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Objective: We sought to assess whether the presence and extent of lung ultrasound (LUS) findings were associated with asthma exacerbation severity in children., Methods: We enrolled a convenience sample of patients aged 5-18 years presenting with acute asthma exacerbation to a tertiary care pediatric emergency department. Severity of an asthma exacerbation (mild, moderate, severe) was assessed within 1 hour of the LUS using the Hospital Asthma Severity Score, a validated asthma assessment tool. LUS was performed by trained pediatric emergency providers. The presence of LUS findings (B-lines, consolidations, pleural effusion, and pleural line abnormalities) was assessed using a standardized criterion based on consensus guidelines., Results: A total of 111 patients with a median age of 8 years (interquartile range 6-12) were enrolled. LUS was positive in 57% of patients. Pleural line abnormalities were observed in 34%, B-lines in 29%, consolidations <1 cm in 24%, and consolidations ≥1 cm in 7%. Patients with moderate and severe asthma exacerbations were more likely to have any B-lines (31% and 43%, respectively) than patients with mild exacerbations (12%; P = .021); however, the presence of ≥3 B-lines or confluent B-lines did not differ across severity groups. The presence of other findings did not differ based on asthma severity., Conclusions: LUS findings are observed in a substantial portion of children presenting with asthma exacerbations. B-lines were the only LUS finding significantly associated with asthma severity, while lung consolidations <1 cm and >1 cm were not correlated with severity. These findings provide valuable information for the diagnostic use of LUS in pediatric patients with asthma exacerbation., (© 2024 American Institute of Ultrasound in Medicine.)

Obesity is a recognized factor influencing immune function and infectious disease outcomes. Characterization of the influence of obesity on SARS-CoV-2 humoral vaccine immunogenicity is required to properly tailor vaccine type (mRNA, viral-vector, protein subunit vaccines) and dosing schedule. Data from a prospective cohort study collected over 34 months was used to evaluate the slope of antibody production and decay and neutralizing capacity following SARS-CoV-2 vaccination in individuals with and without obesity at baseline. Most participants were female (65.4%), white (92.4%), and received mRNA vaccines. 210 were obese and 697 non-obese. Sex and infection-acquired immunity were identified as effect modifiers for the relationship between obesity and COVID-19 vaccine humoral immunogenicity. No consistent influence of obesity on peak titres, titre retention, antibody isotype (IgG, IgM, IgA), or neutralization was identified when controlling for other key variables. It may not be necessary to consider this variable when developing SARS-CoV-2 vaccine dosing strategies., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background/objectives: Few studies have examined the putative mediating role of eating behaviours linking genetic susceptibility and body weight. The goal of this study was to investigate the extent to which two polygenic scores (PGSs) for body mass index (BMI), based on child and adult data, predicted BMI through over-eating and fussy eating across childhood., Subjects/methods: The study sample involved 692 participants from a birth cohort study. Height and weight were measured on six occasions between ages 6 and 13 years. Over-eating and fussy eating behaviours were assessed five times between ages 2 and 6 years. Longitudinal growth curve mediation analysis was used to estimate the contributions of the PGSs to BMI z-scores mediated by over-eating and fussy eating., Results: Both PGSs predicted BMI z-scores (PGS child : β = 0.26, 95% CI: 0.19-0.33; PGS adult : β = 0.34, 95% CI: 0.27-0.41). Over-eating significantly mediated these associations, but this mediation decreased over time from 6 years (PGS child : 18.0%, 95% CI: 3.1-32.9, p-value = 0.018; PGS adult : 14.2%, 95% CI: 2.8-25.5, p-value = 0.014) to 13 years (PGS child : 11.4%, 95% CI: -0.4-23.1, p-value = 0.057; PGS adult : 6.2%, 95% CI: 0.4-12.0, p-value = 0.037). Fussy eating did not show any mediation., Conclusions: Our results support the view that appetite is key to translating genetic susceptibility into changes in body weight., (© 2024 The Author(s). Pediatric Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background and Objective: It is unclear which comparator is the most appropriate for bias reduction in disproportionality analyses based on spontaneous reports. We conducted a quasi-quantitative bias analysis using two well-studied drug-event combinations to assess how different comparators influence the directionality of bias in pharmacovigilance., Methods: We used the US Food and Drug Administration Adverse Event Reporting System focusing on two drug-event combinations with a propensity for stimulated reporting: rivaroxaban and hepatotoxicity, and canagliflozin and acute kidney injury. We assessed the directionality of three disproportionality analysis estimates (reporting odds ratio, proportional reporting ratio, information component) using one unrestricted comparator (full data) and two restricted comparators (active comparator, active comparator with class exclusion). Analyses were conducted within two calendar time periods, defined based on external events (approval of direct oral anticoagulants, Food and Drug Administration safety warning on acute kidney injury with sodium-glucose cotransporter 2 inhibitors) hypothesized to alter reporting rates., Results: There were no false-positive signals for rivaroxaban and hepatotoxicity irrespective of the comparator. Restricting to the initial post-approval period led to false-positive signals, with restricted comparators performing worse. There were false-positive signals for canagliflozin and acute kidney injury, with restricted comparators performing better. Restricting to the period before the Food and Drug Administration warning weakened the false-positive signal for canagliflozin and acute kidney injury across comparators., Conclusions: We could not identify a consistent and predictable pattern to the directionality of disproportionality analysis estimates with specific comparators. Calendar time-based restrictions anchored on relevant external events had a considerable impact., (© 2024. The Author(s).)

Objective: The aim of the study is to assess diagnostic performance of cardiac point-of-care ultrasound (POCUS) performed by pediatric emergency medicine (PEM) physicians in children with preexisting cardiac disease., Methods: We evaluated the use of cardiac POCUS performed by PEM physicians among a convenience sample of children with preexisting cardiac disease presenting to a tertiary care pediatric ED. We assessed patient characteristics and the indication for POCUS. The test characteristics of the sonologist interpretation for the assessment of both pericardial effusion as well as left ventricular systolic dysfunction were compared with expert POCUS review by PEM physicians with POCUS fellowship training., Results: A total of 104 children with preexisting cardiac disease underwent cardiac POCUS examinations between July 2015 and December 2017. Among children with preexisting cardiac disease, structural defects were present in 72%, acquired conditions in 22%, and arrhythmias in 13% of patients. Cardiac POCUS was most frequently obtained because of chest pain (55%), dyspnea (18%), tachycardia (17%), and syncope (10%). Cardiac POCUS interpretation compared with expert review had a sensitivity of 100% (95% confidence interval [CI], 85.7-100) for pericardial effusion and 100% (95% CI, 71.5-100) for left ventricular systolic dysfunction; specificity was 97.5% (95% CI, 91.3.1-99.7) for pericardial effusion and 98.9% (95% CI, 93.8-99.8) for left ventricular systolic dysfunction., Conclusions: Cardiac POCUS demonstrates good sensitivity and specificity in diagnosing pericardial effusion and left ventricular systolic dysfunction in children with preexisting cardiac conditions when technically adequate studies are obtained. These findings support future studies of cardiac POCUS in children with preexisting cardiac conditions presenting to the ED., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Long COVID is highly heterogeneous, often debilitating, and may last for years after infection. The aetiology of long COVID remains uncertain. Examination of potential serological markers of long COVID, accounting for clinical covariates, may yield emergent pathophysiological insights., Methods: In adherence to PRISMA guidelines, we carried out a rapid review of the literature. We searched Medline and Embase for primary observational studies that compared IgG response in individuals who experienced COVID-19 symptoms persisting ≥12 weeks post-infection with those who did not. We examined relationships between serological markers and long COVID status and investigated sources of inter-study variability, such as severity of acute illness, long COVID symptoms assessed and target antigen(s)., Results: Of 8018 unique records, we identified 29 as being eligible for inclusion in synthesis. Definitions of long COVID varied. In studies that reported anti-nucleocapsid (N) IgG (n = 10 studies; n = 989 participants in aggregate), full or partial anti-Spike IgG (i.e. the whole trimer, S1 or S2 subgroups, or receptor binding domain, n = 19 studies; n = 2606 participants), or neutralizing response (n = 7 studies; n = 1123 participants), we did not find strong evidence to support any difference in serological markers between groups with and without persisting symptoms. However, most studies did not account for severity or level of care required during acute illness, and other potential confounders., Conclusions: Pooling of studies would enable more robust exploration of clinical and serological predictors among diverse populations. However, substantial inter-study variations hamper comparability. Standardized reporting practices would improve the quality, consistency and comprehension of study findings., (© 2023 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Pharmacovigilance studies based on spontaneous reporting systems use disproportionality analysis methods to identify drug-event combinations with higher-than-expected reporting. Enhanced reporting is deemed as a proxy for a detected signal and is used to generate drug safety hypotheses, which can then be tested in pharmacoepidemiologic studies or randomized controlled trials. Higher-than-expected reporting means that the reporting rate of a drug-event combination of interest is disproportionately higher than the rate in a specific comparator or reference set. Currently, it is unclear which comparator is the most appropriate for use in pharmacovigilance. Moreover, it is also unclear how the selection of a comparator may affect the directionality of the various reporting and other biases. This paper reviews commonly used comparators chosen for signal detection studies (active comparator, class-exclusion comparator, and full data reference set). We give an overview of the advantages and disadvantages of each method based on examples from the literature. We also touch upon the challenges related to the derivation of general recommendations for the selection of comparators when mining spontaneous reports for pharmacovigilance., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Aims: Recent case reports have suggested that sodium-glucose co-transporter 2 (SGLT2) inhibitors may interact with statins to increase their risk of myotoxicity. We assessed the risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins., Methods: We queried the US Food and Drug Administration Adverse Event Reporting System (FAERS) from 2013 to 2021 for reports including SGLT2 inhibitors, statins or both. We estimated several measures of disproportionate reporting of myopathy and rhabdomyolysis associated with concomitant use of SGLT2 inhibitors and statins: reporting odds ratio (ROR) with 95% confidence interval (CI), Ω shrinkage measure (safety signal if >0) and an extension of the proportional reporting ratio (PRR) (two-criteria set, safety signal if both criteria are met), using the full FAERS dataset as the reference set. In sensitivity analyses, we focussed on specific SGLT2 inhibitor-statin pairs with higher interaction potential (canagliflozin-rosuvastatin, empagliflozin-rosuvastatin) and accounted for stimulated reporting., Results: There were 456 myopathy and 77 rhabdomyolysis reports involving both an SGLT2 inhibitor and a statin. Concomitant use of SGLT2 inhibitors and statins was not associated with an increased risk of myopathy (ROR 0.79, 95% CI 0.70 to 0.89) or rhabdomyolysis (ROR 0.58, 95% CI 0.41 to 0.83) reporting. For both outcomes, the Ω shrinkage measure was negative and only one criterion of the PRR extension was met. SGLT2 inhibitor-statin pairs with higher interaction potential yielded potential signals for rhabdomyolysis; these signals disappeared after accounting for stimulated reporting., Conclusion: There was no increased risk of myotoxicity reporting associated with concomitant use of SGLT2 inhibitors and statins or for specific drug pairs., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

During the rapid deployment of COVID-19 vaccines in 2021, safety concerns may have led some pregnant individuals to postpone vaccination until after giving birth. This study aimed to describe temporal patterns and factors associated with COVID-19 vaccine series initiation after recent pregnancy in Ontario, Canada. Using the provincial birth registry linked with the COVID-19 vaccine database, we identified all individuals who gave birth between January 1 and December 31, 2021, and had not yet been vaccinated by the end of pregnancy, and followed them to June 30, 2022 (follow-up ranged from 6 to 18 months). We used cumulative incidence curves to describe COVID-19 vaccine initiation after pregnancy and assessed associations with sociodemographic, pregnancy-related, and health behavioral factors using Cox proportional hazards regression to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). Among 137,198 individuals who gave birth in 2021, 87,376 (63.7%) remained unvaccinated at the end of pregnancy; of these, 65.0% initiated COVID-19 vaccination by June 30, 2022. Lower maternal age (<25 vs. 30-34 y aHR: 0.73, 95%CI: 0.70-0.77), smoking during pregnancy (vs. nonsmoking aHR: 0.68, 95%CI: 0.65-0.72), lower neighborhood income (lowest quintile vs. highest aHR: 0.79, 95%CI: 0.76-0.83), higher material deprivation (highest quintile vs. lowest aHR: 0.74, 95%CI: 0.70-0.79), and exclusive breastfeeding (vs. other feeding aHR: 0.81, 95%CI: 0.79-0.84) were associated with lower likelihood of vaccine initiation. Among unvaccinated individuals who gave birth in 2021, COVID-19 vaccine initiation after pregnancy reached 65% by June 30, 2022, suggesting persistent issues with vaccine hesitancy and/or access to vaccination in this population.

Concerns remain regarding the rare cardiovascular adverse events, myocarditis and pericarditis (myo/pericarditis), particularly in younger individuals following mRNA COVID-19 vaccination. Our study aimed to comprehensively assess potential safety signals related to these cardiac events following the primary and booster doses, with a specific focus on younger populations, including children as young as 6 months of age. Using the Vaccine Adverse Events Reporting System (VAERS), the United States national passive surveillance system, we conducted a retrospective pharmacovigilance study analyzing spontaneous reports of myo/pericarditis. We employed both frequentist and Bayesian methods and conducted subgroup analyses by age, sex, and vaccine dose. We observed a higher reporting rate of myo/pericarditis following the primary vaccine series, particularly in males and mainly after the second dose. However, booster doses demonstrated a lower number of reported cases, with no significant signals detected after the fourth or fifth doses. In children and young adults, we observed notable age and sex differences in the reporting of myo/pericarditis cases. Males in the 12-17 and 18-24-year-old age groups had the highest number of cases, with significant signals for both males and females after the second dose. We also identified an increased reporting for a spectrum of cardiovascular symptoms such as chest pain and dyspnea, which increased with age, and were reported more frequently than myo/pericarditis. The present study identified signals of myo/pericarditis and related cardiovascular symptoms after mRNA COVID-19 vaccination, especially among children and adolescents. These findings underline the importance for continued vaccine surveillance and the need for further studies to confirm these results and to determine their clinical implications in public health decision-making, especially for younger populations.

Objective: To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had completed both doses of primary covid-19 vaccine series before pregnancy., Design: Population based, retrospective cohort study., Setting: Ontario, Canada, from 20 December 2021 to 31 August 2022., Participants: Individuals were included if they were pregnant with an expected date of delivery from 20 December 2021 (start date of third dose eligibility for everyone ≥18 years) to 31 August 2022, who had completed the two doses of primary covid-19 messenger RNA vaccine series before pregnancy, and became eligible for a third dose (≥six months since dose two) before the end of pregnancy., Main Outcome Measures: Pregnancy outcomes included hypertensive disorders of pregnancy, placental abruption, caesarean delivery, chorioamnionitis, and postpartum hemorrhage. Fetal and neonatal outcomes included stillbirth, preterm birth, admission to neonatal intensive care unit for >24 h, newborn 5 min Apgar score <7, and small-for-gestational age infant (<10th percentile). We estimated hazard ratios and 95% confidence intervals for study outcomes, treating dose three as a time varying exposure and adjusting for confounding using inverse probability weighting., Results: Among 32 689 births, 18 491 (56.6%) were born to individuals who received a third covid-19 dose during pregnancy. Compared with eligible individuals who did not receive a third dose during pregnancy, no increased risks were associated with receiving a third covid-19 vaccine dose during pregnancy for placental abruption (adjusted hazard ratio 0.84 (95% confidence interval 0.70 to 1.02)), chorioamnionitis (0.67 (0.49 to 0.90)), postpartum haemorrhage (1.01 (0.89 to 1.16)), caesarean delivery (0.90 (0.87 to 0.94)), stillbirth (0.56 (0.39 to 0.81)), preterm birth (0.91 (0.84 to 0.99)), neonatal intensive care unit admission (0.96 (0.90 to 1.03)), 5 min Apgar score<7 (0.96 (0.82 to 1.14)), or small-for-gestational age infant (0.86 (0.79 to 0.93))., Conclusion: Receipt of a third covid-19 vaccine dose during pregnancy was not associated with an increased risk of adverse pregnancy, fetal, or neonatal outcomes. These findings can help to inform evidence based decision making about the risks and benefits of covid-19 booster doses during pregnancy., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; KW is Chief Scientific Officer and a Director for CANImmunize Inc. He has served as a member of safety advisory boards for Medicago and Moderna., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To summarise the available evidence on the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccination, compared with the risk among unvaccinated individuals in the absence of COVID-19 infection., Design: Systematic review and meta-analysis., Data Sources: Electronic databases (Medline, Embase, Web of Science and WHO Global Literature on Coronavirus Disease), preprint repositories (medRxiv and bioRxiv), reference lists and grey literature were searched from 1 December 2020 until 31 October 2022., Study Selection: Epidemiological studies of individuals of any age who received at least one dose of an mRNA COVID-19 vaccine, reported a risk of myo/pericarditis and compared the risk of myo/pericarditis to individuals who did not receive any dose of an mRNA COVID-19 vaccine., Data Extraction and Synthesis: Two reviewers independently conducted screening and data extraction. The rate of myo/pericarditis among vaccinated and unvaccinated groups was recorded, and the rate ratios were calculated. Additionally, the total number of individuals, case ascertainment criteria, percentage of males and history of SARS-CoV-2 infection were extracted for each study. Meta-analysis was done using a random-effects model., Results: Seven studies met the inclusion criteria, of which six were included in the quantitative synthesis. Our meta-analysis indicates that within 30-day follow-up period, vaccinated individuals were twice as likely to develop myo/pericarditis in the absence of SARS-CoV-2 infection compared to unvaccinated individuals, with a rate ratio of 2.05 (95% CI 1.49-2.82)., Conclusion: Although the absolute number of observed myo/pericarditis cases remains quite low, a higher risk was detected in those who received mRNA COVID-19 vaccinations compared with unvaccinated individuals in the absence of SARS-CoV-2 infection. Given the effectiveness of mRNA COVID-19 vaccines in preventing severe illnesses, hospitalisations and deaths, future research should focus on accurately determining the rates of myo/pericarditis linked to mRNA COVID-19 vaccines, understanding the biological mechanisms behind these rare cardiac events and identifying those most at risk., Competing Interests: Competing interests: KW is a co-founder and Chief Scientific Officer of CAN Immunize Inc. (www.canimmunize.ca). He served on the Independent Data Monitoring Committee for Medicago, and is a member of the Moderna Global Advisory Core Consultancy Group. DK serves as Chief Risk Scientist (www.risksciences.com) and has conducted work on vaccines for public sector clients., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Population-based COVID-19 vaccine coverage estimates among pregnant individuals are limited. We assessed temporal patterns in vaccine coverage (≥1 dose before or during pregnancy) and evaluated factors associated with vaccine series initiation (receiving dose 1 during pregnancy) in Ontario, Canada., Methods: We linked the provincial birth registry with COVID-19 vaccination records from December 14, 2020 to December 31, 2021 and assessed coverage rates among all pregnant individuals by month, age, and neighborhood sociodemographic characteristics. Among individuals who gave birth since April 2021-when pregnant people were prioritized for vaccination-we assessed associations between sociodemographic, behavioral, and pregnancy-related factors with vaccine series initiation using multivariable regression to estimate adjusted risk ratios (aRR) and risk differences (aRD) with 95% confidence intervals (CI)., Results: Among 221,190 pregnant individuals, vaccine coverage increased to 71.2% by December 2021. Gaps in coverage across categories of age and sociodemographic characteristics decreased over time, but did not disappear. Lower vaccine series initiation was associated with lower age (<25 vs. 30-34 years: aRR 0.53, 95%CI 0.51-0.56), smoking (vs. non-smoking: 0.64, 0.61-0.67), no first trimester prenatal care visit (vs. visit: 0.80, 0.77-0.84), and residing in neighborhoods with the lowest income (vs. highest: 0.69, 0.67-0.71). Vaccine series initiation was marginally higher among individuals with pre-existing medical conditions (vs. no conditions: 1.07, 1.04-1.10)., Conclusions: COVID-19 vaccine coverage among pregnant individuals remained lower than in the general population, and there was lower vaccine initiation by multiple characteristics., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: K. Wilson is CEO of CANImmunize Inc, which hosts a national digital immunization record, and is a member of the independent data safety board for the Medicago COVID-19 vaccine trial; there were no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess the risk of preterm birth, small for gestational age at birth, and stillbirth after covid-19 vaccination during pregnancy., Design: Population based retrospective cohort study., Setting: Ontario, Canada, 1 May to 31 December 2021., Participants: All liveborn and stillborn infants from pregnancies conceived at least 42 weeks before the end of the study period and with gestational age ≥20 weeks or birth weight ≥500 g., Main Outcome Measures: Using Cox regression, hazard ratios and 95% confidence intervals were estimated for preterm birth before 37 weeks (overall and spontaneous preterm birth), very preterm birth (<32 weeks), small for gestational age at birth (<10th centile), and stillbirth. Vaccination against covid-19 was treated as a time varying exposure in the outcome specific risk window, and propensity score weighting was used to adjust hazard ratios for potential confounding., Results: Among 85 162 births, 43 099 (50.6%) occurred in individuals who received one dose or more of a covid-19 vaccine during pregnancy-42 979 (99.7%) received an mRNA vaccine. Vaccination during pregnancy was not associated with any increased risk of overall preterm birth (6.5% among vaccinated v 6.9% among unvaccinated; adjusted hazard ratio 1.02, 95% confidence interval 0.96 to 1.08), spontaneous preterm birth (3.7% v 4.4%; 0.96, 0.90 to 1.03), or very preterm birth (0.59% v 0.89%; 0.80, 0.67 to 0.95). No increase was found in risk of small for gestational age at birth (9.1% v 9.2%; 0.98, 0.93 to 1.03) or stillbirth (0.25% v 0.44%; 0.65, 0.51 to 0.84). Findings were similar by trimester of vaccination, mRNA vaccine product, and number of doses received during pregnancy., Conclusion: The findings suggest that vaccination against covid-19 during pregnancy is not associated with a higher risk of preterm birth, small for gestational age at birth, or stillbirth., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the Public Health Agency of Canada through the Vaccine Surveillance Reference Group and the COVID-19 Immunity Task Force; SEH and LO were partly funded by the Norwegian Research Council. KW is chief executive officer of CANImmunize, which hosts a national digital immunisation record, and is a member of the independent data safety board for the Medicago covid-19 vaccine trial. There are no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

There have been reports of cases of myocarditis and pericarditis as rare complications following mRNA COVID-19 vaccinations among young adults. While most reported cases are mild, this potential vaccine safety signal should be closely monitored. Using data from the CDC and the Vaccine Adverse Event Reporting System (VAERS), we calculated the combined reporting rate of myocarditis and pericarditis stratified by age group, sex, vaccine dose, and manufacturer, and compared these rates to the crude background incidence rates. Compared to the general population prior to the administration of the first COVID-19 vaccines in December 2020, we identified a higher-than-expected reporting rate of myocarditis and pericarditis following mRNA vaccination; the risk was higher after a second vaccine dose, higher in males than in females, and decreased with age. The highest risk was seen in males 12-17 years of age with approximately 6 cases per 100,000 second doses. Our findings suggest an increased risk of myocarditis and pericarditis in young males following a second dose of an mRNA COVID-19 vaccine. Since these findings are based on safety signals derived from passive surveillance data, confirmatory epidemiological studies should be undertaken.

Importance: There is limited comparative epidemiological evidence on outcomes associated with COVID-19 vaccination during pregnancy; monitoring pregnancy outcomes in large populations is required., Objective: To evaluate peripartum outcomes following COVID-19 vaccination during pregnancy., Design, Setting, and Participants: Population-based retrospective cohort study in Ontario, Canada, using a birth registry linked with the provincial COVID-19 immunization database. All births between December 14, 2020, and September 30, 2021, were included., Exposures: COVID-19 vaccination during pregnancy, COVID-19 vaccination after pregnancy, and no vaccination., Main Outcomes and Measures: Postpartum hemorrhage, chorioamnionitis, cesarean delivery (overall and emergency cesarean delivery), admission to neonatal intensive care unit (NICU), and low newborn 5-minute Apgar score (<7). Linear and robust Poisson regression was used to generate adjusted risk differences (aRDs) and risk ratios (aRRs), respectively, comparing cumulative incidence of outcomes in those who received COVID-19 vaccination during pregnancy with those vaccinated after pregnancy and those with no record of COVID-19 vaccination at any point. Inverse probability of treatment weights were used to adjust for confounding., Results: Among 97 590 individuals (mean [SD] age, 31.9 [4.9] years), 22 660 (23%) received at least 1 dose of COVID-19 vaccine during pregnancy (63.6% received dose 1 in the third trimester; 99.8% received an mRNA vaccine). Comparing those vaccinated during vs after pregnancy (n = 44 815), there were no significantly increased risks of postpartum hemorrhage (incidence: 3.0% vs 3.0%; aRD, -0.28 per 100 individuals [95% CI, -0.59 to 0.03]; aRR, 0.91 [95% CI, 0.82-1.02]), chorioamnionitis (0.5% vs 0.5%; aRD, -0.04 per 100 individuals [95% CI, -0.17 to 0.09]; aRR, 0.92 [95% CI, 0.70-1.21]), cesarean delivery (30.8% vs 32.2%; aRD, -2.73 per 100 individuals [95% CI, -3.59 to -1.88]; aRR, 0.92 [95% CI, 0.89-0.95]), NICU admission (11.0% vs 13.3%; aRD, -1.89 per 100 newborns [95% CI, -2.49 to -1.30]; aRR, 0.85 [95% CI, 0.80-0.90]), or low Apgar score (1.8% vs 2.0%; aRD, -0.31 per 100 newborns [95% CI, -0.56 to -0.06]; aRR, 0.84 [95% CI, 0.73-0.97]). Findings were qualitatively similar when compared with individuals who did not receive COVID-19 vaccination at any point (n = 30 115)., Conclusions and Relevance: In this population-based cohort study in Ontario, Canada, COVID-19 vaccination during pregnancy, compared with vaccination after pregnancy and with no vaccination, was not significantly associated with increased risk of adverse peripartum outcomes. Study interpretation should consider that the vaccinations received during pregnancy were primarily mRNA vaccines administered in the second and third trimester.

Objectives: To investigate the rates of radiographic pneumonia and clinical outcomes of children with suspected pneumonia and subcentimeter, subpleural consolidations on point-of-care lung ultrasound., Study Design: We enrolled a prospective convenience sample of children aged 6 months to 18 years undergoing chest radiography (CXR) for pneumonia evaluation in a single tertiary-care pediatric emergency department. Point-of-care lung ultrasound was performed by an emergency medicine physician with subsequent expert review. We determined rates of radiographic pneumonia and clinical outcomes in the children with subcentimeter, subpleural consolidations, stratified by the presence of larger (>1 cm) sonographic consolidations. The children were followed prospectively for 2 weeks to identify a delayed diagnosis of pneumonia., Results: A total of 188 patients, with a median age of 5.8 years (IQR, 3.5-11.0 years), were evaluated. Of these patients, 62 (33%) had subcentimeter, subpleural consolidations on lung ultrasound, and 23 (37%) also had larger (>1 cm) consolidations. Patients with subcentimeter, subpleural consolidations and larger consolidations had the highest rates of definite radiographic pneumonia (61%), compared with 21% among children with isolated subcentimeter, subpleural consolidations. Overall, 23 children with isolated subcentimeter, subpleural consolidations (59%) had no evidence of pneumonia on CXR. Among 16 children with isolated subcentimeter, subpleural consolidations and not treated with antibiotics, none had a subsequent pneumonia diagnosis within the 2-week follow-up period., Conclusions: Children with subcentimeter, subpleural consolidations often had radiographic pneumonia; however, this occurred most frequently when subcentimeter, subpleural consolidations were identified in combination with larger consolidations. Isolated subcentimeter, subpleural consolidations in the absence of larger consolidations should not be viewed as synonymous with pneumonia; CXR may provide adjunctive information in these cases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Importance: The wide variation in the accuracy and reliability of the Focused Assessment With Sonography for Trauma (FAST) and the extended FAST (E-FAST) for children after blunt abdominal trauma reflects user expertise. FAST and E-FAST that are performed by experts tend to be more complete, better quality, and more often clinically valuable., Objective: To develop definitions of a complete, high-quality, and accurate interpretation for the FAST and E-FAST in children with injury using an expert, consensus-based modified Delphi technique., Design, Setting, and Participants: This consensus-based qualitative study was conducted between May 1 to June 30, 2021. It used a scoping review and iterative Delphi technique and involved 2 rounds of online surveys and a live webinar to achieve consensus among a 26-member panel. This panel consisted of international experts in pediatric emergency point-of-care ultrasonography., Main Outcomes and Measures: Definitions of complete, high-quality, and accurate FAST and E-FAST studies for children after injury., Results: Of the 29 invited pediatric FAST experts, 26 (15 men [58%]) agreed to participate in the panel. All 26 panelists completed the 2 rounds of surveys, and 24 (92%) participated in the live and asynchronous online discussions. Consensus was reached on FAST and E-FAST study definitions, and the panelists rated these 5 anatomic views as important and appropriate for a complete FAST: right upper-quadrant abdominal view, left upper-quadrant abdominal view, suprapubic views (transverse and sagittal), and subxiphoid cardiac view. For E-FAST, the same FAST anatomic views with the addition of the lung or pneumothorax view were deemed appropriate and important. In addition, the panelists rated a total of 32 landmarks as important for assessing completeness. Similarly, the panelists rated 14 statements on quality and 20 statements on accurate interpretation as appropriate., Conclusions and Relevance: This qualitative study generated definitions for complete FAST and E-FAST studies with high image quality and accurate interpretation in children with injury. These definitions are similar to those in adults with injury and may be used for future education, quality assurance, and research. Future research may focus on interpretation of trace volumes of abdominal free fluid and the use of serial FAST.

Background: Quinolones comprise a class of antibiotics that are globally preferred for treating a wide range of bacterial infections due to their potency, broad coverage, favorable pharmacologic profile, and mostly mild to moderate adverse reactions. Spontaneous reports on adverse drug events (ADE) and data from some pharmacoepidemiologic studies have raised concerns regarding quinolones and risk of retinal detachment (RD). This study examined ADE reports submitted to FDA adverse event reporting system (FAERS) for evidence on quinolone-associated RD risk., Research Design and Methods: We identified all RD reports in FAERS between 2010-2019. We compared ADE signals between quinolones and selected medications that were previously associated with RD, and with reference medications not known to cause RD. For signal detection, we used two techniques: the proportional reporting ratio (PRR) and multi-item gamma Poisson shrinker (MGPS), which are known for their higher sensitivity and specificity for ADE signal detection, respectively., Results: Moxifloxacin showed a positive and significant PRR signal for RD [PRR: 2.54 (1.60, 4.04)], and a marginally significant EBGM signal [EBGM: 2.21 (1.41, 3.02)]., Conclusion: Moxifloxacin is the only quinolone showing a positive disproportionality signal for RD. Further epidemiologic research is needed to clarify the association between moxifloxacin and RD risk.

Objectives: We sought to describe the test characteristics of cardiac point-of-care ultrasound (POCUS) performed by pediatric emergency medicine (PEM) physicians after structured cardiac POCUS training., Methods: We evaluated the use of clinically indicated cardiac POCUS by PEM physicians in a single tertiary care pediatric emergency department after implementation of a focused cardiac POCUS training curriculum. The test characteristics of the sonologist interpretation were compared with expert POCUS review, by PEM physicians who have completed PEM POCUS fellowship training, for the assessment of both pericardial effusion and left ventricular systolic dysfunction., Results: A total of 1241 cardiac POCUS examinations were performed between July 2015 and December 2017, of which 456 were clinically indicated and underwent expert POCUS review and comprised the study sample. These examinations were performed by 33 different PEM attending sonologists. Chest pain (52%), dyspnea (20%), and tachycardia (18%) were the most common indications for cardiac POCUS. Prevalence of pericardial effusion and global systolic dysfunction based on expert POCUS review were 11% (48/443) and 4% (16/435), respectively. Real-time cardiac POCUS interpretation had a sensitivity and specificity of 100% and 99.5%, respectively, for both pericardial effusion and left ventricular systolic dysfunction when compared with expert POCUS review., Conclusions: Cardiac POCUS is both sensitive and specific for identifying pericardial effusion and left ventricular systolic dysfunction when performed by PEM attendings with focused training., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Traditionally, patient-reported fasting time has been the primary objective presedation measure of aspiration risk. Recently, gastric ultrasound has been used to assess gastric volume for the determination of aspiration risk in patients undergoing anesthesia in the operative setting. We sought to determine the correlation of gastric volume estimated by point-of-care ultrasound (POCUS) to reported fasting time., Methods: We included children 4 to 18 years of age who presented with an acute traumatic injury. Enrolled children underwent POCUS to calculate gastric volume, which was calculated using a validated formula: Volume (mL) = -7.8 + (3.5 × Cross-sectional Area [CSA]) + (0.127 × Age in months). The CSA was measured (CSA = (anterior-posterior diameter × craniocaudal diameter × π)/4). We analyzed the relationship between time since last reported oral intake and measured gastric volume using Spearman rank correlation (ρ)., Results: A total of 103 patients with a median age of 10.5 years (interquartile range, 7.3-13.7 years) were enrolled. The gastric antrum was identified and measured in 88 (85%) patients; air obstructing the posterior surface of the gastric antrum prevented measurement in 14 of the 15 remaining patients. We observed a weak inverse correlation between fasting time (either liquid or solid) and estimated gastric volume (ρ = -0.33), with no significant difference based on type of intake (solids, ρ = 0.28; liquids, ρ = 0.22)., Conclusion: Gastric volume can be estimated by POCUS and is not strongly correlated with fasting time in children in the emergency department setting., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Children with limp or hip pain often undergo radiographs and ultrasound as part of their initial evaluation. Previous research suggests that hip radiography may have limited utility, and early use of ultrasound may safely reduce the use of radiographs., Objectives: We sought to assess the utility of radiography in addition to ultrasound by evaluating the rate of bony abnormalities present on hip radiographs among children with and without effusion on ultrasound. We also assessed the agreement of point-of-care and Radiology-performed ultrasounds for the detection of effusion., Methods: This is a retrospective cohort study of children presenting to a pediatric emergency department with acute atraumatic limp or hip pain. Data from patients who received both hip ultrasound and hip radiography as part of their evaluation were analyzed. We included both point-of-care and Radiology-performed hip ultrasounds., Results: We identified 134 patients who received both hip ultrasound and hip radiographs. Sixty-eight patients (51%) had a hip effusion present on ultrasound and none of these had bony abnormalities on radiography (0%, 95% confidence interval 0-5.3%). Of the 66 patients (49%) who had no effusion on hip ultrasound, 2 patients were found to have a bony abnormality (3%, 95% confidence interval 0.4-10.5%). For patients who received both point-of-care and Radiology-performed ultrasound, the overall agreement for diagnosis of effusion was 92.6% (kappa = 0.82)., Conclusions: We observed that no children with an effusion on ultrasound had bony pathology on plain radiography, suggesting that the routine performance of hip radiography may not be indicated in all children. Future studies are needed to evaluate the negative predictive value of effusion in larger numbers of patients with known bony abnormalities., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Aim: Quinolones are a potent and globally popular group of antibiotics that are used to treat a wide range of infections. Some case reports have raised concern about their possible association with acute hepatic failure (AHF). Data from the US FDA Adverse Event Reporting System were evaluated for signals of AHF in association with systemically administered quinolone antibiotics., Methods: AHF reports between 1969 and 2019q2, with a focus on 2010-2019q2, were analyzed. Specifically, AHF reports linked to non-quinolone antibiotics of known hepatotoxicity were compared to reports with non-quinolone, non-hepatotoxic (reference) antibiotics; and AHF reports with quinolones were also compared to reports with the same group of reference antibiotics. Two disproportionality signal detection techniques (proportional reporting ratio, PRR, and empirical Bayes geometric mean, EBGM) were used to assess the AHF signal for both analyses., Results: Only ciprofloxacin showed a marginal and significant AHF signal (PRR: 1.85 [1.21, 2.81]; EBGM: 1.54 [1.06, 1.81]); moxifloxacin, levofloxacin, and ofloxacin showed weak and nonsignificant signals., Conclusion: Further pharmacovigilance studies are required to confirm the association between ciprofloxacin and AHF seen in the present analysis., (© 2021 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Observational healthcare data can be used for drug safety and effectiveness research. The use of inverse probability of treatment weights (IPW) reduces measured confounding under the assumption of accurate measurement of the outcome variable; however, many datasets suffer from systematic outcome misclassification., Methods: We introduced a modification to IPW to correct for the presence of outcome misclassification. To demonstrate the utility of these modified weights in realistic settings, we investigated postmyocardial infarction statin use and the 1-year risk of stroke in the Clinical Practice Research Datalink., Results: We computed an IPW-adjusted odds ratio (OR = 0.67; 95% confidence interval (CI) = 0.48, 0.93). We employed a technique to modify IPW for the presence of outcome misclassification using linked hospital records for outcome validation (modified IPW adjusted OR = 0.77; 95% CI = 0.52, 1.15) and compared the results with a meta-analysis of randomized controlled trials (RCTs) (pooled OR = 0.80; 95% CI = 0.74, 0.87). Finally, we present simulation studies to investigate the impact of model selection on bias reduction and variability., Conclusion: Ignoring outcome misclassification yielded biased estimates whereas the use of the modified IPW approach produced encouraging results when compared with the meta-analytic RCT findings.

This paper describes data from a systematic review and meta-analysis [1] conducted to identify and evaluate published peer reviewed evidence on the association between perineal use of talc powder and risk of ovarian cancer. These data were collected from multiple electronic bibliographic databases, as well as from grey literature sources, without applying time, language or other filters. A meta-analysis was conducted to quantitatively assess the ovarian cancer risk in relation to talc use and other potential risk factors., (© 2020 The Authors.)

Objective: We sought to assess interrater reliability (IRR) of lung point-of-care ultrasound (POCUS) findings among pediatric patients with suspected pneumonia., Methods: A convenience sample of patients between the ages of 6 months and 18 years with a clinical suspicion of pneumonia had a lung ultrasound performed by a POCUS-credentialed emergency medicine physician with subsequent expert review. Each lung zone was assessed as either normal or abnormal, and specific ultrasound findings were recorded. IRR was assessed by intraclass correlation coefficient (ICC) and kappa statistics., Results: Seventy-one patients, with a total of 852 lung zones imaged, were included. The sonographer assessment of normal versus abnormal, across each of the zones, demonstrated moderate agreement with ICC 0.46 (95% CI: 0.41, 0.52) and kappa 0.56. Right-sided zones demonstrated moderate agreement [0.43 (CI 0.35, 0.51)] while left-sided zones, specifically left-sided anterior zones, showed only fair agreement [0.36 (0.28, 0.44)]. IRR varied between specific findings: ICC for B-lines 0.52 (95% CI: 0.46, 0.57), pleural effusion 0.40 (0.34, 0.45), consolidation 0.39 (0.33, 0.44), subpleural consolidation 0.31 (0.25, 0.37), and pleural line irregularity 0.16 (0.10, 0.23). A composite indicator of typical pneumonia findings (consolidation, B-lines, and pleural effusion) demonstrated moderate [ICC 0.52 (0.46, 0.57)] reliability., Conclusions: We found moderate interrater reliability of lung POCUS findings for the assessment of pediatric patients with suspected pneumonia. B-lines had the highest reliability. Further assessment of lung POCUS is necessary to guide proper training and optimal scanning techniques to ensure adequate reliability of ultrasound findings in the assessment of pediatric pneumonia., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Over the past four decades, there has been increasing concern that perineal use of talc powder, a commonly used personal care product, might be associated with an increased risk of ovarian cancer., Objectives: To critically review all available human epidemiological data on the relationship between perineal use of talc powder and ovarian cancer, with consideration of other relevant experimental evidence., Methodology: We identified 30 human studies for qualitative assessment of evidence, including 27 that were retained for further quantitative analysis., Results: A positive association between perineal use of talc powder and ovarian cancer was found [OR: 1.28 (95% CI: 1.20-1.37)]. A significant risk was noted in Hispanics and Whites, in women applying talc to underwear, in pre-menopausal women and in post-menopausal women receiving hormonal therapy. A negative association was noted with tubal ligation., Conclusion: Perineal use of talc powder is a possible cause of human ovarian cancer., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Misclassification of a binary outcome can introduce bias in estimation of the odds-ratio associated with an exposure of interest in pharmacoepidemiology research. It has been previously demonstrated that utilizing information from an internal randomly selected validation sample can help mitigate this bias., Methods: Using a Monte Carlo simulation-based approach, we study the properties of misclassification bias-adjusted odds-ratio estimators in a contingency table setting. We consider two methods of internal validation sampling; namely, simple random sampling and sampling conditional on the original (possibly incorrect) outcome status. Additional simulation studies are conducted to investigate these sampling approaches in a multi-table setting., Results: We demonstrate that conditional validation sampling, across a range of subsampling fractions, can produce better estimates than those based on an unconditional simple random sample. This approach allows for greater flexibility in the chosen categorical composition of the validation data, as well as the potential for obtaining a more efficient estimator of the odds-ratio. We further demonstrate that this relationship holds for the Mantel-Haenszel misclassification bias-adjusted odds-ratio in stratified samples. Recommendations for the choice of validation subsampling fraction are also provided., Conclusions: Careful consideration when choosing the sampling scheme used to draw internal validation samples can improve the properties of the outcome misclassification bias-adjusted odds-ratio estimator in a (multiple) contingency table., (© 2019 John Wiley & Sons, Ltd.)

Patient electronic health records, viewed as continuous-time right-censored survival data, can be used to estimate adverse drug reaction risk. Temporal outcome misclassification may occur as a result of errors in follow-up. These errors can be due to a failure to observe the incidence time of the adverse event of interest (due to misdiagnosis or nonreporting, etc) or an actual misdiagnosis of a competing adverse event. As the misclassifying event is often unobservable in the original data, we apply an internal validation sampling approach to produce consistent estimation in the presence of such errors. We introduce a univariate survival model and a cause-specific hazards model in which misclassification may also manifest as a diagnosis of an alternate adverse health outcome other than that of interest. We develop a method of maximum likelihood estimation of the model parameters and establish consistency and asymptotic normality of the estimators using standard results. We also conduct simulation studies to numerically investigate the finite sample properties of these estimators and the impact of ignoring the misclassification error., (© 2018 John Wiley & Sons, Ltd.)

Background: There is a growing body of evidence to support the utility of lung point-of-care ultrasound (POCUS) in pediatric patients with multiple pulmonary pathologies, particularly pneumonia. As we increase our use of lung POCUS for pediatric patients with respiratory complaints, we must be mindful of the normal anatomy and sonographic findings within the pediatric chest and aware of how to distinguish normal findings (e.g., thymus) from pathologic findings (e.g., consolidation)., Case Reports: We report four cases of pediatric patients who presented to the Emergency Department with respiratory complaints for which POCUS was able to distinguish lung consolidation and normal thymus in the anterior chest. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The use of lung ultrasound to detect pneumonia is extensively documented in the pediatric literature. Emergency physicians may not be aware of how to discriminate the normal sonographic appearance of the thymus from lung consolidation on POCUS. The ability to identify normal and pathologic findings within the pediatric chest by POCUS will be increasingly important to appropriately reduce the use of plain radiography for pediatric patients with respiratory complaints., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: We sought to determine which interventions have effectively increased point-of-care ultrasound (US) use in a pediatric emergency department (ED)., Design/methods: We evaluated the impact of specific interventions conducted over a 5-year period (2010-2015) on point-of-care US performance in a tertiary care pediatric ED. Ultrasound use by attending physicians and fellows was ascertained from a departmental database. Interventions assessed included the following: (1) initiation of an US fellowship, (2) acquisition of a second US machine, (3) performance of an US-related research project in the department, (4) initiation of faculty US curriculum, (5) earlier introduction of US education for pediatric emergency medicine fellows, and (6) administrative mandate dictating faculty requirements for credentialing. Mean monthly US use was trended over time using statistical process control methodology, and the impact of major interventions was analyzed using interrupted time-series analyses., Results: The mean number of US scans increased from 2.0 to 5.9 per attending per month and from 4.3 to 7.1 per fellow per month over the study period. Using interrupted time-series analyses, we observed the only intervention to significantly increase attending US utilization was an administrative credentialing mandate, with an associated increase of 6% per month (incidence rate ratio, 1.06; 95% confidence interval, 1.01-1.11)., Conclusions: Point-of-care US use has increased over time for both fellows and attending physicians. We observed that an administrative mandate led to a significant increase in US use among attending physicians.

In the presence of confounding, the consistency assumption required for identification of causal effects may be violated due to misclassification of the outcome variable. We introduce an inverse probability weighted approach to rebalance covariates across treatment groups while mitigating the influence of differential misclassification bias. First, using a simplified example taken from an administrative health care dataset, we introduce the approach for estimation of the marginal causal odds ratio in a simple setting with the use of internal validation information. We then extend this to the presence of additional covariates and use simulated data to investigate the finite sample properties of the proposed weighted estimators. Estimation of the weights is done using logistic regression with misclassified outcomes, and a bootstrap approach is used for variance estimation., (Copyright © 2017 John Wiley & Sons, Ltd.)

Neoadjuvant chemotherapy potentially can have an adverse effect on bone healing in distraction osteogenesis whether given before or concomitant with distraction osteogenesis. It was the purpose of the current study to determine if administration of chemotherapy before distraction adversely affects bone generation in distraction osteogenesis. Twenty-four adult dairy goats were divided randomly into two groups: a control group having distraction osteogenesis only and a chemotherapy group, receiving one course of Adriamycin before distraction osteogenesis. The animals were sacrificed at 6 weeks, 12 weeks, or 24 weeks and the lengthened tibias were evaluated by radiologic studies, biomechanical testing, and histologic analysis. All goats receiving chemotherapy showed systemic adverse effects. In a multifactorial analysis of the lengthened bones, there was no statistically significant difference between the control goats versus goats that received chemotherapy; indicating that there was no sustained inhibitory effect on bone formation by the chemotherapy. These findings suggest that a prior course of chemotherapy with Adriamycin may not be a contraindication to limb lengthening for limb salvage after resection of an osteosarcoma.