Prospective Validation of Computed Tomography to Identify Patients at High Risk for Stroke After Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Computed tomography (CT) findings of acute and chronic ischemia are associated with subsequent stroke risk in patients with transient ischemic attack. We sought to validate these associations in a large prospective cohort of patients with transient ischemic attack or minor stroke. METHODS: This prospective cohort study enrolled emergency department patients from 13 hospitals with transient ischemic attack who had CT imaging. Primary outcome was stroke within 90 days. Secondary outcomes were stroke within 2 or 7 days. CT findings were abstracted from radiology reports and classified for the presence of acute ischemia, chronic ischemia, or microangiopathy. Multivariable logistic regression was used to test associations with primary and secondary end points. RESULTS: From 8670 prospectively enrolled patients between May 2010 and May 2017, 8382 had a CT within 24 hours. From this total population, 4547 (54%) patients had evidence of acute ischemia, chronic ischemia, or microangiopathy on CT, of whom 175 had a subsequent stroke within 90 days (3.8% subsequent stroke rate; adjusted odds ratio [aOR], 2.33 [95% CI, 1.62-3.36]). This was in comparison to those with CT imaging without ischemia. Findings associated with an increased risk of stroke at 90 days were isolated acute ischemia (6.0%; aOR, 2.42 [95% CI, 1.03-5.66]), acute ischemia with microangiopathy (10.7%; aOR, 3.34 [95% CI, 1.57-7.14]), chronic ischemia with microangiopathy (5.2%; aOR, 1.83 [95% CI, 1.34-2.50]), and acute ischemia with chronic ischemia and microangiopathy (10.9%; aOR, 3.49 [95% CI, 1.54-7.91]). Acute ischemia with chronic ischemia and microangiopathy were most strongly associated with subsequent stroke within 2 days (aOR, 4.36 [95% CI, 1.31-14.54]) and 7 days (aOR, 4.50 [95% CI, 1.73-11.69]). CONCLUSIONS: In patients with transient ischemic attack or minor stroke, CT evidence of acute ischemia with chronic ischemia or microangiopathy significantly increases the risk of subsequent stroke within 90 days of index visit. The combination of all 3 findings results in the greatest early risk.

Cell cycle progression and transmitotic apoptosis resistance promote escape from extrinsic apoptosis.

Extrinsic apoptosis relies on TNF-family receptor activation by immune cells or receptor-activating drugs. Here, we monitored cell cycle progression at a resolution of minutes to relate apoptosis kinetics and cell-to-cell heterogeneities in death decisions to cell cycle phases. Interestingly, we found that cells in S phase delay TRAIL receptor-induced death in favour of mitosis, thereby passing on an apoptosis-primed state to their offspring. This translates into two distinct fates, apoptosis execution post mitosis or cell survival from inefficient apoptosis. Transmitotic resistance is linked to Mcl-1 upregulation and its increased accumulation at mitochondria from mid-S phase onwards, which allows cells to pass through mitosis with activated caspase-8, and with cells escaping apoptosis after mitosis sustaining sublethal DNA damage. Antagonizing Mcl-1 suppresses cell cycle-dependent delays in apoptosis, prevents apoptosis-resistant progression through mitosis and averts unwanted survival after apoptosis induction. Cell cycle progression therefore modulates signal transduction during extrinsic apoptosis, with Mcl-1 governing decision making between death, proliferation and survival. Cell cycle progression thus is a crucial process from which cell-to-cell heterogeneities in fates and treatment outcomes emerge in isogenic cell populations during extrinsic apoptosis. This article has an associated First Person interview with the first author of the paper.

Ovarian Masses: The Value of Acoustic Shadowing on Ultrasound Examination.

Adnexal lesions are a common finding in women and pose a clinical challenge since ovarian cancer is a highly lethal disease. However, most adnexal masses are benign, benefiting from a more conservative approach. In preoperative assessment, transvaginal ultrasound plays a key role in evaluating morphologic features that correlate with the risk of malignancy. The acoustic shadow is the loss of echo behind sound-absorbing components, such as calcifications or fibrous tissues, which are predominantly found in benign lesions. However, recognizing the acoustic shadow is a difficult skill to master, and its usefulness may be underappreciated.

Pathogenic Variants in USH1G/SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome.

Pre-mRNA splicing is an essential process orchestrated by the spliceosome, a dynamic complex assembled stepwise on pre-mRNA. We have previously identified that USH1G protein SANS regulates pre-mRNA splicing by mediating the intranuclear transfer of the spliceosomal U4/U6.U5 tri-snRNP complex. During this process, SANS interacts with the U4/U6 and U5 snRNP-specific proteins PRPF31 and PRPF6 and regulates splicing, which is disturbed by variants of USH1G/SANS causative for human Usher syndrome (USH), the most common form of hereditary deaf-blindness. Here, we aim to gain further insights into the molecular interaction of the splicing molecules PRPF31 and PRPF6 to the CENTn domain of SANS using fluorescence resonance energy transfer assays in cells and in silico deep learning-based protein structure predictions. This demonstrates that SANS directly binds via two distinct conserved regions of its CENTn to the two PRPFs. In addition, we provide evidence that these interactions occur sequentially and a conformational change of an intrinsically disordered region to a short α-helix of SANS CENTn2 is triggered by the binding of PRPF6. Furthermore, we find that pathogenic variants of USH1G/SANS perturb the binding of SANS to both PRPFs, implying a significance for the USH1G pathophysiology.

Prevalence, management and outcomes of unrecognized delirium in a National Sample of 1,493 older emergency department patients: how many were sent home and what happened to them?

BACKGROUND: Retrospective studies estimate Emergency Department (ED) delirium recognition at <20%; few prospective studies have assessed delirium recognition and outcomes for patients with unrecognized delirium. OBJECTIVES: To prospectively measure delirium recognition by ED nurses and physicians, document their confidence in diagnosis and disposition, actual dispositions, and patient outcomes. METHODS: Prospective observational study of people ≥65 years. We assessed delirium using the Confusion Assessment Method, then asked ED staff if the patient had delirium, confidence in their assessment, if the patient could be discharged, and contacted patients 1 week postdischarge. We report proportions and 95% confidence intervals (Cls). RESULTS: We enrolled 1,493 participants; mean age was 77.9 years; 49.2% were female, 79 (5.3%, 95% CI 4.2-6.5%) had delirium. ED nurses missed delirium in 43/78 cases (55.1%, 95% CI 43.4-66.4%). Nurses considered 12/43 (27.9%) patients with unrecognized delirium safe to discharge. Median confidence in their delirium diagnosis for patients with unrecognized delirium was 7.0/10. Physicians missed delirium in 10/20 (50.0%, 95% CI 27.2-72.8) cases and considered 2/10 (20.0%) safe to discharge. Median confidence in their delirium diagnosis for patients with unrecognized delirium was 8.0/10. Fifteen patients with unrecognized delirium were sent home: 6.7% died at 1 week follow-up vs. none in those with recognized delirium and 1.1% in the rest of the cohort. CONCLUSION: Delirium recognition by nurses and physicians was sub-optimal at ~50% and may be associated with increased mortality. Research should explore root causes of unrecognized delirium, and novel strategies to systematically improve delirium recognition and patient outcomes.

Ultrasound for Aesthetic Applications: A Review of Biophysical Mechanisms and Safety.

Aesthetic ultrasound is used for fat reduction and to improve skin appearance. In this review, the fundamental mechanisms by which ultrasound can alter tissue are outlined. The technologies that are commercially available or under development are discussed. Finally, recommendations are made for safe and effective use of aesthetic ultrasound.

Ocular Ultrasound: Review of Bioeffects and Safety, Including Fetal and Point of Care Perspective: Review of Bioeffects and Safety, Including Fetal and Point-of-Care Perspective.

Ocular ultrasound is an invaluable tool for the evaluation of the eye and orbit. However, the eye and orbit are potentially sensitive to the thermal and mechanical effects of ultrasound. When performing B-mode imaging, dedicated ocular settings should be used. If these settings are not available, limiting the acoustic output to Food and Drug Administration (FDA) recommended maximum levels is strongly advised. Especially important is the acoustic output in spectral (pulsed) and color Doppler modes, which can exceed the FDA's maximum recommended levels for the eye. Adjusting settings to decrease acoustic output and limiting the time of the examination should be done when performing a Doppler examination. The acoustic output of shear wave elastography is significantly higher than FDA guidelines for the eye and should be considered experimental.

Safety Aspects of Perinatal Ultrasound.

Ultrasound safety is of particular importance in fetal and neonatal scanning. Fetal tissues are vulnerable and often still developing, the scanning depth may be low, and potential biological effects have been insufficiently investigated. On the other hand, the clinical benefit may be considerable. The perinatal period is probably less vulnerable than the first and second trimesters of pregnancy, and ultrasound is often a safer alternative to other diagnostic imaging modalities. Here we present step-by-step procedures for obtaining clinically relevant images while maintaining ultrasound safety. We briefly discuss the current status of the field of ultrasound safety, with special attention to the safety of novel modalities, safety considerations when ultrasound is employed for research and education, and ultrasound of particularly vulnerable tissues, such as the neonatal lung. This CME is prepared by ECMUS, the safety committee of EFSUMB, with contributions from OB/GYN clinicians with a special interest in ultrasound safety.

Prospective Validation of the Emergency Heart Failure Mortality Risk Grade for Acute Heart Failure.

BACKGROUND: Improved risk stratification of acute heart failure in the emergency department may inform physicians' decisions regarding patient admission or early discharge disposition. We aimed to validate the previously-derived Emergency Heart failure Mortality Risk Grade for 7-day (EHMRG7) and 30-day (EHMRG30-ST) mortality. METHODS: We conducted a multicenter, prospective validation study of patients with acute heart failure at 9 hospitals. We surveyed physicians for their estimates of 7-day mortality risk, obtained for each patient before knowledge of the model predictions, and compared these with EHMRG7 for discrimination and net reclassification improvement. We also prospectively examined discrimination of the EHMRG30-ST model, which incorporates all components of EHMRG7 as well as the presence of ST-depression on the 12-lead ECG. RESULTS: We recruited 1983 patients seeking emergency department care for acute heart failure. Mortality rates at 7 days in the 5 risk groups (very low, low, intermediate, high, and very high risk) were 0%, 0%, 0.6%, 1.9%, and 3.9%, respectively. At 30 days, the corresponding mortality rates were 0%, 1.9%, 3.9%, 5.9%, and 14.3%. Compared with physician-estimated risk of 7-day mortality (PER7; c-statistic, 0.71; 95% CI, 0.64-0.78) there was improved discrimination with EHMRG7 (c-statistic, 0.81; 95% CI, 0.75-0.87; P=0.022 versus PER7) and with EHMRG7 combined with physicians' estimates (c-statistic, 0.82; 95% CI, 0.76-0.88; P=0.003 versus PER7). Model discrimination increased nonsignificantly by 0.014 (95% CI, -0.009-0.037) when physicians' estimates combined with EHMRG7 were compared with EHMRG7 alone ( P=0.242). The c-statistic for EHMRG30-ST alone was 0.77 (95% CI, 0.73-0.81) and 30-day model discrimination increased nonsignificantly by addition of physician-estimated risk to 0.78 (95% CI, 0.73-0.82; P=0.187). Net reclassification improvement with EHMRG7 was 0.763 (95% CI, 0.465-1.062) when assessed continuously and 0.820 (0.560-1.080) using risk categories compared with PER7. CONCLUSIONS: A clinical model allowing simultaneous prediction of mortality at both 7 and 30 days identified acute heart failure patients with a low risk of events. Compared with physicians' estimates, our multivariable model was better able to predict 7-day mortality and may guide clinical decisions. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02634762.

Diagnostic Ultrasound Safety Review for Point-of-Care Ultrasound Practitioners.

Potential ultrasound exposure safety issues are reviewed, with guidance for prudent use of point-of-care ultrasound (POCUS). Safety assurance begins with the training of POCUS practitioners in the generation and interpretation of diagnostically valid and clinically relevant images. Sonographers themselves should minimize patient exposure in accordance with the as-low-as-reasonably-achievable principle, particularly for the safety of the eye, lung, and fetus. This practice entails the reduction of output indices or the exposure duration, consistent with the acquisition of diagnostically definitive images. Informed adoption of POCUS worldwide promises a reduction of ionizing radiation risks, enhanced cost-effectiveness, and prompt diagnoses for optimal patient care.

Developmental trajectories of neuroanatomical alterations associated with the 16p11.2 Copy Number Variations.

Most of human genome is present in two copies (maternal and paternal). However, segments of the genome can be deleted or duplicated, and many of these genomic variations (known as Copy Number Variants) are associated with psychiatric disorders. 16p11.2 copy number variants (breakpoint 4-5) confer high risk for neurodevelopmental disorders and are associated with structural brain alterations of large effect-size. Methods used in previous studies were unable to investigate the onset of these alterations and whether they evolve with age. In this study, we aim at characterizing age-related effects of 16p11.2 copy number variants by analyzing a group with a broad age range including younger individuals. A large normative developmental dataset was used to accurately adjust for effects of age. We normalized volumes of segmented brain regions as well as volumes of each voxel defined by tensor-based morphometry. Results show that the total intracranial volumes, the global gray and white matter volumes are respectively higher and lower in deletion and duplication carriers compared to control subjects at 4.5 years of age. These differences remain stable through childhood, adolescence and adulthood until 23 years of age (range: 0.5 to 1.0 Z-score). Voxel-based results are consistent with previous findings in 16p11.2 copy number variant carriers, including increased volume in the calcarine cortex and insula in deletions, compared to controls, with an inverse effect in duplication carriers (1.0 Z-score). All large effect-size voxel-based differences are present at 4.5 years and seem to remain stable until the age of 23. Our results highlight the stability of a neuroimaging endophenotype over 2 decades during which neurodevelopmental symptoms evolve at a rapid pace.

A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

Association between DRD2 and DRD3 gene polymorphisms and gastrointestinal symptoms induced by levodopa therapy in Parkinson's disease.

Levodopa is the most used drug to treat motor symptoms in Parkinson's disease (PD). However, dopaminergic side effects such as nausea and vomiting may occur. Several evidences indicate a major role for dopamine receptors D2 (DRD2) and D3 (DRD3) in emetic activity. The aim of this study was to investigate the relationship of DRD2 rs1799732 and DRD3 rs6280 gene polymorphisms with gastrointestinal (GI) symptoms induced by levodopa in PD patients. Two hundred and seventeen PD patients on levodopa therapy were investigated. DRD2 rs1799732 and DRD3 rs6280 polymorphisms were genotyped by PCR-based methods. Multiple Poisson regression method with robust variance estimators was performed to assess the association between polymorphisms and gastrointestinal symptoms. The analyses showed that DRD2 Ins/Ins (prevalence ratio (PR)=2.374, 95% confidence interval (CI): 1.105-5.100; P=0.027) and DRD3 Ser/Ser genotypes (PR=1.677, 95% CI 1.077-2.611; P=0.022) were independent and predictors of gastrointestinal symptoms associated with levodopa therapy. Despite all the efforts to alleviate GI symptoms, this adverse effect still occurs in PD patients. Pharmacogenetic studies of GI symptoms induced by levodopa therapy have the potential to display new ways to better understand the molecular mechanisms involved in these side effects.

KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant.

Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome--which encompasses 29 genes--that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.

What do we know about frailty in the acute care setting? A scoping review.

BACKGROUND: The ability of acute care providers to cope with the influx of frail older patients is increasingly stressed, and changes need to be made to improve care provided to older adults. Our purpose was to conduct a scoping review to map and synthesize the literature addressing frailty in the acute care setting in order to understand how to tackle this challenge. We also aimed to highlight the current gaps in frailty research. METHODS: This scoping review included original research articles with acutely-ill Emergency Medical Services (EMS) or hospitalized older patients who were identified as frail by the authors. We searched Medline, CINAHL, Embase, PsycINFO, Eric, and Cochrane from January 2000 to September 2015. RESULTS: Our database search initially resulted in 8658 articles and 617 were eligible. In 67% of the articles the authors identified their participants as frail but did not report on how they measured frailty. Among the 204 articles that did measure frailty, the most common disciplines were geriatrics (14%), emergency department (14%), and general medicine (11%). In total, 89 measures were used. This included 13 established tools, used in 51% of the articles, and 35 non-frailty tools, used in 24% of the articles. The most commonly used tools were the Clinical Frailty Scale, the Frailty Index, and the Frailty Phenotype (12% each). Most often (44%) researchers used frailty tools to predict adverse health outcomes. In 74% of the cases frailty predicted the outcome examined, typically mortality and length of stay. CONCLUSIONS: Most studies (83%) were conducted in non-geriatric disciplines and two thirds of the articles identified participants as frail without measuring frailty. There was great variability in tools used and more recently published studies were more likely to use established frailty tools. Overall, frailty appears to be a good predictor of adverse health outcomes. For frailty to be implemented in clinical practice frailty tools should help formulate the care plan and improve shared decision making. How this will happen has yet to be determined.

Early 2D/3D ultrasound diagnosis of pleural effusion in fetuses with Turner syndrome.

Most guidelines on ultrasound examinations during pregnancy do not recommend routine early pregnancy scan in uncomplicated and asymptomatic pregnancies (ie, before 10 weeks based on last menstrual period). There is, however, a growing patient's expectation to have an early scan to confirm dating and verify the pregnancy is intrauterine and viable. We present three well-documented cases of patients who had an early (7-8 weeks) dating transvaginal scan revealing pleural effusion in the embryo. In all cases cytogenetic analysis confirmed monosomy for the X chromosome, consistent with a clinical diagnosis of Turner syndrome.

A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders.

Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 × 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 × 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (>400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs < 400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.

Ovarian mass-differentiating benign from malignant: the value of the International Ovarian Tumor Analysis ultrasound rules.

Ovarian cancer, the fifth most common cause of cancer death among women, has the highest mortality rate of all gynecologic cancers. General survival rate is <50% but can reach 90% if disease is detected early. Ultrasound is presently the best modality to differentiate between benign and malignant status. The patient with a malignant mass should be referred to an oncology surgeon since results have been shown to be superior to treatment by a specialist. Several ultrasound-based scoring systems exist for assessing the risk of an ovarian tumor to be malignant. The International Ovarian Tumor Analysis group published 2 such systems: the ultrasound Simple Rules and the Assessment of Different NEoplasias in the adneXa model. The Simple Rules classifies a tumor as benign, malignant, or indeterminate and the Assessment of Different NEoplasias in the adneXa model determines the risk for a tumor to be benign or malignant and, if malignant, the risk of various stages. Sensitivity of the Simple Rules and Assessment of Different NEoplasias in the adneXa model (using a cut-off of 10% to predict malignancy) are 92% and 96.5%, respectively, and specificities are 96% and 71.3%, respectively. These models are the best predictive tests for the preoperative classification of adnexal tumors. Their intent is to help the specialist make management decisions when faced with a patient with a persistent ovarian mass. The models are simple, are easy to use, and have been validated in multiple reports but not in the United States. We suggest they should be validated and widely introduced into medical practice in the United States.

Push-Alert Notification of Troponin Results to Physician Smartphones Reduces the Time to Discharge Emergency Department Patients: A Randomized Controlled Trial.

STUDY OBJECTIVE: For emergency department (ED) patients with chest pain, discharge decisions often hinge on troponin results. Push-alert notifications deliver results immediately to physician smartphones. Our objective is to determine whether troponin push alerts improve the time to discharge decisions for ED patients with chest pain. METHODS: In an academic ED, we assessed the effect of a quality improvement initiative using troponin push alerts to physician smartphones, with a cluster-randomized evaluation. Participating physicians were randomized to receive troponin push alerts (intervention) or not receive them (control). We retrospectively identified patients treated by participating physicians during the study period who were discharged from the ED with chest pain. The primary outcome was the time from final troponin result to discharge decision. Secondary outcomes included length of stay. A linear mixed model was used to adjust for physician clustering. RESULTS: During the study, 1,554 patients were discharged from the ED with chest pain. There were 551 patients in the control group and 554 in the intervention group who met inclusion criteria. The overall median interval from final troponin result to discharge decision was 79.7 minutes (interquartile range [IQR] 33.6 to 167.8 minutes); it was 94.3 minutes (IQR 36.2 to 177.8 minutes) in the control group and 68.5 minutes (IQR 30.5 to 157.2 minutes) in the intervention group. This 25.8-minute difference in medians (95% confidence interval 24.6 to 28.0 minutes) was statistically significant. Total ED length of stay was 345 minutes (IQR 261 to 419 minutes) in the control group and 328 minutes (IQR 250 to 408 minutes) in the intervention group. CONCLUSION: Physicians who received troponin push alerts discharged their patients with chest pain 26 minutes faster than those without troponin notifications. Total ED length of stay did not significantly improve for these patients.