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In recent years, there has been an increase in the use of accelerated diagnostic protocols (ADPs) and high-sensitivity troponin assays (hsTn) for the assessment of chest pain in emergency departments (EDs). This study aimed to quantitatively summarize the operational and clinical outcomes of ADPs implemented for patients with suspected cardiac chest pain. To be considered eligible for inclusion, studies must have implemented some form of ADP within the ED for evaluating adult (age ≥18 years) patients presenting with chest pain using Tn assays. The primary outcome was ED length of stay (LOS). Secondary outcomes included the proportion of patients admitted and the proportion with 30-day major adverse cardiac events (MACE). Thirty-seven articles involving 404,566 patients met the inclusion criteria, including five randomized controlled trials (RCTs) and 32 observational studies. A significant reduction in total ED LOS was reported in 22 observational studies and four RCTs. Emergency departments with longer baseline ED LOS showed significantly larger reductions in LOS after ADP implementation. This observed association persisted after adjusting for both the change in serial Tn measurement interval and transition from conventional Tn assay to an hsTn assay (β = -0.26; 95% CI, -0.43 to -0.10). Three studies reported an increase in the proportion of patients admitted after introducing an ADP, one of which was significant while 15 studies reported a significant decrease in admission proportion. There was moderate heterogeneity among the 13 studies that reported MACE proportions, with a non-significant pooled risk ratio of 0.95 (95% CI, 0.86−1.04). Implementation of ADPs for chest pain presentations decreases ED LOS, most noticeably within sites with a high baseline LOS; this decreased LOS is seen even in the absence of any change in troponin assay type. The decrease in LOS occurred alongside reductions in hospital admissions, while not increasing MACE. The observed benefits translated across multiple countries and health regions.

Although patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) may be investigated for pulmonary embolism (PE) in the emergency department (ED), little is known about the prevalence of PE and factors associated with investigation. We sought to evaluate the PE prevalence among patients presenting to the ED with AECOPD. All adult patients presenting with AECOPD to six EDs between January 2015 and June 2021 using ICD-10-CA codes from administrative data. The primary outcomes were the investigation for and prevalence of PE. Conventional, age-adjusted D-dimer (AADD) and chest imaging are reported. A multivariable logistic regression was used to identify predictors of investigations for PE among patients with AECOPD, including demographic characteristics, comorbidities, and ED presentation data as covariates. Of the 25,510 patients with AECOPD, 12,164 (48%) patients (median age 70 years, 50% males, 46% hospitalized) were included after applying exclusion criteria. Overall, 2,072 (17%) patients received at least one test for PE: 84% had a D-dimer, 44% had a chest CT and 2% had lung scans. Overall, 68 (0.5%) patients received a diagnosis of PE; 41 (0.3%) received a PE co-diagnosis in the ED and 27 (0.2%) patients received a primary PE diagnosis while hospitalized. Use of an AADD could reduce CT image ordering by approximately 13%. Overall, 852 (7%) returned to the ED and 490 (4%) died within 30 days. The presence of chest pain (aOR=2.71; 95% CI: 2.24-3.28) and cough/congestion (aOR=0.57; 95% CI: 0.46-0.70) increased and decreased PE investigations, respectively. The overall prevalence of PE among patients presenting to the ED with AECOPD was low (less than 1%). While acknowledging PE may occur concurrently with AECOPD, clinicians should be cautious to avoid over-investigation, which has a negative impact on operational flow, increases costs, and may be harmful to patients. Evidence-based pathways using information readily available at presentation and selective investigations (e.g., decision rules and AADD cut-offs) have the potential to improve resource use and facilitate shared decision-making in the acute setting.

Although patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) may be investigated for pulmonary embolism (PE) in the emergency department (ED), little is known about the prevalence of PE and factors associated with investigation. We sought to evaluate the PE prevalence among patients presenting to the ED with AECOPD. All adult patients presenting with AECOPD to six EDs between January 2015 and June 2021 using ICD-10-CA codes from administrative data. The primary outcomes were the investigation for and prevalence of PE. Conventional, age-adjusted D-dimer (AADD) and chest imaging are reported. A multivariable logistic regression was used to identify predictors of investigations for PE among patients with AECOPD, including demographic characteristics, comorbidities, and ED presentation data as covariates. Of the 25,510 patients with AECOPD, 12,164 (48%) patients (median age 70 years, 50% males, 46% hospitalized) were included after applying exclusion criteria. Overall, 2,072 (17%) patients received at least one test for PE: 84% had a D-dimer, 44% had a chest CT and 2% had lung scans. Overall, 68 (0.5%) patients received a diagnosis of PE; 41 (0.3%) received a PE co-diagnosis in the ED and 27 (0.2%) patients received a primary PE diagnosis while hospitalized. Use of an AADD could reduce CT image ordering by approximately 13%. Overall, 852 (7%) returned to the ED and 490 (4%) died within 30 days. The presence of chest pain (aOR=2.71; 95% CI: 2.24-3.28) and cough/congestion (aOR=0.57; 95% CI: 0.46-0.70) increased and decreased PE investigations, respectively. The overall prevalence of PE among patients presenting to the ED with AECOPD was low (less than 1%). While acknowledging PE may occur concurrently with AECOPD, clinicians should be cautious to avoid over-investigation, which has a negative impact on operational flow, increases costs, and may be harmful to patients. Evidence-based pathways using information readily available at presentation and selective investigations (e.g., decision rules and AADD cut-offs) have the potential to improve resource use and facilitate shared decision-making in the acute setting.

Low back pain is a common presentation to emergency departments, but the reasons why people choose to attend the emergency department have not been explored. We aimed to fill this gap with this study to understand why persons with low back pain choose to attend the emergency department. Between July 4, 2017 and October 1, 2018, consecutive patients with a complaint of low back pain presenting to the University of Alberta Hospital emergency department were screened. Those enrolled completed a 13-item questionnaire to assess reasons and expectations related to their presentation. Demographics, acuity and disposition were obtained electronically. Factors associated with admission were examined in a logistic regression model. After screening 812 patients, 209 participants met the study criteria. The most common Canadian Triage and Acuity Scale score was 3 (73.2%). Overall, 37 (17.7%) received at least one consultation, 89.0% of participants were discharged home, 9.6% were admitted and 1.4% were transferred. Participants had a median pain intensity of 8/10 and a median daily functioning of 3/10. When asked, 64.6% attended for pain control while 44.5% stated ease of access. Most participants expected to obtain pain medication (67%) and advice (56%). Few attended because of cost savings (3.8%). After adjustment, only advanced age and ambulance arrival were significantly associated with admission. In conclusion, most low back pain patients came to the emergency department for pain control yet few were admitted and the majority did not receive a consultation. Timely alternatives for management of low back pain in the emergency department appear needed, yet are lacking.

Autism spectrum disorder (ASD) is a neurodevelopmental disability condition arising from a combination of genetic and environmental factors. Despite the blood-brain barrier (BBB) serving as a crucial gatekeeper, conveying environmental influences into the brain parenchyma, the contributions of BBB in ASD pathogenesis remain largely uncharted. Here we report that SHANK3 , an ASD-risk gene, expresses in the BBB-forming brain endothelial cells (BECs) and regulates tight junctional (TJ) integrity essential for BBB’s barrier function. Endothelium-specific Shank3 ( eShank3 ) knockout (KO) neonatal mice exhibit male-specific BBB-hyperpermeability, reduced neuronal excitability, and impaired ultra-sonic communications. Although BBB permeability is restored during adult age, the male mutant mice display reduced neuronal excitability and impaired sociability. Further analysis reveals that the BBB-hyperpermeability is attributed to the β-Catenin imbalance triggered by eShank3 -KO. These findings highlight a pathogenic mechanism stemming from the ASD-risk Shank3 , emphasizing the significance of neonatal BECs in the BBB as a potential therapeutic target for ASD. This study reveals that SHANK3 deficiency in brain endothelial cells disrupts BBB function during the neonatal period through β-Catenin imbalance, leading to ASD-related neuronal and behavioral abnormalities.

Transcranial brain stimulation is a promising technology for safe modulation of brain function without invasive procedures. Recent advances in transcranial optogenetic techniques with external light sources, using upconversion particles and highly sensitive opsins, have shown promise for precise neuromodulation with improved spatial resolution in deeper brain regions. However, these methods have not yet been used to selectively excite or inhibit specific neural populations in multiple brain regions. In this study, we created a wireless transcranial optogenetic brain modulator that combines highly sensitive opsins and upconversion particles and allows for precise bimodal neuromodulation of multiple brain regions without optical crosstalk. We demonstrate the feasibility of our approach in freely behaving mice. Furthermore, we demonstrate its usefulness in studies of complex behaviors and brain dysfunction by controlling extorting behavior in mice in food competition tests and alleviating the symptoms of Parkinson’s disease. Our approach has potential applications in the study of neural circuits and development of treatments for various brain disorders. Transcranial brain stimulation offers promising control of brain function. Here, the authors present a wireless transcranial optogenetic brain modulator for precise control of multiple brain regions, demonstrating its potential in studying complex behaviors and alleviating Parkinson’s symptoms.

This study examined emergency department (ED) presentations of patients with end of life (EOL) conditions and patients having met and unmet palliative care needs were compared. Presentations for EOL conditions were prospectively identified and screened for palliative care needs. Descriptive data were reported as proportions, means or medians. Bi-variable analysis for dichotomous and continuous variables were performed by chi-squared and T-tests (p≤0.01), respectively. A multivariable logistic regression model identified factors associated with having unmet palliative needs and reported adjusted odds ratios (aOR) with 95% confidence intervals (CI). Overall, 663 presentations for EOL conditions were identified; 518 (78%) involved patients with unmet palliative care needs. Presentations by patients with unmet palliative needs were more likely to involve consultations (80% vs. 67%, p = 0.001) and result in hospitalization (69% vs. 51%, p<0.001) compared to patients whose palliative needs were met. Patients with unmet palliative care needs were more likely to have previous ED visits (73% unmet vs. 48% met; p<0.001). While medication, procedures, investigations and imaging ordering were high across all patients with EOL conditions, there were no significant differences between the groups. Consultations with palliative specialists in the ED (6% unmet vs. 1% met) and following discharge (29% unmet vs. 18% met) were similarly uncommon. Patients having two or more EOL conditions (aOR = 2.41; 95% CI: 1.16, 5.00), requiring hospitalization (aOR = 1.93; 95% CI: 1.30, 2.87), and dying during the ED visit (aOR = 2.15; 95% CI: 1.02, 4.53) were strongly associated with having unmet palliative care needs. Most ED presentations for EOL conditions were made by patients with unmet palliative care needs, who were significantly more likely to require consultation, hospitalization, and to die. Referrals to palliative care services during and after the ED visit were infrequent, indicating important opportunities to promote these services.

Suppressed NMDA receptor (NMDAR) function contributes to multiple brain disorders, including schizophrenia, autism spectrum disorder (ASD), and NMDAR encephalitis. Previous attempts to restore NMDAR activity by increasing ambient glycine, a critical co-agonist, through GlyT1 inhibition have yielded mixed outcomes, partly due to GlyT1’s extensive expression in essential brainstem regions. Slc6a20a, a glycine transporter widely expressed in cognition-relevant regions such as the cortex and hippocampus, offers a targeted alternative. Here we show that antisense oligonucleotide (ASO)-mediated Slc6a20a inhibition ( Slc6a20a -ASO) normalizes ASD-related phenotypes in male Shank2 - and Shank3 -mutant mice, with model-dependent rescue profiles. Slc6a20a -ASO rescues NMDAR hypofunction and synaptic phospho-proteomic profiles in the prefrontal cortex. Furthermore, ASO targeting human SLC6A20 rescues suppressed NMDAR function in cortical organoids harboring SHANK2 or SHANK3 mutations. These findings underscore the potential and limitations of Slc6a20a / SLC6A20 -ASO for treating disorders characterized by NMDAR hypofunction. Antisense oligonucleotides targeting the glycine transporter SLC6A20 restore NMDA -receptor function and rescue behavioral and synaptic phospho-proteomic deficits in Shank2- and Shank3-mutant mice and in human SHANK2/SHANK3 cortical organoids.

Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2 , which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions. Seizures can occur in autism spectrum disorders (ASD). Here, the authors report that mice lacking the ASD related Ank2 gene show abnormal behaviours, and juvenile seizure related death, through impaired Kv7 potassium channel function.

Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic l -amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivity of VTA dopaminergic neurons. Effective stress regulation is essential for the survival of vertebrates. Here, the authors show that the lateral habenula trace aminergic signalling activates the mesolimbic pathway through suppressing the rostromedial tegmental nucleus to manage stress.