Chemotherapy roadmaps in pediatric oncology: A digital electronic medical record integrated solution.

BACKGROUND: Delivery of antineoplastic regimens in the pediatric setting is facilitated by a paper roadmap. Paper roadmaps are the key safety tool required for safe ordering. Electronic medical record systems offer technological solutions for ordering antineoplastic regimens, however, do not offer a solution that integrates paper roadmaps digitally. METHODS: A multidisciplinary project team implemented real-time clinician scanning of paper roadmaps into the electronic medical record. RESULTS: The rate of missing roadmaps decreased from an average of 1.6 to 0.8 per week. Pharmacists gained 3 h of productivity daily. Providers spend an average of 35-45 s and a total of seven clicks each time a roadmap is scanned. Overall, the clinical systems analyst spent less than 1 h of total build time. CONCLUSION: Implementing roadmap scanning decreased the rate of missing roadmaps, increased pharmacist productivity, and required a nominal amount of analyst and provider time. In addition, this solution allows for concurrent viewing of the roadmap files from any connected computer, facilitating an easier co-signature process for providers, pharmacists, and nurses. PRACTICE IMPLICATIONS: These results suggest that implementing real-time scanning of roadmaps can improve oncology care efficiency while maintaining the same safety rigor that paper roadmaps offer.

Care Coordination in a SARS-CoV-2-infected Child With Newly Diagnosed Medulloblastoma and Fanconi Anemia.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is responsible for a global pandemic that can cause severe infections in children, especially those with comorbid conditions. Here, we report a case of a child with a newly diagnosed medulloblastoma, Fanconi Anemia, and SARS-CoV-2 infection. Through multidisciplinary care coordination and meticulous planning, we were able to safely initiate this patient's oncology care and implement a long-term model to address the patient's care. This approach could be replicated with any newly diagnosed pediatric patient that requires monitoring for signs of COVID-19 with concurrent oncology care.

Use of Electronic Visibility Boards to Improve Patient Care Quality, Safety, and Flow on Inpatient Pediatric Acute Care Units.

PURPOSE: Effective information exchange among healthcare providers is critical to the delivery of high quality care. Electronic visibility boards (EVB) are an established tool for improving health care efficiency and promoting communication between healthcare team members. DESIGN AND METHODS: Seattle Children's Hospital (SCH) sought to evaluate the use of EVBs as a tool to improve patient care quality, safety and flow in a pediatric inpatient setting. EVBs were placed on the cancer and surgical patient care units at SCH, and displayed data flowing directly from the electronic health record. RESULTS: This paper describes the conceptual framework used for designing these boards, and details on the design methodology, testing approach, and successful deployment of the boards. CONCLUSIONS: The close collaboration between development analysts and clinical nursing is highlighted as a key to successful EVB implementation. Initial metrics indicate improvements in incentive spirometry compliance, nursing documentation of care plans, and flow awareness on the units. PRACTICE IMPLICATIONS: These results suggest that with appropriate design, EVBs can effectively enhance patient safety and care, and may be a useful tool for implementation on other pediatric inpatient units.

VaxCelerate II: rapid development of a self-assembling vaccine for Lassa fever.

Development of effective vaccines against emerging infectious diseases (EID) can take as much or more than a decade to progress from pathogen isolation/identification to clinical approval. As a result, conventional approaches fail to produce field-ready vaccines before the EID has spread extensively. Lassa is a prototypical emerging infectious disease endemic to West Africa for which no successful vaccine is available. We established the VaxCelerate Consortium to address the need for more rapid vaccine development by creating a platform capable of generating and pre-clinically testing a new vaccine against specific pathogen targets in less than 120 d A self-assembling vaccine is at the core of the approach. It consists of a fusion protein composed of the immunostimulatory Mycobacterium tuberculosis heat shock protein 70 (MtbHSP70) and the biotin binding protein, avidin. Mixing the resulting protein (MAV) with biotinylated pathogen-specific immunogenic peptides yields a self-assembled vaccine (SAV). To meet the time constraint imposed on this project, we used a distributed R&D model involving experts in the fields of protein engineering and production, bioinformatics, peptide synthesis/design and GMP/GLP manufacturing and testing standards. SAV immunogenicity was first tested using H1N1 influenza specific peptides and the entire VaxCelerate process was then tested in a mock live-fire exercise targeting Lassa fever virus. We demonstrated that the Lassa fever vaccine induced significantly increased class II peptide specific interferon-γ CD4(+) T cell responses in HLA-DR3 transgenic mice compared to peptide or MAV alone controls. We thereby demonstrated that our SAV in combination with a distributed development model may facilitate accelerated regulatory review by using an identical design for each vaccine and by applying safety and efficacy assessment tools that are more relevant to human vaccine responses than current animal models.

IL-15 participates in the respiratory innate immune response to influenza virus infection.

Following influenza infection, natural killer (NK) cells function as interim effectors by suppressing viral replication until CD8 T cells are activated, proliferate, and are mobilized within the respiratory tract. Thus, NK cells are an important first line of defense against influenza virus. Here, in a murine model of influenza, we show that virally-induced IL-15 facilitates the trafficking of NK cells into the lung airways. Blocking IL-15 delays NK cell entry to the site of infection and results in a disregulated control of early viral replication. By the same principle, viral control by NK cells can be therapeutically enhanced via intranasal administration of exogenous IL-15 in the early days post influenza infection. In addition to controlling early viral replication, this IL-15-induced mobilization of NK cells to the lung airways has important downstream consequences on adaptive responses. Primarily, depletion of responding NK1.1+ NK cells is associated with reduced immigration of influenza-specific CD8 T cells to the site of infection. Together this work suggests that local deposits of IL-15 in the lung airways regulate the coordinated innate and adaptive immune responses to influenza infection and may represent an important point of immune intervention.

Cutting edge: IL-15-independent maintenance of mucosally generated memory CD8 T cells.

Effective vaccines against intracellular pathogens rely on the generation and maintenance of memory CD8 T cells (T(mem)). Hitherto, evidence has indicated that CD8 T(mem) use the common γ-chain cytokine IL-15 for their steady-state maintenance in the absence of Ag. This evidence, however, has been amassed predominantly from models of acute, systemic infections. Given that the route of infection can have significant impact on the quantity and quality of the resultant T(mem), reliance on limited models of infection may restrict our understanding of long-term CD8 T(mem) survival. In this article, we show IL-15-independent generation, maintenance, and function of CD8 T(mem) after respiratory infection with influenza virus. Importantly, we demonstrate that alternating between mucosal and systemic deliveries of the identical virus prompts this change in IL-15 dependence, necessitating a re-evaluation of the current model of CD8 T(mem) maintenance.

A role for IL-15 in the migration of effector CD8 T cells to the lung airways following influenza infection.

The cytokines generated locally in response to infection play an important role in CD8 T cell trafficking, survival, and effector function, rendering these signals prime candidates for immune intervention. In this paper, we show that localized increases in the homeostatic cytokine IL-15 induced by influenza infection is responsible for the migration of CD8 effector T cells to the site of infection. Moreover, intranasal delivery of IL-15-IL-15Rα soluble complexes (IL-15c) specifically restores the frequency of effector T cells lost in the lung airways of IL-15-deficient animals after influenza infection. Exogenous IL-15c quantitatively augments the respiratory CD8 T cell response, and continued administration of IL-15c throughout the contraction phase of the anti-influenza CD8 T cell response magnifies the resultant CD8 T cell memory generated in situ. This treatment extends the ability of these cells to protect against heterologous infection, immunity that typically depreciates over time. Overall, our studies describe what to our knowledge is a new function for IL-15 in attracting effector CD8 T cells to the lung airways and suggest that adjuvanting IL-15 could be used to prolong anti-influenza CD8 T cell responses at mucosal surfaces to facilitate pathogen elimination.

Protein phosphatase 2A and Ca2+-activated K+ channels contribute to 11,12-epoxyeicosatrienoic acid analog mediated mesenteric arterial relaxation.

Epoxyeicosatrienoic acids (EETs) are considered to be endothelium-derived hyperpolarizing factors, and are potent activators of the large-conductance, Ca(2+)-activated K(+) (BK(Ca)) channel in vascular smooth muscle. Here, we investigate the signal transduction pathway involved in the activation of BK(Ca) channels by 11,12-EET and 11,12-EET stable analogs in rat mesenteric vascular smooth muscle cells. 11,12-EET and the 11,12-EET analogs, 11-nonyloxy-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE), 11-(9-hydroxy-nonyloxy)-undec-8(Z)-enoic acid (11,12-ether-EET-8-ZE-OH) and 11,12-trans-oxidoeicosa-8(Z)-enoic acid (11,12-tetra-EET-8-ZE), caused vasorelaxation of mesenteric resistance arteries. Mesenteric myocyte whole-cell (perforated-patch) currents were substantially (approximately 150%) increased by 11,12-EET and 11,12-EET analogs. Single-channel recordings were conducted to identify the target for 11,12-EET. 11,12-EET and 11,12-EET analogs also increased mesenteric myocyte BK(Ca) channel activity in cell-attached patches. Similar results were obtained in cell-free patches. Baseline mesenteric myocyte BK(Ca) channel activity (NPo) in cell-free patches averaged less than 0.001 at +50 mV and 11,12-EET (1 micromol/L) increased NPo to 0.03+/-0.02 and 11,12-EET analogs (1 micromol/L) increased NPo to 0.09+/-0.006. Inhibition of protein phosphatase 2A (PP2A) activity with okadaic acid (10 nmol/L) completely reversed 11,12-EET stimulated BK(Ca) channel activity and greatly attenuated 11,12-ether-EET-8-ZE mesenteric resistance artery vasorelaxation. 11,12-EET and 11,12-EET analogs increased mesenteric myocyte PP2A activity by 3.5-fold. Okadaic acid and the EET inhibitor, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE) inhibited the 11,12-EET mediated increase in PP2A activity. These findings provide initial evidence that PP2A activity contributes to 11,12-EET and 11,12-EET analog activation of mesenteric resistant artery BK(Ca) channels and vasorelaxation.

Substituted adamantyl-urea inhibitors of the soluble epoxide hydrolase dilate mesenteric resistance vessels.

The epoxyeicosatrienoic acids (EETs) have been identified as endothelium-derived hyperpolarizing factors. Metabolism of the EETs to the dihydroxyeicosatrienoic acids is catalyzed by soluble epoxide hydrolase (sEH). Administration of urea-based sEH inhibitors provides protection from hypertension-induced renal injury at least in part by lowering blood pressure. Here, we investigated the hypothesis that a mechanism by which sEH inhibitors elicit their cardiovascular protective effects is via their action on the vasculature. Mesenteric resistance arteries were isolated from Sprague-Dawley rats, pressurized, and constricted with the thromboxane A2 agonist U46619 (9,11-dideoxy-11,9-epoxymethano-prostaglandin F2alpha). Mesenteric arteries were then incubated with increasing concentrations of the sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). AUDA resulted in a concentration-dependent relaxation of mesenteric arteries, with 10 microM resulting in a 48 +/- 7% relaxation. Chain-shortened analogs of AUDA had an attenuated vasodilatory response. Interestingly, at 10 microM, the sEH inhibitors 1-cyclohexyl-3-dodecylurea, 12-(3-cyclohexylureido)dodecanoic acid, and 950 [adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea] were significantly less active, resulting in a 25 +/- 8%, 10 +/- 9%, and -8 +/- 3% relaxation, respectively. Treatment of mesenteric arteries with tetraethylammonium, iberiotoxin, ouabain, or glibenclamide did not alter AUDA-induced relaxation. The AUDA-induced relaxation was completely inhibited when constricted with KCl. In separate experiments, denuding mesenteric resistance vessels did not alter AUDA-induced relaxation. Taken together, these data demonstrate that adamantyl-urea inhibitors have unique dilator actions on vascular smooth muscle compared with other sEH inhibitors and that these dilator actions depend on the adamantyl group and carbon chain length.

Impaired Ca2+ signaling attenuates P2X receptor-mediated vasoconstriction of afferent arterioles in angiotensin II hypertension.

This study tested the hypothesis that afferent arteriolar responses to purinoceptor activation are attenuated, and Ca2+ signaling mechanisms are responsible for the blunted preglomerular vascular reactivity in angiotensin II (Ang II) hypertension. Experiments determined the effects of ATP, the P2X1 agonist beta,gamma-methylene ATP or the P2Y agonist UTP on arteriolar diameter using the juxtamedullary nephron technique and on renal myocyte intracellular Ca2+ concentration ([Ca2+]i) using single cell fluorescence microscopy. Six or 13 days of Ang II infusion significantly attenuated the vasoconstrictor responses to ATP and beta,gamma-methylene ATP (P<0.05). During exposure to ATP (1, 10, and 100 micromol/L), afferent diameter declined by 17+/-2%, 29+/-3%, and 30+/-2% in normal control rats and 8+/-3%, 7+/-3%, and 22+/-3% in kidneys of Ang II-infused rats (13 days). Renal myocyte intracellular calcium responses to ATP or beta,gamma-methylene ATP were also decreased in Ang II hypertensive rats. In myocytes of control rats, peak increases in [Ca2+]i averaged 107+/-21, 170+/-38, and 478+/-79 nmol/L at ATP concentrations of 1, 10, and 100 micromol/L, respectively. Ang II infusion for 13 days decreased the peak responses to ATP (1, 10, and 100 micromol/L) to 65+/-13, 102+/-20, and 367+/-73 nmol/L, respectively. The peak increases in [Ca2+]i in response to beta,gamma-methylene ATP were also reduced in Ang II hypertensive rats. However, angiotensin hypertension did not change the UTP-mediated vasoconstrictor responses or the myocyte calcium responses to UTP. These results indicate that the impaired autoregulatory response observed in Ang II-dependent hypertension can be attributed to impairment of P2X1 receptor-mediated signal transduction.