Toxicologic Pathology Forum: Opinion on Digital Primary Read and Peer Review-Are We There Yet?

Recent trends in toxicological pathology include implementation of digital platforms that have gained rapid momentum in the field. Are we ready to fully implement this new modality? This opinion piece provides some practical perspectives on digital pathology such as its cost limitations, relative time requirements, and a few technical issues, some of which are encountered for specific lesions, that warrant caution. Although the potential for digital pathology assessment with whole slide images has made great strides, we are of the opinion that it is not yet ready for complete replacement of glass slides in toxicologic pathology safety assessments.

The interplay of sex and genotype in disease associations: a comprehensive network analysis in the UK Biobank.

Background: Disease comorbidities and longer-term complications, arising from biologically related associations across phenotypes, can lead to increased risk of severe health outcomes. Given that many diseases exhibit sex-specific differences in their genetics, our objective was to determine whether genotype-by-sex (GxS) interactions similarly influence cross-phenotype associations. Through comparison of sex-stratified disease-disease networks (DDNs)-where nodes represent diseases and edges represent their relationships-we investigate sex differences in patterns of polygenicity and pleiotropy between diseases.

Assessing psychosocial risk factors in children with Sickle Cell Disease.

Background: Individuals with Sickle Cell Disease (SCD) are a minoritized and marginalized community that have disparate health outcomes as a result of systemic racism and disease-related stigma. The purpose of this study was to determine the psychosocial risk factors for families caring for children with SCD at a pediatric SCD center through use of the Psychosocial Assessment Tool (PAT), a validated caregiver-report screener.

Methods: The PAT was administered annually during routine clinical visits and scored by the SCD Social Worker to provide tailored resources to families.

Enhancing prehospital decision-making: exploring user needs and design considerations for clinical decision support systems.

Background: In prehospital emergency care, providers face significant challenges in making informed decisions due to factors such as limited cognitive support, high-stress environments, and lack of experience with certain patient conditions. Effective Clinical Decision Support Systems (CDSS) have great potential to alleviate these challenges. However, such systems have not yet been widely adopted in real-world practice and have been found to cause workflow disruptions and usability issues.

Interferon-α promotes HLA-B-restricted presentation of conventional and alternative antigens in human pancreatic β-cells.

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis-splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8 T cells.

Toward Sustainable Polydienes.

The sustainable management of polydiene waste represents a formidable challenge in the realm of polymer chemistry, given the extensive industrial utilization of polydienes due to their superior elastomeric properties. This comprehensive Perspective addresses the multifaceted obstacles hindering efficient recycling of polydienes, encompassing environmental concerns, technical limitations, and economic disincentives. We systematically dissect the influence of polydienes' chemical structures on their recyclability, tracing the evolution of polydiene utilization and disposal practices while assessing the current landscape of waste management strategies.

Association of Immune-Related Adverse Events With Efficacy in Consolidation Nivolumab Plus Ipilimumab or Nivolumab Alone After Chemoradiation in Patients With Unresectable Stage III Nonsmall Cell Lung Cancer: An Exploratory Analysis From the Big 10 Cancer Research Consortium Study BTCRC LUN 16-081.

Background: Immunotherapy has been widely incorporated into the treatment of patients with non-small-cell lung cancer (NSCLC). Many of these patients will experience immune-related adverse events (irAEs) without decreased efficacy. We report a retrospective analysis of the association between irAEs and efficacy outcomes from the BTCRC LUN 16-081 randomized phase 2 trial of consolidation nivolumab (N) plus ipilimumab (IPI) vs N alone following chemoradiotherapy in unresectable Stage IIIA/IIIB NSCLC.

Muscarinic cannabinoid suppression of excitation, a novel form of coincidence detection.

Δ-tetrahydrocannabinol (THC), the chief psychoactive ingredient of cannabis, acts in the brain primarily via cannabinoid CB1 receptors. These receptors are implicated in several forms of synaptic plasticity - depolarization-induced suppression of excitation (DSE), metabotropic suppression of excitation (MSE), long term depression (LTD) and activation-dependent desensitization. Cultured autaptic hippocampal neurons express all of these, illustrating the rich functional and temporal heterogeneity of CB1 at a single set of synapses.

Combining steric exclusion with anion exchange - development of a universal and scalable adeno-associated virus downstream process.

Adeno-associated viruses (AAV) are among the leading vectors for in vivo gene therapy. The purification of AAV remains a bottleneck as it typically requires multiple individual process steps, often resulting in product loss and high costs. Current downstream processes are usually serotype-specific and rely primarily on expensive affinity resins.

Creating a collaborative culture of learning within a network of community mental health early psychosis programs in Texas.

Learning Health Systems (LHSs) promise meaningful health care improvement through the ongoing use of data, including the lived experience of diverse constituents, such as people participating in and providing services. Most LHSs operate within a specific healthcare system, typically hospital-based, under a common electronic health record (EHR) and management structure. The Early Psychosis Intervention Network in Texas (EPINET-TX) is a novel case study of a developing LHS across 16 independent community mental health clinics operating state-funded coordinated specialty care (CSC) programs for early psychosis.

Influence of positive consequences on subsequent incentive ratings and drinking quantity.

Alcohol use is prevalent among young adults, with significant rates of binge drinking and frequent reports of both positive and negative consequences. The current study investigates how positive drinking consequences influence subsequent incentives ratings and drinking behavior. Utilizing mobile daily diary data from 104 young adults over two weeks (event N = 507), we assessed the impact of event-specific positive consequences on future incentive ratings and drinking quantity.

Life Cycle Economic and Environmental Assessment for Emerging Heavy-Duty Truck Powertrain Technologies in China: A Comparative Study of Battery Electric, Fuel Cell Electric, and Hydrogen Combustion Engine Trucks.

Amid ambitious net-zero goals and growing demands for freight logistics, addressing the climate challenges posed by the heavy-duty truck (HDT) sector is an urgent and pivotal task. This study develops an integrated HDT model by incorporating vehicle dynamic simulation and life cycle analysis to quantify energy consumption, greenhouse gas (GHG) emissions, and total cost of ownership associated with three emerging powertrain technologies in various truck use scenarios in China, including battery electric, fuel cell electric, and hydrogen combustion engine trucks. The results reveal varying levels of economic suitability for these powertrain alternatives depending on required driving ranges and duty cycles: the battery electric for regional-haul applications, the hydrogen fuel cell for longer-haul and low-load driving conditions, and the hydrogen combustion engine to meet high power requirements.

Prevalence of Pulmonary Embolism in COVID-19 Positive Critically Ill Children.

Objectives: To investigate the prevalence of pulmonary embolism (PE) in children admitted to critical care diagnosed with COVID-19 infection.

Design: Retrospective database study.

Setting: Data reported to the Virtual Pediatric Systems, 2018-2021.

The nuclear localization signal of CPSF6 governs post-nuclear import steps of HIV-1 infection.

The early stages of HIV-1 infection include the trafficking of the viral core into the nucleus of infected cells. However, much remains to be understood about how HIV-1 accomplishes nuclear import and the consequences of the import pathways utilized on nuclear events. The host factor cleavage and polyadenylation specificity factor 6 (CPSF6) assists HIV-1 nuclear localization and post-entry integration targeting.

Viroporin activity is necessary for intercellular calcium signals that contribute to viral pathogenesis.

Viruses engage in a variety of processes to subvert host defenses and create an environment amenable to replication. Here, using rotavirus as a prototype, we show that calcium conductance out of the endoplasmic reticulum by the virus encoded ion channel, , induces intercellular calcium waves that extend beyond the infected cell and contribute to pathogenesis. Viruses that lack the ability to induce this signaling show diminished viral shedding and attenuated disease in a mouse model of rotavirus diarrhea.

Taking the Next Step in Neurologic Rehabilitation: Contributions of Intensity and Variability of Stepping Tasks during Locomotor Training.

Research over the past 20 years indicates the amount of task-specific walking practice provided to individuals with stroke, brain injury, or incomplete spinal cord injury can strongly influence walking recovery. However, more recent data suggest that attention towards 2 other training parameters, including the intensity and variability of walking practice, may maximize walking recovery and facilitate gains in non-walking outcomes. The combination of these training parameters represents a stark contrast from traditional strategies, and confusion regarding the potential benefits and perceived risks may limit their implementation in clinical practice.

Adjusting for bias due to measurement error in functional quantile regression models with error-prone functional and scalar covariates.

Wearable devices enable the continuous monitoring of physical activity (PA) but generate complex functional data with poorly characterized errors. Most work on functional data views the data as smooth, latent curves obtained at discrete time intervals with some random noise with mean zero and constant variance. Viewing this noise as homoscedastic and independent ignores potential serial correlations.

Predicting Body Fat Percentage from Anthropometric Measurements in Asian Athletes.

Purpose: Researchers have predicted body fat percentage (BF%), as indicated by dual energy X-ray absorptiometry (DXA), from skinfold thicknesses in North American and European athletes, but not athletes from other regions. We sought to estimate an equation to predict BF% in elite Asian athletes from their skinfold thickness and girth measurements, with DXA as a reference method.

Methods: We collected data from two samples of athletes on Singaporean national teams.

A clinical audit on the utilization of group O-negative red cells and the lesson learnt.

Background: Ideal blood inventory management involves guaranteeing maximal availability of blood while minimizing wastage. Benchmark for the guidance of O (Rh) D-negative red blood cells (ONEG RBCs) is not widely available. In this study, we aimed to identify the areas of improvement in blood center inventory of ONEG RBCs through a clinical audit.

Leveraging digital health systems maturity assessments to guide strategic priorities.

Background: Many low- and middle-income countries (LMICs) face the daunting task of digitising, maturing and deciding where to invest in digital health systems.

Aim: Describing the facilitators and barriers to conducting digital health maturity assessments and how health leaders can prioritise the assessments.

Setting: eHealth leaders from 10 African countries, working or supporting Ministries of Health's digital health and participating in the eHealth Leaders' Forum from July 2023 to September 2023.

LD-informed deep learning for Alzheimer's gene loci detection using WGS data.

Introduction: The exponential growth of genomic datasets necessitates advanced analytical tools to effectively identify genetic loci from large-scale high throughput sequencing data. This study presents Deep-Block, a multi-stage deep learning framework that incorporates biological knowledge into its AI architecture to identify genetic regions as significantly associated with Alzheimer's disease (AD). The framework employs a three-stage approach: (1) genome segmentation based on linkage disequilibrium (LD) patterns, (2) selection of relevant LD blocks using sparse attention mechanisms, and (3) application of TabNet and Random Forest algorithms to quantify single nucleotide polymorphism (SNP) feature importance, thereby identifying genetic factors contributing to AD risk.

Prevalence of Pulmonary Embolism in COVID-19 Positive Critically Ill Children.

Objectives: To investigate the prevalence of pulmonary embolism (PE) in children admitted to critical care diagnosed with COVID-19 infection.

Design: Retrospective database study.

Setting: Data reported to the Virtual Pediatric Systems, 2018-2021.

Defining the Speciation, Coordination Chemistry, and Lewis Acid Catalysis of Electronically Diverse Zinc Benzoates.

Zinc benzoates may provide an element of tunability that is not available to their ubiquitous acetate analogues. Unfortunately, the synthesis, speciation, and coordination chemistry of zinc benzoates are less developed than the acetates. In this study, we systematically investigate zinc benzoates to understand their propensity to favor solvate (Zn(OCAr)(L)) or cluster (ZnO(OCAr)) formation as well as their utility as metal complex precursors.