Dedifferentiation of a Chondrosarcoma of the Larynx: A Case Report.

Background: Chondrosarcomas of the larynx, relatively rare tumors with low grade pathology in approximately 95% of cases, can most often be managed with conservation laryngeal procedures. Dedifferentiated chondrosarcomas are much more rare and aggressive requiring more aggressive surgical extirpation.

Methods: A patient underwent three debulking procedures for a laryngeal chondrosarcoma Grade I/II histologically over a 2.

Antifouling Immunomodulatory Copolymer Architectures That Inhibit the Fibrosis of Implants.

Immune reactions to medical implants often lead to encapsulation by fibrotic tissue and impaired device function. This process is thought to initiate by protein adsorption, which enables immune cells to attach and mount an inflammatory response. Previously, several antifibrotic materials have been either designed to reduce protein adsorption or discovered via high-throughput screens (HTS) to favorably regulate inflammation.

Zwitterionic Polymer-Functionalized Lipid Nanoparticles for the Nebulized Delivery of mRNA.

Lipid nanoparticles (LNPs) have great potential to enable inhaled delivery of mRNA to treat pulmonary diseases. However, this potential has been limited by the challenge of nebulizing the LNPs. Nebulization of LNPs can cause LNPs to aggregate and release encapsulated mRNA, limiting their delivery efficacy.

Longitudinal Pain Management Claims in Maryland: Implications.

The study is a longitudinal review of pain management claims filed in the state of Maryland. Adverse outcomes associated with pain-related claims are often severe and include death, brain damage, and back and spinal cord sequelae. There is a lot to be learned from past experiences, identified in closed pain management claims, specifically on how to improve patient education, outcomes, quality, and safety.

Therapeutic silencing in TREM2 cardiac macrophages suppresses atrial fibrillation.

Atrial fibrillation (AFib) and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2 macrophages secrete osteopontin (encoded by ), a matricellular signaling protein that engenders fibrosis and AFib. Here we show that silencing in TREM2 cardiac macrophages with an antibody-siRNA conjugate reduces atrial fibrosis and suppresses AFib in mice, thus offering a new immunotherapy for the most common arrhythmia.

Caseous Calcification of the Mitral Annulus: Calcified Toothpaste of the Heart.

Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annular calcification (MAC) usually described as an antemortem finding. We report a case of sudden cardiac arrest in a 39-year-old male with end-stage renal disease undergoing hemodialysis with a history of Fabry disease by kidney biopsy. Autopsy revealed significant circumferential annular calcification in both mitral and aortic valves with a caseous gross appearance.

A Case of Non-Syndromic Congenital Cataracts Caused by a Novel Variant in the C-Terminal DNA-Binding Domain-Case Report and Literature Review.

The gene encodes a transcription factor in which pathogenic variants have been associated with both isolated and syndromic congenital cataracts. We aim to review the variants in the C-terminal DNA-binding domain associated with non-syndromic congenital cataracts and describe a patient with a novel, disease-causing de novo missense variant. Published reports of C-terminal variants and their associated congenital cataracts and ophthalmic findings were reviewed.

In vitro to in vivo extrapolation from 3D hiPSC-derived cardiac microtissues and physiologically based pharmacokinetic modeling to inform next-generation arrhythmia risk assessment.

Proarrhythmic cardiotoxicity remains a substantial barrier to drug development as well as a major global health challenge. In vitro human pluripotent stem cell-based new approach methodologies have been increasingly proposed and employed as alternatives to existing in vitro and in vivo models that do not accurately recapitulate human cardiac electrophysiology or cardiotoxicity risk. In this study, we expanded the capacity of our previously established 3D human cardiac microtissue model to perform quantitative risk assessment by combining it with a physiologically based pharmacokinetic model, allowing a direct comparison of potentially harmful concentrations predicted in vitro to in vivo therapeutic levels.

Integrating gene expression and splicing dynamics across dose-response oxidative modulators.

Toxicological risk assessment increasingly utilizes transcriptomics to derive point of departure (POD) and modes of action (MOA) for chemicals. One essential biological process that allows a single gene to generate several different RNA isoforms is called alternative splicing. To comprehensively assess the role of splicing dysregulation in toxicological evaluation and elucidate its potential as a complementary endpoint, we performed RNA-seq on A549 cells treated with five oxidative stress modulators across a wide dose range.

Passivating the Background of Living Microbes with a Zwitterionic Peptide for Therapies.

Living microbial therapies have been proposed as a course of action for a variety of diseases. However, problematic interactions between the host immune system and the microbial organism present significant clinical concerns. Previously, we developed a genetically encoded superhydrophilic zwitterionic peptide, termed EKP, to mimic low-immunogenic zwitterionic materials, which have been used for the chemical modification of biologics such as protein and nucleic acid drugs to increase their in vivo circulation time and reduce their immunogenicity.

Extracellular vesicles incorporating retrovirus-like capsids for the enhanced packaging and systemic delivery of mRNA into neurons.

The blood-brain barrier (BBB) restricts the systemic delivery of messenger RNAs (mRNAs) into diseased neurons. Although leucocyte-derived extracellular vesicles (EVs) can cross the BBB at inflammatory sites, it is difficult to efficiently load long mRNAs into the EVs and to enhance their neuronal uptake. Here we show that the packaging of mRNA into leucocyte-derived EVs and the endocytosis of the EVs by neurons can be enhanced by engineering leucocytes to produce EVs that incorporate retrovirus-like mRNA-packaging capsids.

Sustained Implementation of an Evidence-Based Extubation Checklist Reduced Extubation Failure in Trauma Patients.

Extubation failure remains a challenge in the perioperative setting. The aim of this intervention was to decrease the rate of perioperative extubation failure through the utilization of an extubation checklist. A five-item evidence-based extubation readiness checklist was implemented at a level I trauma center on all patients who were electively extubated in the operating room (OR).

Carotid Intimal Sarcoma Presenting as Large Vessel Occlusion and Diagnosed by Embolus Histopathology: Case Report.

Objective: The objective of this study was to present the clinical, histopathologic, and radiographic findings of a unique case of intimal sarcoma (IS) embolus presenting as a large vessel occlusion causing an ischemic stroke without a detectable primary tumor site.

Methods: Extensive examinations, multimodal imaging, laboratory testing, and histopathologic analysis were used in evaluation.

Results: We report the case of a patient who presented with acute embolic ischemic stroke and was found to have IS based on a histopathologic evaluation of his embolectomy specimen.

Hidden hydrophobicity impacts polymer immunogenicity.

Antibodies against poly(ethylene glycol) (PEG) have been found to be the culprit of side reactions and efficacy loss of a number of PEGylated drugs. Fundamental mechanisms of PEG immunogenicity and design principles for PEG alternatives still have not been fully explored. By using hydrophobic interaction chromatography (HIC) under varied salt conditions, we reveal the "hidden" hydrophobicity of those polymers which are generally considered as hydrophilic.

Research focused doctoral nursing education in the 21st century: Curriculum, evaluation, and postdoctoral considerations.

The AACN position statement on The Research-Focused Doctoral Program in Nursing: Pathways to Excellence was revised in 2022 by an AACN Task Force charged with creating a new vision for the PhD and similar programs in nursing. This document, which was informed by hundreds of academic nursing stakeholders, yields expectations and recommendations for PhD program curriculum, program evaluation, post-doctoral competencies, and resources. Results of an AACN 2021 survey indicated increased enrollment in PhD programs 2017-2000.

Comparison of Rat Hepatocyte 2D-Monocultures and Hepatocytes Non-Parenchymal Cell Co-Cultures for Assessing Chemical Toxicity.

Liver responses are the most common endpoints used as the basis for setting exposure standards. Liver hepatocytes play a vital role in biotransformation of xenobiotics, but non-parenchymal cells (NPCs) in the liver are also involved in certain liver responses. Development of in vitro systems that more faithfully capture liver responses to reduce reliance on animals is a major focus of New Approach Methodology (NAMs).

Anesthesia-Related Malpractice Claims in Maryland 1994-2017.

This article presents data on anesthesia cases filed with the Maryland Health Claims Alternative Dispute Office between 1994 and 2017, a publicly available resource that includes all anesthesia-related claims filed in Maryland, regardless of whether they were reported to any national claims repository. Analysis of anesthesia malpractice claims offers critical information that can both decrease legal liability and improve patient outcomes for those receiving anesthesia. A total of 276 claims were filed.

Motif-based zwitterionic peptides impact their structure and immunogenicity.

The linkage of zwitterionic peptides containing alternating glutamic acid (E) and lysine (K) amino acids exhibits protective effects on protein drugs due to their high hydration capacity. Previously, short EK peptides covering the surface of a protein drug showed significant protective effects and low immunogenicity. However, for high-molecular-weight single-chain (HMWSC) zwitterionic peptides, the incorporation of structure-disrupting amino acids such as proline (P), serine (S), and glycine (G) is necessary to improve their protective ability.

Estimating provisional margins of exposure for data-poor chemicals using high-throughput computational methods.

Current computational technologies hold promise for prioritizing the testing of the thousands of chemicals in commerce. Here, a case study is presented demonstrating comparative risk-prioritization approaches based on the ratio of surrogate hazard and exposure data, called margins of exposure (MoEs). Exposures were estimated using a U.

NAM-based prediction of point-of-contact toxicity in the lung: A case example with 1,3-dichloropropene.

Time, cost, ethical, and regulatory considerations surrounding in vivo testing methods render them insufficient to meet existing and future chemical safety testing demands. There is a need for the development of in vitro and in silico alternatives to replace traditional in vivo methods for inhalation toxicity assessment. Exposures of differentiated airway epithelial cultures to gases or aerosols at the air-liquid interface (ALI) can assess tissue responses and in vitro to in vivo extrapolation can align in vitro exposure levels with in-life exposures expected to give similar tissue exposures.

Lymphatic coagulation and neutrophil extracellular traps in lung-draining lymph nodes of COVID-19 decedents.

Clinical manifestations of severe COVID-19 include coagulopathies that are exacerbated by the formation of neutrophil extracellular traps (NETs). Here, we report that pulmonary lymphatic vessels, which traffic neutrophils and other immune cells to the lung-draining lymph node (LDLN), can also be blocked by fibrin clots in severe COVID-19. Immunostained tissue sections from COVID-19 decedents revealed widespread lymphatic clotting not only in the lung but also in the LDLN, where the extent of clotting correlated with the presence of abnormal, regressed, or missing germinal centers (GCs).

Impacts of a Zwitterionic Peptide on its Fusion Protein.

Therapeutic proteins frequently need to be modified with high-molecular-weight molecules to improve their pharmacokinetic properties. The genetic linkage of therapeutic proteins to a high-molecular-weight zwitterionic peptide, termed EKP, offers a promising approach. As with any protein modification, EKP could impact the structural behavior and receptor binding properties of the linked therapeutic protein, thereby altering its bioactivity.

Beyond pharmaceuticals: Fit-for-purpose new approach methodologies for environmental cardiotoxicity testing.

Environmental factors play a substantial role in determining cardiovascular health, but data informing the risks presented by environmental toxicants is insufficient. In vitro new approach methodologies (NAMs) offer a promising approach with which to address the limitations of traditional in vivo and in vitro assays for assessing cardiotoxicity. Driven largely by the needs of pharmaceutical toxicity testing, considerable progress in developing NAMs for cardiotoxicity analysis has already been made.