Standardizing Postoperative Handoffs Using the Evidence-Based IPASS Framework Improves Handoff Communication for Postoperative Neurosurgical Patients in the Neuro-Intensive Care Unit

Aims for Improvement Within one year of initiation of the process improvement plan, we wanted to improve: Direct communication of airway and hemodynamic concerns Direct communication of operative events, complications, and perioperative management goals. Attendance at postoperative handoffs Confirmation of information by receiving teams Staff perceptions of handoff efficacy and teamwork

Doctor of Philosophy

dissertationDuring development, axons are generated by specialized structures called growth cones in response to chemical guidance cues. When a growth cone reaches its target, a synapse is formed, the growth cone collapses, and the axon is stable. In mature neurons, the architecture and synaptic connections are then maintained as the neuron is subjected to growth, physical forces and age. I am studying this developmental transition: How do neurons switch from an embryonic state to a mature differentiated state? And how is the mature state maintained? To identify new genes required for axon stability we screened for C. elegans mutants with phenotypes in which growth cones do not collapse after synapse formation, but continue to sprout into adulthood. We found that mutations in casein kinase 1δ (kin- 20 in C. elegans) disrupt nervous system architecture as a result of continued growth cone sprouting; thus, a function of casein kinase 1δ is to stabilize neuronal architecture and inhibit growth cone sprouting. The identification of a kinase in this process suggests that the stabilization of axon morphology requires a signaling pathway. To identify the signaling pathway downstream of casein kinase 1δ, we performed a kin-20 suppressor screen. These screens identified 11 genes that when mutated restore stable mature neurons in the kin-20 mutant. Most of the suppressor mutations are in 9 genes associated with transcriptional pausing and termination: one mutation likely disinhibits the closely related CK1α and two of the suppressor mutations directly disrupt the termination site for the short form of unc-44. We found that casein kinase 1δ is required iv for the expression of the giant isoform of ankyrin / UNC-44, and that second-site mutations in the RNA polymerase-II termination complex restore expression of ankyrin and rescue the kin-20 casein kinase mutants. We found that CK1δ can phosphorylate the RNA polymerase II phosphatase SSUP-72 (found as a suppressor of kin-20) directly and based on genetics experiments, phosphorylation of SSUP-72 is sufficient for expression of long ankyrin. In summary, my dissertation led to the discovery of a novel axon maturation signaling pathway (Chapter 2). This pathway begins with a conserved kinase, which acts through an RNA-polymerase II termination phosphatase, to express a neuron-specific giant isoform of ankyrin, required for axon maturation and maintenance

Improving Postoperative Handoffs in the Neuro-Intensive Care Unit

Introduction Transitions of care represent a major source of medical errors, patient morbidity/mortality, and increased healthcare waste. 2018 CLER report indicated largely unfavorable responses toward handoffs and care transitions for perioperative services and neurointensive care. Use of the IPASS handoff tool is associated with up to 30% reduction in adverse events and 23% reduction in medical errors. Implementation of IPASS for postoperative handoffs in the SICU resulted in improved organization, safety, and communication.https://jdc.jefferson.edu/patientsafetyposters/1146/thumbnail.jp

Genomic and Phenotypic Analysis of COVID-19-Associated Pulmonary Aspergillosis Isolates of Aspergillus fumigatus

The ongoing global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for coronavirus disease 2019 (COVID-19), first described in Wuhan, China. A subset of COVID-19 patients has been reported to have acquired secondary infections by microbial pathogens, such as opportunistic fungal pathogens from the genus Aspergillus. To gain insight into COVID-19-associated pulmonary aspergillosis (CAPA), we analyzed the genomes and characterized the phenotypic profiles of four CAPA isolates of Aspergillus fumigatus obtained from patients treated in the area of North Rhine-Westphalia, Germany. By examining the mutational spectrum of single nucleotide polymorphisms, insertiondeletion polymorphisms, and copy number variants among 206 genes known to modulate A. fumigatus virulence, we found that CAPA isolate genomes do not exhibit significant differences from the genome of the Af293 reference strain. By examining a number of factors, including virulence in an invertebrate moth model, growth in the presence of osmotic, cell wall, and oxidative stressors, secondary metabolite biosynthesis, and the MIC of antifungal drugs, we found that CAPA isolates were generally, but not always, similar to A. fumigatus reference strains Af293 and CEA17. Notably, CAPA isolate D had more putative loss-of-function mutations in genes known to increase virulence when deleted. Moreover, CAPA isolate D was significantly more virulent than the other three CAPA isolates and the A. fumigatus reference strains Af293 and CEA17, but similarly virulent to two other clinical strains of A. fumigatus. These findings expand our understanding of the genomic and phenotypic characteristics of isolates that cause CAPA. IMPORTANCE The global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID19), has already killed millions of people. COVID-19 patient outcome can be further complicated by secondary infections, such as COVID-19-associated pulmonary aspergillosis (CAPA). CAPA is caused by Aspergillus fungal pathogens, but there is little information about the genomic and phenotypic characteristics of CAPA isolates. We conducted genome sequencing and extensive phenotyping of four CAPA isolates of Aspergillus fumigatus from Germany. We found that CAPA isolates were often, but not always, similar to other reference strains of A. fumigatus across 206 genetic determinants of infection-relevant phenotypes, including virulence. For example, CAPA isolate D was more virulent than other CAPA isolates and reference strains in an invertebrate model of fungal disease, but similarly virulent to two other clinical strains. These results expand our understanding of COVID-19-associated pulmonary aspergillosis

Reporting Guidelines, Review of Methodological Standards, and Challenges Toward Harmonization in Bone Marrow Adiposity Research. Report of the Methodologies Working Group of the International Bone Marrow Adiposity Society

The interest in bone marrow adiposity (BMA) has increased over the last decade due to its association with, and potential role, in a range of diseases (osteoporosis, diabetes, anorexia, cancer) as well as treatments (corticosteroid, radiation, chemotherapy, thiazolidinediones). However, to advance the field of BMA research, standardization of methods is desirable to increase comparability of study outcomes and foster collaboration. Therefore, at the 2017 annual BMA meeting, the International Bone Marrow Adiposity Society (BMAS) founded a working group to evaluate methodologies in BMA research. All BMAS members could volunteer to participate. The working group members, who are all active preclinical or clinical BMA researchers, searched the literature for articles investigating BMA and discussed the results during personal and telephone conferences. According to the consensus opinion, both based on the review of the literature and on expert opinion, we describe existing methodologies and discuss the challenges and future directions for (1) histomorphometry of bone marrow adipocytes, (2) ex vivo BMA imaging, (3) in vivo BMA imaging, (4) cell isolation, culture, differentiation and in vitro modulation of primary bone marrow adipocytes and bone marrow stromal cell precursors, (5) lineage tracing and in vivo BMA modulation, and (6) BMA biobanking. We identify as accepted standards in BMA research: manual histomorphometry and osmium tetroxide 3D contrast-enhanced μCT for ex vivo quantification, specific MRI sequences (WFI and H-MRS) for in vivo studies, and RT-qPCR with a minimal four gene panel or lipid-based assays for in vitro quantification of bone marrow adipogenesis. Emerging techniques are described which may soon come to complement or substitute these gold standards. Known confounding factors and minimal reporting standards are presented, and their use is encouraged to facilitate comparison across studies. In conclusion, specific BMA methodologies have been developed. However, important challenges remain. In particular, we advocate for the harmonization of methodologies, the precise reporting of known confounding factors, and the identification of methods to modulate BMA independently from other tissues. Wider use of existing animal models with impaired BMA production (e.g., Pfrt-/-, KitW/W-v) and development of specific BMA deletion models would be highly desirable for this purpose.status: publishe

Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling

<p>Abstract</p> <p>Background</p> <p>Multiple adverse events are associated with the use of morphine for the treatment of chronic non-cancer pain, including opioid-induced hyperalgesia (OIH). Mechanisms of OIH are independent of opioid tolerance and may involve the morphine metabolite morphine-3-glucuronide (M3G). M3G exhibits limited affinity for opioid receptors and no analgesic effect. Previous reports suggest that M3G can act via the Toll-like receptor 4 (TLR4)/myeloid differentiation protein-2 (MD-2) heterodimer in the central nervous system to elicit pain.</p> <p>Methods</p> <p>Immunoblot and immunocytochemistry methods were used to characterize the protein expression of TLR4 present in lumbar dorsal root ganglion (DRG). Using <it>in vitro</it> intracellular calcium and current clamp techniques, we determined whether TLR4 activation as elicited by the prototypical agonists of TLR4, lipopolysaccharide (LPS) and M3G, contributed to changes in intracellular calcium and increased excitation. Rodents were also injected with M3G to determine the degree to which M3G-induced tactile hyperalgesia could be diminished using either a small molecule inhibitor of the MD-2/TLR4 complex in rats or TLR4 knockout mice. Whole cell voltage-clamp recordings were made from small- and medium-diameter DRG neurons (25 μm < DRG diameter <45 μm) for both control and M3G-treated neurons to determine the potential influence on voltage-gated sodium channels (NaVs).</p> <p>Results</p> <p>We observed that TLR4 immunoreactivity was present in peptidergic and non-peptidergic sensory neurons in the DRG. Non-neuronal cells in the DRG lacked evidence of TLR4 expression. Approximately 15% of assayed small- and medium-diameter sensory neurons exhibited a change in intracellular calcium following LPS administration. Both nociceptive and non-nociceptive neurons were observed to respond, and approximately 40% of these cells were capsaicin-insensitive. Increased excitability observed in sensory neurons following LPS or M3G could be eliminated using Compound 15, a small molecule inhibitor of the TLR4/MD-2 complex. Likewise, systemic injection of M3G induced rapid tactile, but not thermal, nociceptive behavioral changes in the rat, which were prevented by pre-treating animals with Compound 15. Unlike TLR4 wild-type mice, TLR4 knockout mice did not exhibit M3G-induced hyperalgesia. As abnormal pain sensitivity is often associated with NaVs, we predicted that M3G acting via the MD-2/TLR4 complex may affect the density and gating of NaVs in sensory neurons. We show that M3G increases tetrodotoxin-sensitive and tetrodotoxin-resistant (NaV1.9) current densities.</p> <p>Conclusions</p> <p>These outcomes provide evidence that M3G may play a role in OIH via the TLR4/MD-2 heterodimer complex and biophysical properties of tetrodotoxin-sensitive and tetrodotoxin-resistant NaV currents.</p