Evaluating the Reliability of a Remote Acuity Prediction Tool in a Canadian Academic Emergency Department.

STUDY OBJECTIVE: There is increasing interest in harnessing artificial intelligence to virtually triage patients seeking care. The objective was to examine the reliability of a virtual machine learning algorithm to remotely predict acuity scores for patients seeking emergency department (ED) care by applying the algorithm to retrospective ED data. METHODS: This was a retrospective review of adult patients conducted at an academic tertiary care ED (annual census 65,000) from January 2021 to August 2022. Data including ED visit date and time, patient age, sex, reason for visit, presenting complaint and patient-reported pain score were used by the machine learning algorithm to predict acuity scores. The algorithm was designed to up-triage high-risk complaints to promote safety for remote use. The predicted scores were then compared to nurse-led triage scores previously derived in real time using the electronic Canadian Triage and Acuity Scale (eCTAS), an electronic triage decision-support tool used in the ED. Interrater reliability was estimated using kappa statistics with 95% confidence intervals (CIs). RESULTS: In total, 21,469 unique ED patient encounters were included. Exact modal agreement was achieved for 10,396 (48.4%) patient encounters. Interrater reliability ranged from poor to fair, as estimated using unweighted kappa (0.18, 95% CI 0.17 to 0.19), linear-weighted kappa (0.25, 95% CI 0.24 to 0.26), and quadratic-weighted kappa (0.36, 95% CI 0.35 to 0.37) statistics. Using the nurse-led eCTAS score as the reference, the machine learning algorithm overtriaged 9,897 (46.1%) and undertriaged 1,176 (5.5%) cases. Some of the presenting complaints under-triaged were conditions generally requiring further probing to delineate their nature, including abnormal lab/imaging results, visual disturbance, and fever. CONCLUSION: This machine learning algorithm needs further refinement before being safely implemented for patient use.

Cost Evaluation of the Ontario Virtual Urgent Care Pilot Program: Population-Based, Matched Cohort Study.

BACKGROUND: In 2020, the Ministry of Health (MoH) in Ontario, Canada, introduced a virtual urgent care (VUC) pilot program to provide alternative access to urgent care services and reduce the need for in-person emergency department (ED) visits for patients with low acuity health concerns. OBJECTIVE: This study aims to compare the 30-day costs associated with VUC and in-person ED encounters from an MoH perspective. METHODS: Using administrative data from Ontario (the most populous province of Canada), a population-based, matched cohort study of Ontarians who used VUC services from December 2020 to September 2021 was conducted. As it was expected that VUC and in-person ED users would be different, two cohorts of VUC users were defined: (1) those who were promptly referred to an ED by a VUC provider and subsequently presented to an ED within 72 hours (these patients were matched to in-person ED users with any discharge disposition) and (2) those seen by a VUC provider with no referral to an in-person ED (these patients were matched to patients who presented in-person to the ED and were discharged home by the ED physician). Bootstrap techniques were used to compare the 30-day mean costs of VUC (operational costs to set up the VUC program plus health care expenditures) versus in-person ED care (health care expenditures) from an MoH perspective. All costs are expressed in Canadian dollars (a currency exchange rate of CAD $1=US $0.76 is applicable). RESULTS: We matched 2129 patients who presented to an ED within 72 hours of VUC referral and 14,179 patients seen by a VUC provider without a referral to an ED. Our matched populations represented 99% (2129/2150) of eligible VUC patients referred to the ED by their VUC provider and 98% (14,179/14,498) of eligible VUC patients not referred to the ED by their VUC provider. Compared to matched in-person ED patients, 30-day costs per patient were significantly higher for the cohort of VUC patients who presented to an ED within 72 hours of VUC referral ($2805 vs $2299; difference of $506, 95% CI $139-$885) and significantly lower for the VUC cohort of patients who did not require ED referral ($907 vs $1270; difference of $362, 95% CI 284-$446). Overall, the absolute 30-day costs associated with the 2 VUC cohorts were $18.9 million (ie, $6.0 million + $12.9 million) versus $22.9 million ($4.9 million + $18.0 million) for the 2 in-person ED cohorts. CONCLUSIONS: This costing evaluation supports the use of VUC as most complaints were addressed without referral to ED. Future research should evaluate targeted applications of VUC (eg, VUC models led by nurse practitioners or physician assistants with support from ED physicians) to inform future resource allocation and policy decisions.

Regulation of extracellular progranulin in medial prefrontal cortex.

Progranulin is a secreted pro-protein that has anti-inflammatory and neurotrophic effects and is necessary for maintaining lysosomal function. Mutations in progranulin (GRN) are a major cause of frontotemporal dementia. Most pathogenic GRN mutations cause progranulin haploinsufficiency, so boosting progranulin levels is a promising therapeutic strategy. Progranulin is constitutively secreted, then taken up and trafficked to lysosomes. Before being taken up from the extracellular space, progranulin interacts with receptors that may mediate anti-inflammatory and growth factor-like effects. Modifying progranulin trafficking is a viable approach to boosting progranulin, but progranulin secretion and uptake by cells in the brain is poorly understood and may involve distinct mechanisms from other parts of the body. Understanding the cell types and processes that regulate extracellular progranulin in the brain could provide insight into progranulin's mechanism of action and inform design of progranulin-boosting therapies. To address this question we used microdialysis to measure progranulin in interstitial fluid (ISF) of mouse medial prefrontal cortex (mPFC). Grn+/- mice had approximately 50% lower ISF progranulin than wild-type mice, matching the reduction of progranulin in cortical tissue. Fluorescent in situ hybridization and immunofluorescence confirmed that microglia and neurons are the major progranulin-expressing cell types in the mPFC. Studies of conditional microglial (Mg-KO) and neuronal (N-KO) Grn knockout mice revealed that loss of progranulin from either cell type results in approximately 50% reduction in ISF progranulin. LPS injection (i.p.) produced an acute increase in ISF progranulin in mPFC. Depolarizing cells with KCl increased ISF progranulin, but this response was not altered in N-KO mice, indicating progranulin secretion by non-neuronal cells. Increasing neuronal activity with picrotoxin did not increase ISF progranulin. These data indicate that microglia and neurons are the source of most ISF progranulin in mPFC, with microglia likely secreting more progranulin per cell than neurons. The acute increase in ISF progranulin after LPS treatment is consistent with a role for extracellular progranulin in regulating inflammation, and may have been driven by microglia or peripheral immune cells. Finally, these data indicate that mPFC neurons engage in constitutive progranulin secretion that is not acutely changed by neuronal activity.

Health care utilization and outcomes of patients seen by virtual urgent care versus in-person emergency department care.

BACKGROUND: Virtual urgent care (VUC) is intended to support diversion of patients with low-acuity complaints and reduce the need for in-person emergency department visits. We aimed to describe subsequent health care utilization and outcomes of patients who used VUC compared with similar patients who had an in-person emergency department visit. METHODS: We used patient-level encounter data that were prospectively collected for patients using VUC services provided by 14 pilot programs in Ontario, Canada. We linked the data to provincial administrative databases to identify subsequent 30-day health care utilization and outcomes. We defined 2 subgroups of VUC users; those with a documented prompt referral to an emergency department by a VUC provider, and those without. We matched patients in each cohort to an equal number of patients presenting to an emergency department in person, based on encounter date, medical concern and the logit of a propensity score. For the subgroup of patients not promptly referred to an emergency department, we matched patients to those who were seen in an emergency department and then discharged home. RESULTS: Of the 19 595 patient VUC visits linked to administrative data, we matched 2129 patients promptly referred to the emergency department by a VUC provider to patients presenting to the emergency department in person. Index visit hospital admissions (9.4% v. 8.7%), 30-day emergency department visits (17.0% v. 17.5%), and hospital admissions (12.9% v. 11.0%) were similar between the groups. We matched 14 179 patients who were seen by a VUC provider with no documented referral to the emergency department. Patients seen by VUC were more likely to have a subsequent in-person emergency department visit within 72 hours (13.7% v. 7.0%), 7 days (16.5% v. 10.3%) and 30 days (21.9% v. 17.9%), but hospital admissions were similar within 72 hours (1.1% v. 1.3%), and higher within 30 days for patients who were discharged home from the emergency department (2.6% v. 3.4%). INTERPRETATION: The impact of the provincial VUC pilot program on subsequent health care utilization was limited. There is a need to better understand the inherent limitations of virtual care and ensure future virtual providers have timely access to in-person outpatient resources, to prevent subsequent emergency department visits.

Development of a machine learning-based acuity score prediction model for virtual care settings.

OBJECTIVE: Healthcare is increasingly digitized, yet remote and automated machine learning (ML) triage prediction systems for virtual urgent care use remain limited. The Canadian Triage and Acuity Scale (CTAS) is the gold standard triage tool for in-person care in Canada. The current work describes the development of a ML-based acuity score modelled after the CTAS system. METHODS: The ML-based acuity score model was developed using 2,460,109 de-identified patient-level encounter records from three large healthcare organizations (Ontario, Canada). Data included presenting complaint, clinical modifiers, age, sex, and self-reported pain. 2,041,987 records were high acuity (CTAS 1-3) and 416,870 records were low acuity (CTAS 4-5). Five models were trained: decision tree, k-nearest neighbors, random forest, gradient boosting regressor, and neural net. The outcome variable of interest was the acuity score predicted by the ML system compared to the CTAS score assigned by the triage nurse. RESULTS: Gradient boosting regressor demonstrated the greatest prediction accuracy. This final model was tuned toward up triaging to minimize patient risk if adopted into the clinical context. The algorithm predicted the same score in 47.4% of cases, and the same or more acute score in 95.0% of cases. CONCLUSIONS: The ML algorithm shows reasonable predictive accuracy and high predictive safety and was developed using the largest dataset of its kind to date. Future work will involve conducting a pilot study to validate and prospectively assess reliability of the ML algorithm to assign acuity scores remotely.

A method for estimating binding affinity from primary DEL selection data.

DEL selections are binding assays conducted with mixtures of chemically diverse DNA-tagged ligands and a screening target. DEL selections use DNA sequence counts to measure target binding, where ideally higher affinity ligands will have higher counts than weaker affinity ligands. However, there is not always a clear relationship between DNA sequence count (assay signal) and binding affinity. This disconnect may be due to the fidelity of library chemistry, where reactions often do not go to completion, and also to repetitive rounds of binding and elution that are standard practice in most DEL selection experiments. We describe here a strategy that addresses both of these issues and provides a means to calculate ligand affinity from primary selection data. The reaction yields of selected compounds during DEL library synthesis can also be predicted with this method.

A simple method for determining compound affinity and chemical yield from DNA-encoded library selections.

DNA-encoded libraries (DELs) can contain billions of unique chemical species; selecting against such large inputs, it is typical to find more candidate binders than is reasonable to pursue for follow-up synthesis and testing. Given this wealth of choices, common practice is to limit synthesis to only those compounds estimated to have the greatest chance of being high-affinity binders; of the many potential factors contributing to this estimation, the strength of the selection signal of a candidate binder is always important. We define here methods and equations which relate the theoretical selection signal of a compound to its affinity and chemical yield. Tests using known binders of BRD4 and ROCK2 support the theory backing these equations and suggest they should be of use for prospectively determining affinity and chemical yield from primary DEL selection data.

Cytokine gene expression at the maternal-fetal interface after somatic cell nuclear transfer pregnancies in small ruminants.

The present retrospective study investigated pregnancy rates, the incidence of pregnancy loss and large offspring syndrome (LOS) and immune-related gene expression of sheep and goat somatic cell nuclear transfer (SCNT) pregnancies. We hypothesised that significantly higher pregnancy losses observed in sheep compared with goat SCNT pregnancies are due to the increased amounts of T-helper 1 cytokines and proinflammatory mediators at the maternal-fetal interface. Sheep and goat SCNT pregnancies were generated using the same procedure. Control pregnancies were established by natural breeding. Although SCNT pregnancy rates at 45 days were similar in both species, pregnancy losses between 45 and 60 days of gestation and the incidence of LOS were significantly greater in sheep than in goats. At term, the expression of proinflammatory genes in sheep SCNT placentas was increased, whereas that in goats was similar to that in control animals. Genes with altered expression in sheep SCNT placentas included cytotoxic T-lymphocyte-associated protein 4 (CTLA4), interleukin 2 receptor alpha (IL2RA), cluster of differentiation 28 (CD28), interferon gamma (IFNG), interleukin 6 (IL6), interleukin 10 (IL10), transforming growth factor beta 1 (TGFB1), tumor necrosis factor alpha (TNF-α), interleukin 1 alpha (IL1A) and chemokine (C-X-C motif) ligand 8 (CXCL8). Major histocompatibility complex-I protein expression was greater in sheep and goat SCNT placentas at term than in control pregnancies. An unfavourable immune environment is present at the maternal-fetal interface in sheep SCNT pregnancies.

Increased Susceptibility to Atrial Fibrillation Secondary to Atrial Fibrosis in Transgenic Goats Expressing Transforming Growth Factor-ß1.

INTRODUCTION: Large animal models of progressive atrial fibrosis would provide an attractive platform to study relationship between structural and electrical remodeling in atrial fibrillation (AF). Here we established a new transgenic goat model of AF with cardiac specific overexpression of TGF-ß1 and investigated the changes in the cardiac structure and function leading to AF. METHODS AND RESULTS: Transgenic goats with cardiac specific overexpression of constitutively active TGF-ß1 were generated by somatic cell nuclear transfer. We examined myocardial tissue, ECGs, echocardiographic data, and AF susceptibility in transgenic and wild-type control goats. Transgenic goats exhibited significant increase in fibrosis and myocyte diameters in the atria compared to controls, but not in the ventricles. P-wave duration was significantly greater in transgenic animals starting at 12 months of age, but no significant chamber enlargement was detected, suggesting conduction slowing in the atria. Furthermore, this transgenic goat model exhibited a significant increase in AF vulnerability. Six of 8 transgenic goats (75%) were susceptible to AF induction and exhibited sustained AF (>2 minutes), whereas none of 6 controls displayed sustained AF (P < 0.01). Length of induced AF episodes was also significantly greater in the transgenic group compared to controls (687 ± 212.02 seconds vs. 2.50 ± 0.88 seconds, P < 0.0001), but no persistent or permanent AF was observed. CONCLUSION: A novel transgenic goat model with a substrate for AF was generated. In this model, cardiac overexpression of TGF-ß1 led to an increase in fibrosis and myocyte size in the atria, and to progressive P-wave prolongation. We suggest that these factors underlie increased AF susceptibility.

Delivery of Therapeutic Proteins via Extracellular Vesicles: Review and Potential Treatments for Parkinson's Disease, Glioma, and Schwannoma.

Extracellular vesicles present an attractive delivery vehicle for therapeutic proteins. They intrinsically contain many proteins which can provide information to other cells. Advantages include reduced immune reactivity, especially if derived from the same host, stability in biologic fluids, and ability to target uptake. Those from mesenchymal stem cells appear to be intrinsically therapeutic, while those from cancer cells promote tumor progression. Therapeutic proteins can be loaded into vesicles by overexpression in the donor cell, with oligomerization and membrane sequences increasing their loading. Examples of protein delivery for therapeutic benefit in pre-clinical models include delivery of: catalase for Parkinson's disease to reduce oxidative stress and thus help neurons to survive; prodrug activating enzymes which can convert a prodrug which crosses the blood-brain barrier into a toxic chemotherapeutic drug for schwannomas and gliomas; and the apoptosis-inducing enzyme, caspase-1 under a Schwann cell specific promoter for schwannoma. This therapeutic delivery strategy is novel and being explored for a number of diseases.

Accuracy and reliability testing of two methods to measure internal rotation of the glenohumeral joint.

BACKGROUND: We compared accuracy and reliability of a traditional method of measurement (most cephalad vertebral spinous process that can be reached by a patient with the extended thumb) to estimates made with the shoulder in abduction to determine if there were differences between the two methods. METHODS: Six physicians with fellowship training in sports medicine or shoulder surgery estimated measurements in 48 healthy volunteers. Three were randomly chosen to make estimates of both internal rotation measurements for each volunteer. An independent observer made objective measurements on lateral scoliosis films (spinous process method) or with a goniometer (abduction method). Examiners were blinded to objective measurements as well as to previous estimates. RESULTS: Intraclass coefficients for interobserver reliability for the traditional method averaged 0.75, indicating good agreement among observers. The difference in vertebral level estimated by the examiner and the actual radiographic level averaged 1.8 levels. The intraclass coefficient for interobserver reliability for the abduction method averaged 0.81 for all examiners, indicating near-perfect agreement. Confidence intervals indicated that estimates were an average of 8° different from the objective goniometer measurements. Pearson correlation coefficients of intraobserver reliability for the abduction method averaged 0.94, indicating near-perfect agreement within observers. Confidence intervals demonstrated repeated estimates between 5° and 10° of the original. CONCLUSIONS: Internal rotation estimates made with the shoulder abducted demonstrated interobserver reliability superior to that of spinous process estimates, and reproducibility was high. On the basis of this finding, we now take glenohumeral internal rotation measurements with the shoulder in abduction and use a goniometer to maximize accuracy and objectivity.

Building bridges to outpatient treatment services for post-overdose care via paramedic buprenorphine field initiation.

INTRODUCTION: Despite sustained efforts to reduce opioid-related overdose fatalities, rates have continued to rise. In many areas, overdose response involves emergency medical service (EMS) personnel administering naloxone and transporting patients to the emergency department (ED). However, a substantial number of patients decline transport, and many EDs do not provide medication for opioid use disorder (MOUD). One approach to filling this gap involves delivering MOUD to overdose patients in the field with trained post-overdose EMS teams who can initiate buprenorphine. In this MOUD field initiation pilot program, a trained EMS Community Paramedicine team initiates buprenorphine in the field and links patients to care. The program includes three pathways to treatment with the first designed for EMS to initiate buprenorphine after overdose reversal when the patient is in withdrawal from naloxone; a second pathway initiates buprenorphine after overdose when the patient is not in withdrawal; and a third enables self-referral via a connection to the community EMS team not necessarily related to a recent overdose. METHODS: We conducted a retrospective cohort study of the MOUD field initiation pilot program. Data are from 28 patients who entered care immediately post-overdose initiation of buprenorphine, 21 patients who initiated on buprenorphine while not in naloxone withdrawal, and 37 patients who self-referred to treatment following outreach efforts by paramedicine and peer support professionals. RESULTS: A total of 118 patients initiated buprenorphine during the 12-month study period and 104 (83 %) visited the clinic for their first appointment. Over two thirds (68 %, n = 80) remained engaged in care after 30 days. Retained patients tended to be male, white, uninsured, food insecure, have unstable housing, lack reliable transportation, and report prior involvement with the criminal legal system. CONCLUSION: The initial 12-month period of the pilot program demonstrated the feasibility of initiating buprenorphine at the site of overdose without requiring transport to the ED and offer self-referral pathways for people experiencing barriers to treatment. Specialized EMS can play a critical role in expanding access to MOUD treatment by bridging the gap between overdose and comprehensive community-based care.

Diversion of hospital admissions from the emergency department using an interprofessional team: a propensity score analysis.

PURPOSE: To examine if an ED interprofessional team ("ED1Team") could safely decrease hospital admissions among older persons. METHODS: This single-center, retrospective, propensity score matched study was performed at a single ED during a control (December 2/2018-March 31/2019) and intervention (December 2/2019-March 31/2020) period. The intervention was assessed by the ED1Team, which could include an occupational therapist, physiotherapist, and social worker. We compared admission rates between period in persons age ≥ 70 years. Next, we compared visits attended by the ED1Team to (a) control period visits, and (b) intervention period visits without ED1Team attendance. SECONDARY OUTCOMES: ED length-of-stay, 7-day subsequent hospital admission and mortality in discharged patients. RESULTS: There were 5496 and 4876 eligible ED visits during the control and intervention periods, respectively. In the latter group, 556 (11.4%) received ED1Team assessment. After matching, there was an absolute 2.3% (p = 0.07) reduction in the admission rate between control and intervention periods. After matching the 556 ED1Team attended visits to control period visits, and to intervention period visits without the intervention, admission rates decreased by 10.0% (p = 0.006) and 13.5% (p < 0.001), respectively. For discharged patients, median ED length-of-stay decreased by 1.0 h (p < 0.001) between control and intervention periods and increased by 2.3 h (p < 0.001) compared to intervention period without the intervention. For patients discharged by the ED1Team, subsequent readmissions after 7 days were slightly higher, but mortality was not significantly different. CONCLUSION: ED1Team consultation was associated with a decreased hospital admission rate in older ED patients. It was associated with a slightly longer ED length-of-stay and subsequent early hospitalizations. Given that even a small increase in freed hospital beds would release some of the pressure on an overextended healthcare system, these results suggest that upscaling of the intervention might procure systems-wide benefits.

RéSUMé: OBJECTIF: Examiner si une équipe interprofessionnelle de DE (« ED1Team ¼) pourrait réduire en toute sécurité les admissions à l'hôpital chez les personnes âgées. MéTHODES: Cette étude rétrospective, à un seul centre et correspondant au score de propension a été réalisée à un seul DE pendant une période de contrôle (2/2018-31 mars/2019) et d'intervention (2/2019-31 mars/2020). L'intervention était une évaluation par l'équipe de l'ED1, qui pouvait comprendre un ergothérapeute, un physiothérapeute et un travailleur social. Nous avons comparé les taux d'admission entre périodes chez des personnes âgées de 70 ans. Ensuite, nous avons comparé les visites auxquelles a assisté l'équipe de DE1 à des visites pendant la période de contrôle et b) des visites pendant la période d'intervention sans présence de l'équipe. Résultats secondaires Durée du séjour en salle d'opération, hospitalisation subséquente de 7 jours et mortalité chez les patients libérés. RéSULTATS: Il y a eu 5496 et 4876 visites admissibles à la DE pendant les périodes de contrôle et d'intervention, respectivement. Dans ce dernier groupe, 556 (11,4 %) ont reçu une évaluation de l'équipe ED1. Après appariement, il y a eu une réduction absolue de 2,3 % (p=0,07) du taux d'admission entre les périodes de contrôle et d'intervention. Après avoir comparé les 556 visites de l'équipe ED1P aux visites des périodes de contrôle et aux visites des périodes d'intervention sans intervention, les taux d'admission ont diminué de 10,0 % (p=0,006) et 13,5 % (p<0,001), respectivement. Chez les patients ayant reçu leur congé, la durée médiane de séjour en DE a diminué de 1,0 heure (p<0,001) entre les périodes de contrôle et d'intervention et a augmenté de 2,3 heures (p<0,001) par rapport à la période d'intervention sans l'intervention. Pour les patients libérés par l'équipe ED1, les réadmissions subséquentes après 7 jours étaient légèrement plus élevées, mais la mortalité n'était pas significativement différente. CONCLUSION: La consultation d'Ed1Team a été associée à une diminution du taux d'admission hospitalière chez les patients âgés atteints de DE. Elle était associée à une durée de séjour légèrement plus longue en salle d'opération et à des hospitalisations précoces subséquentes. Étant donné que même une petite augmentation du nombre de lits d'hôpitaux libérés allégerait en partie la pression exercée sur un système de soins de santé surdimensionné, ces résultats suggèrent qu'une mise à l'échelle de l'intervention pourrait procurer des avantages à l'échelle du système.

A qualitative study on the Virtual Emergency Department care experiences of equity-deserving populations.

Patients from equity-deserving populations, such as those who are from racialized communities, the 2SLGBTQI+ community, who are refugees or immigrants, and/or who have a disability, may experience a unique set of challenges accessing virtual models of care. The objective of this qualitative study was to describe the experiences of patients from equity-deserving communities and their family members who received care from a Virtual Emergency Department (ED) in Toronto, Canada. Forty-three participants (36 patients and 7 family caregivers) with different and intersecting identities who used the Virtual ED participated in the study. Semi-structured interviews were conducted to explore reasons for accessing the Virtual ED, barriers to access, and how the Virtual ED met their care needs and expectations, including ways their experience could have been improved. Thematic analysis was used to identify themes from the data. Patients from equity-deserving populations described negative past experiences with ED in-person care, which included recounts of discrimination or culturally insensitive care while waiting to see the ED physician or nurse. Conversely, participants found the Virtual ED to be a socially and culturally safe space since they could now by-pass the waiting room experience. However, virtual care could not replace in-person care for certain issues (e.g., physical exam), and there was a need for greater promotion of the service to specific communities that might benefit from having access to the Virtual ED. Targeted outreach to help raise awareness of the service to equity-deserving communities is an important future direction.

Structural features of LC8-induced self-association of swallow.

Cell functions depend on the collective activity of protein networks within which a few proteins, called hubs, participate in a large number of interactions. Dynein light chain LC8, first discovered as a subunit of the motor protein dynein, is considered to have a role broader than that of dynein, and its participation in diverse systems fits the description of a hub. Among its partners is Swallow with which LC8 is essential for proper localization of bicoid mRNA at the anterior cortex of Drosophila oocytes. Why LC8 is essential in this process is not clear, but emerging evidence suggests that LC8 functions by promoting self-association and/or structural organization of its diverse binding partners. This work addresses the energetics and structural features of LC8-induced Swallow self-association distant from LC8 binding. Mutational design based on a hypothetical helical wheel, intermonomer nuclear Overhauser effects assigned to residues expected at interface positions, and circular dichroism spectral characteristics indicate that the LC8-promoted dimer of Swallow is a coiled coil. Secondary chemical shifts and (15)N backbone relaxation identify the boundaries and distinguishing structural features of the coiled coil. Thermodynamic analysis of Swallow polypeptides designed to decouple self-association from LC8 binding reveals that the higher binding affinity of the engineered bivalent Swallow is of purely entropic origin and that the linker separating the coiled coil from the LC8 binding site remains disordered. We speculate that the LC8-promoted coiled coil is critical for bicoid mRNA localization because it favors structural organization of Swallow, which except for the central LC8-promoted coiled coil is primarily disordered.

Biophysical and mechanistic insights into novel allosteric inhibitor of spleen tyrosine kinase.

Extracellular stimulation of the B cell receptor or mast cell FcεRI receptor activates a cascade of protein kinases, ultimately leading to antigenic or inflammation immune responses, respectively. Syk is a soluble kinase responsible for transmission of the receptor activation signal from the membrane to cytosolic targets. Control of Syk function is, therefore, critical to the human antigenic and inflammation immune response, and an inhibitor of Syk could provide therapy for autoimmune or inflammation diseases. We report here a novel allosteric Syk inhibitor, X1, that is noncompetitive against ATP (K(i) 4 ± 1 µM) and substrate peptide (K(i) 5 ± 1 µM), and competitive against activation of Syk by its upstream regulatory kinase LynB (K(i) 4 ± 1 µM). The inhibition mechanism was interrogated using a combination of structural, biophysical, and kinetic methods, which suggest the compound inhibits Syk by reinforcing the natural regulatory interactions between the SH2 and kinase domains. This novel mode of inhibition provides a new opportunity to improve the selectivity profile of Syk inhibitors for the development of safer drug candidates.

Learning From a Regional Approach: Integration to Scale, Spread, and Sustain Virtual Urgent Care.

While new offerings of virtual urgent care services from peer hospitals faltered after initial provincial pilot funding lapsed, our 3 regional academic health sciences centers decided to partner to enhance patient access, achieve efficiencies, and support long-term sustainability. Utilizing the Development Model for Integrated Care framework, we progressed through the 4 phases to ensure joint success and high-quality care: (1) initiative and design phase-individual parallel projects but with strong collaborations and broad stakeholder engagement; (2) experimental and execution phase-continuous quality improvement approach for governance, policies, and processes; (3) expansion and monitoring phase-weekly leadership touchpoints on key performance indicators; and (4) consolidation and transformation phase-sustainability through ongoing funding.

Training Residents for the Future: A Virtual Care Rotation for Emergency Medicine.

OBJECTIVES: Virtual care (VC) is increasingly becoming a part of emergency medicine (EM) physician workflows, yet no formal digital health curricula exist within Canadian EM training programs. The objective was to design and pilot a VC elective rotation for EM residents to help address this gap and better prepare them for future VC practice. METHODS: The current work describes the design and implementation of a 4-week VC elective rotation for EM residents. The rotation consisted of VC shifts, medical transport shifts, one-on-one discussions with various stakeholders, weekly thematic articles, and a final project deliverable. RESULTS: The rotation was well received by all stakeholders, and the quality of feedback and one-on-one teaching were highlighted as strengths. Future work will consider the optimal delivery timing of this type of curricula, whether all EM residents should receive basic training in VC, and how our current findings may be generalizable to other VC sites. CONCLUSION: A formal digital health curriculum for EM residents supports competency development for delivering VC as part of future EM practice.

The Implementation of a Virtual Emergency Department: Multimethods Study Guided by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) Framework.

BACKGROUND: While the COVID-19 pandemic dramatically increased virtual care uptake across many health settings, it remains significantly underused in urgent care. OBJECTIVE: This study evaluated the implementation of a pilot virtual emergency department (VED) at an Ontario hospital that connected patients to emergency physicians through a web-based portal. We sought to (1) assess the acceptability of the VED model, (2) evaluate whether the VED was implemented as intended, and (3) explore the impact on quality of care, access to care, and continuity of care. METHODS: This evaluation used a multimethods approach informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) framework. Data included semistructured interviews with patients and physicians as well as postvisit surveys from patients. Interviews were transcribed and analyzed using thematic analysis. Data from the surveys were described using summary statistics. RESULTS: From December 2020 to December 2021, the VED had a mean of 153 (SD 25) visits per month. Among them, 67% (n=677) were female, and 75% (n=758) had a family physician. Patients reported that the VED provided high-quality, timely access to care and praised the convenience, shorter appointments, and benefit of the calm, safe space afforded through virtual appointments. In instances where patients were directed to come into the emergency department (ED), physicians were able to provide a "warm handoff" to improve efficiency. This helped manage patient expectations, and the direct advice of the ED physician reassured them that the visit was warranted. There was broad initial uptake of VED shifts among ED physicians with 60% (n=22) completing shifts in the first 2 months and 42% (n=15) completing 1 or more shifts per month over the course of the pilot. There were no difficulties finding sufficient ED physicians for shifts. Most physicians enjoyed working in the VED, saw value for patients, and were motivated by patient satisfaction. However, some physicians were hesitant as they felt their expertise and skills as ED physicians were underused. The VED was implemented using an iterative staged approach with increased service capabilities over time, including access to ultrasounds, virtual follow-ups after a recent ED visit, and access to blood work, urine tests, and x-rays (at the hospital or a local community laboratory). Physicians recognized the value in supporting patients by advising on the need for an in-person visit, booking a diagnostic test, or referring them to a specialist. CONCLUSIONS: The VED had the support of physicians and facilitated care for low-acuity presentations with immediate benefits for patients. It has the potential to benefit the health care system by seeing patients through the web and guiding patients to in-person care only when necessary. Long-term sustainability requires a focus on understanding digital equity and enhanced access to rapid testing or investigations.