Feasibility of "Symptom Discovery," a Longitudinal and Comprehensive Data Collection Tool During COVID-19.

There are few patient- or public-facing tools for longitudinal and comprehensive symptom assessment, especially when faced with an uncharacterized condition such as COVID-19 or a chronic condition in which symptoms have not been adequately specified. To address this need, we developed the Symptom Discovery mobile application and tested its feasibility with the US public early in the COVID-19 pandemic. Although there were challenges, results showed feasibility and acceptance.

Protocol-Driven Initiation and Weaning of High-Flow Nasal Cannula for Patients With Bronchiolitis: A Quality Improvement Initiative.

OBJECTIVES: Bronchiolitis is the most common cause for nonelective infant hospitalization in the United States with increasing utilization of high-flow nasal cannula (HFNC). We standardized initiation and weaning of HFNC for bronchiolitis and quantified the impact on outcomes. Our specific aim was to reduce hospital and ICU length of stay (LOS) by 10% between two bronchiolitis seasons after implementation. DESIGN: A quality improvement (QI) project using statistical process control methodology. SETTING: Tertiary-care children's hospital with 24 PICU and 48 acute care pediatric beds. PATIENTS: Children less than 24 months old with bronchiolitis without other respiratory diagnoses or underlying cardiac, respiratory, or neuromuscular disorders between December 2017 and November 2018 (baseline), and December 2018 and February 2020 (postintervention). INTERVENTIONS: Interventions included development of an HFNC protocol with initiation and weaning guidelines, modification of protocol and respiratory assessment classification, education, and QI rounds with a focus on efficient HFNC weaning, transfer, and/or discharge. MEASUREMENTS AND MAIN RESULTS: A total of 223 children were included (96 baseline and 127 postintervention). The primary outcome metric, average LOS per patient, decreased from 4.0 to 2.8 days, and the average ICU LOS per patient decreased from 2.8 to 1.9 days. The secondary outcome metric, average HFNC treatment hours per patient, decreased from 44.0 to 36.3 hours. The primary and secondary outcomes met criteria for special cause variation. Balancing measures included ICU readmission rates, 30-day readmission rates, and adverse events, which were not different between the two periods. CONCLUSIONS: A standardized protocol for HFNC management for patients with bronchiolitis was associated with decreased hospital and ICU LOS, less time on HFNC, and no difference in readmissions or adverse events.

Identification and characterization of a MAPT-targeting locked nucleic acid antisense oligonucleotide therapeutic for tauopathies.

Tau is a microtubule-associated protein (MAPT, tau) implicated in the pathogenesis of tauopathies, a spectrum of neurodegenerative disorders characterized by accumulation of hyperphosphorylated, aggregated tau. Because tau pathology can be distinct across diseases, a pragmatic therapeutic approach may be to intervene at the level of the tau transcript, as it makes no assumptions to mechanisms of tau toxicity. Here we performed a large library screen of locked-nucleic-acid (LNA)-modified antisense oligonucleotides (ASOs), where careful tiling of the MAPT locus resulted in the identification of hot spots for activity in the 3' UTR. Further modifications to the LNA design resulted in the generation of ASO-001933, which selectively and potently reduces tau in primary cultures from hTau mice, monkey, and human neurons. ASO-001933 was well tolerated and produced a robust, long-lasting reduction in tau protein in both mouse and cynomolgus monkey brain. In monkey, tau protein reduction was maintained in brain for 20 weeks post injection and corresponded with tau protein reduction in the cerebrospinal fluid (CSF). Our results demonstrate that LNA-ASOs exhibit excellent drug-like properties and sustained efficacy likely translating to infrequent, intrathecal dosing in patients. These data further support the development of LNA-ASOs against tau for the treatment of tauopathies.

"Good Catch, Kiddo"-Enhancing Patient Safety in the Pediatric Emergency Department Through Simulation.

OBJECTIVES: Adverse events that affect patient safety are a significant concern in pediatrics. Increasing situational awareness, identifying errors and near misses, and reporting them using organizational incident reporting systems enables mitigation of harm. METHODS: We designed and tested a brief, interactive, and easily replicable simulation activity for medical students, and emergency medicine interns and pediatric interns to strengthen their skills and enhance their self-efficacy in identifying and reporting patient safety hazards. Hazards fell into the categories of situational safety, patient identification and privacy, infection prevention, treatment errors, and issues with electronic health records (EHRs). RESULTS: The simulation training significantly increased the self-efficacy of medical students and interns in identifying and reporting patient safety hazards. Learners were very satisfied with the simulation training, successfully recognized key patient safety hazards, provided feedback to improve the training, and improved their ability to report hazards through organizational incident reporting systems. Patient safety hazards associated with patient misidentification were recognized most frequently, whereas safety hazards associated with EHRs were missed with the greatest frequency. CONCLUSIONS: The simulation training enabled learners to identify hazards and near misses and enhanced their ability to report hazards through organizational incident reporting systems. Learners at all levels of training identified safety hazards at comparable rates, which demonstrates the role that trainees play in critically observing clinical settings with fresh eyes and identifying and reporting patient safety hazards. Interventions to promote patient safety need to prioritize building situational awareness of potential hazards associated with EHR use.

Improving Pediatric Resident Safety Event Reporting Using Quality Improvement Methods.

BACKGROUND AND OBJECTIVES: Safety event reporting systems facilitate identification of system-level targets to improve patient safety. Resident physicians report few safety events despite their role as frontline providers and the frequent occurrence of events. The objective of this study is to increase the number of pediatric resident safety event submissions from <1 to 4 submissions per 14-day period within 12 months. METHODS: We conducted an iterative quality improvement process with 39 pediatric residents at a children's hospital. Interventions focused on 4 key drivers: user-friendly event submission process, resident buy-in, nonpunitive safety culture, and data transparency. The primary outcome measure of number of pediatric resident event submissions was analyzed by using statistical process control. Balancing measures included time from submission to feedback, duplicate submissions, and nonevent submissions. As a control, the primary outcome measure was monitored for nonpediatric residents during the same period. RESULTS: The mean number of pediatric resident event submissions increased from 0.9 to 5.7 submissions per 14 days. Impactful interventions included a designated space in the resident workroom to list safety events to submit, monthly project updates, and an interresident competition. There were no duplicate submissions or nonevent submissions in the postintervention period. Time to feedback in the postintervention period had both upward and downward shifts, with >8 consecutive points above and below the baseline period's centerline. The control group showed no sustained change in event submissions. CONCLUSIONS: Our improvement process was associated with significant increase in pediatric resident safety event submissions without an increase in the number of submissions categorized as duplicates or nonevents.

Association of Race and Ethnicity with Sedation Management in Pediatric Intensive Care.

Rationale: Racial disparities in pain management have been previously reported for children receiving emergency care.Objectives: To determine whether patient race or ethnicity is associated with the broader goal of pain management and sedation among pediatric patients mechanically ventilated for acute respiratory failure.Methods: Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white, n = 1,233), non-Hispanic Black (Black, n = 502), or Hispanic of any race (Hispanic, n = 536).Results: Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%).Conclusions: Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out.Clinical trial registered with clinicaltrials.gov (NCT00814099).

Testing Pediatric Emergency Telemedicine Implementation Strategies Using Quality Improvement Methods.

Background: Despite the recognized benefits of telemedicine use for pediatric emergency consultations, there are barriers to the widespread uptake of this technology. Quality improvement methods can be used to rapidly test implementation strategies. Our objective was to test telemedicine implementation strategies in real-world application using quality improvement methods. Our quality improvement aim was to achieve high rates of telemedicine use for pediatric transfer consultations. Methods: A multidisciplinary multisite improvement team identified that key drivers of increasing telemedicine use included telemedicine resource awareness, streamlined telemedicine workflow, provider buy-in, and data transparency. Interventions focused on telemedicine trainings, disseminating telemedicine uptake data, telemedicine reminders, telemedicine test calls, and preparing for telemedicine use for every transfer consultation. The outcome measure was percentage of pediatric emergency transfer consultations that used telemedicine. The balancing measure was time (minutes) from the initial transfer center call to completion of the consultation. Results: Multiple plan-do-study-act cycles were associated with special cause variation, with an upward shift in mean percentage of telemedicine use from 5% to 22%. Time from initial call to consultation completion remained unchanged. Conclusion: Our study supports the use of quality improvement methods to test telemedicine implementation strategies for pediatric telemedicine emergency consultations.

Interprofessional/interdisciplinary teamwork during the early COVID-19 pandemic: experience from a children's hospital within an academic health center.

The COVID-19 pandemic has created multiple, complex and intense demands on hospitals, including the need for surge planning in the many locations outside epicenters such as northern Italy or New York City. We here describe such surge planning in an Academic Health Center that encompasses a children's hospital. Interprofessional teams from every aspect of inpatient care and hospital operations worked to prepare for a COVID-19 surge. In so doing, they successfully innovated ways to integrate pediatric and adult care and maximize bed capacity. The success of this intense collaborative effort offers an opportunity for ongoing teamwork to enhance efficient, effective, and high-quality patient care.

Developing an Interfacility Transfer Handoff Intervention: Applying the Person-Based Approach Method.

OBJECTIVE: To develop an interfacility transfer handoff intervention by applying the person-based approach method. METHODS: We conducted a qualitative study that used nominal group technique (NGT) and focus groups to apply the person-based approach for intervention development. NGT methods were used to determine prioritized pediatric transfer handoff elements to design the initial intervention prototype. Five focus group sessions were then held to solicit feedback on the intervention, perceptions on implementing the intervention, and outcomes for evaluating the intervention. Data were analyzed by using content analysis. Iterative improvements were made to the intervention prototype as data emerged. RESULTS: Forty-two clinical providers in total participated in NGT and focus group sessions, including physicians, advanced practitioners, nurses, and a respiratory therapist. The initial intervention prototype was a handoff mnemonic tool, "SHARING" (short introduction, how the patient appeared, action taken, responses and results, interpretation, next steps, gather documents). Perceived benefits of the intervention included clarifying handoff expectations, reducing handoff deficits, supporting less experienced clinical providers, and setting the stage for ongoing effective communication. Outcomes perceived to be meaningful were related to triage appropriateness, workflow and use, and communication and information sharing. The final version of the intervention consisted of a SHARING reference card and a SHARING electronic medical record note template. CONCLUSIONS: Using qualitative methods to apply the person-based approach to intervention development, we developed a transfer handoff intervention. Future research is needed to examine impacts of this tool; outcomes can include those identified as meaningful by participants in our present study.

Risk Stratification and Personal Protective Equipment Use in Pediatric Endoscopy During the Coronavirus Disease 2019 Outbreak: A Single-center Protocol.

SARS-CoV-2, the novel coronavirus causing coronavirus disease 2019 (COVID-19), is now a global pandemic. Human-to-human transmission has been documented to occur through respiratory secretions, feces, aerosols, and contaminated environmental surfaces. Pediatric patients present a unique challenge as they may have minimal symptoms and yet transmit disease. Endoscopists face risk for infection with viruses like SARS-CoV-2, as the aerosol generating nature of endoscopy diffuses respiratory disease that can be spread via an airborne and droplet route. We describe our center's methodology for pediatric patient risk stratification to facilitate responsible use of endoscopic resources during this crisis. We also describe our recommendations for use of personal protective equipment by endoscopists, with the goal of ensuring the safety of ourselves, our anesthesiology and endoscopy staff, and our patients.

Allele-Selective Knockdown of MYH7 Using Antisense Oligonucleotides.

Hundreds of dominant-negative myosin mutations have been identified that lead to hypertrophic cardiomyopathy, and the biomechanical link between mutation and disease is heterogeneous across this patient population. To increase the therapeutic feasibility of treating this diverse genetic population, we investigated the ability of locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) to selectively knock down mutant myosin transcripts by targeting single-nucleotide polymorphisms (SNPs) that were found to be common in the myosin heavy chain 7 (MYH7) gene. We identified three SNPs in MYH7 and designed ASO libraries to selectively target either the reference or alternate MYH7 sequence. We identified ASOs that selectively knocked down either the reference or alternate allele at all three SNP regions. We also show allele-selective knockdown in a mouse model that was humanized on one allele. These results suggest that SNP-targeting ASOs are a promising therapeutic modality for treating cardiac pathology.

Interprofessional Approach to the Sustained Reduction in Ventilator-Associated Pneumonia in a Pediatric Intensive Care Unit.

BACKGROUND: Ventilator-associated pneumonia (VAP) increases morbidity, mortality, and health care costs. OBJECTIVE: To reduce the VAP rate in the pediatric/cardiac intensive care unit to fewer than 2 events per 1000 ventilator days within 2 years and to sustain a rate near 0 for the next 5 years. METHODS: An evidence-based VAP prevention bundle was developed and implemented by an interprofessional team using the Six Sigma Define, Measure, Analyze, Improve, Control methodology. The mixed unit's 5-element VAP prevention bundle consisted of age-appropriate oral care, proper airway suction technique, maintenance of safe endotracheal-tube cuff pressures, aspiration precautions, and head-of-bed elevation. Knowledge and practice were reinforced through multidisciplinary education and one-on-one teaching. Practice compliance was monitored through regular, unannounced bedside audits linked to just-in-time teaching. RESULTS: Within 2 years, the annual VAP rate fell from 7.86 to 1.16 events per 1000 ventilator days; VAP bundle-element compliance ranged from 86% to 99%. There were no VAP events during a 10-quarter period in 2012 through 2014. CONCLUSIONS: Development, implementation, and revision of a VAP prevention strategy using the Define, Measure, Analyze, Improve, Control methodology was associated with marked, sustained reduction in VAP rates, notably during the unit's expansion from 16 to 24 beds, the opening of a pediatric cardiothoracic unit, and the hiring of more than 80 new nurses. After 7 years, the VAP rate continues to be low at 0.86 for 2016 and 0 through June 2017.

Illness Severity of Children Admitted to the PICU From Referring Emergency Departments.

OBJECTIVES: To compare patient factors and outcomes among children admitted to PICUs from referring versus children's hospital emergency departments (EDs). METHODS: Pediatric patients (<19 years old) admitted to PICUs from referring and children's hospital EDs from July 1, 2011 to June 30, 2013. We compared demographic and clinical factors, including severity of illness as measured by a recalibrated Pediatric Index of Mortality, version 2 score. RESULTS: Of 80 045 children from 109 PICUs, 35.6% were admitted from referring EDs and 64.4% were admitted from children's hospital EDs. Children from referring EDs had higher illness severity (Pediatric Index of Mortality, version 2-predicted risk of mortality, 3.1% vs 2.2%, P < .001), were more likely to be mechanically ventilated within their first hour in the PICU (28.4% vs 23.4%, P < .001), and had higher observed mortality (3.3% vs 2.1%, P < .001). Once adjusted for illness severity and other confounders in a multivariable logistic regression model, there was no difference in the odds of mortality between children from referring and children's hospital EDs (odds ratio: 0.90; 95% confidence interval: 0.79 to 1.02, P = .09) CONCLUSIONS: Children transferred to PICUs from referring EDs had higher illness severity on arrival compared with children admitted from children's hospital EDs. Variations in patient selection for transfer or pretransfer treatment at referring EDs may contribute to the greater illness severity of transferred children. Referring hospitals may benefit from leveraging existing resources to improve patient stabilization before transfer.

Racial and Ethnic Disparities in Parental Refusal of Consent in a Large, Multisite Pediatric Critical Care Clinical Trial.

OBJECTIVE: To evaluate whether race or ethnicity was independently associated with parental refusal of consent for their child's participation in a multisite pediatric critical care clinical trial. STUDY DESIGN: We performed a secondary analyses of data from Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE), a 31-center cluster randomized trial of sedation management in critically ill children with acute respiratory failure supported on mechanical ventilation. Multivariable logistic regression modeling estimated associations between patient race and ethnicity and parental refusal of study consent. RESULT: Among the 3438 children meeting enrollment criteria and approached for consent, 2954 had documented race/ethnicity of non-Hispanic White (White), non-Hispanic Black (Black), or Hispanic of any race. Inability to approach for consent was more common for parents of Black (19.5%) compared with White (11.7%) or Hispanic children (13.2%). Among those offered consent, parents of Black (29.5%) and Hispanic children (25.9%) more frequently refused consent than parents of White children (18.2%, P < .0167 for each). Compared with parents of White children, parents of Black (OR 2.15, 95% CI 1.56-2.95, P < .001) and Hispanic (OR 1.44, 95% CI 1.10-1.88, P = .01) children were more likely to refuse consent. Parents of children offered participation in the intervention arm were more likely to refuse consent than parents in the control arm (OR 2.15, 95% CI 1.37-3.36, P < .001). CONCLUSIONS: Parents of Black and Hispanic children were less likely to be approached for, and more frequently declined consent for, their child's participation in a multisite critical care clinical trial. Ameliorating this racial disparity may improve the validity and generalizability of study findings. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00814099.

Development of spiroguanidine-derived α7 neuronal nicotinic receptor partial agonists.

We describe the synthesis of quinuclidine-containing spiroguanidines and their utility as α7 neuronal nicotinic acetylcholine receptor (nAChR) partial agonists. The convergent synthetic route developed for this study allowed for rapid SAR investigation and provided access to a structurally diverse set of analogs. A potent and selective α7 nAChR partial agonist, N-(6-methyl-1,3-benzoxazol-2-yl)-3',5'-dihydro-4-azaspiro[bicyclo[2.2.2]octane-2,4'-imidazole]-2'-amine (BMS-910731, 16), was identified. This compound induced immediate early genes c-fos and Arc in a preclinical rodent model of α7 nAChR-derived cellular activation and plasticity. Importantly, the ability to incorporate selectivity for the α7 nACh receptor over the 5-HT3A receptor in this series suggested a significant difference in steric requirements between the two receptors.

The Association Between Insurance and Transfer of Noninjured Children From Emergency Departments.

STUDY OBJECTIVE: Among children requiring hospital admission or transfer, we seek to determine whether insurance is associated with the decision to either admit locally or transfer to another hospital. METHODS: This cross-sectional study used Healthcare Cost and Utilization Project 2012 Nationwide Emergency Department Sample. Pediatric patients receiving care in emergency departments (EDs) who were either admitted or transferred were included. Clinical Classifications Software was used to categorize patients into noninjury diagnostic cohorts. Multivariable logistic regression models adjusting for potential confounders, including severity of illness and comorbidities, and incorporating nationally representative weights were used to determine the association between insurance and the odds of transfer relative to admission. RESULTS: A total of 240,620 noninjury pediatric ED events met inclusion criteria. Patient and hospital characteristics, including older age and nonteaching hospitals, were associated with greater odds of transfer relative to admission. Patients who were uninsured or had self-pay had higher odds of transfer (odds ratio [OR] 3.84; 95% confidence interval [CI] 2.08 to 7.09) relative to admission compared with those with private insurance. Uninsured and self-pay patients also had higher odds of transfer across all 13 diagnostic categories, with ORs ranging from 2.96 to 12.00. Patients with Medicaid (OR 1.05; 95% CI 0.90 to 1.22) and other insurances (OR 1.14; 95% CI 0.87 to 1.48) had similar odds of transfer compared with patients with private insurance. CONCLUSION: Children without insurance and those considered as having self-pay are more likely to be transferred to another hospital than to be admitted for inpatient care within the same receiving hospital compared with children with private insurance. This study reinforces ongoing concerns about disparities in the provision of pediatric ED and inpatient care.

Design and Synthesis of a New Series of 4-Heteroarylamino-1'-azaspiro[oxazole-5,3'-bicyclo[2.2.2]octanes as α7 Nicotinic Receptor Agonists. 1. Development of Pharmacophore and Early Structure-Activity Relationship.

The design and synthesis of a series of quinuclidine-containing spirooxazolidines ("spiroimidates") and their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members of the series demonstrated excellent selectivity for α7 over the highly homologous 5-HT3A receptor. Modification of the N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'oxazol]-2'-amine (BMS-902483), a potent α7 partial agonist, which improved cognition in preclinical rodent models.