Orchestrating Resilience: How Neuropilin-2 and Macrophages Contribute to Cardiothoracic Disease.

Immunity has evolved to balance the destructive nature of inflammation with wound healing to overcome trauma, infection, environmental insults, and rogue malignant cells. The inflammatory response is marked by overlapping phases of initiation, resolution, and post-resolution remodeling. However, the disruption of these events can lead to prolonged tissue damage and organ dysfunction, resulting long-term disease states. Macrophages are the archetypic phagocytes present within all tissues and are important contributors to these processes. Pleiotropic and highly plastic in their responses, macrophages support tissue homeostasis, repair, and regeneration, all while balancing immunologic self-tolerance with the clearance of noxious stimuli, pathogens, and malignant threats. Neuropilin-2 (Nrp2), a promiscuous co-receptor for growth factors, semaphorins, and integrins, has increasingly been recognized for its unique role in tissue homeostasis and immune regulation. Notably, recent studies have begun to elucidate the role of Nrp2 in both non-hematopoietic cells and macrophages with cardiothoracic disease. Herein, we describe the unique role of Nrp2 in diseases of the heart and lung, with an emphasis on Nrp2 in macrophages, and explore the potential to target Nrp2 as a therapeutic intervention.

The Occupational and Environmental Hazards of Uncovered Toilets.

ABSTRACT: Substantial evidence demonstrates that plumes from uncovered toilets potentially expose nurses and other health care workers to aerosols containing infectious agents and hazardous drugs, including antineoplastic drugs. Most hospitals in the United States utilize flushometer-type toilets, which operate under high pressure and do not have a permanently attached closure or lid, which is known to reduce the aerosols generated by flushing. This article aims to raise awareness among nurses of the potential exposure risks associated with toilet plume aerosols, so they can educate other health care workers and take part in initiatives to address these risks.

Prototyping an ionization source for non-engineers.

Novel mass spectrometry (MS) based analytical platforms have enabled scientists to detect and quantify molecules within biological and environmental samples more accurately. Novel MS instrumentation starts as a prototype and, after years of development, can become a commercial product to be used by the larger MS community. Without the initial prototype, many MS-based instruments today would not be produced. Additionally, biotechnology companies are the main drivers for research, development, and production of novel instruments, but the tools for prototyping instrumentation have never been more accessible. Here, we present a tutorial on prototyping instrumentation through the case study of developing the Next Generation IR-MALDESI source to show that an engineering degree is not required to design and construct a prototype instrument with modern hardware and software. We discuss the prototyping process, the necessary skills required for efficient prototyping, and information about common hardware and software used within initial prototypes.

Comparing Two Methods of Reducing Hospital Toilet Aerosols.

BACKGROUND: When flushed, uncovered hospital toilets have been shown to generate aerosols potentially containing bacteria, viruses, and hazardous drugs, which can be inhaled by healthcare workers and contaminate surfaces. Guidelines recommend placing a plastic-backed absorbent pad (PBP) over the toilet, although no studies have evaluated the effectiveness of this intervention. OBJECTIVES: The purpose of this study was to evaluate the effectiveness of using a PBP versus the Splashblocker®, a solid, reusable engineering barrier control, to reduce post-flush aerosol particles. METHODS: Aerosol measurements were taken with an optical particle counter in a bathroom testing chamber equipped with a commercial hospital toilet and flushometer valve. Three tests were performed at a height of 16 inches above the floor and 40 inches above the floor. FINDINGS: Both the PBP and the Splashblocker significantly reduced the number of post-flush particles by more than 99% at 16 inches above the floor and 40 inches above the floor. The results indicate that both interventions are equally beneficial in reducing aerosols after flushing a hospital toilet.

Metabolite Annotation Confidence Score (MACS): A Novel MSI Identification Scoring Tool.

Mass spectrometry imaging (MSI) is an analytical technique capable of measuring and visualizing the spatial distribution of thousands of ions across a sample. Measured ions can be putatively identified and annotated by comparing their mass-to-charge ratio (m/z) to a database of known compounds. For high-resolution, accurate mass (HRAM) imaging data sets, this is commonly performed by the annotation platform METASPACE. Annotations are reported with a metabolite-signal-match (MSM) score as a measure of the annotation's confidence level. However, the MSM scores reported by METASPACE often do not reflect a reasonable confidence level of an annotation and are not assigned consistently. The metabolite annotation confidence score (MACS) is an alternative scoring system based on fundamental mass spectrometry imaging metrics (mass measurement accuracy, spectral accuracy, and spatial distribution) to generate values that reflect the confidence of a specific annotation in HRAM-MSI data sets. Herein, the MACS system is characterized and compared to MSM scores from ions annotated by METASPACE.

Sequential Wipe Testing for Hazardous Drugs: A Quality Improvement Project.

BACKGROUND: Monitoring for the presence of hazardous drug (HD) residue is recommended as part of a comprehensive HD safety program. However, a single wipe test provides limited information without the ability to evaluate interventions. OBJECTIVES: This quality improvement project was designed to evaluate the benefits of performing sequential HD wipe testing during a six-month period in an ambulatory cancer center. METHODS: Four areas in the pharmacy department and two areas in the infusion department were selected for testing, which was conducted at three time points. Cyclophosphamide, doxorubicin, 5-fluorouracil, methotrexate, and paclitaxel were tested using liquid chromatography coupled with tandem mass spectrometry. FINDINGS: The initial test demonstrated HD contamination on the legs of the IV pole and the pharmacy transport bin. All other areas were below the limit of detection. Changes were made to cleaning practices in the pharmacy and infusion departments prior to the subsequent tests at the three- and six-month time points, which produced levels below the limit of detection.

Development of an object-based image analysis tool for mass spectrometry imaging ion classification.

Mass spectrometry imaging (MSI) is an analytical technique that can detect and visualize thousands of m/z values resolved in two- and three-dimensional space. These m/z values lead to hundreds of molecular annotations, including on-tissue and background ions. Discrimination of sample-related analytes from ambient ions conventionally involves manual investigation of each ion heatmap, which requires significant researcher time and effort (for a single tissue image, it can take an hour to determine on-tissue and off-tissue species). Moreover, manual investigation lends itself to subjectivity. Herein, we present the utility of an ion classification tool (ICT) developed using object-based image analysis in MATLAB. The ICT functions by segmenting ion heatmap images into on-tissue and off-tissue objects through binary conversion. The binary images are analyzed and within seconds used to classify the ions as on-tissue or background using a binning approach based on the number of detected objects. In a representative dataset with 50 randomly selected annotations, the ICT was able to accurately classify 45/50 ions as on-tissue or background.

Preclinical evaluation of new C-11 labeled benzo-1,4-dioxane PET radiotracers for brain α2C adrenergic receptors.

As one of the nine subtypes of adrenergic receptors (ARs) in the brain, α2C-ARs play essential roles in emotion and memory, and are implicated in neuropsychiatric disorders, including depression, Alzheimer's disease, substance use disorder, and schizophrenia. A recently developed α2C-AR specific positron emission tomography (PET) radiotracer, [11C]ORM-13070, showed promise for imaging α2C-ARs in the brain. Herein, we prepared highly potent C-11 labeled benzo-1,4-dioxane derivatives and compared them with [11C]ORM-13070, aiming to improve the specific binding signal, as evaluated by in vivo rodent brain PET imaging.© 2022 Elsevier Inc. All rights reserved.

Closed safety system for administration (CSSA): proposal for a new cytotoxic chemotherapy acronym.

Exposure to cytotoxic chemotherapy can result in acute and chronic conditions including nausea, headaches, rashes, miscarriages, infertility and genetic aberrations. Surface contamination can occur during drug administration, and can subsequently spread throughout the healthcare environment. Dermal contact with contaminated surfaces can lead to drug absorption. Closed system drug-transfer devices (CSTDs) were initially developed to protect pharmacists during compounding. Components include a vial adapter to prevent pressurisation leakage and a syringe connector for transferring the drug to the intravenous infusion bag. Membrane-based CSTDs require a Luer adapter for drug administration whereas Luer system-based products do not. Most European nurses are familiar with needleless connectors. Unfortunately, these devices do not provide protection from chemotherapy exposure. To decrease confusion, CytoPrevent, a multi-national, primarily European organisation has proposed the term 'closed safety system for administration' (CSSA) for Luer based CSTDs. Along with education, the new term can help promote safety for nurses administering cytotoxic chemotherapy.

Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer.

Tumor-associated macrophages (TAMs) exert profound influence over breast cancer progression, promoting immunosuppression, angiogenesis, and metastasis. Neuropilin-2 (NRP2), consisting of the NRP2a and NRP2b isoforms, is a co-receptor for heparin-binding growth factors including VEGF-C and Class 3 Semaphorins. Selective upregulation in response to environmental stimuli and independent signaling pathways endow the NRP2 isoforms with unique functionality, with NRP2b promoting increased Akt signaling via receptor tyrosine kinases including VEGFRs, MET, and PDGFR. Although NRP2 has been shown to regulate macrophage/TAM biology, the role of the individual NRP2a/NRP2b isoforms in TAMs has yet to be evaluated. Using transcriptional profiling and spectral flow cytometry, we show that NRP2 isoform expression was significantly higher in TAMs from murine mammary tumors. NRP2a/NRP2b levels in human breast cancer metastasis were dependent upon the anatomic location of the tumor and significantly correlated with TAM infiltration in both primary and metastatic breast cancers. We define distinct phenotypes of NRP2 isoform-expressing TAMs in mouse models of breast cancer and within malignant pleural effusions from breast cancer patients which were exclusive of neuropilin-1 expression. Genetic depletion of either NRP2 isoform in macrophages resulted in a dramatic reduction of LPS-induced IL-10 production, defects in phagosomal processing of apoptotic breast cancer cells, and increase in cancer cell migration following co-culture. By contrast, depletion of NRP2b, but not NRP2a, inhibited production of IL-6. These results suggest that NRP2 isoforms regulate both shared and unique functionality in macrophages and are associated with distinct TAM subsets in breast cancer.

Naloxone's dose-dependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain.

The continuous rise in opioid overdoses in the United States is predominantly driven by very potent synthetic opioids, mostly fentanyl and its derivatives (fentanyls). Although naloxone (NLX) has been shown to effectively reverse overdoses by conventional opioids, there may be a need for higher or repeated doses of NLX to revert overdoses from highly potent fentanyls. Here, we used positron emission tomography (PET) to assess NLX's dose-dependence on both its rate of displacement of [11C]carfentanil ([11C]CFN) binding and its duration of mu opioid receptor (MOR) occupancy in the male rat brain. We showed that clinically relevant doses of intravenously (IV) administered NLX (0.035 mg/kg, Human Equivalent Dose (HED) 0.4 mg; 0.17 mg/kg, HED 2 mg) rapidly displaced the specific binding of [11C]CFN in the thalamus in a dose-dependent manner. Brain MOR occupancy by IV NLX was greater than 90% at 5 min after NLX administration for both doses, but at 27.3 min after 0.035 mg/kg dose and at 85 min after 0.17 mg/kg NLX, only 50% occupancy remained. This indicates that the duration of NLX occupancy at MORs is short-lived. Overall, these results show that clinically relevant doses of IV NLX can promptly displace fentanyls at brain MORs, but repeated or higher NLX doses may be required to prevent re-narcotization following overdoses with long-acting fentanyls.

Subcutaneous Administration: Evolution, Challenges, and the Role of Hyaluronidase.

BACKGROUND: The subcutaneous (SC) route has evolved significantly. More than two dozen chemotherapy and supportive therapies have been approved for use in the oncology setting. Several IV therapies have been approved for the SC route and require a significantly higher volume than historical maximum limits. Differences exist in how these drugs are administered as compared to older chemotherapy agents. OBJECTIVES: The purpose of this article is to provide a brief history of the SC route and describe its role in cancer treatment. The use of recombinant hyaluronidase is reviewed within the context of SC monoclonal antibodies. Proper administration techniques and interventions for reducing patient discomfort are discussed. METHODS: Sentinel medical texts, pharmacokinetic studies, manufacturer's recommendations, and peer-reviewed articles were examined. FINDINGS: The SC route offers several advantages over the oral and IV routes. A clear understanding of anatomical site selection and injection techniques is beneficial for providing requisite patient education.

Discovery of Highly Potent Adenosine A1 Receptor Agonists: Targeting Positron Emission Tomography Probes.

Adenosine receptor (AR) radiotracers for positron emission tomography (PET) have provided knowledge on the in vivo biodistribution of ARs in the central nervous system (CNS), which is of therapeutic interest for various neuropsychiatric disorders. Additionally, radioligands that can image changes in endogenous adenosine levels in different physiological and pathological conditions are still lacking. The binding of known antagonist adenosine A1 receptor (A1R) radiotracer, [11C]MDPX, failed to be inhibited by elevated endogenous adenosine in a rodent PET study. Since most of the known AR PET radiotracers were antagonists, we propose that an A1R agonist radioligand may possess higher sensitivity to measure changes in endogenous adenosine concentration. Herein, we report our latest findings toward the development of a full agonist adenosine A1 radioligand for PET. Based on a 3,5-dicyanopyridine template, 16 new derivatives were designed and synthesized to optimize both binding affinity and functional activity, resulting in two full agonists (compounds 27 and 29) with single-digit nanomolar affinities and good subtype selectivity (A1/A2A selectivity of ∼1000-fold for compound 27 and 29-fold for compound 29). Rapid O-[11C]methylation provided [11C]27 and [11C]29 in high radiochemical yields and radiochemical purity. However, subsequent brain PET imaging in rodents showed poor brain permeability for both radioligands. An in vivo PET study using knockout mice for MDR 1a/a, BCRP, and MRP1 indicated that these compounds might be substrates for brain efflux pumps. In addition, in silico evaluation using multiparameter optimization identified high molecular weight and high polar surface area as the main molecular descriptors responsible for low brain penetration. These results will provide further insight toward development of full agonist adenosine A1 radioligands and also highly potent CNS A1AR drugs.

Experimental respiratory exposure to putative Gulf War toxins promotes persistent alveolar macrophage recruitment and pulmonary inflammation.

AIMS: Respiratory disorders are a prominent component of Gulf War Illness. Although much of the underlying mechanisms of Gulf War Illness remain undefined, chronic immune dysfunction is a consistent feature of this multi-symptomatic, multi-organ disorder. Alveolar macrophages represent the predominant mononuclear phagocytes of the pulmonary mucosa, orchestrating the host response to pathogens and environmental stimuli. Herein, we sought to characterize the innate immune response of the pulmonary mucosa, with a focus on macrophages, to experimental respiratory exposure to two putative Gulf War Toxins (GWTs). MATERIALS AND METHODS: Utilizing commercially available instrumentation, we evaluated the effect of aerosolized exposure to the pesticide malathion and diesel exhaust particulate (DEP) on the immune composition and inflammatory response of the lung in FVB/N mice using multiparametric spectral cytometry, cytokine analysis, and histology. KEY FINDINGS: Aerosolized GWTs induced gross pulmonary pathology with transient recruitment of neutrophils and sustained accumulation of alveolar macrophages to the lung for up to two weeks after exposure cessation. High-dimensional cytometry and unbiased computational analysis identified novel myeloid subsets recruited to the lung post-exposure driven by an influx of peripheral monocyte-derived progenitors. DEP and malathion, either alone or in combination, induced soluble mediators in bronchoalveolar lavage indicative of oxidative stress (PGF2α), inflammation (LTB4, TNFα, IL-12), and immunosuppression (IL-10), that were sustained or increased two weeks after exposures concluded. SIGNIFICANCE: These findings indicate that macrophage accumulation and pulmonary inflammation induced by GWTs continue in the absence of toxin exposure and may contribute to the immunopathology of respiratory Gulf War Illness.

Safe Handling of Hazardous Drugs in Home Infusion.

Chemotherapy agents used for cancer treatment are considered hazardous drugs (HDs). Guidelines and standards for handling HDs have been in place for several decades to protect oncology nurses working in hospitals and outpatient infusion areas. However, chemotherapy is frequently being administered in home settings, often by infusion nurses who do not necessarily have the requisite knowledge and training. Providing appropriate education for home infusion nurses is key to ensuring they are practicing in a manner that minimizes potential exposure to HDs.

Hazardous Drug Contamination: Presence of Bathroom Contamination in an Ambulatory Cancer Center.

BACKGROUND: Many hazardous drugs (HDs) are excreted in urine and feces, and evidence has shown that bathrooms of patients receiving chemotherapy at home are contaminated with HDs. However, little information exists on bathroom contamination in ambulatory clinics where HDs are administered. OBJECTIVES: This project aimed to determine the presence of HD residue in the patient and staff bathrooms of an ambulatory cancer center. METHODS: A quality improvement project was initiated to examine potential contamination by the HDs 5-fluorouracil and oxaliplatin in a patient bathroom and a secured badge-access staff bathroom in the infusion department of an ambulatory comprehensive cancer center. Twice-daily wipe testing was conducted on the floor in front of the toilet and the flush handle for five consecutive days. FINDINGS: Sixty-five percent of the samples from the floor of the patient bathroom were positive for at least one of the HDs. In the staff bathroom, 35% of the floor samples were positive for at least one HD. None of the flush handle samples were above the level of detection.

Characteristics of Malignant Pleural Effusion Resident CD8+ T Cells from a Heterogeneous Collection of Tumors.

While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 108 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8+ T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8+ T cells with autologous CD45- tumor containing cells demonstrated cytotoxicity (p = 0.030) and IFNγ production (p = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8+ T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.

A Dedicated Education Unit and a Novel Resident Nurse Transition-to-Practice Program in an Ambulatory Oncology Setting.

OBJECTIVE: To summarize an innovative initiative in oncology nurse workforce development that addresses critical current and future gaps and encompasses use of dedicated education units for student nurse rotation and a transition-to-practice residency program. DATA SOURCES: Review of institutional data including original pilot analysis and ongoing programmatic metrics (N=8 years), consensus, professional guidelines, and published literature. CONCLUSION: The dedicated education unit serves as a conduit for recruitment into institutional oncology nurse residency positions, and retention rates in the residency program continue to exceed national averages. Subsequent mentoring of these nurses in transition to practice has manifested high rates of promotion into nurse leadership roles year over year. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurse practice incorporates state-of-the-science approved therapies, early phase clinical trial implementation, and evidence-based complex oncology patient care management. A new model of student clinical nurse rotations in ambulatory settings, nurse resident transition to practice, and ongoing leadership mentoring is essential in creating a sustainable, highly skilled, and robust oncology nurse work force.

Response to "Personal Protective Equipment: Evaluating Usage Among Inpatient and Outpatient Oncology Nurses".

I read with great interest the recent article entitled "Personal Protective Equipment: Evaluating Usage Among Inpatient and Outpatient Oncology Nurses" by Menonna-Quinn, Polovich, and Marshall (2019). In addition to furthering the body of knowledge regarding personal protective equipment (PPE) usage in the USP <800> era, the Hazardous Drug Handling Questionnaire that was used in the study can help other organizations improve their adherence by gaining a deeper understanding of barriers.

A Case of Myocardial Ischemia Detected by Global Longitudinal Strain Using Intraoperative Speckle-Tracking Echocardiography in a High-Risk Patient Undergoing Abdominal Aortic Aneurysm Repair.

BACKGROUND Global longitudinal strain (GLS) detected by echocardiography has been shown to have a prognostic role in the evaluation of myocardial ischemia in several clinical settings. A case is presented where GLS was used to detect intraoperative myocardial ischemia in a high-risk patient undergoing open abdominal aortic aneurysm repair. CASE REPORT A 75-year-old Caucasian man with non-insulin dependent diabetes mellitus and a 60 pack-year smoking history presented with a one-week history of exertional chest pain. Two-dimensional (2D) speckle-tracking echocardiography was used to calculate myocardial velocities and deformation parameters, including GLS. A reduced baseline GLS of -18.2% was found with dysfunction of the basal anterior, inferior, and mid anterolateral wall of the left ventricle. During aortic cross-clamping, his basal segments became mildly hypokinetic, although his ejection fraction (EF) remained unchanged at 50-55%. Despite normal left ventricular systolic function on visual assessment, his GLS decreased to -14.2% during aortic cross-clamping with similar segmental changes noted in the baseline GLS analysis. After the release of the aortic cross-clamp, his basal segments returned to normal and his left ventricular systolic function improved with an EF of 60-65% and the GLS recovered to -18.4% with improvement in the basal segmental function. CONCLUSIONS This case report showed that detection of GLS by echocardiography was a sensitive indicator of myocardial dysfunction that was superior to regional ventricular wall assessment. Detection of early changes in myocardial function by evaluating GLS may assist in guiding anesthetic management in high-risk patients with ischemic heart disease.