Search

We present a case of a previously healthy adolescent male who initially presented to his primary care physician with the chief complaint of a “large and white tongue,” who subsequently was diagnosed with end-stage kidney disease (ESKD) and associated uremic stomatitis. This patient required admission to a PICU for acute renal replacement therapy with intermittent hemodialysis, and his hospital course was complicated by generalized tonic-clonic seizures. ESKD is difficult to diagnose in the pediatric population because these patients are often asymptomatic in the early stages given the insidiousness of underlying disorders. Renal disease should be considered in the differential diagnosis of a child with a white tongue not being the result of oral candidiasis.

Summary Background In May, 2018, Children's Hospital Colorado noted an outbreak of enterovirus A71 (EV-A71) neurological disease. We aimed to characterise the clinical features of EV-A71 neurological disease during this outbreak. Methods In this retrospective observational cohort study, children (younger than 18 years) who presented to Children's Hospital Colorado (Aurora, CO, USA) between March 1 and November 30, 2018, with neurological disease (defined by non-mutually exclusive criteria, including meningitis, encephalitis, acute flaccid myelitis, and seizures) and enterovirus detected from any biological specimen were eligible for study inclusion. The clinical characteristics of children with neurological disease associated with EV-A71 were compared with those of children with neurological disease associated with other enteroviruses during the same period. To explore the differences in clinical presentation of acute flaccid myelitis, we also used a subgroup analysis to compare clinical findings in children with EV-A71-associated acute flaccid myelitis during the study period with these findings in those with enterovirus D68 (EV-D68)-associated acute flaccid myelitis at the same hospital between 2013 and 2018. Findings Between March 10 and Nov 10, 2018, 74 children presenting to Children's Hospital Colorado were found to have enterovirus neurological disease; EV-A71 was identified in 43 (58%) of these children. The median age of the children with EV-A71 neurological disease was 22·7 months (IQR 4·0–31·9), and most of these children were male (34 [79%] children). 40 (93%) children with EV-A71 neurological disease had findings suggestive of meningitis, 31 (72%) children showed evidence of encephalitis, and ten (23%) children met our case definition of acute flaccid myelitis. All children with EV-A71 disease had fever and 18 (42%) children had hand, foot, or mouth lesions at or before neurological onset. Children with EV-A71 disease were best differentiated from those with other enteroviruses (n=31) by the neurological findings of myoclonus, ataxia, weakness, and autonomic instability. Of the specimens collected from children with EV-A71, this enterovirus was detected in 94% of rectal, 79% of oropharyngeal, 56% of nasopharyngeal, and 20% of cerebrospinal fluid specimens. 39 (93%) of 42 children with EV-A71 neurological disease who could be followed up showed complete recovery by 1–2 months. Compared with children with EV-D68-associated acute flaccid myelitis, children with EV-A71-associated acute flaccid myelitis were younger, showed neurological onset earlier after prodromal symptom onset, had milder weakness, showed more rapid improvement, and were more likely to completely recover. Interpretation This outbreak of EV-A71 neurological disease, the largest reported in the Americas, was characterised by fever, myoclonus, ataxia, weakness, autonomic instability, and full recovery in most patients. Because EV-A71 epidemiology outside of Asia remains difficult to predict, identification of future outbreaks will be aided by prompt recognition of these distinct clinical findings, testing of non-sterile and sterile site specimens, and enhanced enterovirus surveillance. Funding None.

OBJECTIVES To compare initial treatment with intravenous immunoglobulin (IVIG) versus IVIG plus infliximab in multisystem inflammatory syndrome in children (MIS-C). METHODS Single-center retrospective cohort study of patients with MIS-C who met Centers for Disease Control and Prevention criteria and received treatment from April 2020 to February 2021. Patients were included and compared on the basis of initial therapy of either IVIG alone or IVIG plus infliximab. The primary outcome was need for additional therapy 24 hours or more after treatment initiation. RESULTS Seventy-two children with MIS-C met inclusion criteria. Additional therapy was needed in 13 of 20 (65%) who received IVIG alone and 16 of 52 (31%) who received IVIG plus infliximab (P = .01). The median (interquartile range) ICU lengths of stay were 3.3 (2.2 to 3.8) and 1.8 (1.1 to 2.1) days, respectively (P = .001). New or worsened left ventricular dysfunction developed in 4 of 20 (20%) and 2 of 52 (4%) (P = .05), and new vasoactive medication requirement developed in 3 of 20 (15%) and 2 of 52 (4%), respectively (P = .13). The median percentage changes in the C-reactive protein level at 24 hours posttreatment compared with pretreatment were 0% (−29% to 66%) and −46% (−62% to −15%) (P < .001); and at 48 hours posttreatment, −5% (−41% to 57%) and −70% (−79% to −49%) respectively (P < .001). There was no significant difference in hospital length of stay, time to fever resolution, vasoactive medication duration, or need for diuretics. CONCLUSIONS Patients with MIS-C initially treated with IVIG plus infliximab compared with those treated with IVIG alone were less likely to require additional therapy and had decreased ICU length of stay, decreased development of left ventricular dysfunction, and more rapid decline in C-reactive protein levels.

A previously healthy 11-year-old female, who emigrated from Central America four years prior, was admitted with eight days of fever, night sweats, and anorexia. Past medical history included severe bronchiolitis, varicella, and hepatitis A as a child. Upon admission, her physical exam was significant for nontender cervical lymphadenopathy, intermittent erythematous papules on the upper extremities, and mild abdominal tenderness. Initial laboratory studies revealed leukopenia, anemia, elevated inflammatory markers, and antibodies to HIV-1 in the patient’s serum and cerebrospinal fluid. Computed tomography scan was remarkable for many small nodules throughout the lungs and widespread lymphadenopathy. Additional testing confirmed the diagnosis of HIV/AIDS with a CD4 count of 52 cells/mm3, complicated by disseminated histoplasmosis. This case is significant because it represents a late presentation of vertically transmitted HIV with disseminated histoplasmosis in a nonendemic region as the AIDS-defining illness. This highlights the importance of maintaining a broad differential for opportunistic infections, especially among those who have spent a significant amount of time in a country where unusual pathogens may be more common. This case also considers the utility of antigen testing as a sensitive diagnostic test in immunocompromised patients.

We sought to determine whether temporal changes in the lower airway microbiome are associated with ventilator-associated pneumonia (VAP) in children.Using a multicentre prospective study of children aged 31 days to 18 years requiring mechanical ventilation support for >72 h, daily tracheal aspirates were collected and analysed by sequencing of the 16S rRNA gene. VAP was assessed using 2008 Centers for Disease Control and Prevention paediatric criteria. The association between microbial factors and VAP was evaluated using joint longitudinal time-to-event modelling, matched case–control comparisons and unsupervised clustering.Out of 366 eligible subjects, 66 (15%) developed VAP at a median of 5 (interquartile range 3–5) days post intubation. At intubation, there was no difference in total bacterial load (TBL), but Shannon diversity and the relative abundance ofStreptococcus, Lactobacillales andPrevotellawere lower for VAP subjectsversusnon-VAP subjects. However, higher TBL on each sequential day was associated with a lower hazard (hazard ratio 0.39, 95% CI 0.23–0.64) for developing VAP, but sequential values of diversity were not associated with VAP. Similar findings were observed from the matched analysis and unsupervised clustering. The most common dominant VAP pathogens includedPrevotellaspecies (19%),Pseudomonas aeruginosa(14%) andStreptococcus mitis/pneumoniae(10%).MycoplasmaandUreaplasmawere also identified as dominant organisms in several subjects.In mechanically ventilated children, changes over time in microbial factors were marginally associated with VAP risk, although these changes were not suitable for predicting VAP in individual patients. These findings suggest that focusing exclusively on pathogen burden may not adequately inform VAP diagnosis.

Objective To describe the similarities and differences in the evaluation and treatment of multisystem inflammatory syndrome in children (MIS-C) at hospitals in the United States. Study design We conducted a cross-sectional survey from June 16 to July 16, 2020 of U.S. children’s hospitals regarding protocols for management of patients with MIS-C. Elements included characteristics of the hospital, clinical definition of MIS-C, evaluation, treatment, and follow up. We summarized key findings and compared results from centers in which >5 patients had been treated vs those in which 5 patients vs.

Background The purpose of this study was to evaluate the rate and domains of cognitive impairment in out-of-hospital cardiac arrest (OHCA) survivors, as compared to patients who experienced a myocardial infarction (MI), and to explore mechanisms and predictors of this impairment. Methods and results OHCA survivors with “good” neurological recovery (i.e., Cerebral Performance Categories Scale ≤ 2) (n = 79), as well as a control group of MI patients (n = 69), underwent a comprehensive neuropsychological assessment. Forty-three percent of OHCA survivors were cognitively impaired (in the lowest decile on a global measure of cognitive functioning). Rates of impairment were approximately six times higher in the OHCA group than the MI group. Attention, memory, language and executive function were affected. Downtime was a significant predictor of cognitive impairment; the interaction between downtime and immediate intervention was significant such that, at short downtimes, receiving cardiopulmonary resuscitation (CPR) or defibrillation within 1 min of collapse predicted less cognitive impairment. Conclusions OHCA survivors – even those with seemingly good neurological recovery – are at risk for cognitive impairment. Cognitive rehabilitation may be an important consideration post-OHCA.

Introduction: Comatose survivors of OHCA develop a post cardiac arrest syndrome (PCAS) characterized by myocardial dysfunction and cerebrovascular dysregulation. Hemodynamic derangements related to PCAS can jeopardize cerebral oxygen delivery and therefore impair neurologic recovery. However, optimal hemodynamic targets to ensure adequate cerebral oxygen delivery following OHCA remain undefined. Accordingly, we examined the relationship between cardiac index (CI), mean arterial pressure (MAP), and regional cerebral oxygen saturation (rO 2 %) following OHCA. Methods: CAPITAL-RETURN was a prospective, single-center observational study examining hemodynamics in comatose survivors of OHCA undergoing targeted temperature management after an initial shockable rhythm. Between August 2016 and December 2017, comatose survivors of OHCA underwent continuous, blinded, non-invasive monitoring of CI and rO 2 % using bioimpedance (Cheetah Medical, Portland, OR, USA) and near-infrared spectroscopy (Covidien, Boulder, CO, USA), respectively, for 96 hours after intensive care unit admission. In the present study, we examined the relationship between CI, MAP, and rO 2 % using multivariable linear regression. Results: In 56 patients in this analysis, the mean CI and MAP during the first 96 hours of intensive care unit admission were 3.2±0.5 L/min/m 2 and 76±6 mmHg, respectively (Figure). The mean rO 2 % was 63±9% and increased over time (+0.1% per hour; p2 % (+3.2% per L/min/m2 increase in CI; p2 % (p=0.42). After adjustment for MAP, the association between CI and rO 2 % remained significant (+3.1% per L/min/m2 increase in CI; p Conclusion: In comatose survivors of OHCA with an initial shockable rhythm, a higher CI is associated with improved rO 2 %. Further studies are needed to determine whether CI targets improve rO2% and neurologic outcomes following OHCA.

Introduction: Comatose survivors of out-of-hospital cardiac arrest (OHCA) have decreased cardiac index (CI) following return of spontaneous circulation. Although reversible, a reduced CI can contribute to cerebral hypoperfusion and impaired neurologic outcomes. We sought to examine the relationship between CI and clinical outcomes following OHCA. Methods: CAPITAL-RETURN was a prospective study examining hemodynamics in comatose survivors of OHCA undergoing targeted temperature management. Between August 2016 and December 2017, comatose survivors of OHCA with an initial shockable rhythm underwent continuous, blinded monitoring of CI using bioimpedance (Cheetah Medical, Portland, OR, USA) for 96 hours after intensive care unit (ICU) admission. In the present study, we examined the association between CI and the composite of death or severe neurologic dysfunction at 6 months (primary outcome) using logistic regression. Severe neurologic dysfunction was defined as a modified Rankin Scale score ≥4. We excluded patients who died or had withdrawal of advanced life support within 72 hours of ICU admission. Results: In 53 patients in this analysis (mean age 59±13 years, downtime 24±13 minutes, STEMI 35%), the rate of the primary outcome was 25%. The mean CI was lower in patients with (3.0±0.5 L/min/m 2 ) versus without (3.3±0.5 L/min/m 2 ) the primary outcome (p=0.018). A higher mean CI during the first 96 hours of ICU admission was associated with lower rates of the primary outcome (OR 0.85 per 0.1L/min/m 2 increase in CI; p=0.025). This association persisted after adjusting for age and downtime (OR 0.78 per 0.1L/min/m2 increase in CI; p=0.014). Cardiac index was similar in patients with versus without the primary outcome at the end of the 96-hour monitoring period (Figure). Conclusion: In comatose survivors of OHCA with an initial shockable rhythm, a higher CI during the first 96 hours of ICU admission is associated with lower rates of death or severe neurologic dysfunction.

BackgroundIn the absence of evidence-based therapies for Multisystem Inflammatory Syndrome in Children (MIS-C), we aimed to describe the similarities and differences in the evaluation and treatment of MIS-C at hospitals in the United States.MethodsWe conducted a cross-sectional survey from June 16 to July 16, 2020 of U.S. children’s hospitals regarding protocols for patients with MIS-C. Elements included hospital characteristics, clinical definition of MIS-C, evaluation, treatment, and follow-up. We summarized key findings and compared results from centers that had treated >5 patients vs. those that had treated ≤5 patients.ResultsForty centers of varying size and experience with MIS-C participated. About half (21/40) of centers required only 1 day of fever for MIS-C to be considered. In the evaluation of patients, there was often a tiered approach. Intravenous immunoglobulin was the most widely used medication to treat MIS-C (98% of centers). Corticosteroids were listed in 93% of protocols for primarily the moderate or severe cases. Aspirin was commonly used including for mild cases, whereas heparin or low molecular weight heparin were used primarily in severe cases. In severe cases, anakinra and vasopressors were frequently recommended. Nearly all centers (39/40) recommended follow up with cardiology. There were similar findings between centers that had treated >5 patients vs. those that had treated ≤5 patients. A supplement containing hospital protocols is provided.ConclusionThere are many similarities yet some key differences between hospital protocols for MIS-C. These findings can help healthcare providers learn from others regarding options for managing MIS-C patients.Article SummaryThis survey of U.S. hospitals highlights the interhospital similarities and differences in management of Multisystem Inflammatory Syndrome in Children.What’s Known on This SubjectMIS-C is a novel and life-threatening disease in children associated with COVID-19. Early cases were treated with immunomodulatory agents similar to current guidelines for Kawasaki disease. There are currently no evidence-based guidelines for treatment of MIS-C.What This Study AddsThis study describes the protocolized evaluation and treatment of children with MIS-C at 40 hospitals in the U.S. These findings can help other hospitals create protocols to care for these children at their centers.

Background Among those aged 5 years or younger, foreign bodies are the fourth most common pediatric exposure reported to the American Association of Poison Control Centers. Although the majority of ingested foreign bodies pass through the gastrointestinal tract without complication, those that do not spontaneously pass can lead to a number of serious complications, such as gastrointestinal obstruction or perforation, which can be complicated by bleeding from aortoesophageal fistula, secondary mediastinitis, peritonitis, esophageal or gastrointestinal fistula formation, and abscesses. Case Report We present the case of a 10-month-old child who presented with new-onset focal seizure in the setting of multiple brain abscesses, ultimately found to be due to esophageal perforation from a retained, metallic esophageal foreign body. Why Should an Emergency Physician Be Aware of This? Foreign bodies that are retained for longer than 24 h after ingestion have been associated with a higher risk of complications because they are less likely to pass spontaneously through the gastrointestinal tract. Early identification and removal of foreign bodies is necessary to prevent subsequent complications. In patients who have a subacute history of cough, gagging, vomiting, and decreased oral intake with an otherwise unknown cause, foreign-body ingestion or aspiration should be considered. In addition, central nervous system abscess and infection should be considered in patients with concerns about previous foreign body ingestion or aspiration and who are newly presenting with fever, focal neurologic changes, and irritability.

The overwhelming majority of pediatric cases of SARS-CoV-2 infection are mild or asymptomatic with only a handful of pediatric deaths reported. We present a case of severe COVID-19 infection in a pediatric patient with signs of hyperinflammation and consumptive coagulopathy requiring intubation and extracorporeal membrane oxygenation (ECMO) and eventual death due to ECMO complications.

Background: The optimal blood glucose target during the early hospitalisation of comatose survivors of out-of-hospital cardiac arrest (OHCA) has not been established. Methods: In a retrospective cohort study, we examined clinical outcomes in relation to mean blood glucose during the first 96 hours of hospital admission in comatose survivors of OHCA with an initial shockable rhythm. Mean blood glucose was assessed as a continuous (primary analysis) and categorical variable: Results: Among 122 eligible patients, death and severe neurological dysfunction occurred in 29 (24%) and 40 (33%) patients, respectively. Higher mean blood glucose levels during the first 96 hours of admission were associated with increased odds of death (odds ratio (OR): 1.50; 95% confidence interval (CI): 1.17–1.92; p = 0.001) and severe neurological dysfunction (OR: 1.42; 95% CI: 1.11–1.80; p = 0.004). The associations between mean blood glucose and the odds of death (OR: 1.35; 95% CI: 1.04–1.76; p = 0.02) and severe neurological dysfunction (OR: 1.28; 95% CI: 1.00–1.64; p = 0.05) persisted after adjusting for age, time from cardiac arrest to return of spontaneous circulation (ROSC) and vasoactive agent use. There was no interaction between age, time from cardiac arrest to ROSC or a history of diabetes mellitus and the relationship between mean blood glucose and co-primary outcomes. Conclusions: In comatose survivors of OHCA with initial shockable rhythms, higher mean blood glucose levels during the first 96 hours of admission are associated with increased rates of death and severe neurological dysfunction.

Problem: Student mistreatment represents an ongoing challenge for US medical schools. Students experiencing mistreatment may become marginalized and cynical, and they have higher rates of burnout, depression and substance use disorders. Although numerous attempts to eliminate mistreatment have been proposed, best practices remain elusive. We formed a unique student-faculty collaboration (the Ending Mistreatment Task Force) that allowed all voices to be heard and enabled identification of five interventions to reduce mistreatment. Intervention: The EMTF developed and implemented five key interventions: 1) a shared mistreatment definition; 2) measures to increase faculty accountability, including adding professionalism expectations to faculty members’ contracts and performance reviews; 3) a Professionalism Office to respond promptly to students’ reports of mistreatment and provide feedback to faculty; 4) tools to help teachers provide authentic learning environments for students, while addressing generational misunderstandings; and 5) student-produced videos, helping faculty understand the impact of mistreatment as seen through students’ eyes. Context: These interventions occurred at one medical school where mistreatment reports were consistently above national averages. Impact: Over 6 years, the interventions helped reduce the rate of student-reported mistreatment by 36% compared with a 4% decline across all US medical schools. Lessons: The collaborations between students and faculty helped each party identify unexpected misunderstandings and challenges. We learned that students want hard questions, although faculty are often afraid to challenge students for fear of offending them or being reported. We clarified differences between mistreatment and sub-optimal learning environments and openly discussed the pervasive opinion that ‘some’ mistreatment is important for learning. We also identified ongoing challenges, including the need to solicit residents’ perspectives regarding mistreatment and develop proper responses to disrespectful comments directed at patients, family and colleagues. The collaboration reinforced students’ and faculty members’ shared commitment to upholding a respectful learning and clinical care environment and ending mistreatment.

Background: In May 2018, Children's Hospital Colorado (CHCO) noted an outbreak of enterovirus (EV) A71-associated neurologic disease. Methods: A case of EV-associated neurologic disease was defined as any child presenting to CHCO with meningitis, encephalitis, acute flaccid myelitis (AFM), and/or seizures between March 1 and November 30, 2018 with an EV detected from a biologic specimen. EV-A71 cases were compared to other EV cases during the same period. EV-A71-associated AFM cases were also compared to EV-D68-associated AFM cases from 2013-2018. Findings: Of seventy-four children with EV-associated neurologic disease, forty-three (58%) were EV-A71-associated. Median age of EV-A71 cases was 22.7 months (IQR: 4-31.9 months); 34 (79%) were male. Neurologic involvement in EV-A71 cases included meningitis (93%), encephalitis (72%), and AFM (23%). All EV-A71 cases had fever; eighteen (42%) had hand, foot, or mouth (HFM) lesions. Neurologic findings distinguishing EV-A71-associated cases from other EV-associated cases (n=31) included myoclonus (60% vs. 16%, p

Objectives This study investigated the safety and efficacy of a pharmacoinvasive strategy compared with a primary percutaneous coronary intervention (PCI) strategy for ST-segment elevation myocardial infarction (STEMI) in the context of a real-world system. Background Primary PCI continues to be the optimal reperfusion therapy; however, in areas where PCI centers are not readily available, a pharmacoinvasive strategy has been proposed. Methods The University of Ottawa Heart Institute regional STEMI system provides a primary PCI strategy for patients presenting within a 90-km radius from the PCI center, and a pharmacoinvasive strategy for patients outside this limit. We included all confirmed STEMI patients between April 2009 and May 2011. The primary efficacy outcome was a composite of mortality, reinfarction, or stroke and the primary safety outcome was major bleeding. Results We identified 236 and 980 consecutive patients enrolled in pharmacoinvasive and primary PCI strategies, respectively. The median door-to-needle time was 31 min in the pharmacoinvasive group and the median door-to-balloon time was 95 min in the primary PCI group. In a multivariable model, there was no significant difference in the primary efficacy outcome (odds ratio: 1.54; p = 0.21); however, the propensity for more bleeding with a pharmacoinvasive strategy approached statistical significance (odds ratio: 2.02; p = 0.08). Conclusions Within the context of a STEMI system, a pharmacoinvasive strategy was associated with similar rates of the composite of mortality, reinfarction, or stroke as compared with a primary PCI strategy; however, there was a propensity for more bleeding with a pharmacoinvasive strategy.

Medical care in Canadian cardiac units has changed considerably over the past 3 decades in response to an increasingly complex and diverse patient population admitted with acute cardiac pathology. To maintain the highest level of care for these patients, there is a pressing need to evolve traditional coronary care units into contemporary cardiac intensive care units. In this article we aim to highlight the current variations in Canadian units, develop approaches to overcome logistical and infrastructural obstacles, and propose staffing and training recommendations that would allow for the establishment of contemporary cardiac intensive care units.

Background Universal pre-operative screening with SARS-CoV-2 PCR has been adopted by institutions to mitigate risk to healthcare workers (HCW) during aerosol-generating procedures such as intubation. However, there remains uncertainty regarding rates of false negative results and optimal sampling type. The objective was to determine the reliability of single, pre-operative SARS-CoV-2 testing from the nasopharynx in children undergoing general anesthesia. Methods Children < 18 years of age who underwent intubation for a procedure received pre-operative testing 24–48 hours prior with a nasopharyngeal (NP) swab or wash, in conjunction with intra-operative nasal wash (NW) and tracheal aspirate (TA) sampling. All paired samples underwent testing using the Simplexa DiaSorin platform or a modified Centers for Disease Control assay. Cohen’s Kappa was used for interrater reliability of each sample result. McNemar’s Test was used to compare result proportions by sample type. Positive and negative predictive values (PPV, NPV) were calculated based on the intraoperative NW as the reference standard. Analyses were conducted using SAS (v 9.4). Results We collected full sample sets from 364 children from April 14 to May 15; 66% of pre-operative samples were NP swabs. The median age was 6 years (IQR 2,13), 55% were male, 68% were white and 41% of children had a high-risk comorbidity. Most surgeries were conducted by general surgery (23%), followed by orthopedics (19%). Only 2.5% of children had respiratory symptoms, and 4.8% had a documented fever within a week of the procedure. SARS-CoV-2 positive samples occurred in 4/364 (1%) of pre-operative samples, 8/363 (2.2%) of intra-operative samples, and 8/348 (2.3%) of TA samples. The pre-operative test had 100% PPV and 99% NPV, and the TA had 100% PPV and 98.6% NPV (Table 1). There was very good agreement (Figure) between pre- and intraoperative upper respiratory sampling, with a Kappa of 0.66, (95% CI 0.35–0.97). There was no statistical difference in results by sample type. Table 1. Comparison of intra-operative and pre-operative nasopharyngeal sample results, test characteristics and test concordance Table 2. Comparison of intra-operative nasopharyngeal and tracheal aspirate sample results, test characteristics and test concordance Figure 1 Percent agreement between pre-operative and intra-operative samples Conclusion There is a high PPV and NPV of pre-operative SARS-CoV-2 PCR testing among children undergoing anesthesia. These data can help inform guidelines regarding appropriate precautions for HCW performing high risk procedures in asymptomatic pediatric patients. Disclosures Suchitra Rao, MD, BioFire (Grant/Research Support) Samuel Dominguez, MD, PhD, BioFire (Consultant, Research Grant or Support)

Importance Among patients with ST-segment elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention (PCI), a survival benefit associated with radial access compared with femoral access remains controversial. Objective To assess whether there is a survival benefit when radial access is used instead of femoral access among patients with STEMI referred for primary PCI. Design, Setting, and Participants This multicenter, open-label, randomized clinical trial was conducted at 5 PCI centers in Canada. In total, 2292 patients with STEMI referred for primary PCI were enrolled between July 2011 and December 2018, with a 30-day follow-up. The primary analyses were conducted based on the intention-to-treat population. Interventions Patients were randomized to radial access (n = 1136) or to femoral access (n = 1156) for PCI. Main Outcomes and Measures Initially, the primary outcome was bleeding, but this outcome was modified to 30-day all-cause mortality following the recommendation of the granting agency. Secondary outcomes included recurrent myocardial infarction, stroke, and Thrombolysis in Myocardial Infarction–defined major or minor bleeding. Results Among the 2292 patients enrolled, the mean (SD) age of the patients randomized to radial access was 61.6 (12.3) years and to femoral access was 62.0 (12.1) years, with 883 male patients in the radial access and 901 male patients in the femoral access group. The trial was stopped early following a futility analysis. Primary PCI was performed in 1082 of 1136 patients (95.2%) in the radial access group and 1109 of 1156 patients (95.9%) in the femoral access group. Bivalirudin was administered to 1001 patients (88.1%) in the radial access group and to 1068 patients (92.4%) in the femoral access group, whereas glycoprotein IIb/IIIa inhibitors were administered in only 69 patients (6.1%) in the radial access group and 68 patients (5.9%) in the femoral access group. A vascular closure device was used in 789 patients (68.3%) in the femoral group. The primary outcome, 30-day all-cause mortality, occurred in 17 patients (1.5%) assigned to radial access and in 15 patients (1.3%) assigned to femoral access (relative risk [RR], 1.15; 95% CI, 0.58-2.30;P = .69). There were no significant differences between patients assigned to radial and femoral access in the rates of reinfarction (1.8% vs 1.6%; RR, 1.07; 95% CI, 0.57-2.00;P = .83), stroke (1.0% vs 0.4%; RR, 2.24; 95% CI, 0.78-6.42;P = .12), and bleeding (1.4% vs 2.0%; RR, 0.71; 95% CI, 0.38-1.33;P = .28). Conclusions and Relevance No significant differences were found for survival or other clinical end points at 30 days after the use of radial access vs femoral access in patients with STEMI referred for primary PCI. However, small absolute differences in end points cannot be definitively refuted given the premature termination of the trial. Trial Registration ClinicalTrials.gov identifier:NCT01398254

Among 182 children with influenza infection in 2016–2017, 18% had neurologic manifestations of influenza (NMI), including seizures and encephalopathy; 85% of these children were infected with the H3N2 strain. Children with NMI had 3.5-times-higher odds of having a neurologic comorbidity than those without NMI and a 10-fold increased odds of hospitalization.

OBJECTIVES We sought to describe the safety and efficacy outcomes of patients on warfarin presenting with ST-elevation myocardial infarction (STEMI). BACKGROUND Limited data exist on the outcomes and optimal management of STEMI patients on warfarin undergoing primary percutaneous coronary intervention (PCI). METHODS Baseline characteristics and outcomes were prospectively collected for 2,390 consecutive STEMI patients referred for primary PCI. Patients were stratified based on warfarin use at baseline. The primary safety endpoint was the rate of in-hospital bleeding (a composite of major bleeding or minor bleeding) according to the thrombolysis in myocardial infarction (TIMI) classification. Efficacy endpoints included major adverse cardiovascular events (MACE), defined as death, myocardial infarction, or stroke, as well as intracranial bleeding, cardiogenic shock, and length of stay. Multiple logistic regression was used to determine if warfarin was independently associated with bleeding and MACE. RESULTS Warfarin patients (n = 59 vs. n = 2,331) were significantly older (73.2 years vs. 61.7 years; P

To determine the optimal mean arterial pressure (MAP) during the early-to-intermediate phase care of comatose survivors of out-of-hospital cardiac arrest (OHCA).We identified consecutive comatose survivors of OHCA with an initial shockable rhythm. Using blood pressure-over-time plots, we calculated the area below pre-specified MAP thresholds (ABT; mmHg*hours) during the first 96 h of admission. We used incremental MAP thresholds ranging between 65 and 85 mmHg. Logistic regression analyses were used to examine the association between ABT and clinical outcomes for each MAP threshold and to adjust for age, duration of cardiac arrest, and bystander CPR. The primary outcome was severe neurological dysfunction as defined by a cerebral performance category (CPC) ≥3.We identified 122 consecutive OHCA patients meeting inclusion criteria. The rate of the primary outcome was 33%. There was a significant association between ABT and the rate of the primary outcome when MAP thresholds of 60 (p = 0.01), 65 (p 0.01), 70 (p 0.01), 75 (p 0.01), and 80 mmHg (p 0.01) were used. This association was lost once a MAP threshold of 85 mmHg was reached (p = 0.63). In the adjusted analysis, the association between ABT and the primary outcome was no longer present when the MAP threshold reached 75 mmHg.In comatose survivors of OHCA with an initial shockable rhythm, higher ABT is associated with increased rates of severe neurological dysfunction when MAP thresholds75 mmHg are used. The current findings support the hypothesis that higher MAP targets (≥75 mmHg) may be indicated in this patient population.

One of the fundamental tools of undergraduate calculus is the chain rule. The notion of higher order directional derivatives was developed by Huang, Marcantognini, Young in Huang et al. (Math. Intell. 28(2):61–69, 2006), along with a corresponding higher order chain rule. When Johnson and McCarthy established abelian functor calculus, they proved a chain rule for functors that is analogous to the directional derivative chain rule when n = 1. In joint work with Bauer, Johnson, and Riehl, we defined an analogue of the iterated directional derivative and provided an inductive proof of the analogue to the chain rule of Huang et al.

Background Several enteroviruses (EVs), including EV-A71 and EV-D68, have been associated with acute flaccid myelitis (AFM). Clinical features distinguishing AFM presentations associated with specific EV types are not well described. Methods EV-associated AFM was defined as any child presenting to Children’s Hospital Colorado in 2013–2018 who met the Council of State and Territorial Epidemiologists definition for confirmed AFM (flaccid limb weakness with longitudinal gray-matter-predominant spinal cord lesion on MRI) and had EV-A71 or EV-D68 identified in any biologic specimen (cerebrospinal fluid [CSF], nasopharyngeal [NP], oropharyngeal [OP], rectal) by VP1-specific RT-PCR and sequencing. Summative limb strength scores (SLSS) were calculated by adding Medical Research Council strength scores (1–5) for all limbs. Results Ten cases of EV-A71-associated AFM were identified, all from 2018; 8 cases of EV-D68-associated AFM were identified from 2013 (1), 2014 (4), 2016 (1), and 2018 (2) [Table 1]. Viral detection rates were higher in rectal and OP swabs in EV-A71 cases and NP specimens in EV-D68 cases. Virus was not detected in CSF of EV-D68 cases and in 1 EV-A71 case. EV-A71 cases were younger (median 19 vs. 100 months) and had neurologic onset earlier after prodromal symptom onset (median 1 vs. 5.5 days) than EV-D68 cases. Hand, foot, and/or mouth lesions distinguished EV-A71 cases, whereas respiratory symptoms were uniformly noted in EV-D68 cases. Associated neurologic findings more commonly associated with EV-A71 cases than EV-D68 cases included irritability, myoclonus, and ataxia. Weakness was more generalized with EV-A71 and more asymmetric with EV-D68, though patterns of brainstem and spinal cord involvement on MRI were similar. Compared with EV-D68, EV-A71 cases had milder weakness at onset and improved strength at 1- to 2-month follow-up (Figure 1), shorter length of stay (median 5.5 vs. 32 days) and a greater rate of full neurologic recovery (90% vs. 13%). Conclusion EV-D68 and EV-A71 are both associated with AFM with similar MRI findings, but cases can be distinguished by associated prodromal symptoms, neurologic findings, and outcomes. Timely collection and testing of nonsterile site specimens, particularly NP for EV-D68 and OP and rectal for EV-A71, are key to case identification. Disclosures All Authors: No reported Disclosures.

Coronavirus spike (S) glycoproteins mediate receptor binding, membrane fusion, and virus entry and determine host range. Murine betacoronavirus (β-CoV) in group A uses the N-terminal domain (NTD) of S protein to bind to its receptor, whereas the β-CoVs severe acute respiratory syndrome CoV in group B and Middle East respiratory syndrome CoV in group C and several α-CoVs use the downstream C domain in their S proteins to recognize their receptor proteins. To identify the receptor-binding domain in the spike of human β-CoV HKU1 in group A, we generated and mapped a panel of monoclonal antibodies (MAbs) to the ectodomain of HKU1 spike protein. They did not cross-react with S proteins of any other CoV tested. Most of the HKU1 spike MAbs recognized epitopes in the C domain between amino acids 535 and 673, indicating that this region is immunodominant. Two of the MAbs blocked HKU1 virus infection of primary human tracheal-bronchial epithelial (HTBE) cells. Preincubation of HTBE cells with a truncated HKU1 S protein that includes the C domain blocked infection with HKU1 virus, but preincubation of cells with truncated S protein containing only the NTD did not block infection. These data suggest that the receptor-binding domain (RBD) of HKU1 spike protein is located in the C domain, where the spike proteins of α-CoVs and β-CoVs in groups B and C bind to their specific receptor proteins. Thus, two β-CoVs in group A, HKU1 and murine CoV, have evolved to use different regions of their spike glycoproteins to recognize their respective receptor proteins. IMPORTANCE Mouse hepatitis virus, a β-CoV in group A, uses the galectin-like NTD in its spike protein to bind its receptor protein, while HCoV-OC43, another β-CoV in group A, uses the NTD to bind to its sialic-acid containing receptor. In marked contrast, the NTD of the spike glycoprotein of human respiratory β-CoV HKU1, which is also in group A, does not bind sugar. In this study, we showed that for the spike protein of HKU1, the purified C domain, downstream of the NTD, could block HKU1 virus infection of human respiratory epithelial cells, and that several monoclonal antibodies that mapped to the C domain neutralized virus infectivity. Thus, the receptor-binding domain of HKU1 spike glycoprotein is located in the C domain. Surprisingly, two β-CoVs in group A, mouse hepatitis virus and HKU1, have evolved to use different regions of their spike glycoproteins to recognize their respective receptors.

Acute gastroenteritis accounts for a significant burden of medically attended illness in children under the age of five. For this study, four multiplex reverse transcription PCR assays were used to determine the incidence of adenovirus, astrovirus, coronavirus, norovirus GI and GII, rotavirus, and sapovirus in stool samples submitted for viral electron microscopy (EM) to the Children's Hospital Colorado. Of 1105 stool samples available, viral RNA/DNA was detected in 247 (26.2%) of 941 pediatric samples (median age = 2.97 years, 54% male) with 28 (3.0%) positive for more than one virus. Adenovirus, astrovirus, norovirus GI, norovirus GII, rotavirus, and sapovirus were detected in 95 (10.0%), 33 (3.5%), 8 (0.9%), 90 (9.6%), 49 (5.2%), and 2 (0.2%) of the pediatric samples, respectively. No coronaviruses were identified. Sequencing of norovirus positive samples indicated an outbreak of norovirus strain GII.4 in 2006 with evidence of numerous circulating strains. Multiple samples from the same immunocompromised patients demonstrated symptomatic shedding of norovirus for up to 32 weeks and astrovirus for 12 weeks. RT-PCR detected 99 of 111 (89%) adenovirus-positive samples versus 12 (11%) by EM, and 186 of 192 (97%) sapovirus/astrovirus/norovirus-positive samples versus 21 (11%) by EM. Noroviruses and adenoviruses are common causes of gastroenteritis in children. Immunocompromised patients can be infected with multiple viruses and shed viruses in their stools for prolonged periods. This data support the superiority of RT-PCR compared to EM for diagnosis of viral gastroenteritis. J. Med. Virol. 87:931–939, 2015. © 2015 Wiley Periodicals, Inc.

Aim of the study We sought to assess the relationship between mean arterial pressure (MAP) and clinical outcomes in comatose survivors of out-of-hospital cardiac arrest (OHCA). Methods We identified consecutive comatose survivors of OHCA with an initial shockable rhythm treated with targeted temperature management. We examined clinical outcomes in relation to mean MAP (measured hourly) during the first 96h of hospitalization. Co-primary outcomes were the rates of death and severe neurological dysfunction at discharge. Results In 122 patients meeting inclusion criteria, death occurred in 29 (24%) and severe neurological dysfunction in 39 (32%). Higher mean MAPs were associated with lower odds of death (OR 0.55 per 5mmHg increase; 95%CI 0.38–0.79; p=0.002) and severe neurological dysfunction (OR 0.66 per 5mmHg increase; 95%CI 0.48–0.90; p=0.01). After adjustment for differences in patient, index event, and treatment characteristics, higher mean MAPs remained associated with lower odds of death (OR 0.60 per 5mmHg increase; 95%CI 0.40–0.89; p=0.01) but not severe neurological dysfunction (OR 0.73 per 5mmHg increase; 95%CI 0.51–1.03; p=0.07). The relationship between mean MAP and the odds of death (p-interaction=0.03) and severe neurological dysfunction (p-interaction=0.03) was attenuated by increased patient age. Conclusion In comatose survivors of OHCA treated with target temperature management, a higher mean MAP during the first 96h of admission is associated with increased survival. The association between mean MAP and clinical outcomes appears to be attenuated by increased age.

This study investigated the safety and efficacy of a pharmacoinvasive strategy compared with a primary percutaneous coronary intervention (PCI) strategy for ST-segment elevation myocardial infarction (STEMI) in the context of a real-world system.Primary PCI continues to be the optimal reperfusion therapy; however, in areas where PCI centers are not readily available, a pharmacoinvasive strategy has been proposed.The University of Ottawa Heart Institute regional STEMI system provides a primary PCI strategy for patients presenting within a 90-km radius from the PCI center, and a pharmacoinvasive strategy for patients outside this limit. We included all confirmed STEMI patients between April 2009 and May 2011. The primary efficacy outcome was a composite of mortality, reinfarction, or stroke and the primary safety outcome was major bleeding.We identified 236 and 980 consecutive patients enrolled in pharmacoinvasive and primary PCI strategies, respectively. The median door-to-needle time was 31 min in the pharmacoinvasive group and the median door-to-balloon time was 95 min in the primary PCI group. In a multivariable model, there was no significant difference in the primary efficacy outcome (odds ratio: 1.54; p = 0.21); however, the propensity for more bleeding with a pharmacoinvasive strategy approached statistical significance (odds ratio: 2.02; p = 0.08).Within the context of a STEMI system, a pharmacoinvasive strategy was associated with similar rates of the composite of mortality, reinfarction, or stroke as compared with a primary PCI strategy; however, there was a propensity for more bleeding with a pharmacoinvasive strategy.

In this paper, we consider abelian functor calculus, the calculus of functors of abelian categories established by the second author and McCarthy. We carefully construct a category of abelian categories and suitably homotopically defined functors, and show that this category, equipped with the directional derivative, is a cartesian differential category in the sense of Blute, Cockett, and Seely. This provides an abstract framework that makes certain analogies between classical and functor calculus explicit. Inspired by Huang, Marcantognini, and Young's chain rule for higher order directional derivatives of functions, we define a higher order directional derivative for functors of abelian categories. We show that our higher order directional derivative is related to the iterated partial directional derivatives of the second author and McCarthy by a Fa\`a di Bruno style formula. We obtain a higher order chain rule for our directional derivatives using a feature of the cartesian differential category structure, and with this provide a formulation for the $n$th layers of the Taylor tower of a composition of functors $F\circ G$ in terms of the derivatives and directional derivatives of $F$ and $G$, reminiscent of similar formulations for functors of spaces or spectra by Arone and Ching. Throughout, we provide explicit chain homotopy equivalences that tighten previously established quasi-isomorphisms for properties of abelian functor calculus., Comment: v2: final journal version with a number of clarifications and an expanded appendix written in response to the referee's report; 51 pages

Background Influenza A H1N1 and B are associated with neurological complications including seizures, encephalopathy and encephalitis. However, this season, when H3N2 was the predominant strain, many patients were admitted with neurological manifestations of influenza (NMI). The study objectives were to: 1) identify clinical characteristics of children with NMI and 2) compare demographics and clinical characteristics with influenza-positive controls. Methods We conducted a retrospective cohort/case control study of children with NMI at Children’s Hospital Colorado from Dec 2016-Apr 2017. We reviewed the medical records to identify children with NMI, and assessed clinical characteristics and outcomes. We conducted unadjusted conditional logistic regression using influenza-positive sex, race and time-matched controls to identify risk factors associated with NMI. Results Of 126 inpatients with influenza, 20 (16%) had NMI; 11 (55%) had encephalopathy, meningitis or encephalitis, 13 (65%) had a seizure presentation, 4 children had both presentations (Table). Nineteen (95%) had infection with influenza H3N2. Of those with known vaccination status, 13/19 (68%) were unvaccinated against influenza. Compared with matched controls, children with NMI were more likely to have a neurological comorbidity, (40% vs 11%, OR 4.1, 95% CI 1.5–11.3) and a secondary bacterial infection (35% vs 13%, OR 4.2, 95% CI 1.2–15). Conclusion NMI was associated with H3N2 strains, and most cases were brief, reversible, yet required intensive care. Our findings suggest consideration of influenza testing among febrile children with altered mental status/seizures, and the importance of influenza vaccination among children with underlying neurological disorders. Characteristics of children with NMI Variable Seizure N (%)a Encephalitis /Encephalopathy /Meningitis N (%)a Prior Neurological Condition (n = 8) n = 7 n = 2 Age yrs b 4 (2–10) 12 (10–13) Male 3 (43) 1 (50) ICU c 3 (43) 1 (50) CSF WCC bd, n = 3 2 (2–2) 3 (2–3) Abnormal brain imaging n = 4 1 (50) 1 (50) No Prior Neurological Condition (n = 12) n = 6 n = 9 Age, yearsb 4 (1–11) 11 (2–12) Male 3 (50) 6 (67) ICU c 4 (67) 7 (78) CSF WCC bd n = 9 29 (3–545) 9 (1–29) Abnormal brain imaging n = 10 3 (60) 4 (67) aUnless otherwise specified b Median (IQR) cIntensive Care Unit dCerebrospinal fluid white cell count Disclosures S. Rao, GSK: Investigator, Research support; A. Dempsey, Merck, Pfizer, sanofi pasteur: Consultant, no research funding