Unscheduled return visits to the emergency department with ICU admission: A trigger tool for diagnostic error.

BACKGROUND: It is believed that patients who return to the Emergency Department (ED) and require admission are thought to represent failures in diagnosis, treatment or discharge planning. Screening readmission rates or patients who return within 72 h have been used in ED Quality Assurance efforts. These metrics require significant effort in chart review and only rarely identify care deviations. OBJECTIVE: This study was conducted to evaluate the yield of reviewing ED return visits that resulted in an ICU admission. This study was conducted to evaluate the yield of reviewing ED return visits that resulted in an ICU admission. We planned to assess if the return visits with ICU admission were associated with deviations in care, and secondarily, to understand the common causes of error in this group. METHODS: Retrospective review of patients presenting to a university affiliated ED between January 1, 2005 and December 31, 2015 and returned within 14 days requiring ICU admission. RESULTS: From 1,106,606 ED visits, 511 patients returned within 14 days and were admitted to an ICU. 223 patients returned for a reason related to the index visit (43.6%). Of these related returns, 31 (13.9%) had a deviation in care on the index visit. When a standard diagnostic process of care framework was applied to these 31 cases, 47.3% represented failures in the initial diagnostic pathway. CONCLUSION: Reviewing 14-day returns leading to ICU admission, while an uncommon event, has a higher yield in the understanding of quality issues involving diagnostic as well as systems errors.

Dorsal BNST α2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors.

Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.

Delays in the Air or Ground Transfer of Patients for Endovascular Thrombectomy.

BACKGROUND AND PURPOSE: For suspected large vessel occlusion patients efficient transfer to centers that provide endovascular therapy (ET) is critical to maximizing treatment opportunity. Our objective was to examine associations between transfer time, modes of transfer, ET, and outcomes within a hub-and-spoke telestroke network. METHODS: Patients with ischemic stroke were included if transferred to a single hub hospital between January 2011 and October 2015 with National Institutes of Health Stroke Scale>6, onset<12 hours from hub arrival with complete clinical, imaging, and transfer data. Transfer time was the interval between initiation of telestroke consult and arrival at the hub. Algorithms were created for ideal transfer times; ideal time was subtracted from actual time to calculate delay. We examined bivariate relationships between transfer time and several clinical outcomes and used multivariable regression modeling to explore possible predictors of delay. RESULTS: Of 234 patients that met inclusion criteria, 51% were transferred by ambulance and 49% by helicopter; 27% underwent ET (36% achieved modified Rankin Scale score of 0-2 at 90 days). Median actual transfer time was 132 minutes (interquartile range, 103-165), compared with median ideal transfer time at 102 minutes (interquartile range, 96-123). Longer transfer time was associated with decreased likelihood of undergoing ET (odds ratio, 0.990; P=0.003). Nocturnal transfer (18:00 to 06:00 hours) was associated with significantly longer delay (ß=20.5; P<0.0005), whereas intravenous tissue-type plasminogen activator (tPA) delivery at spoke hospital was not. The median delay for nocturnal transfer was 31 minutes (interquartile range, 11-51), compared with daytime at 14 minutes (interquartile range, -9 to 36). CONCLUSIONS: Within a large telestroke network, there was an association between longer transfer time and decreased likelihood of undergoing ET. Nocturnal transfers were associated with a substantial delay relative to daytime transfers. In contrast, delivery of tPA was not associated with delays, underscoring the impact of effective protocols at spoke hospitals. More efficient transfer may enable higher ET treatment rates. Metrics and protocols for transfer, especially at night, may improve transfer times.

α(2A)-adrenergic receptors filter parabrachial inputs to the bed nucleus of the stria terminalis.

α2-adrenergic receptors (AR) within the bed nucleus of the stria terminalis (BNST) reduce stress-reward interactions in rodent models. In addition to their roles as autoreceptors, BNST α(2A)-ARs suppress glutamatergic transmission. One prominent glutamatergic input to the BNST originates from the parabrachial nucleus (PBN) and consists of asymmetric axosomatic synapses containing calcitonin gene-related peptide (CGRP) and vGluT2. Here we provide immunoelectron microscopic data showing that many asymmetric axosomatic synapses in the BNST contain α(2A)-ARs. Further, we examined optically evoked glutamate release ex vivo in BNST from mice with virally delivered channelrhodopsin2 (ChR2) expression in PBN. In BNST from these animals, ChR2 partially colocalized with CGRP, and activation generated EPSCs in dorsal anterolateral BNST neurons that elicited two cell-type-specific outcomes: (1) feedforward inhibition or (2) an EPSP that elicited firing. We found that the α(2A)-AR agonist guanfacine selectively inhibited this PBN input to the BNST, preferentially reducing the excitatory response in ex vivo mouse brain slices. To begin to assess the overall impact of α(2A)-AR control of this PBN input on BNST excitatory transmission, we used a Thy1-COP4 mouse line with little postsynaptic ChR2 expression nor colocalization of ChR2 with CGRP in the BNST. In slices from these mice, we found that guanfacine enhanced, rather than suppressed, optogenetically initiated excitatory drive in BNST. Thus, our study reveals distinct actions of PBN afferents within the BNST and suggests that α(2A)-AR agonists may filter excitatory transmission in the BNST by inhibiting a component of the PBN input while enhancing the actions of other inputs.

Noradrenergic control of the bed nucleus of the stria terminalis in stress and reward.

The bed nucleus of the stria terminalis (BNST) is a group of inter-connected subnuclei that play critical roles in stress-reward interactions. An interesting feature of this brain region is the massive noradrenergic input that it receives. Important roles for norepinephrine in this region have been documented in a number of stress and reward related behaviors. This work has been paralleled over the last several years by efforts to understand the actions of norepinephrine on neuronal function in the region. In this review, we will summarize the current state of these research areas.

Patterning of embryonic stem cells using the bio flip chip.

Cell-cell interactions consisting of diffusible signaling and cell-cell contact (juxtacrine signaling) are important in numerous biological processes such as tumor growth, stem cell differentiation, and stem cell self-renewal. A number of methods currently exist to modulate cell signaling in vitro. One method of modulating the total amount of diffusible signaling is to vary the cell seeding density during culture. Due to the random nature of cell seeding, this results in considerable variation in the actual cell-cell spacing and amount of cell-cell contact, and cannot prescribe the local environment. A more specific approach for modulating cell signaling is to use molecular inhibitors or genetic approaches to knock down specific signaling proteins, but both of these methods are best suited to manipulating small numbers of molecules. Here, we demonstrate a new approach to modulating cell-cell signaling that modulates the local environment of a cluster of cells by placing different numbers of cells at desired locations on a substrate. This method provides a complementary way to control the local diffusible and juxtacrine signaling between cells. Our method makes use of the Bio Flip Chip (BFC), a microfabricated silicone chip containing hundreds-to-thousands of microwells, each sized to hold either a single cell or small numbers of cells. We load the chip with cells simply by pipetting them onto the array of wells and washing unloaded cells off the array. The chip is then flipped onto a substrate, whereby the cells fall out of the wells and onto the substrate, maintaining their patterning. After the cells have attached, the chip can be removed (or left on). This approach to cell patterning is unique in that it: 1) doesn't alter the chemistry of the substrate, thus allowing cells to proliferate and migrate; 2) allows patterning onto any substrate, including tissue-culture polystyrene, glass, matrigel, and even feeder cell layers; and 3) is compatible with traditional microcontact printing, allowing the creation of extracellular matrix islands with cells placed inside those islands. In this video, we demonstrate the patterning of mouse embryonic stem cells onto tissue-culture polystyrene using the BFC.