Faculty Bibliography

BACKGROUND:Endotracheal intubation in the emergency department (ED) is a critical and time-sensitive procedure requiring both technical skills and cognitive-based reasoning. Evidence on supervised resident-attending dyads with differing years of seniority on decision making during clinical encounters with endotracheal intubations is nascent. OBJECTIVE:To investigate the intersection of postgraduate years in clinical practice between resident and attending supervisor dyads and its associations for clinician choice of laryngoscopy technique and paralytic agent during ED intubations. METHODS:We conducted a retrospective analysis of intubations performed at a multi-site, urban, academic emergency medicine training program, analyzing institutional airway registry data from 2013 to 2023. Using a standardized predictor that accounted for similarity in years of clinical experience within a dyad between a resident and their supervising attending, we performed adjusted mixed-effects logistic regression examining the association of this dyad on two primary outcomes in endotracheal intubation decision making. Our primary outcome measures were the selection of a laryngoscopy technique (either DL or VL), and of a paralytic agent (either short-acting or long-acting) analyzed as categorical variables with a linear mixed effects model, using a binomial response distribution. RESULTS:We examined 2969 intubations for choice of laryngoscopy technique (n = 1117, 37.6 %) and paralytic agent (n = 967, 32.6 %). Higher adjusted odds (aOR) were associated with resident choice of DL over VL when years of experience between residents and supervising attendings were more concordant (aOR 3.05, 95 % CI: 1.1-8.2). Choice of paralytic agent was not associated with differing years of experience. CONCLUSION/CONCLUSIONS:Concordant years of experience between residents and their attendings were associated with technical skill-based laryngoscopy technique choice but not for cognitive-based reasoning in paralytic agent choice among ED intubations, suggesting supervising attending's years in clinical practice may influence decision making during time-sensitive procedures.

OBJECTIVE:To evaluate urinalysis testing patterns within the Veterans Health Administration (VHA), estimate the proportion and likelihood of patients who completed a urinalysis to have microscopic hematuria (MH), and explore how urinalysis testing patterns may influence MH detection. METHODS:This was a retrospective cross-sectional study using VHA data. We identified adult patients without a known urologic cancer history who had at least 1 outpatient visit at any VHA site and at least 1 interpretable urinalysis performed in 2015. The factors associated with the number or urinalyses performed on each patient and associations with the presence of MH were investigated. RESULTS:Among 5,719,966 adults, 39% completed a urinalysis. Variation in the proportion of patients who completed urinalyses was highest by age, among patients with hypertension and diabetes, and by region. Of patients who underwent urinalysis and had no prior genitourinary cancer history, 54% did not have an interpretable urinalysis result. Among patients with at least one interpretable microscopic urinalysis, 37% had MH. This was more common among older patients, females, current smokers, and patients with more comorbidities. Variation in the likelihood of patients having MH remained after adjusting for multiple factors and when contextualized by urinalysis completion and interpretability patterns. CONCLUSION/CONCLUSIONS:The number of urinalyses performed in the VHA system is remarkably high. Detection of MH is influenced by the frequency of urinalysis testing and interpretability of results. The presence and detection of MH varies by factors which should be considered when adjudicating the need for further evaluation of MH.

Astrocytic Ca²⁺ activity regulates activity-dependent synaptic plasticity, but its role in learning-related synaptic changes in the living brain remains unclear. We found that motor training induced synaptic potentiation on apical dendrites of layer 5 pyramidal neurons, as well as astrocytic Ca²⁺ rises in the mouse motor cortex. Reducing astrocytic Ca²⁺ led to synaptic depotentiation during motor training and subsequent impairment in performance improvement. Notably, synaptic depotentiation occurred on a fraction of dendrites with repetitive dendritic Ca²⁺ activity. On those dendrites, dendritic spines that were active before dendritic Ca²⁺ activity underwent CaMKII-dependent size reduction. In addition, the activation of adenosine receptors prevented repetitive dendritic Ca²⁺ activity and synaptic depotentiation caused by the reduction of astrocytic Ca²⁺, suggesting the involvement of ATP released from astrocytes and adenosine signaling in the processes. Together, these findings reveal the function of astrocytic Ca²⁺ in preventing synaptic depotentiation by limiting repetitive dendritic activity during learning.

OBJECTIVES/OBJECTIVE:To determine the relationships between the number and class of xerogenic medications on whole stimulated salivary flow rates and oral health-related quality of life (OH-QOL) measures in patients who received high-dose external beam radiation therapy (RT) for head and neck cancer (HNC). STUDY DESIGN/METHODS:Complete medication lists were generated using patient electronic health records from every attended study visit for 146 HNC patients. Whole stimulated salivary flow was measured before RT, and 6 and 18-months after RT. Ten single-item questions and two composite scales of swallowing problems and senses problems (taste and smell) were assessed at baseline and at 6-month intervals up to 24 months after RT. Linear mixed-effects models examined associations between the total number and class of medications and stimulated salivary flow and OH-QOL. RESULTS:There was no detected association between the total number of medications and stimulated salivary flow (p-value = .18). Only antidepressant usage was significantly associated with stimulated salivary flow (P = .006). Number of medications, narcotic analgesic, and antidepressant usage were significantly associated with a clinically meaningful decrease in OH-QOL. CONCLUSION/CONCLUSIONS:Antidepressants were associated with reduced stimulated salivary flow, but no cumulative negative effect on whole stimulated salivary flow was identified. Polypharmacy was associated with worse OH-QOL.

Cajal-Retzius (CR) cells are glutamatergic neurons that transiently populate the most superficial layer of the isocortex and allocortex during development, serving an essential role during both prenatal and early postnatal brain development. Notably, these cells disappear from most cortical areas by postnatal day 14 but persist for much longer in the hippocampus. We developed a novel intersectional genetic labeling approach for CR cells that captures almost all of the TRP73-positive CR cells throughout the isocortex and allocortex. This intersectional strategy offers several advantages over previous methods commonly used for CR cell targeting. Here, we applied this new CR cell-labeling strategy to investigate the distribution and persistence of CR cells throughout the whole mouse brain at four different postnatal ages. We observed that the initial CR cell density and the rate of their disappearance vary substantially across different brain areas during development. Strikingly, we observed variation in cell death rate even between adjacent cortical subregions: comparing the medial and the lateral entorhinal cortex, the former retains a high density of CR cells for several months in contrast to the latter. Our results present a necessary revision of the phenomenon of CR cell persistence, showing that, in addition to the hippocampus, several other cortical areas maintain a high density of these cells beyond the first 2 postnatal weeks.

Focused transcranial ultrasound stimulation (TUS) can affect neural activity with high spatial precision, advancing noninvasive neuromodulation toward targeted treatment of brain disorders. Direct monitoring of TUS responses is crucial for ensuring optimal outcomes. Blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging has primarily been used for studying TUS effects in both human and nonhuman primate brains. However, the physiology and mechanisms underlying BOLD remain largely unknown due to its highly convoluted nature. To address these limitations, we developed a hybrid system for concurrent optoacoustic and magnetic resonance imaging of TUS (OMRITUS) to comprehensively characterize the hemodynamic changes in murine brains. Our findings reveal paradoxical negative BOLD signals in the activated cortical regions, coupled with increased total hemoglobin levels simultaneously monitored with optoacoustic tomography. Multispectral optoacoustic readings further demonstrated a stronger increase in deoxygenated versus oxygenated hemoglobin, suggesting a potential molecular basis for the negative BOLD responses. OMRITUS enables the study of complex TUS-hemodynamic interactions, paving the way for precise neuromodulatory interventions.

Flexibility and stability of neuronal ensembles are crucial features of brain function. Little is known about how these properties of local circuits are influenced by long-range inputs. We show that lateral entorhinal cortex glutamatergic (LEC_GLU) and GABAergic (LEC_GABA) projections to CA3 recruit specific microcircuits that conjunctively provide stability to neuronal ensembles supporting learning. LEC_GLU drives excitation in CA3 but also substantial feedforward inhibition that prevents somatic and dendritic spikes. Conversely, LEC_GABA suppresses this local inhibition to disinhibit CA3 activity with compartment- and pathway-specificity by selectively boosting somatic output to integrated LEC_GLU and CA3 recurrent inputs. This synergy allows the stabilization of spatial representations relevant to learning, as both LEC_GLU and LEC_GABA control the formation and maintenance of CA3 place cells across contexts and over time.

Soluble tau oligomeric assemblies display neurotoxic properties and may provide a pathogenic link between neurofibrillary tangle evolution and selective neuronal vulnerability in Alzheimer's disease (AD). However, the precise molecular and cellular pathways mediating tau oligomer toxicity are unclear. We combined single-neuron laser capture microdissection with custom microarrays to investigate differences in the molecular signatures of basal forebrain neurons within the nucleus basalis of Meynert (nbM) labeled for p75^NTR, a cholinergic cell marker, or dual-labeled for p75^NTR and TOC1, a tau oligomer marker. Tissue was obtained postmortem from Rush Religious Orders Study participants who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Using clinical diagnosis as a covariate to isolate tau oligomer-specific mechanisms, we identified 140 differentially expressed genes (DEGs) in p75^NTR + /TOC1 + cholinergic nbM neurons compared to p75^NTR + /TOC1- neurons. STRING interactome and pathway analysis revealed that downregulated genes were associated with pre- and postsynaptic function, with additional enrichment in glutamate and acetylcholine signaling. By contrast, upregulated genes related to cellular stress responses and apoptosis were clustered with a subset of downregulated DEGs regulating mitochondrial metabolism and redox function, indicative of bioenergetic failure. Weighted gene co-expression correlation network analysis of the entire dataset revealed only two significantly correlated modules, which were either negatively correlated with the presence of TOC1 and enriched for synaptic signaling or positively correlated with TOC1 and enriched for cellular responses to hypoxia. These data show with single-neuron resolution that oligomeric tau formation in vulnerable cholinergic nbM neurons, even prior to MCI, is associated with the dysregulation of multiple classes of genes driving cell/mitochondrial stress and synaptic imbalances, which may be amenable for disease-modifying therapeutic approaches.

PURPOSE/OBJECTIVE:Establish the minimally clinically important difference (MCID) for the Orthostatic Hypotension Questionnaire (OHQ). BACKGROUND:Neurogenic orthostatic hypotension (nOH) causes disabling symptoms that impair daily function and quality of life. The OHQ is a validated patient-reported outcome with a symptom assessment (OHSA) and daily activity scale (OHDAS), widely used in clinical trials, despite the MCID being unestablished. METHODS:We analyzed data from two phase 3, randomized placebo-controlled trials (SEQUOIA and REDWOOD), evaluating ampreloxetine for symptomatic nOH in patients with Parkinson disease, multiple system atrophy, and pure autonomic failure. Using anchor-based and distribution-based methods, we calculated the MCID for the total OHQ score, OHSA and OHDAS composite subscales, and for the single dizziness/lightheadedness question (OHSA1). RESULTS:The analysis included 184 subjects from SEQUOIA and 128 from REDWOOD. The total OHQ MCID for improvement was a reduction of 0.9-1.2 points and for worsening was an increase of 0.7-1.1 points. The MCID for the OHSA composite ranged from a reduction of 0.9-1.3 points for improvement and an increase of 0.7-1.1 points for worsening. For the single-item OHSA1, the MCID was a reduction of 2.0-3.0 points for improvement and an increase of 1.0 point for worsening. Owing to poor correlation with the symptom-based anchors, a reliable MCID for the OHDAS component was not established. CONCLUSIONS:These MCID thresholds for the OHQ, OHSA and OHSA item 1 alone, enhance the interpretability of scores and support their use in evaluating clinical benefit.