INTRODUCTION: Observational studies have demonstrated an association between use of digoxin and reduced interstage mortality after Norwood operation for hypoplastic left heart syndrome (HLHS). Digoxin use has increased significantly but remains variable between different hospitals, independent of case-mix. Instrumental variable analyses have the potential to overcome unmeasured confounding, the major limitation of previous observational studies and to generate an estimate of the attributable benefit of treatment with digoxin.

METHODS: A cohort of neonates with HLHS born from 1/1/2007 to 12/31/2021 who underwent Norwood operation at Pediatric Health Information Systems Database hospitals and survived >14 days after operation were studied. Using hospital-specific, 6-month likelihood of administering digoxin as an instrumental variable, analyses adjusting for both unmeasured confounding (using the instrumental variable) and measured confounders with multivariable logistic regression were performed.

RESULTS: The study population included 5,148 subjects treated at 47 hospitals of which 63% were male and 46% non-Hispanic white. Of these, 44% (n=2,184) were prescribed digoxin. Treatment with digoxin was associated with superior 1-year transplant-free survival in unadjusted analyses (85% vs. 82%, p=0.02). This survival benefit persisted in an instrumental-variable analysis (OR: 0.71, 95% CI: 0.54-0.94, p=0.01), which can be converted to an absolute risk reduction of 5% (number needed to treat of 20).

CONCLUSION: In this observational study of patients with HLHS after Norwood using instrumental variable techniques, a significant benefit in one-year transplant-free survival attributable to digoxin was demonstrated. In the absence of clinical trial data, this should encourage the use of digoxin in this vulnerable population.

Quality improvement efforts have focused on reducing interstage mortality for infants with hypoplastic left heart syndrome (HLHS). In 1/2016, two publications reported that use of digoxin was associated with reduced interstage mortality. The degree to which these findings have affected real world practice has not been evaluated. The discharge medications of neonates with HLHS undergoing Norwood operation between 1/2007 and 12/2018 at Pediatric Health Information Systems Database hospitals were studied. Mixed effects models were calculated to evaluate the hypothesis that the likelihood of digoxin prescription increased after 1/2016, adjusting for measurable confounders with furosemide and aspirin prescription measured as falsification tests. Interhospital practice variation was measured using the median odds ratio. Over the study period, 6091 subjects from 45 hospitals were included. After adjusting for measurable covariates, discharge after 1/2016 was associated with increased odds of receiving digoxin (OR 3.9, p < 0.001). No association was seen between date of discharge and furosemide (p = 0.26) or aspirin (p = 0.12). Prior to 1/2016, the likelihood of receiving digoxin was decreasing (OR 0.9 per year, p < 0.001), while after 1/2016 the rate has increased (OR 1.4 per year, p < 0.001). However, there remains significant interhospital variation in the likelihood of receiving digoxin even after adjusting for known confounders (median odds ratio = 3.5, p < 0.0001). Following publication of studies describing an association between digoxin and improved interstage survival, the likelihood of receiving digoxin at discharge increased without similar changes for furosemide or aspirin. Despite concerted efforts to standardize interstage care, interhospital variation in pharmacotherapy in this vulnerable population persists.

<p>Evidence for the effectiveness of masking on SARS-CoV-2 transmission at the individual level has accumulated, but the additional benefit of community-level mandates is less certain. In this observational study of matched cohorts from 394 US counties between March 21 and October 20, 2020, we estimated the association between county-level public masking mandates and daily COVID-19 case incidence. On average, the daily case incidence per 100,000 people in masked counties compared with unmasked counties declined by 23&nbsp;percent at four weeks, 33&nbsp;percent at six weeks, and 16&nbsp;percent across six weeks postintervention. The beneficial effect varied across regions of different population densities and political leanings. The most concentrated effects of masking mandates were seen in urban counties; the benefit of the mandates was potentially stronger within Republican-leaning counties. Although benefits were not equally distributed in all regions, masking mandates conferred benefit in reducing community case incidence during an early period of the COVID-19 pandemic.</p>

<p><strong>BACKGROUND: </strong>There are conflicting data regarding the benefit of compression-only bystander cardiopulmonary resuscitation (CO-CPR) compared with CPR with rescue breathing (RB-CPR) after pediatric out-of-hospital cardiac arrest (OHCA).</p>

<p><strong>OBJECTIVES: </strong>This study sought to test the hypothesis that RB-CPR is associated with improved neurologically favorable survival compared with CO-CPR following pediatric OHCA, and to characterize age-stratified outcomes with CPR type compared with no bystander CPR (NO-CPR).</p>

<p><strong>METHODS: </strong>Analysis of the CARES registry (Cardiac Arrest Registry to Enhance Survival) for nontraumatic pediatric OHCAs (patients aged&nbsp;≤18 years) from 2013-2019 was performed. Age groups included infants (&lt;1 year), children (1 to 11 years), and adolescents (≥12 years). The primary outcome was neurologically favorable survival at hospital discharge.</p>

<p><strong>RESULTS: </strong>Of 13,060 pediatric OHCAs, 46.5% received bystander CPR. CO-CPR was the most common bystander CPR type. In the overall cohort, neurologically favorable survival was associated with RB-CPR (adjusted OR: 2.16; 95%&nbsp;CI: 1.78-2.62) and CO-CPR (adjusted OR: 1.61; 95%&nbsp;CI: 1.34-1.94) compared with NO-CPR. RB-CPR was associated with a higher odds of neurologically favorable survival compared with CO-CPR (adjusted OR: 1.36; 95%&nbsp;CI: 1.10-1.68). In age-stratified analysis, RB-CPR was associated with better neurologically favorable survival versus NO-CPR in all age groups. CO-CPR was associated with better neurologically favorable survival compared with NO-CPR in children and adolescents, but not in infants.</p>

<p><strong>CONCLUSIONS: </strong>CO-CPR was the most common type of bystander CPR in pediatric OHCA. RB-CPR was associated with better outcomes compared with CO-CPR. These results support present guidelines for RB-CPR as the preferred CPR modality for pediatric OHCA.</p>

<p>Tetralogy of Fallot (TOF) repair is associated with excellent operative survival. However, a subset of patients experiences post-operative complications, which can significantly alter the early and late post-operative course. We utilized a machine learning approach to identify risk factors for post-operative complications after TOF repair. We conducted a single-center prospective cohort study of children &lt;2 years of age with TOF undergoing surgical repair. The outcome was occurrence of post-operative cardiac complications, measured between TOF repair and hospital discharge or death. Predictors included patient, operative, and echocardiographic variables, including pre-operative right ventricular strain and fractional area change as measures of right ventricular function. Gradient-boosted quantile regression models (GBM) determined predictors of post-operative complications. Cross-validated GBMs were implemented with and without a filtering stage non-parametric regression model to select a subset of clinically meaningful predictors. Sensitivity analysis with gradient-boosted Poisson regression models was used to examine if the same predictors were identified in the subset of patients with at least one complication. Of the 162 subjects enrolled between March 2012 and May 2018, 43 (26.5%) had at least one post-operative cardiac complication. The most frequent complications were arrhythmia requiring treatment ( = 22, 13.6%), cardiac catheterization ( = 17, 10.5%), and extracorporeal membrane oxygenation (ECMO) ( = 11, 6.8%). Fifty-six variables were used in the machine learning analysis, of which there were 21 predictors that were already identified from the first-stage regression. Duration of cardiopulmonary bypass (CPB) was the highest ranked predictor in all models. Other predictors included gestational age, pre-operative right ventricular (RV) global longitudinal strain, pulmonary valve Z-score, and immediate post-operative arterial oxygen level. Sensitivity analysis identified similar predictors, confirming the robustness of these findings across models. Cardiac complications after TOF repair are prevalent in a quarter of patients. A prolonged surgery remains an important predictor of post-operative complications; however, other perioperative factors are likewise important, including pre-operative right ventricular remodeling. This study identifies potential opportunities to optimize the surgical repair for TOF to diminish post-operative complications and secure improved clinical outcomes. Efforts toward optimizing pre-operative ventricular remodeling might mitigate post-operative complications and help reduce future morbidity.</p>

<p><strong>OBJECTIVES: </strong>Multiple states have passed legislation permitting marijuana use. The impact of legalization on trends in hospital encounters for marijuana exposures in young children across states remains unknown. We aimed to describe trends in marijuana-related hospital encounters over time in children &lt;6 years and assess the association of state-level marijuana legislation with the rate of marijuana-related hospitalizations.</p>

<p><strong>METHODS: </strong>We identified inpatient, emergency department and observation encounters for children &lt;6 years with marijuana exposures (defined by International Classification of Diseases diagnosis codes) unique on the patient-year level at 52 children's hospitals in the Pediatric Health Information System database from 01/01/2004-12/31/2018. Trends in encounters across the study period were evaluated using negative binomial regression with outcome of marijuana-related hospital encounters and year as the predictor variable accounting for clustering by hospital. We then estimated a negative binomial regression difference-in-differences model to examine the association between the main outcome and state recreational and medical marijuana legalization.</p>

<p><strong>RESULTS: </strong>Of the 1296 included unique patient-year encounters, 50% were female with mean age 2.1 years (SD=1.4). Fifty percent were inpatient (n=645) and 15% required intensive care with 4% requiring mechanical ventilation. There was a 13.3-fold increase in exposures in 2018 compared to 2004 (p &lt;0.001). We did not find an effect of state legalization status for recreational (p=0.24) or medical (p=0.30) marijuana.</p>

<p><strong>CONCLUSIONS: </strong>The observed dramatic increase in marijuana-related hospital encounters highlights the need for prevention strategies aimed at reducing unintentional marijuana exposures in young children, even in states without legislation permitting marijuana use.</p>

<p><strong>Importance: </strong>Escherichia coli is a leading cause of serious infection among term and preterm newborn infants. Surveillance of antibiotic susceptibility patterns of E coli among infants admitted to neonatal intensive care units should inform empirical antibiotic administration.</p>

<p><strong>Objective: </strong>To assess the epidemiologic characteristics and antibiotic susceptibility patterns of E coli in infants admitted to neonatal intensive care units in the US over time.</p>

<p><strong>Design, Setting, and Participants: </strong>This retrospective cohort study used the Premier Health Database, a comprehensive administrative database of inpatient encounters from academic and community hospitals across the US. Participants included newborn infants admitted to centers contributing microbiology data from January 1, 2009, to December 31, 2017, with E coli isolated from blood, cerebrospinal fluid, or urine cultures. Data were collected and analyzed from December 1, 2018, to November 30, 2019.</p>

<p><strong>Main Outcomes and Measures: </strong>Changes in annual antibiotic susceptibility of E coli during the study period. The proportion of infants with nonsusceptible organisms (resistant or intermediate susceptibility) in antibiotic categories by year, birth weight, infection source, and timing of infection and patient and center characteristics associated with neonatal E coli infection and antibiotic susceptibility were assessed.</p>

<p><strong>Results: </strong>A total of 721 infants (434 male [60.2%]; median age at E coli infection, 14 days [interquartile range, 1-33 days]) from 69 centers had at least 1 episode of E coli infection and available susceptibility results. No significant changes were observed over time in the overall annual proportions of antibiotic nonsusceptibility to ampicillin (mean [SD], 66.8% [1.5%]; range, 63.3% to 68.6%; estimated yearly change, -0.28% [95% CI, -1.75% to 1.18%]), nonsusceptibility to aminoglycosides (mean [SD], 16.8% [4.5%]; range, 10.7% to 23.2%; estimated yearly change, -0.85% [95% CI, -1.93% to 0.23%]), or extended-spectrum β-lactamase phenotype (mean [SD], 5.0% [3.7%]; range, 0% to 11.1%; estimated yearly change, 0.46% [95% CI, -0.18% to 1.11%]). No isolates with nonsusceptibility to carbapenems were identified. Among 218 infants with early-onset infection, 22 (10.1%) had isolates with nonsusceptibility to both ampicillin and gentamicin, the antibiotics most commonly administered to newborns as empirical therapy.</p>

<p><strong>Conclusions and Relevance: </strong>In this cohort study, nonsusceptibility to commonly administered antibiotics was found in substantial proportions of neonatal E coli isolates, with no significant change from 2009 to 2017. These findings may inform empirical antibiotic choices for newborn infants.</p>

<p><strong>Importance: </strong>Local variation in the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across the United States has not been well studied.</p>

<p><strong>Objective: </strong>To examine the association of county-level factors with variation in the SARS-CoV-2 reproduction number over time.</p>

<p><strong>Design, Setting, and Participants: </strong>This cohort study included 211 counties, representing state capitals and cities with at least 100 000 residents and including 178 892 208 US residents, in 46 states and the District of Columbia between February 25, 2020, and April 23, 2020.</p>

<p><strong>Exposures: </strong>Social distancing, measured by percentage change in visits to nonessential businesses; population density; and daily wet-bulb temperatures.</p>

<p><strong>Main Outcomes and Measures: </strong>Instantaneous reproduction number (Rt), or cases generated by each incident case at a given time, estimated from daily case incidence data.</p>

<p><strong>Results: </strong>The 211 counties contained 178 892 208 of 326 289 971 US residents (54.8%). Median (interquartile range) population density was 1022.7 (471.2-1846.0) people per square mile. The mean (SD) peak reduction in visits to nonessential business between April 6 and April 19, as the country was sheltering in place, was 68.7% (7.9%). Median (interquartile range) daily wet-bulb temperatures were 7.5 (3.8-12.8) °C. Median (interquartile range) case incidence and fatality rates per 100 000 people were approximately 10 times higher for the top decile of densely populated counties (1185.2 [313.2-1891.2] cases; 43.7 [10.4-106.7] deaths) than for counties in the lowest density quartile (121.4 [87.8-175.4] cases; 4.2 [1.9-8.0] deaths). Mean (SD) Rt in the first 2 weeks was 5.7 (2.5) in the top decile compared with 3.1 (1.2) in the lowest quartile. In multivariable analysis, a 50% decrease in visits to nonessential businesses was associated with a 45% decrease in Rt (95% CI, 43%-49%). From a relative Rt at 0 °C of 2.13 (95% CI, 1.89-2.40), relative Rt decreased to a minimum as temperatures warmed to 11 °C, increased between 11 and 20 °C (1.61; 95% CI, 1.42-1.84) and then declined again at temperatures greater than 20 °C. With a 70% reduction in visits to nonessential business, 202 counties (95.7%) were estimated to fall below a threshold Rt of 1.0, including 17 of 21 counties (81.0%) in the top density decile and 52 of 53 counties (98.1%) in the lowest density quartile.2.</p>

<p><strong>Conclusions and Relevance: </strong>In this cohort study, social distancing, lower population density, and temperate weather were associated with a decreased Rt for SARS-CoV-2 in counties across the United States. These associations could inform selective public policy planning in communities during the coronavirus disease 2019 pandemic.</p>

<p><strong>OBJECTIVE: </strong>To determine the association between daily water intake and 24-hour urine volume among adolescents with nephrolithiasis in order to estimate a "fluid prescription", the additional water intake needed to increase urine volume to a target goal.</p>

<p><strong>METHODS: </strong>We conducted a secondary analysis of an ecological momentary assessment study that prospectively measured daily water intake of 25 adolescents with nephrolithiasis over 7 days. We identified 24-hour urine volumes obtained for clinical care within 12 months of water intake assessment. A linear regression model was fit to estimate the magnitude of the association between daily water intake and 24-hour urine volume, adjusting for age, sex, race, and daily temperature.</p>

<p><strong>RESULTS: </strong>Twenty-two participants completed fifty-seven 24-hour urine collections within 12 months of the study period. Median daily water intake was 1.4 L (IQR 0.67-1.94). Median 24-hour urine volume was 2.01 L (IQR 1.20-2.73). A 1 L increase in daily water intake was associated with a 710 mL increase in 24-hour urine output (95% CI 0.55-0.87). Using the model output, the equation was generated to estimate the additional fluid intake needed (fluid prescription; FP) to produce the desired increase in urine output (dUOP): FP=dUOP/0.71.</p>

<p><strong>CONCLUSIONS: </strong>The fluid prescription equation (FP = dUOP)/0.71), which reflects the relationship between water intake and urine volume, could be used to help adolescents with nephrolithiasis achieve urine output goals to decrease stone recurrence.</p>

<p><strong>PURPOSE: </strong>Shockwave lithotripsy (SWL) and ureteroscopy (URS) are the most commonly performed surgeries for kidney and ureteral stones, but the comparative effectiveness of these interventions at the population level is unclear. The purpose of our study was to compare retreatment for SWL and URS.</p>

<p><strong>MATERIALS AND METHODS: </strong>A retrospective cohort study using all-payer claims data for all patients who underwent SWL or URS from 1997-2016 at 74 hospitals in South Carolina was performed. The primary outcome measure was subsequent SWL or URS within 6 months of initial surgery. Pseudorandomized trials of URS versus SWL were performed for each year, applying propensity scores to balance hospital and patient characteristics. Discrete time failure models were fit using propensity-score weighted logistic regression.</p>

<p><strong>RESULTS: </strong>Overall, 136,152 URS and SWL surgeries were performed on 95,227 unique patients with retreatment representing 9% of all surgeries. 74,251 index surgeries were SWL (59.9%) and 49,743 were URS (40.1%). SWL was associated with a 20% increased odds of retreatment (OR 1.20, 95% CI 1.13, 1.26). The probability of retreatment was 7.5% for URS and 10.4% for SWL. SWL had the greatest risk for retreatment at months 2 (OR 1.85, 95% CI 1.64, 2.10) and 3 (OR 1.76, 95% CI: 1.50, 2.06). Initial SWL patients were more likely to have SWL for retreatment (84.6%) than were patients who had initial URS to have URS (29.3%).</p>

<p><strong>CONCLUSIONS: </strong>Compared to URS, SWL was associated with increased odds of retreatment. These results have implications for shared decision-making and value-based surgical treatment of nephrolithiasis.</p>