Bayesian Gene Set Benchmark Dose Estimation for "omic" responses.

Motivation: Estimating a toxic reference point using tools like the benchmark dose (BMD) is a critical step in setting policy to regulate pollution and ensure safe environments. Toxicity can be measured for different endpoints, including changes in gene expression and histopathology for various tissues, and is typically explored one gene or tissue at a time in a univariate setting that ignores correlation. In this work, we develop a multivariate estimation procedure to estimate the BMD for specified gene sets.

Data science shows that entropy correlates with accelerated zeolite crystallization in Monte Carlo simulations.

We have performed a data science study of Monte Carlo (MC) simulation trajectories to understand factors that can accelerate the formation of zeolite nanoporous crystals, a process that can take days or even weeks. In previous work, MC simulations predicted and experiments confirmed that using a secondary organic structure-directing agent (OSDA) accelerates the crystallization of all-silica LTA zeolite, with experiments finding a three-fold speedup [Bores et al., Phys.

Adjudicating Registry Data: Benefits and Pitfalls-The ACTION Experience.

The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry collects data and adjudicates adverse events on pediatric patients receiving mechanical circulatory support at participating centers. To date, the registry includes over 1500 patients from 48 centers. Data collected has been used for research publications, quality improvement projects, and the regulatory support of several ventricular assist devices.

Bioinformatic Workflows for Deriving Transcriptomic Points of Departure: Current status, Data Gaps, and Research Priorities.

There is a pressing need to increase the efficiency and reliability of toxicological safety assessment for protecting human health and the environment. While conventional toxicology tests rely on measuring apical changes in vertebrate models, there is increasing interest in the use of molecular information from animal and in vitro studies to inform safety assessment. One promising and pragmatic application of molecular information involves the derivation of transcriptomic points of departure (tPODs).

A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling.

Current methods for cancer risk assessment are resource-intensive and not feasible for most of the thousands of untested chemicals. In earlier studies, we developed a new approach methodology (NAM) to identify liver tumorigens using gene expression biomarkers and associated tumorigenic activation levels (TALs) after short-term exposures in rats. The biomarkers are used to predict the six most common rodent liver cancer molecular initiating events.

Longitudinal Changes in Estimated Glomerular Filtration Rate Following Repeat Heart Transplant in Children and Young Adults.

Background: Chronic kidney disease (CKD) is common after heart transplantation (HT). There are scarce studies looking at longitudinal changes in estimated glomerular filtration rate (eGFR) after repeat HT (RT) and risk factors for the presence of CKD3 post-RT.

Methods: First-time HT recipients (FT) were matched with RT, based on age at transplant, sex, race, and transplant era.

ACTION-ARC Pediatric and Adult Congenital Heart Disease Ventricular Assist Device Adverse Event Definitions-2023.

Adverse events (AEs) experienced by children and adults with congenital heart disease (CHD) on ventricular assist devices (VADs) are sometimes unique to these populations. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and the Academic Research Consortium (ARC) aimed to harmonize definitions of pediatric and CHD AEs for use in clinical trials, registries, and regulatory evaluation. Data from the ACTION registry and adjudication committee were used to adapt general mechanical circulatory support ARC definitions.

Efficacy and safety of insomnia treatment with lemborexant in older adults: analyses from three clinical trials.

Background: Insomnia is more common as people age. Several common hypnotics used to treat insomnia often do not adequately alleviate sleep issues in older adults and may be associated with negative residual effects such as an increased risk of falls, cognitive impairment, automobile accidents, and lack of response to auditory stimuli. The objective of these analyses of three clinical studies was to investigate the efficacy and safety of the dual orexin-receptor antagonist lemborexant (LEM) in older adults.

Unlocking the Potential of Clustering and Classification Approaches: Navigating Supervised and Unsupervised Chemical Similarity.

Background: The field of toxicology has witnessed substantial advancements in recent years, particularly with the adoption of new approach methodologies (NAMs) to understand and predict chemical toxicity. Class-based methods such as clustering and classification are key to NAMs development and application, aiding the understanding of hazard and risk concerns associated with groups of chemicals without additional laboratory work. Advances in computational chemistry, data generation and availability, and machine learning algorithms represent important opportunities for continued improvement of these techniques to optimize their utility for specific regulatory and research purposes.

Correction: Pannala et al. High-Throughput Transcriptomics Differentiates Toxic versus Non-Toxic Chemical Exposures Using a Rat Liver Model. 2023, , 17425.

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Subjective Cognitive Decline Plus and Longitudinal Assessment and Risk for Cognitive Impairment.

Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting.

Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults.

Waitlist Outcomes for Pediatric Heart Transplantation in the Current Era: An Analysis of the Pediatric Heart Transplant Society Database.

Background: Waitlist mortality (WM) remains elevated in pediatric heart transplantation. Allocation policy is a potential tool to help improve WM. This study aims to identify patients at highest risk for WM to potentially inform future allocation policy changes.

Exposure to PFAS chemicals induces sex-dependent alterations in key rate-limiting steps of lipid metabolism in liver steatosis.

Toxicants with the potential to bioaccumulate in humans and animals have long been a cause for concern, particularly due to their association with multiple diseases and organ injuries. Per- and polyfluoro alkyl substances (PFAS) and polycyclic aromatic hydrocarbons (PAH) are two such classes of chemicals that bioaccumulate and have been associated with steatosis in the liver. Although PFAS and PAH are classified as chemicals of concern, their molecular mechanisms of toxicity remain to be explored in detail.

Metabolomics Simultaneously Derives Benchmark Dose Estimates and Discovers Metabolic Biotransformations in a Rat Bioassay.

Benchmark dose (BMD) modeling estimates the dose of a chemical that causes a perturbation from baseline. Transcriptional BMDs have been shown to be relatively consistent with apical end point BMDs, opening the door to using molecular BMDs to derive human health-based guidance values for chemical exposure. Metabolomics measures the responses of small-molecule endogenous metabolites to chemical exposure, complementing transcriptomics by characterizing downstream molecular phenotypes that are more closely associated with apical end points.

Recent Advances towards the Understanding of Secondary Acute Myeloid Leukemia Progression.

Secondary acute myeloid leukemia (sAML) is a heterogeneous malignant hematopoietic disease that arises either from an antecedent hematologic disorder (AHD) including myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), aplastic anemia (AA), or as a result of exposure to genotoxic chemotherapeutic agents or radiotherapy (therapy related AML, tAML). sAML is diagnosed when the number of blasts is ≥20% in the bone marrow or peripheral blood, and it is characterized by poor prognosis, resistance to therapy and low overall survival rate. With the recent advances in next generation sequencing technologies, our understanding of the molecular events associated with sAML evolution has significantly increased and opened new perspectives for the development of novel therapies.

Impact of prolonged ischemic time on pediatric heart transplantation outcomes: Improved outcomes in the most recent era.

Background: Impacts of ischemic time (IT) on pediatric heart transplant outcomes are multifactorial. We aimed to analyze the effect of prolonged IT on graft loss after pediatric heart transplantation. We hypothesized that graft survival with prolonged IT has improved across eras.

Anti-spike antibody durability after SARS-CoV-2 vaccination in adolescent solid organ transplant recipients.

Background: Adolescent solid organ transplant recipients (aSOTRs) who received three doses of the COVID-19 mRNA vaccine experience high seroconversion rates and antibody persistence for up to 3 months. Long-term antibody durability beyond this timeframe following three doses of the SARS-CoV-2 mRNA vaccine remains unknown. We describe antibody responses 6 months following the third vaccine dose (D3) of the BNT162b2 mRNA vaccination among aSOTRs.

Toxicogenomics Approaches to Address Toxicity and Carcinogenicity in the Liver.

Toxicogenomic technologies query the genome, transcriptome, proteome, and the epigenome in a variety of toxicological conditions. Due to practical considerations related to the dynamic range of the assays, sensitivity, cost, and technological limitations, transcriptomic approaches are predominantly used in toxicogenomics. Toxicogenomics is being used to understand the mechanisms of toxicity and carcinogenicity, evaluate the translational relevance of toxicological responses from in vivo and in vitro models, and identify predictive biomarkers of disease and exposure.

Research Gaps in Pediatric Heart Failure: Defining the Gaps and Then Closing Them Over the Next Decade.

Given the numerous opportunities and the wide knowledge gaps in pediatric heart failure, an international group of pediatric heart failure experts with diverse backgrounds were invited and tasked with identifying research gaps in each pediatric heart failure domain that scientists and funding agencies need to focus on over the next decade.

Percutaneous Stenting of a Stenotic Berlin Heart Outflow Cannula Graft in a 2-Year-Old Child.

Left ventricular assist device (LVAD) outflow obstruction is a rare complication of long-term LVAD support. We present the first case of successful percutaneous stent implantation in a pediatric patient with LVAD outflow obstruction.