Multimodal Assessment and Intramodal Comparison of Imaging Techniques for Pediatric Pulmonary Vein Stenosis with Pulmonary Hypertension.

Pulmonary vein stenosis (PVS) is a rare, serious, and progressive disease in the pediatric population. Evaluation is complex and involves multimodality imaging. Diagnosis is important as early treatment to prevent progressive pulmonary hypertension and right ventricular dysfunction is essential. Adult studies have shown good correlation between various imaging modalities; however, there are limited data in children. This is a single-center retrospective pilot study to determine the reliability of measurement of pulmonary vein stenosis and pulmonary hypertension across different imaging modalities-computed tomography angiography (CTA), echocardiography (echo), lung perfusion scan (LPS), and cardiac catheterization (cath). PVS was defined as > 2 mmHg by echo and cath and/or 50% reduction in diameter by CTA. Patients had to have an echo, CTA and cath performed within a 1-month timeframe of one another to be included in the study, with LPS data included if testing was completed at initial evaluation. Fifteen total patients were enrolled; 87% were categorized as primary PVS; a condition not directly related to direct injury or prior surgical intervention. Twenty-seven total stenotic pulmonary veins were identified (mean 1.8, range 1-4). CTA had a slightly better agreement with cath than echo in identifying PVS in different vein locations except in the LLPV. Additionally, echo and CTA had excellent sensitivity (91%) and specificity (100%) compared to cath for diagnosis of PH. We conclude that non-invasive imaging of echo and CTA has an acceptable correlation to cardiac catheterization for screening and initial evaluation of PVS and PH, as directly related to PVS, in pediatrics.

Operative Complications, Vaginal Bleeding, and Practice Considerations for Patients on Testosterone Undergoing Gender-Affirming Hysterectomy.

STUDY OBJECTIVE: To evaluate operative complications and healthcare utilization in transgender patients on testosterone undergoing minimally invasive gender-affirming hysterectomy compared to control patients. DESIGN: We performed a retrospective cohort study. Operative reports were used to gather information on intraoperative complications. We collected information on postoperative complications, electronic medical record (EMR) messages, phone calls, emergency department utilization, and clinic visits through a 90-day postoperative period. Healthcare utilization reasons were categorized as vaginal bleeding, pain, vaginal discharge, dysuria, urinary retention, bowel concern, incision concern, or other. SETTING: Tertiary care academic medical center. PATIENTS: Patients aged 18 to 55 who underwent a benign minimally invasive hysterectomy with or without oophorectomy performed between January 2014 and December 2022. The testosterone-using cohort consisted of patients who had a gender identity of male, transgender male, genderqueer, or nonbinary with documented testosterone use prior to surgery (n = 88). The control cohort consisted of patients who identified as female, genderqueer, or nonbinary with no documented testosterone use (n = 242). INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Patients using testosterone were younger, had a lower body mass index, lower American Society of Anesthesiologists class, and were more likely to be nulliparous. The median time patients used testosterone was 2.5 years (1.5-5.0). Patients on testosterone are at increased risk of intraoperative perineal lacerations requiring repair (RR 3.3, CI 95% [1.03-10.5]). A higher number of patients on testosterone reported vaginal bleeding via EMR message or phone call (RR 1.74 CI 95% [1.1-2.7]) compared to controls. No difference in reasons for emergency department visits was noted. The use of postoperative vaginal estrogen started at the postoperative visit was more frequent in the testosterone-using patients (7 [8.0%] vs 4 [1.7%], p = .01). CONCLUSION: This study demonstrates that testosterone use preoperatively may increase risk of intraoperative vaginal laceration requiring repair. Testosterone use also correlates with increased reports of vaginal bleeding through EMR message, phone call, and clinic visit. These results contribute new evidence to include in preoperative counseling and support existing evidence surrounding the safety of gender-affirming hysterectomy.

Use of central venous access devices outside of the pediatric intensive care units.

BACKGROUND: Central venous access devices (CVAD) are associated with central line associated bloodstream infection (CLABSI) and venous thromboembolism (VTE). We identified trends in non-intensive care unit (ICU) CVAD utilization, described complication rates, and compared resources between low and high CVAD sites. METHODS: We combined data from the Pediatric Health Information System (PHIS) database and surveys from included hospitals. We analyzed 10-year trends in CVAD encounters for non-ICU children between 01/2012-12/2021 and described variation and complication rates between 01/2017-12/2021. Using Fisher's exact test, we compared resources between low and high CVAD users. RESULTS: CVAD use decreased from 6.3% to 3.8% of hospitalizations over 10 years. From 2017-2021, 67,830 encounters with CVAD were identified. Median age was 7 (IQR 2-13) years; 46% were female. Significant variation in CVAD utilization exists (range 1.4-16.9%). Rates of CLABSI and VTE were 4.0% and 3.4%, respectively. Survey responses from 33/41 (80%) hospitals showed 91% had vascular access teams, 30% used vascular access selection guides, and 70% used midline/long peripheral catheters. Low CVAD users were more likely to have a team guiding device selection (100% vs 43%, p = 0.026). CONCLUSIONS: CVAD utilization decreased over time. Significant variation in CVAD use remains and may be associated with hospital resources. IMPACT: Central venous access device (CVAD) use outside of the ICU is trending down; however, significant variation exists between institutions. Children with CVADs hospitalized on the acute care units had a CLABSI rate of 4% and VTE rate of 3.4%. 91% of surveyed institutions have a vascular access team; however, the services provided vary between institutions. Even though 70% of the surveyed institutions have the ability to place midline/long peripheral catheters, the majority use these catheters less than a few times per month. Institutions with low CVAD use are more likely to have a vascular access team that guides device selection.

Differences in intestinal bacteria in traumatic injury survivors with and without probable posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a common consequence of traumatic injury, yet certain biological factors contributing to PTSD are poorly understood. The gut microbiome may influence mental health outcomes, but its role in heterogeneous PTSD presentations requires elucidation. METHODS: Bacterial composition was examined in adults 2-4 years post-trauma with probable PTSD (n = 24) versus trauma-exposed controls without probable PTSD (n = 24). 16S rRNA sequencing and bioinformatic tools assessed microbial diversity and abundance. Relationships between taxa and PTSD symptom clusters were evaluated. RESULTS: No differences were found in overall microbial community structure between groups. The probable PTSD group exhibited significantly reduced Actinobacteriota and increased Verrucomicrobiota phylum abundance compared to controls. Specific taxa showed notable inverse associations with negative mood/cognition versus hyperarousal symptoms. Prevotella and Ruminococcaceae were negatively associated with negative mood but positively associated with hyperarousal. CONCLUSIONS: Results demonstrate microbial signatures of probable PTSD subtypes, highlighting the microbiome as a potential mediator of heterogeneous trauma psychopathology. Definition of PTSD microbial correlates provides a foundation for personalized psychobiotic interventions targeting predominant symptom profiles.

Consensus reporting guidelines to address gaps in descriptions of ultra-rare genetic conditions.

Genome-wide sequencing and genetic matchmaker services are propelling a new era of genotype-driven ascertainment of novel genetic conditions. The degree to which reported phenotype data in discovery-focused studies address informational priorities for clinicians and families is unclear. We identified reports published from 2017 to 2021 in 10 genetics journals of novel Mendelian disorders. We adjudicated the quality and detail of the phenotype data via 46 questions pertaining to six priority domains: (I) Development, cognition, and mental health; (II) Feeding and growth; (III) Medication use and treatment history; (IV) Pain, sleep, and quality of life; (V) Adulthood; and (VI) Epilepsy. For a subset of articles, all subsequent published follow-up case descriptions were identified and assessed in a similar manner. A modified Delphi approach was used to develop consensus reporting guidelines, with input from content experts across four countries. In total, 200 of 3243 screened publications met inclusion criteria. Relevant phenotypic details across each of the 6 domains were rated superficial or deficient in >87% of papers. For example, less than 10% of publications provided details regarding neuropsychiatric diagnoses and "behavioural issues", or about the type/nature of feeding problems. Follow-up reports (n = 95) rarely contributed this additional phenotype data. In summary, phenotype information relevant to clinical management, genetic counselling, and the stated priorities of patients and families is lacking for many newly described genetic diseases. The PHELIX (PHEnotype LIsting fiX) reporting guideline checklists were developed to improve phenotype reporting in the genomic era.

Objective Quantification of Bilateral Bubble Contrast Echocardiography Correlates with Systemic Oxygenation in Patients with Single Ventricle Circulation.

Bubble contrast echocardiography is commonly used to diagnose pulmonary arteriovenous malformations (PAVMs) in single ventricle congenital heart disease (CHD), yet previous studies inconsistently report a correlation between bubble echoes and oxygenation. In this study, we sought to re-evaluate the correlation between bubble echoes and oxygenation by assessing total bilateral shunting and unilateral shunting. We conducted a single-center, retrospective study of patients with single ventricle CHD and previous Glenn palliation who underwent a cardiac catheterization and bubble echocardiogram during the same procedure from 2011 to 2020. Spearman's rank correlation was performed to examine the relationship between total bilateral shunting and measures of systemic oxygenation, as well as unilateral shunting and ipsilateral pulmonary vein oxygenation. For all patients (n = 72), total bilateral shunting moderately correlated with peripheral oxygen saturation (SpO2) (rs = -0.44, p < 0.0001). For patients with Glenn/Kawashima circulation (n = 49), total bilateral shunting was moderately correlated (SpO2: rs = -0.38, p < 0.01). In contrast, unilateral shunting did not correlate with ipsilateral pulmonary vein oxygenation for any vein measured (p = 0.16-p > 0.99). In conclusion, the total burden of bilateral bubble shunting correlated with systemic oxygenation and may better reflect the total PAVM burden from all lung segments. Unilateral correlation may be adversely influenced by non-standardized approaches to pulmonary vein sampling.

Myocardial Strain for the Differentiation of Myocardial Involvement in the Post-Acute Sequelae of COVID-19-A Multiparametric Cardiac MRI Study.

Myocardial involvement was shown to be associated with an unfavorable prognosis in patients with COVID-19, which could lead to fatal outcomes as in myocardial injury-induced arrhythmias and sudden cardiac death. We hypothesized that magnetic resonance imaging (MRI) myocardial strain parameters are sensitive markers for identifying subclinical cardiac dysfunction associated with myocardial involvement in the post-acute sequelae of COVID-19 (PASC). This study evaluated 115 subjects, including 65 consecutive COVID-19 patients, using MRI for the assessment of either post-COVID-19 myocarditis or other cardiomyopathies. Subjects were categorized, based on the results of the MRI exams, as having either 'suspected' or 'excluded' myocarditis. A control group of 50 matched individuals was studied. Along with parameters of global cardiac function, the MRI images were analyzed for measurements of the myocardial T1, T2, extracellular volume (ECV), strain, and strain rate. Based on the MRI late gadolinium enhancement and T1/T2/ECV mappings, myocarditis was suspected in 7 out of 22 patients referred due to concern of myocarditis and in 9 out of 43 patients referred due to concern of cardiomyopathies. The myocardial global longitudinal, circumferential, and radial strains and strain rates in the suspected myocarditis group were significantly smaller than those in the excluded myocarditis group, which in turn were significantly smaller than those in the control group. The results showed significant correlations between the strain, strain rate, and global cardiac function parameters. In conclusion, this study emphasizes the value of multiparametric MRI for differentiating patients with myocardial involvement in the PASC based on changes in the myocardial contractility pattern and tissue structure.

Inappropriate Use of Peripherally Inserted Central Catheters in Pediatrics: A Multisite Study.

OBJECTIVES: This study aimed to describe how the current practice of peripherally inserted central catheter (PICC) use in hospitalized children aligns with the Michigan Appropriateness Guide for Intravenous Catheters (miniMAGIC) in Children recommendations, explore variation across sites, and describe the population of children who do not receive appropriate PICCs. METHODS: A retrospective study was conducted at 4 children's hospitals in the United States. Children with PICCs placed January 2019 to December 2021 were included. Patients in the NICU were excluded. PICCs were categorized using the miniMAGIC in Children classification as inappropriate, uncertain appropriateness and appropriate. RESULTS: Of the 6051 PICCs identified, 9% (n = 550) were categorized as inappropriate, 9% (n = 550) as uncertain appropriateness, and 82% (n = 4951) as appropriate. The number of PICCs trended down over time, but up to 20% of PICCs each year were not appropriate, with significant variation between sites. Within inappropriate or uncertain appropriateness PICCs (n = 1100 PICC in 1079 children), median (interquartile range) patient age was 4 (0-11) years, 54% were male, and the main reason for PICC placement was prolonged antibiotic course (56%, n = 611). The most common admitting services requesting the inappropriate/uncertain appropriateness PICCs were critical care 24%, general pediatrics 22%, and pulmonary 20%. Complications resulting in PICC removal were identified in 6% (n = 70) of inappropriate/uncertain PICCs. The most common complications were dislodgement (3%) and occlusion (2%), with infection and thrombosis rates of 1% (n = 10 and n = 13, respectively). CONCLUSIONS: Although the majority of PICCs met appropriateness criteria, a substantial proportion of PICCs were deemed inappropriate or of uncertain appropriateness, illustrating an opportunity for quality improvement.

Assessment of rare bleeding disorders in adolescents with heavy menstrual bleeding.

INTRODUCTION: There are a significant number of patients with mucocutaneous bleeding, specifically heavy menstrual bleeding (HMB), who do not have a diagnosed bleeding disorder. These patients receive nontargeted interventions and may have suboptimal treatments. Functional assays, particularly for fibrinolytic and rare platelet function defects, are not robust and not readily available. AIM: We aimed to prospectively evaluate the prevalence of genetic defects associated with rare bleeding disorders and describe alterations of coagulation and fibrinolysis in a cohort of adolescents with HMB. METHODS: We performed a prospective observational cohort study of patients with HMB and unexplained bleeding. The study utilized a next generation sequencing panel and investigational global assays of coagulation and fibrinolysis. Additionally, specific functional assays were performed to help characterize novel variants that were identified. RESULTS: In 10 of the 17 patients (∼59%), genetic variants were identified on molecular testing. Thrombin generation by calibrated thromboelastography was not significantly altered in this patient population. The clot formation and lysis assay showed a trend towards increased fibrinolysis with rapid phase of decline in 23% of the patients. Further corresponding functional assays and study population are described. CONCLUSION: Our study describes a unique correlative model in a homogenous cohort of patients with HMB and unexplained bleeding which may inform future diagnostic algorithms, genotype-phenotype correlations as well as aid in specific targeted treatment approaches. Larger future studies may inform risk stratification of patients and improve health related outcomes in patients with HMB.

A serum-induced gene signature in hepatocytes is associated with pediatric nonalcoholic fatty liver disease.

OBJECTIVE: Pediatric nonalcoholic fatty liver disease (NAFLD) is a growing problem, but its underlying mechanisms are poorly understood. We used transcriptomic reporter cell assays to investigate differences in transcriptional signatures induced in hepatocyte reporter cells by the sera of children with and without NAFLD. METHODS: We studied serum samples from 45 children with NAFLD and 28 children without NAFLD. The sera were used to induce gene expression in cultured HepaRG cells and RNA-sequencing was used to determine gene expression. Computational techniques were used to compare gene expression patterns. RESULTS: Sera from children with NAFLD induced the expression of 195 genes that were significantly differentially expressed in hepatocytes compared to controls with obesity. NAFLD was associated with increased expression of genes promoting inflammation, collagen synthesis, and extracellular matrix remodeling. Additionally, there was lower expression of genes involved in endobiotic and xenobiotic metabolism, and downregulation of peroxisome function, oxidative phosphorylation, and xenobiotic, bile acid, and fatty acid metabolism. A 13-gene signature, including upregulation of TREM1 and MMP1 and downregulation of CYP2C9, was consistently associated with all diagnostic categories of pediatric NAFLD. CONCLUSION: The extracellular milieu of sera from children with NAFLD induced specific gene profiles distinguishable by a hepatocyte reporter system. Circulating factors may contribute to inflammation and extracellular matrix remodeling and impair xenobiotic and endobiotic metabolism in pediatric NAFLD.

Pediatric dermatofibromas: Truncal predominance in younger children.

Pediatric dermatofibromas are considered rare in young children and have not been well characterized, often misdiagnosed clinically. We performed a retrospective case series of children younger than 18 years with histopathologically diagnosed dermatofibromas at our institutions and evaluated age at onset and diagnosis, sex, lesion location, and size, associated symptoms, change over time, and pre-biopsy diagnosis. Overall, dermatofibromas were most common on the back and chest (20/53; 38%), followed by the legs (15/53; 28%) and arms (12/53; 23%) with the most common pre-biopsy diagnosis of "cyst" (23/53; 43%), followed by dermatofibroma (16/53; 30%), and pilomatricoma (12/53; 23%). Our study reinforces previous findings of truncal predominance of pediatric dermatofibromas, different from adults.

Direct thrombin inhibitors fail to reverse the negative effects of heparin on lung growth and function after murine left pneumonectomy.

Neonates with congenital diaphragmatic hernia (CDH) frequently require cardiopulmonary bypass and systemic anticoagulation. We previously demonstrated that even subtherapeutic heparin impairs lung growth and function in a murine model of compensatory lung growth (CLG). The direct thrombin inhibitors (DTIs) bivalirudin and argatroban preserved growth in this model. Although DTIs are increasingly used for systemic anticoagulation clinically, patients with CDH may still receive heparin. In this experiment, lung endothelial cell proliferation was assessed following treatment with heparin-alone or mixed with increasing concentrations of bivalirudin or argatroban. The effects of subtherapeutic heparin with or without DTIs in the CLG model were also investigated. C57BL/6J mice underwent left pneumonectomy and subcutaneous implantation of osmotic pumps. Pumps were preloaded with normal saline, bivalirudin, or argatroban; treated animals received daily intraperitoneal low-dose heparin. In vitro, heparin-alone decreased endothelial cell proliferation and increased apoptosis. The effect of heparin on proliferation, but not apoptosis, was reversed by the addition of bivalirudin and argatroban. In vivo, low-dose heparin decreased lung volume compared with saline-treated controls. All three groups that received heparin demonstrated decreased lung function on pulmonary function testing and impaired exercise performance on treadmill tolerance testing. These findings correlated with decreases in alveolarization, vascularization, angiogenic signaling, and gene expression in the heparin-exposed groups. Together, these data suggest that bivalirudin and argatroban fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of low-dose heparin with DTIs on CDH outcomes are warranted.NEW & NOTEWORTHY Infants with pulmonary hypoplasia frequently require cardiopulmonary bypass and systemic anticoagulation. We investigate the effects of simultaneous exposure to heparin and direct thrombin inhibitors (DTIs) on lung growth and pulmonary function in a murine model of compensatory lung growth (CGL). Our data suggest that DTIs fail to reverse the inhibitory effects of subtherapeutic heparin on lung growth and function. Clinical studies on the impact of heparin with DTIs on clinical outcomes are thus warranted.

Pediatric COVID-19 Hospitalizations During the Omicron Surge.

BACKGROUND: Treatment recommendations for children hospitalized with COVID-19 during the winter 2021-2022 omicron variant surge included remdesivir and dexamethasone for hypoxia and remdesivir for patients at risk of severe illness, including those with comorbidities. The omicron variant caused many otherwise-healthy children without hypoxia to be hospitalized for common viral syndromes like croup. This study aimed to characterize children hospitalized with COVID-19 during the omicron surge and describe their management and clinical trajectory. METHODS: This single-center retrospective study included patients under 19 years old with a COVID-19 discharge diagnosis on the Pediatric Hospital Medicine service in January and February 2022. Hypoxia was defined by sustained oxygen saturation greater than 90%. Primary outcome was return to emergency department or readmission within 14 days. Secondary outcomes were length of stay, multisystem inflammatory syndrome within 6 weeks, and death. RESULTS: During the study time frame, 111 children were hospitalized with COVID-19, including 35 who had an incidental COVID-19 result. In the remaining 76 patients, the median length of stay was 1.9 days (1.0 - 3.3). Eight patients (11%) returned to the emergency department or were readmitted within 14 days of discharge; 3 of the emergency department visits were related to ongoing COVID-19 infection. Of the 10 patients with croup, 1 received remdesivir due to prolonged illness, and none returned to the emergency department or were readmitted. DISCUSSION: Most children hospitalized with COVID-19 were young, previously healthy and unvaccinated for COVID-19 due to age-based ineligibility. Hypoxia was the most common indication for use of remdesivir/corticosteroids (25%). Return to the emergency department for ongoing COVID-19 symptoms was uncommon (4%). Patients with croup, a presentation seen more commonly with the omicron variant than previously, appeared to do well without remdesivir.

The association between cardiac magnetic resonance-derived aortic stiffness parameters and aortic dilation in young adults with bicuspid aortic valve: With and without coarctation of aorta.

Background: Bicuspid aortic valve (BAV) is associated with progressive aortic dilation. Studies in aortopathies have shown a correlation between increased aortic stiffness and aortic dilation. We aimed to evaluate aortic stiffness measures as predictors of progressive aortic dilation by cardiac magnetic resonance (CMR) in BAV patients. Methods: This is a retrospective study of 49 patients with BAV (median age 21.1 years at first CMR visit) with ≥2 CMR at the Wisconsin Adult Congenital Heart Disease Program (WAtCH). Circumferential aortic strain, distensibility, and ß-stiffness index were obtained from CMR-derived aortic root cine imaging, and aortic dimensions were measured at aortic root and ascending aorta. A linear mixed-model and logistic regression were used to identify important predictors of progressive aortic dilation. Results: Over a median of 3.8 years follow-up, the annual growth rates of aortic root and ascending aorta dimensions were 0.25 and 0.16 mm/year, respectively. Aortic strain and distensibility decreased while ß-stiffness index increased with age. Aortic root strain and distensibility were associated with progressive dilation of the ascending aorta. Baseline aortic root diameter was an independent predictor of >1 mm/year growth rate of the aortic root (adjusted OR 1.34, 95 % CI 1.03-1.74, p = 0.028). Most patients (61 %) had coexisting coarctation of aorta. Despite the higher prevalence of hypertension in patients with aortic coarctation, hypertension or coarctation had no effect on baseline aorta dimensions, stiffness, or progressive aortic dilation. Conclusion: Some CMR-derived aortic stiffness parameters correlated with progressive aortic dilation in BAV and should be further investigated in larger and older BAV cohorts.