Systematic Review and Meta-Analysis of Preterm Birth and Later Systolic Blood Pressure

Lower birth weight because of fetal growth restriction is associated with higher blood pressure later in life, but the extent to which preterm birth ( <37 completed weeks' gestation) or very low birth weight ( <1500 g) predicts higher blood pressure is less clear. We performed a systematic review of 27 observational studies that compared the resting or ambulatory systolic blood pressure or diagnosis of hypertension among children, adolescents, and adults born preterm or very low birth weight with those born at term. We performed a meta-analysis with the subset of 10 studies that reported the resting systolic blood pressure difference in millimeters of mercury with 95% CIs or SEs. We assessed methodologic quality with a modified Newcastle-Ottawa Scale. The 10 studies were composed of 1342 preterm or very low birth weight and 1738 term participants from 8 countries. The mean gestational age at birth of the preterm participants was 30.2 weeks (range: 28.8-34.1 weeks), birth weight was 1280 g (range: 1098-1958 g), and age at systolic blood pressure measurement was 17.8 years (range: 6.3-22.4 years). Former preterm or very low birth weight infants had higher systolic blood pressure than term infants (pooled estimate: 2.5 mm Hg [95% CI: 1.7-3.3 mm Hg]). For the 5 highest quality studies, the systolic blood pressure difference was slightly greater, at 3.8 mm Hg (95% CI: 2.6-5.0 mm Hg). We conclude that infants who are born preterm or very low birth weight have modestly higher systolic blood pressure later in life and may be at increased risk for developing hypertension and its sequela

Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity. In turn, incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy. We used high-accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD. We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A. Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients. Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case-control study of 107 patients with suspected KD, with receiver operating characteristic areas under the curve of 0.98 (95% confidence intervals [CI] of 0.97–1 and 0.95–1, respectively). Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD. In all, urine proteome profiles revealed novel candidate molecular markers of KD, including filamin C and meprin A that exhibit excellent diagnostic performance. These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD, lead to the identification of novel therapeutic targets, and allow the development of a biological classification of Kawasaki disease

Exposure and confidence across critical airway procedures in pediatric emergency medicine: An international survey study

Background: Airway management procedures are critical for emergency medicine (EM) physicians, but rarely performed skills in pediatric patients. Worldwide experience with respect to frequency and confidence in performing airway management skills has not been previously described. Objectives: Our aims were 1) to determine the frequency with which emergency medicine physicians perform airway procedures including: bag-mask ventilation (BMV), endotracheal intubation (ETI), laryngeal mask airway (LMA) insertion, tracheostomy tube change (TTC), and surgical airways, and 2) to investigate predictors of procedural confidence regarding advanced airway management in children. Methods: A web-based survey of senior emergency physicians was distributed through the six research networks associated with Pediatric Emergency Research Network (PERN). Senior physician was defined as anyone working without direct supervision at any point in a 24-h cycle. Physicians were queried regarding their most recent clinical experience performing or supervising airway procedures, as well as with hands on practice time or procedural teaching. Reponses were dichotomized to within the last year, or ≥ 1 year. Confidence was assessed using a Likert scale for each procedure, with results for ETI and LMA stratified by age. Response levels were dichotomized to “not confident” or “confident.” Multivariate regression models were used to assess relevant associations. Results: 1602 of 2446 (65%) eligible clinicians at 96 PERN sites responded. In the previous year, 1297 (85%) physicians reported having performed bag-mask ventilation, 900 (59%) had performed intubation, 248 (17%) had placed a laryngeal mask airway, 348 (23%) had changed a tracheostomy tube, and 18 (1%) had performed a surgical airway. Of respondents, 13% of physicians reported the opportunity to supervise but not provide ETI, 5% for LMA and 5% for BMV. The percentage of physicians reporting “confidence” in performing each procedure was: BMV (95%) TTC (43%), and surgical airway (16%). Clinician confidence in ETT and LMA varied by patient age. Supervision of an airway procedure was the strongest predictor of procedural confidence across airway procedures. Conclusion: BMV and ETI were the most commonly performed pediatric airway procedures by emergency medicine physicians, and surgical airways are very infrequent. Supervising airway procedures may serve to maintain procedural confidence for physicians despite infrequent opportunities as the primary proceduralist

Characterization of pediatric beta-adrenergic antagonist ingestions reported to the National Poison Data System from 2000-2020

BACKGROUND: When ingested by children, small quantities of beta-adrenergic antagonists (BAA) are described as dangerous, and even potentially lethal ( one pill can kill ). We characterize demographics, clinical characteristics, and the rate of serious outcomes amongst pediatric patients with reported BAA ingestions. METHODS: Retrospective review of United States patients \u3c 20-years-old with reported single-agent BAA ingestions presenting to a healthcare facility between January 2000 and February 2020 for whom a poison control center (PCC) was consulted. Data was abstracted from the National Poison Data System (NPDS). Medical outcomes were assessed by the NPDS scale of no effect, minor effect, moderate effect, major effect, and death. All relevant NPDS fatality narratives were reviewed. RESULTS: 35,436 reported exposures were identified. 29,155 (82.3%) were \u3c 6-years-old, of which 29,089 (99.8%) were unintentional. 25 patients (\u3c 0.1%) \u3c 6-years-old had major effects. 2,316 (8.8%) of patients with no/mild effects were admitted to a critical care unit. Of all cases, 1,460 (4.1%) had hypotension and 1,403 (4.0%) had bradycardia. 119 (0.3%) developed hypoglycemia. The only four fatalities resulted from intentional ingestions in patients \u3e 10-years-old who sustained cardiac arrest in the pre-hospital setting. CONCLUSIONS: Reported BAA ingestions in this multi-year national pediatric cohort caused infrequent toxicity, and no fatalities resulted from an unintentional ingestion. The frequency of bradycardia, hypotension, and hypoglycemia were low. While severely poisoned patients require aggressive treatment, 8.8% of patients were admitted to a critical care unit despite having no or mild effects, which suggests an opportunity to reduce resource utilization

Intensive Care Interventions Among Children With Toxicologic Exposures to Cardiovascular Medications

OBJECTIVES: Interventions requiring a PICU are rare in toxicologic exposures, but cardiovascular medications are high-risk exposures due to their hemodynamic effects. This study aimed to describe prevalence of and risk factors for PICU interventions among children exposed to cardiovascular medications. DESIGN: Secondary analysis of Toxicology Investigators Consortium Core Registry from January 2010 to March 2022. SETTING: International multicenter research network of 40 sites. PATIENTS: Patients 18 years old or younger with acute or acute-on-chronic toxicologic exposure to cardiovascular medications. Patients were excluded if exposed to noncardiovascular medications or if symptoms were documented as unlikely related to exposure. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1,091 patients in the final analysis, 195 (17.9%) received PICU intervention. One hundred fifty-seven (14.4%) received intensive hemodynamic interventions and 602 (55.2%) received intervention in general. Children less than 2 years old were less likely to receive PICU intervention (odds ratio [OR], 0.42; 95% CI, 0.20-0.86). Exposures to alpha-2 agonists (OR, 2.0; 95% CI, 1.11-3.72) and antiarrhythmics (OR, 4.26; 95% CI, 1.41-12.90) were associated with PICU intervention. In the sensitivity analysis removing atropine from the composite outcome PICU intervention, only exposures to calcium channel antagonists (OR, 2.12; 95% CI, 1.09-4.11) and antiarrhythmics (OR, 4.82; 95% CI, 1.57-14.81) were independently associated with PICU intervention. No independent association was identified between PICU intervention and gender, polypharmacy, intentionality or acuity of exposure, or the other medication classes studied. CONCLUSIONS: PICU interventions were uncommon but were associated with exposure to antiarrhythmic medications, calcium channel antagonists, and alpha-2 agonists. As demonstrated via sensitivity analysis, exact associations may depend on institutional definitions of PICU intervention. Children less than 2 years old are less likely to require PICU interventions. In equivocal cases, age and exposure to certain cardiovascular medication classes may be useful to guide appropriate disposition

Noncompletion and nonpublication of trials studying rare diseases: A cross-sectional analysis.

BackgroundRare diseases affect as many as 60 million people in the United States and Europe. However, most rare diseases lack effective therapies and are in critical need of clinical research. Our objective was to determine the frequency of noncompletion and nonpublication of trials studying rare diseases.Methods and findingsWe conducted a cross-sectional analysis of randomized clinical trials studying rare diseases as defined by the Genetic and Rare Disease Information Center database that were registered in ClinicalTrials.gov between January 1, 2010, and December 31, 2012, and completed or discontinued by December 31, 2014. Our main outcome measures were the frequency of trial noncompletion and, among completed studies, frequency of trial nonpublication at 2 and 4 years following trial completion. Reasons for discontinuation were extracted from the registry, and trial sponsors were contacted for additional information, as needed. Two independent investigators performed publication searches for each trial in PubMed, EMBASE, and GoogleScholar, allowing for a minimum of 45 months between trial completion and publication. When a publication could not be identified, trial sponsors were contacted to confirm publication status. The impact of funding source on trial noncompletion was assessed with multivariable logistic regression, and the effect on time to publication was examined with Cox proportional hazards regression. Control variables included intervention type, trial phase, masking, enrollment, and study population. We analyzed 659 rare disease trials accounting for 70,305 enrolled patients. Industry was the primary funder for 327 trials (49.6%) and academic institutions for 184 trials (27.9%). There were 79 trials (12.0%) focused on pediatric populations. A total of 199 trials (30.2%) were discontinued. Lack of patient accrual (n = 64, 32.1%) and informative termination (n = 41, 20.6%) were the most common reasons for trial noncompletion. Among completed trials, 306 (66.5%) remained unpublished at 2 years and 142 (31.5%) at 4 years. In multivariable analyses, industry-funded trials were less likely to be discontinued than trials funded by healthcare centers (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.34-4.39, P = 0.003). We found no significant association between funding source and time to publication. A total of 18,148 patients were enrolled in trials that were discontinued or unpublished 4 years after completion. A potential limitation of our study is that certain interventional trials for rare diseases may not have been registered in ClinicalTrials.gov, in particular Phase 0 and Phase I trials, which are not required to be registered.ConclusionsIn this study, over half of clinical trials initiated for rare diseases were either discontinued or not published 4 years after completion, resulting in large numbers of patients with rare diseases exposed to interventions that did not lead to informative findings. Concerted efforts are needed to ensure that participation of patients in rare disease trials advances scientific knowledge and treatments for rare diseases

Prescription opioid use and misuse among adolescents and young adults in the United States: A national survey study.

BACKGROUND:Prescription opioid misuse has become a leading cause of unintentional injury and death among adolescents and young adults in the United States. However, there is limited information on how adolescents and young adults obtain prescription opioids. There are also inadequate recent data on the prevalence of additional drug abuse among those misusing prescription opioids. In this study, we evaluated past-year prevalence of prescription opioid use and misuse, sources of prescription opioids, and additional substance use among adolescents and young adults. METHODS AND FINDINGS:This was a retrospective analysis of the National Survey on Drug Use and Health (NSDUH) for the years 2015 and 2016. Prevalence of opioid use, misuse, use disorder, and additional substance use were calculated with 95% confidence intervals (CIs), stratified by age group and other demographic variables. Sources of prescription opioids were determined for respondents reporting opioid misuse. We calculated past-year prevalence of opioid use and misuse with or without use disorder, sources of prescription opioids, and prevalence of additional substance use. We included 27,857 adolescents (12-17 years of age) and 28,213 young adults (18-25 years of age) in our analyses, corresponding to 119.3 million individuals in the extrapolated national population. There were 15,143 respondents (27.5% [95% CI 27.0-28.0], corresponding to 32.8 million individuals) who used prescription opioids in the previous year, including 21.0% (95% CI 20.4-21.6) of adolescents and 32.2% (95% CI 31.4-33.0) of young adults. Significantly more females than males reported using any prescription opioid (30.3% versus 24.8%, P < 0.001), and non-Hispanic whites and blacks were more likely to have had any opioid use compared to Hispanics (28.9%, 28.1%, and 25.8%, respectively; P < 0.001). Opioid misuse was reported by 1,050 adolescents (3.8%; 95% CI 3.5-4.0) and 2,207 young adults (7.8%; 95% CI 7.3-8.2; P < 0.001). Male respondents using opioids were more likely to have opioid misuse without use disorder compared with females (23.2% versus 15.8%, respectively; P < 0.001), with similar prevalence by race/ethnicity. Among those misusing opioids, 55.7% obtained them from friends or relatives, 25.4% from the healthcare system, and 18.9% through other means. Obtaining opioids free from friends or relatives was the most common source for both adolescents (33.5%) and young adults (41.4%). Those with opioid misuse reported high prevalence of prior cocaine (35.5%), hallucinogen (49.4%), heroin (8.7%), and inhalant (30.4%) use. In addition, at least half had used tobacco (55.5%), alcohol (66.9%), or cannabis (49.9%) in the past month. Potential limitations of the study are that we cannot exclude selection bias in the study design or socially desirable reporting among participants, and that longitudinal data are not available for long-term follow-up of individuals. CONCLUSIONS:Results from this study suggest that the prevalence of prescription opioid use among adolescents and young adults in the US is high despite known risks for future opioid and other drug use disorders. Reported prescription opioid misuse is common among adolescents and young adults and often associated with additional substance abuse, underscoring the importance of drug and alcohol screening programs in this population. Prevention and treatment efforts should take into account that greater than half of youths misusing prescription opioids obtain these medications through friends and relatives

Neglected tropical diseases in children: An assessment of gaps in research prioritization.

BACKGROUND:Despite the known burden of neglected tropical diseases (NTDs) on child health, there is limited information on current efforts to increase pediatric therapeutic options. Our objective was to quantify and characterize research activity and treatment availability for NTDs in children in order to inform the prioritization of future research efforts. METHODOLOGY/PRINCIPAL FINDINGS:We conducted a review of the World Health Organization's (WHO) International Clinical Trials Registry Platform to assess research activity for NTDs. The burden of disease of each NTD was measured in terms of disability adjusted life years (DALYs), which was extracted from the Global Health Data Exchange. First- and second-line medications for each NTD were identified from WHO guidelines. We reviewed FDA drug labels for each medication to determine whether they were adequately labeled for use in children. Descriptive statistics, binomial tests, and Spearman's rank order correlations were calculated to assess research activity compared to burden of disease. Children comprised 34% of the 20 million DALYs resulting from NTDs, but pediatric trials contributed just 17% (63/369) of trials studying these conditions (p<0.001 for binomial test). Conditions that were particularly under-represented in pediatric populations compared to adults included rabies, leishmaniasis, scabies, and dengue. Pediatric drug trial activity was poorly correlated with pediatric burden of disease across NTDs (Spearman's rho = 0.41, p = 0.12). There were 47 medications recommended by the WHO for the treatment of NTDs, of which only 47% (n = 22) were adequately labeled for use in children. Of the 25 medications lacking adequate pediatric labeling, three were under study in pediatric trials. CONCLUSIONS/SIGNIFICANCE:There is a substantial gap between the burden of disease for NTDs in children and research devoted to this population. Most medications lack adequate pediatric prescribing information, highlighting the urgency to increase pediatric research activity for NTDs with high burden of disease and limited treatment options