use of fibrin as a delivery vehicle for the macrophage activator lipoprotein peptide (MALP)-2. MALP-2, secreted by mycoplasma, plays an important role in an early influx of leukocytes and infiltration by monocytes and their subsequent activation into macrophages as detected by their secretion of cytokines and chemoattractants. We first showed that MALP-2 activated several monocytic cell lines by increasing the expression of cytokines and chemoattractants in these cells. Furthermore, using a reverse transcription-polymerase chain reaction approach, we found that MALP-2 affected the gene expression of its own receptors: TLR2 and TLR4 in various cell types including fibroblasts, keratinocytes, and endothelial cells. Furthermore, the conditioned medium, containing secreted cytokines and chemoattractants, collected from monocytes treated with MALP-2 enhanced fibroblast migration using a standard wound culture assay. Next, we examined MALP-2's effect on the human monocyte cell line when it is mixed with fibrin. Monocytes seeded on three-dimensional fibrin containing MALP-2 secreted more cytokines such as interleukin-6, tumor necrosis factor-alpha, and chemoattractants such as macrophage inflammatory protein 1 alpha and monocyte chemoattractant protein 1 when compared with monocytes seeded on three-dimensional fibrin in the absence of MALP-2. This study supports the use of fibrin to deliver MALP-2, and possibly other peptides, in an active form that might enhance wound healing.

Human U937 monocyte behavior and protein expression on various formulations of three-dimensional fibrin clots.

Fibrin sealant products such as Tisseel (Baxter Healthcare Corporation) are used in hemostasis and tissue sealing. Tisseel consists of two components, a fibrinogen-containing component and thrombin, which when mixed together form a fibrin clot. There is an interest in delivering monocytes to the wound because they are known to play an important role in the wound-healing process. Therefore, we were interested in finding the best fibrin formulation for delivering monocytes by examining monocyte behavior on 3D-fibrin clots. Using standard adhesion and proliferation assays, we found that monocytes differentially adhere, proliferate, and cluster on and within the 3D-fibrin clots depending on the final fibrinogen and thrombin concentration. Moreover, using a Boyden chamber assay, we found that monocytes migrated through the 3D-fibrin clots in 1-2 days. Furthermore, the protein expression in monocytes seeded on 3D-fibrin clots for various time points varied depending on the fibrinogen and thrombin concentrations in the final 3D-fibrin clots. The above data suggest that various formulations of fibrin sealant Tisseel present a good surface for monocyte adhesion, proliferation and migration in vitro and potentially during the wound-healing process in vivo. Moreover, because the monocytes proliferated well and clustered in the 3D fibrin, Tisseel could be a good delivery vehicle for delivering monocytes into chronic wounds to overcome a healing deficiency.

Behavior of human dermal fibroblasts in three-dimensional fibrin clots: dependence on fibrinogen and thrombin concentration.

Fibrin sealant products are used in hemostasis and tissue sealing, and potentially as a cell delivery vehicle. In this study, fibrin sealant was evaluated as a delivery vehicle for human dermal fibroblasts. Fibroblast proliferation and migration were assessed in various dilutions of fibrin sealant by changing the fibrinogen and thrombin concentration. Fibroblasts proliferated well within three-dimensional (3-D) fibrin clots consisting of fibrinogen (5-17 mg/mL) and thrombin (1-167 U/mL). These fibroblasts also retained good morphology and growth characteristics after migrating out of the 3-D fibrin clots. Furthermore, using Western blot and fluorescence-activated cell-sorting analysis, we found that the expression of growth factors and interleukins in the entire fibroblast-fibrin construct was dependent on the fibrin sealant formulation. For example, in a formulation in which fibroblasts showed modest proliferation and migration, interleukin 8 was secreted to a lesser extent than in a formulation that supported robust proliferation and migration. To our knowledge, this is the first time that it has been shown that modifying the concentration of fibrinogen and thrombin affects fibroblast behavior within formed 3-D fibrin clots. In addition, some of these formulations present an ideal delivery vehicle for fibroblasts that could be used for the treatment of chronic wounds.

Delavirdine malabsorption in HIV-infected subjects with spontaneous gastric hypoacidity.

To determine the impact of gastric hypoacidity and acidic beverages on delavirdine mesylate pharmacokinetics in HIV-infected subjects, matched subjects with (n = 11) and without (n = 10) gastric hypoacidity received delavirdine 400 mg tid with either water or an acidic beverage (usually orange juice). The pharmacokinetics of delavirdine and its N-desalkyl metabolite were determined over 8 hours after 14 days of each treatment. Gastric pH was measured at baseline and during each pharmacokinetic evaluation. Delavirdine exposure (Cmax, AUC0-->8 h, and Cmin) was approximately 50% lower and the extent of delavirdine metabolism was higher in subjects with gastric hypoacidity. Orange juice produced a lower mean gastric pH compared to water and increased delavirdine absorption by 50% to 70% in subjects with gastric hypoacidity. However, orange juice had a marginal impact on delavirdine exposure in subjects without gastric hypoacidity. HIV-infected subjects with gastric hypoacidity significantly malabsorb delavirdine. Delavirdine administration with acidic beverages improves, but dose not normalize, absorption in these subjects.

Effect of Food on the Steady-State Pharmacokinetics of Delavirdine in Patients with HIV Infection.

OBJECTIVE: In a prior single-dose study that examined the effect of food on delavirdine pharmacokinetics in healthy volunteers, the absorption of delavirdine mesylate was delayed and the area under the curve was reduced by 26% in the presence of food. Since the complex, nonlinear pharmacokinetics of delavirdine do not permit a simple extrapolation of the results of a single-dose study to steady state, the present multiple-dose study was performed. PATIENTS AND STUDY DESIGN: Thirteen stable patients with HIV-1 infection (two females, 11 males; CD4 count range 124-588 cells/mm(3)) completed a randomised, crossover study in which subjects received two 14-day treatments with delavirdine mesylate 400mg every 8 hours. In treatment A, all delavirdine doses were administered on an empty stomach and in treatment B were taken with food. A pharmacokinetic evaluation was performed on day 14 of each treatment period. SETTING: An ambulatory AIDS research centre in an academic medical centre. INTERVENTIONS: Administration of delavirdine with and without food. MAIN OUTCOME MEASURES: Pharmacokinetic parameters for delavirdine. RESULTS: The maximum concentration (C(max)) [+/- standard deviation] in treatment A was 29.6 +/- 13.6muM and in treatment B it was 23.0 +/- 8.61muM (p = 0.037). The minimum concentrations (C(min)) were 9.45 +/- 6.7muM and 11.2 +/- 9.2muM, respectively (p > 0.05). The oral clearances (CL(oral)) were 17.8 +/- 41.6 L/h (treatment A) and 18.5 +/- 39.0 L/h (treatment B) [p > 0.05]. Similar patterns were observed for N-dealkylated delavirdine with a significant difference only in C(max) (4.13 vs 3.47muM [p = 0.022], treatment A vs B). CONCLUSIONS: These findings indicated that, in contrast to the increased CL(oral) noted in a prior single-dose study, food did not have a significant effect at steady state on the area under the plasma concentration-time curve or C(min). Although C(max) was significantly lower when the drug was taken taken with food, the clinical relevance of this parameter as compared with the trough concentration is unclear since the current focus for antiretrovirals is on maintaining trough concentrations in excess of in vitro inhibitory concentrations.