Publications by authors named "Lise E Nigrovic"

176 Publications

Changes in Antibiotic Treatment for Children With Lyme Meningitis 2015-2020.

Hosp Pediatr 2021 Sep 22. Epub 2021 Sep 22.

Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts.

Objectives: Although ceftriaxone has been the first-line treatment of Lyme meningitis, the 2020 Infectious Disease Society of America, American College of Rheumatology, and American Academy of Neurology guideline recommends either doxycycline or ceftriaxone. Our objective was to explore recent trends in enteral antibiotic treatment of children with Lyme meningitis.

Methods: Using codes for case identification, we performed a multicenter retrospective study of patients ≤21 years of age presenting to a pediatric hospital contributing to the Pediatric Health Information System who were diagnosed with Lyme meningitis from 2015 to 2020. Our primary outcome was treatment with parenteral antibiotics, defined by either a procedure code for indwelling catheter placement or >7 days of inpatient parenteral Lyme disease-specific therapy. To examine trends over the study period, we used a generalized estimating equation, with parenteral antibiotics as the dependent variable and study year as the independent variable, adjusted for patient age, sex, race, ethnicity, and insurance status clustered by hospital.

Results: We identified 239 patients with Lyme meningitis treated at 24 participating centers. Overall, 48 (20.0%) were treated with parenteral antibiotics, with a declining rate over the study period (43.8% in 2015 to 8.9% in 2020). After adjustment, the odds of treatment with a parenteral antibiotic decreased over the study period (adjusted odds ratio 0.57; 95% confidence interval 0.41-0.80).

Conclusions: Parenteral antibiotic treatment of children with Lyme meningitis has been on the decline in advance of the published clinical guideline. Carefully designed comparative effectiveness studies are needed to examine the effect of oral versus parenteral treatment regimens on clinical outcomes.
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http://dx.doi.org/10.1542/hpeds.2021-005909DOI Listing
September 2021

Predictors of Invasive Herpes Simplex Virus Infection in Young Infants.

Pediatrics 2021 Sep;148(3)

Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Objectives: To identify independent predictors of and derive a risk score for invasive herpes simplex virus (HSV) infection.

Methods: In this 23-center nested case-control study, we matched 149 infants with HSV to 1340 controls; all were ≤60 days old and had cerebrospinal fluid obtained within 24 hours of presentation or had HSV detected. The primary and secondary outcomes were invasive (disseminated or central nervous system) or any HSV infection, respectively.

Results: Of all infants included, 90 (60.4%) had invasive and 59 (39.6%) had skin, eyes, and mouth disease. Predictors independently associated with invasive HSV included younger age (adjusted odds ratio [aOR]: 9.1 [95% confidence interval (CI): 3.4-24.5] <14 and 6.4 [95% CI: 2.3 to 17.8] 14-28 days, respectively, compared with >28 days), prematurity (aOR: 2.3, 95% CI: 1.1 to 5.1), seizure at home (aOR: 6.1, 95% CI: 2.3 to 16.4), ill appearance (aOR: 4.2, 95% CI: 2.0 to 8.4), abnormal triage temperature (aOR: 2.9, 95% CI: 1.6 to 5.3), vesicular rash (aOR: 54.8, (95% CI: 16.6 to 180.9), thrombocytopenia (aOR: 4.4, 95% CI: 1.6 to 12.4), and cerebrospinal fluid pleocytosis (aOR: 3.5, 95% CI: 1.2 to 10.0). These variables were transformed to derive the HSV risk score (point range 0-17). Infants with invasive HSV had a higher median score (6, interquartile range: 4-8) than those without invasive HSV (3, interquartile range: 1.5-4), with an area under the curve for invasive HSV disease of 0.85 (95% CI: 0.80-0.91). When using a cut-point of ≥3, the HSV risk score had a sensitivity of 95.6% (95% CI: 84.9% to 99.5%), specificity of 40.1% (95% CI: 36.8% to 43.6%), and positive likelihood ratio 1.60 (95% CI: 1.5 to 1.7) and negative likelihood ratio 0.11 (95% CI: 0.03 to 0.43).

Conclusions: A novel HSV risk score identified infants at extremely low risk for invasive HSV who may not require routine testing or empirical treatment.
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http://dx.doi.org/10.1542/peds.2021-050052DOI Listing
September 2021

Serologic response to antigens varies with clinical phenotype in children and young adults with Lyme disease.

J Clin Microbiol 2021 Aug 11:JCM0134421. Epub 2021 Aug 11.

Division of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Lyme disease is commonly diagnosed by serologic response to and related species, but the relationship between serologic targets and clinical features is unknown. We developed a multi-antigen Luminex-based panel and evaluated IgG responses in 527 children 1 to 21 years of age assessed for Lyme disease across 4 Pedi Lyme Net emergency departments, including 127 Lyme cases defined by either an erythema migrans (EM) lesion or positive C6 enzyme immunoassay followed by immunoblot and 400 patients considered clinical mimics. Of 42 antigens tested, 26 elicited specific reactivity in Lyme patients, without marked age-dependent variation. Children with single EM lesions typically lacked -specific IgG. By principal component analysis, children with early disseminated and late Lyme disease clustered separately from clinical mimics and also from each other. Neurological disease and arthritis exhibited distinct serologic responses, with OspC variants overrepresented in neurological disease and p100, BmpA, p58 and p45 overrepresented in arthritis. Machine learning identified a 3-antigen panel (VlsE_Bb, p41_Bb, OspC_Bafz) that distinguished Lyme disease from clinical mimics with a sensitivity of 86.6% (95% confidence interval [CI] 80.3-92.1) and a specificity of 95.5% (95% CI 93.4-97.4). Sensitivity was much lower in early Lyme disease (38.5%, 95% CI 15.4-69.2). Interestingly, 17 children classified as Lyme mimics had a positive 3-antigen panel, suggesting that more comprehensive serologic analysis could help refine Lyme diagnosis. In conclusion, multiplex antigen panels provide a novel approach to understanding the immune response in Lyme disease, potentially helping to facilitate accurate diagnosis and to understand differences between clinical stages.
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http://dx.doi.org/10.1128/JCM.01344-21DOI Listing
August 2021

Serum Sodium Concentration and Mental Status in Children With Diabetic Ketoacidosis.

Pediatrics 2021 Sep 9;148(3). Epub 2021 Aug 9.

Department of Psychology, University of California, Davis, Davis, California.

Objectives: Diabetic ketoacidosis (DKA) is typically characterized by low or low-normal serum sodium concentrations, which rise as hyperglycemia resolves. In retrospective studies, researchers found associations between declines in sodium concentrations during DKA and cerebral injury. We prospectively investigated determinants of sodium concentration changes and associations with mental status alterations during DKA.

Methods: Using data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in Diabetic Ketoacidosis Trial, we compared children who had declines in glucose-corrected sodium concentrations with those who had rising or stable concentrations. Children were randomly assigned to 1 of 4 intravenous fluid protocols that differed in infusion rate and sodium content. Data from the first 4, 8, and 12 hours of treatment were analyzed for 1251, 1086, and 877 episodes, respectively.

Results: In multivariable analyses, declines in glucose-corrected sodium concentrations were associated with higher sodium and chloride concentrations at presentation and with previously diagnosed diabetes. Treatment with 0.45% (vs 0.9%) sodium chloride fluids was also associated with declines in sodium concentration; however, higher rates of fluid infusion were associated with declines in sodium concentration only at 12 hours. Frequencies of abnormal Glasgow Coma Scale scores and clinical diagnoses of cerebral injury were similar in patients with and without declines in glucose-corrected sodium concentrations.

Conclusions: Changes in glucose-corrected sodium concentrations during DKA treatment are influenced by the balance of free-water loss versus sodium loss at presentation and the sodium content of intravenous fluids. Declines in glucose-corrected sodium concentrations are not associated with mental status changes during treatment.
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http://dx.doi.org/10.1542/peds.2021-050243DOI Listing
September 2021

Electrocardiogram as a Lyme Disease Screening Test.

J Pediatr 2021 Jul 12. Epub 2021 Jul 12.

Division of Emergency Medicine, Boston Children's Hospital, Boston, MA.

Objective: To examine the association between electrocardiographic (ECG) evidence of carditis at the time of Lyme disease evaluation and a diagnosis of Lyme disease.

Study Design: We performed an 8-center prospective cohort study of children undergoing emergency department evaluation for Lyme disease limited to those who had an ECG obtained by their treating clinicians. The study cardiologist reviewed all ECGs flagged as abnormal by the study sites to assess for ECG evidence of carditis. We defined Lyme disease as the presence of an erythema migrans lesion or a positive 2-tier Lyme disease serology. We used logistic regression to measure the association between Lyme disease and atrioventricular (AV) block or any ECG evidence of carditis.

Results: Of the 546 children who had an ECG obtained, 214 (39%) had Lyme disease. Overall, 42 children had ECG evidence of carditis, of whom 24 had AV block (20 first-degree). Of the patients with ECG evidence of carditis, only 21 (50%) had any cardiac symptoms. The presence of AV block (OR 4.7, 95% CI 1.8-12.1) and any ECG evidence of carditis (OR 2.3, 95% CI 1.2-4.3) were both associated with diagnosis of Lyme disease.

Conclusions: ECG evidence of carditis, especially AV block, was associated with a diagnosis of Lyme disease. ECG evidence of carditis can be used as a diagnostic biomarker for Lyme disease to guide initial management while awaiting Lyme disease test results.
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http://dx.doi.org/10.1016/j.jpeds.2021.07.010DOI Listing
July 2021

The Pediatric Emergency Research Network (PERN): A decade of global research cooperation in paediatric emergency care.

Emerg Med Australas 2021 10 3;33(5):900-910. Epub 2021 Jul 3.

Pediatric Emergency Care Applied Research Network (PECARN).

Objectives: The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in paediatric emergency care to organise globally for the conduct of collaborative research across networks.

Methods: PERN has grown from five to eight member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children.

Results: Beginning as a pandemic response studying H1N1 influenza risk factors in children, PERN research has progressed to multiple observational studies and ongoing global randomised controlled trials (RCTs). As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current COVID-19 pandemic.

Conclusions: Following its success with developing global research, the PERN goal now is to promote the implementation of scientific advances into everyday clinical practice by: (i) expanding the capacity for global RCTs; (ii) deepening the focus on implementation science; (iii) increasing attention to healthcare disparities; and (iv) expanding PERN's reach into resource-restricted regions. Through these actions, PERN aims to meet the needs of acutely ill and injured children throughout the world.
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http://dx.doi.org/10.1111/1742-6723.13801DOI Listing
October 2021

Effects of Fluid Rehydration Strategy on Correction of Acidosis and Electrolyte Abnormalities in Children With Diabetic Ketoacidosis.

Diabetes Care 2021 Sep 29;44(9):2061-2068. Epub 2021 Jun 29.

Department of Pediatrics, University of California Davis Health, University of California, Davis, School of Medicine, Sacramento.

Objective: Fluid replacement to correct dehydration, acidosis, and electrolyte abnormalities is the cornerstone of treatment for diabetic ketoacidosis (DKA), but little is known about optimal fluid infusion rates and electrolyte content. The objective of this study was to evaluate whether different fluid protocols affect the rate of normalization of biochemical derangements during DKA treatment.

Research Design And Methods: The current analysis involved moderate or severe DKA episodes ( = 714) in children age <18 years enrolled in the Fluid Therapies Under Investigation in DKA (FLUID) Trial. Children were assigned to one of four treatment groups using a 2 × 2 factorial design (0.90% or 0.45% saline and fast or slow rate of administration).

Results: The rate of change of pH did not differ by treatment arm, but Pco increased more rapidly in the fast versus slow fluid infusion arms during the initial 4 h of treatment. The anion gap also decreased more rapidly in the fast versus slow infusion arms during the initial 4 and 8 h. Glucose-corrected sodium levels remained stable in patients assigned to 0.90% saline but decreased in those assigned to 0.45% saline at 4 and 8 h. Potassium levels decreased, while chloride levels increased more rapidly with 0.90% versus 0.45% saline. Hyperchloremic acidosis occurred more frequently in patients in the fast arms (46.1%) versus the slow arms (35.2%).

Conclusions: In children treated for DKA, faster fluid administration rates led to a more rapid normalization of anion gap and Pco than slower fluid infusion rates but were associated with an increased frequency of hyperchloremic acidosis.
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http://dx.doi.org/10.2337/dc20-3113DOI Listing
September 2021

Validation of Septic Knee Monoarthritis Prediction Rule in a Lyme Disease Endemic Area.

Pediatr Emerg Care 2021 May 13. Epub 2021 May 13.

From the *Brown University, Providence, RI †Division of Pediatric Emergency Medicine, Children's Hospital of Pittsburgh, Pittsburgh, PA ‡Division of Pediatric Emergency Medicine, Children's Hospital of Wisconsin, Milwaukee, WI §Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA ∥Departments of Pediatrics and Emergency Medicine, Hasbro Children's Hospital, Providence, RI ¶Division of Emergency Medicine, Nemours/A.I. duPont Hospital for Children, Wilmington, DE #Department of Emergency Medicine, Children's Minnesota, Minneapolis, MN **Division of Emergency Medicine, Boston Children's Hospital, Boston, MA.

Objective: In Lyme disease endemic areas, Lyme and septic arthritis often present similarly. A published septic knee arthritis clinical prediction rule includes 2 high-risk predictors: absolute neutrophil count of 10,000 cells/mm or greater and erythrocyte sedimentation rate of 40 mm/h or greater. The objective of the study was to externally validate this prediction rule in a multicenter prospective cohort.

Methods: We enrolled a prospective cohort of children with knee monoarthritis undergoing evaluation for Lyme disease at 1 of 8 Pedi Lyme Net emergency departments located in endemic areas. We defined a case of septic arthritis with a positive synovial fluid culture or a synovial fluid white blood cell count of 50,000 or greater per high powered field with a positive blood culture and Lyme arthritis with a positive or equivocal C6 EIA, followed by a positive supplemental immunoblot. Other children were classified as having inflammatory arthritis. We report the performance of the septic arthritis clinical prediction rule in our study population.

Results: Of the 543 eligible children, 13 had septic arthritis (2.4%), 234 Lyme arthritis (43.1%), and 296 inflammatory arthritis (54.5%). Of the 457 children (84.2%) with available laboratory predictors, all children with septic arthritis were classified as high risk (sensitivity, 100%; 95% confidence interval [CI], 62.8%-100%; specificity, 68.1%; 95% CI, 63.6-73.3; negative predictive value, 278/278 [100%]; 95% CI, 98.6%-100%). Of the 303 low-risk children, 52 (17.2%) underwent diagnostic arthrocentesis.

Conclusions: The septic knee arthritis clinical prediction rule accurately distinguished between septic and Lyme arthritis in an endemic area. Clinical application may reduce unnecessary invasive diagnostic procedures.
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http://dx.doi.org/10.1097/PEC.0000000000002455DOI Listing
May 2021

Research environment and resources to support pediatric emergency medicine fellow research.

AEM Educ Train 2021 Jul 9;5(3):e10585. Epub 2021 Mar 9.

Section of Emergency Medicine Children's Hospital Colorado Aurora Colorado USA.

Background: There is a need for pediatric emergency medicine (PEM) researchers, but the current state of PEM fellow research training is not well described. We sought to (1) describe resources and gaps in PEM fellowship research training and (2) assess agreement between fellow and program director (PD) perceptions of these in fellow research experience.

Methods: Surveys were distributed electronically to U.S. PEM fellows and PDs from March to April 2020. Fellows and PDs were queried on program research infrastructure and current gaps in fellow research experience. For programs that had at least one fellow and PD response, each fellow response was compared to their PD's corresponding response (reference standard). For each binary survey item, we determined the percent of responses with agreement between the fellow and PD.

Results: Of 79 fellowship programs, 70 (89%) were represented with at least one response, including responses from 59 PDs (75%) and 218 fellows (39% of all fellows, representing 80% of programs). Fellows and PDs identified mentorship and faculty engagement as the most important needs for successful fellowship research; for every one fellow there was a median of 0.8 potential faculty mentors in the division. Twenty percent of fellows were not satisfied with mentorship opportunities. There was no association between fellow career research intent (high, defined as ≥20% dedicated time, or low) with current year of training (p = 0.88), program size (p = 0.67), and area of research focus (p = 0.40). Fellows were often unaware of research being performed by division faculty.

Conclusion: PEM fellows were not consistently aware of resources available to support research training. To better support PEM fellows' research training, many programs may need to expand mentorship and increase fellows' awareness of local and external resources and opportunities.
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http://dx.doi.org/10.1002/aet2.10585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8171771PMC
July 2021

The Pediatric Emergency Research Network: A Decade of Global Research Cooperation in Pediatric Emergency Care.

Pediatr Emerg Care 2021 07;37(7):389-396

Objectives: The Pediatric Emergency Research Network (PERN) was launched in 2009 with the intent for existing national and regional research networks in pediatric emergency care to organize globally for the conduct of collaborative research across networks.

Methods: The Pediatric Emergency Research Network has grown from 5- to 8-member networks over the past decade. With an executive committee comprising representatives from all member networks, PERN plays a supportive and collaborative rather than governing role. The full impact of PERN's facilitation of international collaborative research, although somewhat difficult to quantify empirically, can be measured indirectly by the observed growth of the field, the nature of the increasingly challenging research questions now being addressed, and the collective capacity to generate and implement new knowledge in treating acutely ill and injured children.

Results: Beginning as a pandemic response with a high-quality retrospective case-controlled study of H1N1 influenza risk factors, PERN research has progressed to multiple observational studies and ongoing global randomized controlled trials. As a recent example, PERN has developed sufficient network infrastructure to enable the rapid initiation of a prospective observational study in response to the current coronavirus disease 2019 pandemic. In light of the ongoing need for translation of research knowledge into equitable clinical practice and to promote health equity, PERN is committed to a coordinated international effort to increase the uptake of evidence-based management of common and treatable acute conditions in all emergency department settings.

Conclusions: The Pediatric Emergency Research Network's successes with global research, measured by prospective observational and interventional studies, mean that the network can now move to improve its ability to promote the implementation of scientific advances into everyday clinical practice. Achieving this goal will involve focus in 4 areas: (1) expanding the capacity for global randomized controlled trials; (2) deepening the focus on implementation science; (3) increasing attention to healthcare disparities and their origins, with growing momentum toward equity; and (4) expanding PERN's global reach through addition of sites and networks from resource-restricted regions. Through these actions, PERN will be able to build on successes to face the challenges ahead and meet the needs of acutely ill and injured children throughout the world.
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http://dx.doi.org/10.1097/PEC.0000000000002466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244934PMC
July 2021

Managing Diabetic Ketoacidosis in Children.

Ann Emerg Med 2021 09 7;78(3):340-345. Epub 2021 May 7.

Division of Emergency Medicine, Boston Children's Hospital, Boston, MA.

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http://dx.doi.org/10.1016/j.annemergmed.2021.02.028DOI Listing
September 2021

Environmental Correlates of Lyme Disease Emergence in Southwest Virginia, 2005-2014.

J Med Entomol 2021 07;58(4):1680-1685

Nicholas School of the Environment, Duke University, Durham, NC.

Lyme disease is the most common tick-borne disease in North America. Though human infection is mostly transmitted in a limited geography, the range has expanded in recent years. One notable area of recent expansion is in the mountainous region of southwestern Virginia. The ecological factors that facilitate or constrain the range of human Lyme disease in this region remain uncertain. To evaluate this further, we obtained ecological data, including remotely sensed data on forest structure and vegetation, weather data, and elevation. These data were aggregated within the census block groups of a 9,153 km2 area around the cities of Blacksburg and Roanoke, VA, an area with heterogeneous Lyme disease transmission. In this geographic area, 755 individuals were reported to have Lyme disease in the 10 yr from 2006 to 2015, and these cases were aggregated by block group. A zero-inflated negative binomial model was used to evaluate which environmental variables influenced the abundance of Lyme disease cases. Higher elevation and higher vegetation density had the greatest effect size on the abundance of Lyme disease. Measures of forest edge, forest integrity, temperature, and humidity were not associated with Lyme disease cases. Future southward expansion of Lyme disease into the southeastern states may be most likely in ecologically similar mountainous areas.
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http://dx.doi.org/10.1093/jme/tjab038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285012PMC
July 2021

Validation of the Rule of 7's for Identifying Children at Low-risk for Lyme Meningitis.

Pediatr Infect Dis J 2021 04;40(4):306-309

Pediatric Emergency Medicine, Division of Emergency Medicine, Boston Children's Hospital, Boston, Massachusetts.

Background: The Rule of 7's classifies children as low-risk for Lyme meningitis with the absence of the following: ≥7 days of headache, any cranial neuritis or ≥70% cerebrospinal fluid mononuclear cells. We sought to broadly validate this clinical prediction rule in children with meningitis undergoing evaluation for Lyme disease.

Methods: We performed a patient-level data meta-analysis of 2 prospective and 2 retrospective cohorts of children ≤21 years of age with cerebrospinal fluid pleocytosis who underwent evaluation for Lyme disease. We defined a case of Lyme meningitis with a positive 2-tier serology result (positive or equivocal first-tier enzyme immunoassay followed by a positive supplemental immunoblot). We applied the Rule of 7's and report the accuracy for the identification of Lyme meningitis.

Results: Of 721 included children with meningitis, 178 had Lyme meningitis (24.7%) and 543 had aseptic meningitis (75.3%). The pooled data from the 4 studies showed the Rule of 7's has a sensitivity of 98% [95% confidence interval (CI): 89%-100%, I2 = 71%], specificity 40% (95% CI: 30%-50%, I2 = 75%), and a negative predictive value of 100% (95% CI: 95%-100%, I2 = 55%).

Conclusions: The Rule of 7's accurately identified children with meningitis at low-risk for Lyme meningitis for whom clinicians should consider outpatient management while awaiting Lyme disease test results.
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http://dx.doi.org/10.1097/INF.0000000000003003DOI Listing
April 2021

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

Clin Infect Dis 2021 01;72(1):1-8

Michigan State University, East Lansing, Michigan, USA.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.
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http://dx.doi.org/10.1093/cid/ciab049DOI Listing
January 2021

Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease.

Clin Infect Dis 2021 01;72(1):e1-e48

Michigan State University, East Lansing, Michigan, USA.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.
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http://dx.doi.org/10.1093/cid/ciaa1215DOI Listing
January 2021

Marked Escalation in Journal Submissions During COVID-19 Pandemic.

Ann Emerg Med 2021 01 2;77(1):130-131. Epub 2020 Jul 2.

Annals of Emergency Medicine, American College of Emergency Physicians, Irving, TX.

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http://dx.doi.org/10.1016/j.annemergmed.2020.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330553PMC
January 2021

Characteristics of Afebrile Infants ≤60 Days of Age With Invasive Bacterial Infections.

Hosp Pediatr 2021 Jan 14;11(1):100-105. Epub 2020 Dec 14.

Division of Hospital Medicine, Department of Pediatrics, Seattle Children's Hospital and School of Medicine, University of Washington, Seattle, Washington.

Objectives: To describe the characteristics and outcomes of afebrile infants ≤60 days old with invasive bacterial infection (IBI).

Methods: We conducted a secondary analysis of a cross-sectional study of infants ≤60 days old with IBI presenting to the emergency departments (EDs) of 11 children's hospitals from 2011 to 2016. We classified infants as afebrile if there was absence of a temperature ≥38°C at home, at the referring clinic, or in the ED. Bacteremia and bacterial meningitis were defined as pathogenic bacterial growth from a blood and/or cerebrospinal fluid culture.

Results: Of 440 infants with IBI, 78 (18%) were afebrile. Among afebrile infants, 62 (79%) had bacteremia without meningitis and 16 (20%) had bacterial meningitis (10 with concomitant bacteremia). Five infants (6%) died, all with bacteremia. The most common pathogens were (35%), (16%), and (16%). Sixty infants (77%) had an abnormal triage vital sign (temperature <36°C, heart rate ≥181 beats per minute, or respiratory rate ≥66 breaths per minute) or a physical examination abnormality (ill appearance, full or depressed fontanelle, increased work of breathing, or signs of focal infection). Forty-three infants (55%) had ≥1 of the following laboratory abnormalities: white blood cell count <5000 or >15 000 cells per μL, absolute band count >1500 cells per μl, or positive urinalysis. Presence of an abnormal vital sign, examination finding, or laboratory test result had a sensitivity of 91% (95% confidence interval 82%-96%) for IBI.

Conclusions: Most afebrile young infants with an IBI had vital sign, examination, or laboratory abnormalities. Future studies should evaluate the predictive ability of these criteria in afebrile infants undergoing evaluation for IBI.
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http://dx.doi.org/10.1542/hpeds.2020-002204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769208PMC
January 2021

Invasive Bacterial Infections in Afebrile Infants Diagnosed With Acute Otitis Media.

Pediatrics 2021 01 7;147(1). Epub 2020 Dec 7.

Department of Pediatrics, University of Florida, Jacksonville, Jacksonville, Florida.

Objectives: To determine the prevalence of invasive bacterial infections (IBIs) and adverse events in afebrile infants with acute otitis media (AOM).

Methods: We conducted a 33-site cross-sectional study of afebrile infants ≤90 days of age with AOM seen in emergency departments from 2007 to 2017. Eligible infants were identified using emergency department diagnosis codes and confirmed by chart review. IBIs (bacteremia and meningitis) were determined by the growth of pathogenic bacteria in blood or cerebrospinal fluid (CSF) culture. Adverse events were defined as substantial complications resulting from or potentially associated with AOM. We used generalized linear mixed-effects models to identify factors associated with IBI diagnostic testing, controlling for site-level clustering effect.

Results: Of 5270 infants screened, 1637 met study criteria. None of the 278 (0%; 95% confidence interval [CI]: 0%-1.4%) infants with blood cultures had bacteremia; 0 of 102 (0%; 95% CI: 0%-3.6%) with CSF cultures had bacterial meningitis; 2 of 645 (0.3%; 95% CI: 0.1%-1.1%) infants with 30-day follow-up had adverse events, including lymphadenitis (1) and culture-negative sepsis (1). Diagnostic testing for IBI varied across sites and by age; overall, 278 (17.0%) had blood cultures, and 102 (6.2%) had CSF cultures obtained. Compared with infants 0 to 28 days old, older infants were less likely to have blood cultures ( < .001) or CSF cultures ( < .001) obtained.

Conclusion: Afebrile infants with clinician-diagnosed AOM have a low prevalence of IBIs and adverse events; therefore, outpatient management without diagnostic testing may be reasonable.
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http://dx.doi.org/10.1542/peds.2020-1571DOI Listing
January 2021

Frequency and Risk Factors of Acute Kidney Injury During Diabetic Ketoacidosis in Children and Association With Neurocognitive Outcomes.

JAMA Netw Open 2020 12 1;3(12):e2025481. Epub 2020 Dec 1.

Department of Pediatrics, University of California, Davis School of Medicine, Sacramento.

Importance: Acute kidney injury (AKI) occurs commonly during diabetic ketoacidosis (DKA) in children, but the underlying mechanisms and associations are unclear.

Objective: To investigate risk factors for AKI and its association with neurocognitive outcomes in pediatric DKA.

Design, Setting, And Participants: This cohort study was a secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a prospective, multicenter, randomized clinical trial comparing fluid protocols for pediatric DKA in 13 US hospitals. Included DKA episodes occurred among children age younger than 18 years with blood glucose 300 mg/dL or greater and venous pH less than 7.25 or serum bicarbonate level less than 15 mEq/L.

Exposures: DKA requiring intravenous insulin therapy.

Main Outcomes And Measures: AKI occurrence and stage were assessed using serum creatinine measurements using Kidney Disease: Improving Global Outcomes criteria. DKA episodes with and without AKI were compared using univariable and multivariable methods, exploring associated factors.

Results: Among 1359 DKA episodes (mean [SD] patient age, 11.6 [4.1] years; 727 [53.5%] girls; 651 patients [47.9%] with new-onset diabetes), AKI occurred in 584 episodes (43%; 95% CI, 40%-46%). A total of 252 AKI events (43%; 95% CI, 39%-47%) were stage 2 or 3. Multivariable analyses identified older age (adjusted odds ratio [AOR] per 1 year, 1.05; 95% CI, 1.00-1.09; P = .03), higher initial serum urea nitrogen (AOR per 1 mg/dL increase, 1.14; 95% CI, 1.11-1.18; P < .001), higher heart rate (AOR for 1-SD increase in z-score, 1.20; 95% CI, 1.09-1.32; P < .001), higher glucose-corrected sodium (AOR per 1 mEq/L increase, 1.03; 95% CI, 1.00-1.06; P = .001) and glucose concentrations (AOR per 100 mg/dL increase, 1.19; 95% CI, 1.07-1.32; P = .001), and lower pH (AOR per 0.1 increase, 0.63; 95% CI, 0.51-0.78; P < .001) as variables associated with AKI. Children with AKI, compared with those without, had lower scores on tests of short-term memory during DKA (mean [SD] digit span recall: 6.8 [2.4] vs 7.6 [2.2]; P = .02) and lower mean (SD) IQ scores 3 to 6 months after recovery from DKA (100.0 [12.2] vs 103.5 [13.2]; P = .005). Differences persisted after adjusting for DKA severity and demographic factors, including socioeconomic status.

Conclusions And Relevance: These findings suggest that AKI may occur more frequently in children with greater acidosis and circulatory volume depletion during DKA and may be part of a pattern of multiple organ injury involving the kidneys and brain.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.25481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718599PMC
December 2020

Clinical Practice Guidelines by the Infectious Diseases Society of America, American Academy of Neurology, and American College of Rheumatology: 2020 Guidelines for the Prevention, Diagnosis, and Treatment of Lyme Disease.

Neurology 2021 02 30;96(6):262-273. Epub 2020 Nov 30.

From the Duke University School of Medicine (P.M.L.), Durham, NC; Pathway Neurology (J. Rumbaugh), Tampa, FL; Yale University (L.K.B., L.E.R.), New Haven, CT; Case Western Reserve University, VA Northeast Ohio Healthcare System (Y.T.F.-Y.), Cleveland; New York University School of Medicine (M.E.A.-R.), New York; Johns Hopkins University School of Medicine (P.G.A.), Baltimore, MD; Geisinger Medical Center (K.B.), Danville, PA; Tufts Medical Center (R.R.B., H.C.M., M.C.O., E.E.V.), Boston, MA; Childrens Hospital and Clinical of Minnesota (K.K.B.), Minneapolis; University of British Columbia (W.R.B.), Vancouver Canada; Massachusetts General Hospital (J.A.B., A.C.S.), Boston; Washington University School of Medicine (D.B.C.), St. Louis, Missouri; Connecticut Children's Medical Center (F.J.D.M., L.S.Z.), Hartford, CT; Atlantic Health System (J.J.H.), Summit, NJ; Yale School of Public Health (P.J.K.), New Haven, CT; University of Montreal (V.L.), Quebec, Canada; Brigham and Women's Hospital (M.H.L.), Boston, MA; Boston Children's Hospital (L.E.N., R.S.), Massachusetts; Medical College of Wisconsin (J.(J.)J.N.), Waowatosa; University of Pennsylvania (A.A.P.), Philadelphia; Consumer Representative (J. Rips), Omaha, NE; Temple University (M.L.S.), Philadelphia, PA; Northwell Health (S.K.S.), New York, NY; University Medical Centre Ljubljana (F.S.), Slovenia; Michigan State University (J.T.), East Lansing; and New York Medical College (G.P.W.), Valhalla.

This evidence-based clinical practice guideline for the prevention, diagnosis, and treatment of Lyme disease was developed by a multidisciplinary panel representing the Infectious Diseases Society of America (IDSA), the American Academy of Neurology (AAN), and the American College of Rheumatology (ACR). The scope of this guideline includes prevention of Lyme disease, and the diagnosis and treatment of Lyme disease presenting as erythema migrans, Lyme disease complicated by neurologic, cardiac, and rheumatologic manifestations, Eurasian manifestations of Lyme disease, and Lyme disease complicated by coinfection with other tick-borne pathogens. This guideline does not include comprehensive recommendations for babesiosis and tick-borne rickettsial infections, which are published in separate guidelines. The target audience for this guideline includes primary care physicians and specialists caring for this condition such as infectious diseases specialists, emergency physicians, internists, pediatricians, family physicians, neurologists, rheumatologists, cardiologists and dermatologists in North America.
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http://dx.doi.org/10.1212/WNL.0000000000011151DOI Listing
February 2021

Febrile Infants ≤60 Days Old With Positive Urinalysis Results and Invasive Bacterial Infections.

Hosp Pediatr 2020 12;10(12):1120-1125

Departments of Pediatrics and

Objectives: We aimed to describe the clinical and laboratory characteristics of febrile infants ≤60 days old with positive urinalysis results and invasive bacterial infections (IBI).

Methods: We performed a planned secondary analysis of a retrospective cohort study of febrile infants ≤60 days old with IBI who presented to 11 emergency departments from July 1, 2011, to June 30, 2016. For this subanalysis, we included infants with IBI and positive urinalysis results. We analyzed the sensitivity of high-risk past medical history (PMH) (prematurity, chronic medical condition, or recent antimicrobial receipt), ill appearance, and/or abnormal white blood cell (WBC) count (<5000 or >15 000 cells/μL) for identification of IBI.

Results: Of 148 febrile infants with positive urinalysis results and IBI, 134 (90.5%) had bacteremia without meningitis and 14 (9.5%) had bacterial meningitis (11 with concomitant bacteremia). Thirty-five infants (23.6%) with positive urinalysis results and IBI did not have urinary tract infections. The presence of high-risk PMH, ill appearance, and/or abnormal WBC count had a sensitivity of 53.4% (95% confidence interval: 45.0-61.6) for identification of IBI. Of the 14 infants with positive urinalysis results and concomitant bacterial meningitis, 7 were 29 to 60 days old. Six of these 7 infants were ill-appearing or had an abnormal WBC count. The other infant had bacteremia with cerebrospinal fluid pleocytosis after antimicrobial pretreatment and was treated for meningitis.

Conclusions: The sensitivity of high-risk PMH, ill appearance, and/or abnormal WBC count is suboptimal for identifying febrile infants with positive urinalysis results at low risk for IBI. Most infants with positive urinalysis results and bacterial meningitis are ≤28 days old, ill-appearing, or have an abnormal WBC count.
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http://dx.doi.org/10.1542/hpeds.2020-000638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684554PMC
December 2020

Pediatric Lyme Disease Biobank, United States, 2015-2020.

Emerg Infect Dis 2020 12;26(12):3099-3101

In 2015, we founded Pedi Lyme Net, a pediatric Lyme disease research network comprising 8 emergency departments in the United States. Of 2,497 children evaluated at 1 of these sites for Lyme disease, 515 (20.6%) were infected. This network is a unique resource for evaluating new approaches for diagnosing Lyme disease in children.
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http://dx.doi.org/10.3201/eid2612.200920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706969PMC
December 2020

Kicking it through the uprights: getting it published after presenting at PAS.

Pediatr Res 2021 05 1;89(7):1598-1600. Epub 2020 Oct 1.

Emergency Medicine, Boston Children's Hospital, Boston, MA, USA.

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http://dx.doi.org/10.1038/s41390-020-01182-yDOI Listing
May 2021

Cognitive Function Following Diabetic Ketoacidosis in Children With New-Onset or Previously Diagnosed Type 1 Diabetes.

Diabetes Care 2020 11 22;43(11):2768-2775. Epub 2020 Sep 22.

Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT.

Objective: This study assessed whether a single diabetic ketoacidosis (DKA) episode is associated with cognitive declines in children with newly diagnosed type 1 diabetes and whether the same is true in children who had previously been diagnosed after accounting for variations in glycemic control and other relevant factors.

Research Design And Methods: We prospectively enrolled 758 children, 6-18 years old, who presented with DKA in a randomized multisite clinical trial evaluating intravenous fluid protocols for DKA treatment. DKA was moderate/severe in 430 children and mild in 328 children. A total of 392 children with DKA had new onset of type 1 diabetes, and the rest were previously diagnosed. Neurocognitive assessment occurred 2-6 months after the DKA episode. A comparison group of 376 children with type 1 diabetes, but no DKA exposure, was also enrolled.

Results: Among all patients, moderate/severe DKA was associated with lower intelligence quotient (IQ) (β = -0.12, < 0.001), item-color recall (β = -0.08, = 0.010), and forward digit span (β = -0.06, = 0.04). Among newly diagnosed patients, moderate/severe DKA was associated with lower item-color recall (β = -0.08, = 0.04). Among previously diagnosed patients, repeated DKA exposure and higher HbA were independently associated with lower IQ (β = -0.10 and β = -0.09, respectively, < 0.01) and higher HbA was associated with lower item-color recall (β = -0.10, = 0.007) after hypoglycemia, diabetes duration, and socioeconomic status were accounted for.

Conclusions: A single DKA episode is associated with subtle memory declines soon after type 1 diabetes diagnosis. Sizable IQ declines are detectable in children with known diabetes, suggesting that DKA effects may be exacerbated in children with chronic exposure to hyperglycemia.
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http://dx.doi.org/10.2337/dc20-0187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576431PMC
November 2020

Time to Positive Blood and Cerebrospinal Fluid Cultures in Febrile Infants ≤60 Days of Age.

Hosp Pediatr 2020 09;10(9):719-727

Division of Pediatric Infectious Diseases and Center for Vaccines and Immunity, Nationwide Children's Hospital and The Ohio State University, Columbus, Ohio; and.

Objectives: To determine the time to positivity for bacterial pathogens and contaminants in blood and cerebrospinal fluid (CSF) cultures in a cohort of febrile infants ≤60 days of age.

Methods: This was a secondary analysis of prospective observational multicenter study of noncritically ill infants ≤60 days of age with temperatures ≥38°C and blood cultures (December 2008 to May 2013). The main outcome was time to positivity for bacterial pathogens and contaminants.

Results: A total of 256 of 303 (84.49%) patients with positive blood cultures, and 73 of 88 (82.95%) with positive CSF cultures met inclusion criteria. Median time (interquartile range [IQR]) to positivity for blood cultures was 16.6 hours (IQR 12.6-21.9) for bacterial pathogens ( = 74) and 25.1 hours (IQR 19.8-33.0) for contaminants ( = 182); < .001. Time to bacterial pathogen positivity was similar in infants 0 to 28 days of age (15.8 hours [IQR 12.6-21.0]) and 29 to 60 days of age (17.2 [IQR 12.9-24.3]; = .328). Median time to positivity for CSF was 14.0 hours (IQR 1.5-21.0) for bacterial pathogens ( = 22) and 40.5 hours (IQR 21.2-62.6) for contaminants ( = 51); < .001. A total of 82.4% (95% confidence interval, 71.8-90.3) and 81.8% (95% confidence interval, 59.7%-94.8%) of blood and CSF cultures showed bacterial pathogen positivity within 24 hours.

Conclusions: Among febrile infants ≤60 days of age, time to blood and CSF positivity was significantly shorter for bacterial pathogens than contaminants. Most blood and CSF cultures for bacterial pathogens were positive within 24 hours. With our findings, there is potential to reduce duration of hospitalization and avoid unnecessary antibiotics.
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http://dx.doi.org/10.1542/hpeds.2020-0045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446544PMC
September 2020

The Infant Scalp Score: A Validated Tool to Stratify Risk of Traumatic Brain Injury in Infants With Isolated Scalp Hematoma.

Acad Emerg Med 2021 01 19;28(1):92-97. Epub 2020 Aug 19.

From the, Division of Emergency Medicine, Boston Children's Hospital, Boston, MA, USA.

Objectives: The objective was to validate the previously derived Infant Scalp Score (ISS) that uses clinical signs in infants with isolated scalp hematoma (ISH) after head trauma to stratify risk for clinically important traumatic brain injury (ciTBI) or TBI on computed tomography (CT).

Methods: Using the publicly available Pediatric Emergency Care Applied Research Network TBI data set, we selected infants ≤ 1 year with GCS 14 to 15 who had ISH (defined as hematoma without other signs/symptoms of TBI). CT scans were obtained at the treating physician's discretion. We calculated ISS based on age, hematoma size, and location (range = 0-8) for each patient and calculated the sensitivity and specificity of the score for ciTBI and TBI on CT across a range of ISS cut-points.

Results: We included 1,289 infants ≤ 1 year of whom 462 (36%) had CT performed. Twelve had ciTBI and 59 had TBI on CT. An ISS cutoff ≥ 4 had sensitivity of 100% for ciTBI (95% confidence interval [CI] = 0.74 to 1.0) and TBI with specificity of 0.49 (95% CI = 0.46 to 0.51). An ISS cutoff of ≥5 had a sensitivity of 100% for ciTBI (95% CI = 0.74 to 1.0) and specificity of 0.68 (95% CI = 0.66 to 0.71), but missed three infants with TBI on CT (none of whom required intervention). The receiver operating characteristic curves for clinical score to detect ciTBI and TBI had areas under the curve of 0.916 and 0.807, respectively.

Conclusions: The ISS accurately stratified risk for ciTBI and TBI on CT in infants with ISH and is a useful tool to help guide clinical decision making.
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http://dx.doi.org/10.1111/acem.14087DOI Listing
January 2021

Hypertension during Diabetic Ketoacidosis in Children.

J Pediatr 2020 08 6;223:156-163.e5. Epub 2020 May 6.

Department of Pediatrics, University of California Davis Health, University of California Davis, School of Medicine, Sacramento, CA. Electronic address:

Objectives: To characterize hemodynamic alterations occurring during diabetic ketoacidosis (DKA) in a large cohort of children and to identify clinical and biochemical factors associated with hypertension.

Study Design: This was a planned secondary analysis of data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in DKA Study, a randomized clinical trial of fluid resuscitation protocols for children in DKA. Hemodynamic data (heart rate, blood pressure) from children with DKA were assessed in comparison with normal values for age and sex. Multivariable statistical modeling was used to explore clinical and laboratory predictors of hypertension.

Results: Among 1258 DKA episodes, hypertension was documented at presentation in 154 (12.2%) and developed during DKA treatment in an additional 196 (15.6%), resulting in a total of 350 DKA episodes (27.8%) in which hypertension occurred at some time. Factors associated with hypertension at presentation included more severe acidosis, (lower pH and lower pCO), and stage 2 or 3 acute kidney injury. More severe acidosis and lower Glasgow Coma Scale scores were associated with hypertension occurring at any time during DKA treatment.

Conclusions: Despite dehydration, hypertension occurs in a substantial number of children with DKA. Factors associated with hypertension include greater severity of acidosis, lower pCO and lower Glasgow Coma Scale scores during DKA treatment, suggesting that hypertension might be centrally mediated.
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http://dx.doi.org/10.1016/j.jpeds.2020.04.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414786PMC
August 2020
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