Four Opportunities To Revitalize The US Biomedical Research Enterprise.

The US biomedical research enterprise is renowned for its historical and ongoing scientific breakthroughs and advancements. Yet its capacity to solve complex health issues, bridge health equity gaps, and strengthen public trust is constrained by the lack of an overarching national vision, fragmented coordination for research funding, and critical workforce recruitment and retention challenges. To improve national health outcomes and retain global competitiveness, the sector must embrace new approaches.

Diabetes and Early Development: Epigenetics, Biological Stress, and Aging.

Pregestational diabetes, either type 1 or type 2 diabetes, induces structural birth defects including neural tube defects and congenital heart defects in human fetuses. Rodent models of type 1 and type 2 diabetic embryopathy have been established and faithfully mimic human conditions. Hyperglycemia of maternal diabetes triggers oxidative stress in the developing neuroepithelium and the embryonic heart leading to the activation of proapoptotic kinases and excessive cell death.

Glucagon-like peptide-1 receptor agonist use in pregnancy: a review.

Glucagon-like peptide-1 receptor agonists are peptide analogues that are used to treat type 2 diabetes mellitus and obesity. The first medication in this class, exenatide, was approved in 2005, and these medications, specifically semaglutide, have become more popular in recent years due to their pronounced effects on glycemic control, weight reduction, and cardiovascular health. Due to successful weight loss from these medications, many women previously diagnosed with oligomenorrhea and unable to conceive have experienced unplanned pregnancies while taking the medications.

Placental SARS-CoV-2 Infection and Its Implications for Increased Risk of Adverse Pregnancy Outcomes.

Objective:  Pregnant women are at increased risk of coronavirus disease 2019 (COVID-19). This could be explained through the prism of physiologic and immunologic changes in pregnancy. In addition, certain immunological reactions originate in the placenta in response to viral infections.

Remote Measurements of Tear Electrolyte Concentrations on Both Sides of an Inserted Contact Lens.

In this paper, a method is described to perform ion concentration measurements on both sides of an inserted contact lens, without physical contact with the eye or the contact lens. The outer surface of an eye is covered with a tear film that has multiple layers. The central aqueous layer contains electrolytes and proteins.

The Road Well Traveled: Making Choices, Ensuring Progress While Heeding the "Clarion Call".

The career path of everyone is quite unique based on the goals and the choices we make, and success can take time to unfold. My career choices have been greatly influenced by remarkable mentors and opportunities. Reciprocally I have had the pleasure, as a faculty member, department chair, and medical school dean to mentor promising young physicians and scientists to launch successful careers.

Perturbation of 3D nuclear architecture, epigenomic aging and dysregulation, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 2-Metabolome, immunome, synaptome.

The second part of this paper builds upon and expands the epigenomic-aging perspective presented in Part 1 to describe the metabolomic and immunomic bases of the epigenomic-aging changes and then considers in some detail the application of these insights to neurotoxicity, neuronal epigenotoxicity, and synaptopathy. Cannabinoids are well-known to have bidirectional immunomodulatory activities on numerous parts of the immune system. Immune perturbations are well-known to impact the aging process, the epigenome, and intermediate metabolism.

Perturbation of 3D nuclear architecture, epigenomic dysregulation and aging, and cannabinoid synaptopathy reconfigures conceptualization of cannabinoid pathophysiology: part 1-aging and epigenomics.

Much recent attention has been directed toward the spatial organization of the cell nucleus and the manner in which three-dimensional topologically associated domains and transcription factories are epigenetically coordinated to precisely bring enhancers into close proximity with promoters to control gene expression. Twenty lines of evidence robustly implicate cannabinoid exposure with accelerated organismal and cellular aging. Aging has recently been shown to be caused by increased DNA breaks.

MicroRNA-322 overexpression reduces neural tube defects in diabetic pregnancies.

Background: Hyperglycemia from pregestational diabetes mellitus induces neural tube defects in the developing fetus. Folate supplementation is the only effective way to prevent neural tube defects; however, some cases of neural tube defects are resistant to folate. Excess folate has been linked to higher maternal cancer risk and infant allergy.

Cannabis- and Substance-Related Carcinogenesis in Europe: A Lagged Causal Inferential Panel Regression Study.

Recent European data facilitate an epidemiological investigation of the controversial cannabis-cancer relationship. Of particular concern were prior findings associating high-dose cannabis use with reproductive problems and potential genetic impacts. Cancer incidence data age-standardised to the world population was obtained from the European Cancer Information System 2000-2020 and many European national cancer registries.

Clinical Epigenomic Explanation of the Epidemiology of Cannabinoid Genotoxicity Manifesting as Transgenerational Teratogenesis, Cancerogenesis and Aging Acceleration.

As global interest in the therapeutic potential of cannabis and its' derivatives for the management of selected diseases increases, it is increasingly imperative that the toxic profile of cannabinoids be thoroughly understood in order to correctly assess the balance between the therapeutic risks and benefits. Modern studies across a number of jurisdictions, including Canada, Australia, the US and Europe have confirmed that some of the most worrying and severe historical reports of both congenital anomalies and cancer induction following cannabis exposure actually underestimate the multisystem thousand megabase-scale transgenerational genetic damage. These findings from teratogenic and carcinogenic literature are supported by recent data showing the accelerated patterns of chronic disease and the advanced DNA methylation epigenomic clock age in cannabis exposed patients.

Geospatiotemporal and Causal Inferential Study of European Epidemiological Patterns of Cannabis- and Substance-Related Congenital Orofacial Anomalies.

Introduction: Since high rates of congenital anomalies (CAs), including facial CAs (FCAs), causally attributed to antenatal and community cannabis use have been reported in several recent series, it was of interest to examine this subject in detail in Europe.

Methods: CA data were taken from the EUROCAT database. Drug exposure data were downloaded from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

Patterns of Cannabis- and Substance-Related Congenital General Anomalies in Europe: A Geospatiotemporal and Causal Inferential Study.

Introduction: Recent series of congenital anomaly (CA) rates (CARs) have showed the close and epidemiologically causal relationship of cannabis exposure to many CARs. We investigated these trends in Europe where similar trends have occurred.

Methods: CARs from EUROCAT.

Novel Insights into Potential Cannabis-Related Cancerogenesis from Recent Key Whole Epigenome Screen of Cannabis Dependence and Withdrawal: Epidemiological Commentary and Explication of Schrott et al.

Whilst the cannabis-cancer link has been traditionally described as controversial recent whole nation and whole continent studies have demonstrated that well documented laboratory-based multimodal cannabinoid genotoxicity is indeed reflected in numerous cancer types in larger epidemiological series. A recent longitudinal human sperm epigenome-wide DNA methylation screen in both cannabis dependence and cannabis withdrawal has revealed remarkable insights into the manner in which widespread perturbations of DNA methylation may lead to cancerogenic changes in both the exposed and subsequent generations as a result of both cannabis exposure and withdrawal. These results therefore powerfully strengthen and further robustify the causal nature of the relationship between cannabinoid exposure and cancerous outcomes well beyond the previously published extensive mechanistic literature on cannabinoid genotoxicity.

European Epidemiological Patterns of Cannabis- and Substance-Related Congenital Neurological Anomalies: Geospatiotemporal and Causal Inferential Study.

Introduction. Of the many congenital anomalies (CAs) recently linked with community cannabis exposure, arguably the most concerning are neurological CAs (NCAs). We therefore conducted a detailed study of this in fourteen European nations.

Epigenomic and Other Evidence for Cannabis-Induced Aging Contextualized in a Synthetic Epidemiologic Overview of Cannabinoid-Related Teratogenesis and Cannabinoid-Related Carcinogenesis.

Background: Twelve separate streams of empirical data make a strong case for cannabis-induced accelerated aging including hormonal, mitochondriopathic, cardiovascular, hepatotoxic, immunological, genotoxic, epigenotoxic, disruption of chromosomal physiology, congenital anomalies, cancers including inheritable tumorigenesis, telomerase inhibition and elevated mortality.

Methods: Results from a recently published longitudinal epigenomic screen were analyzed with regard to the results of recent large epidemiological studies of the causal impacts of cannabis. We also integrate theoretical syntheses with prior studies into these combined epigenomic and epidemiological results.

Epidemiological Patterns of Cannabis- and Substance- Related Congenital Uronephrological Anomalies in Europe: Geospatiotemporal and Causal Inferential Study.

Introduction: Recent reports linking prenatal and community cannabis exposure to elevated uronephrological congenital anomaly (UCA) rates (UCAR's) raise the question of its European epidemiology given recent increases in community cannabinoid penetration there.

Methods: UCAR data from Eurocat. Drug use data from European Monitoring Centre for Drugs and Drug Addiction.

Socioeconomic, Ethnocultural, Substance- and Cannabinoid-Related Epidemiology of Down Syndrome USA 1986-2016: Combined Geotemporospatial and Causal Inference Investigation.

Background: Down syndrome (DS) is the commonest of the congenital genetic defects whose incidence has been rising in recent years for unknown reasons. This study aims to assess the impact of substance and cannabinoid use on the DS Rate (DSR) and assess their possible causal involvement.

Methods: An observational population-based epidemiological study 1986-2016 was performed utilizing geotemporospatial and causal inferential analysis.