Purpose: SARS-CoV-2 infections cause COVID-19 and have a wide spectrum of morbidity. Severe disease courses among children are rare. To date, data on the variability of morbidity in relation to variant of concern (VOC) in children has been sparse and inconclusive. We compare the clinical severity of SARS-CoV-2 infection among children and adolescents in Germany during the Wildtype and Alpha combined, Delta and Omicron phases of the COVID-19 pandemic. Methods: Comparing risk of COVID-19-related hospitalization, intensive care unit (ICU) admission and death due to COVID-19 in children and adolescents, we used: (1) a multi-center seroprevalence study (SARS-CoV-2-KIDS study); (2) a nationwide registry of pediatric patients hospitalized with SARS-CoV-2 infections; and (3) compulsory national reporting for RT-PCR-confirmed SARS-CoV-2 infections in Germany. Results: During the Delta predominant phase, risk of COVID-19-related hospitalization among all SARS-CoV-2 seropositive children was 3.35, ICU admission 1.19 and fatality 0.09 per 10,000; hence about halved for hospitalization and ICU admission and unchanged for deaths as compared to the Wildtype- and Alpha-dominant period. The relative risk for COVID-19-related hospitalization and ICU admission compared to the alpha period decreased during Delta [0.60 (95% CI 0.54; 0.67) and 0.51 (95% CI 0.42; 0.61)] and Omicron [0.27 (95% CI 0.24; 0.30) and 0.06 (95% CI 0.05; 0.08)] period except for the < 5-year-olds. The rate of case fatalities decreased slightly during Delta, and substantially during Omicron phase. Conclusion: Morbidity caused by SARS-CoV-2 infections among children and adolescents in Germany decreased over the course of the COVID-19 pandemic, as different VOCs) emerged.

Worldwide, 150 children are born each day with congenital diaphragmatic hernia (CDH), a diaphragmatic defect with concomitant abnormal lung development. Patients with CDH with large defects are particularly challenging to treat, have the highest mortality, and are at significant risk of long-term complications. Advances in prenatal and neonatal treatments have improved survival in high-risk patients with CDH, but surgical treatment of large defects lacks standardization. Open repair by an abdominal approach has long been considered the traditional procedure, but the type of defect repair (patch or muscle flap) and patch material (non-absorbable, synthetic or absorbable, biological) remain subjects of debate. Increased experience and improved techniques in minimally invasive surgery (MIS) have expanded selection criteria for thoracoscopic defect repair in cardiopulmonary stable patients with small defects. However, the application of MIS to repair large defects remains controversial due to increased recurrence rates and unknown long-term effects of perioperative hypercapnia and acidosis resulting from capnothorax and reduced ventilation. Current recommendations on the surgical management rely on cohort studies of varying patient numbers and data on the long-term outcomes are sparse. Here, we discuss surgical approaches for diaphragmatic defect repair highlighting advancements, and knowledge gaps in surgical techniques (open surgery and MIS), patch materials and muscle flaps for large defects, as well as procedural adjuncts and management of CDH variants.

The purpose of this study is to investigate the role of platelet bone morphogenetic proteins (BMP)-4 during vascular inflammation and remodeling in a mouse model of carotid wire injury. Transgenic mice with a platelet-specific deletion of BMP-4 (BMP4^Plt−/−) were generated. Intravital microscopy was performed to evaluate leukocyte adhesion to the vessel wall. Expression of adhesion molecules and chemokines were analyzed. Platelet-leukocyte aggregates (PLAs) were evaluated using flow cytometry. For carotid wire injury, BMP4^Plt−/− mice were further crossed with LDLr^−/− mice (BMP4^Plt−/−/LDLr^−/−) and fed with a high cholesterol diet for 2-weeks. Carotid wire injury was performed, and re-endothelialization and neointimal formation were evaluated. In comparison to the control mice, stimulation with TNFα resulted in fewer rolling and adherent leukocytes to the vessel wall in the BMP4^Plt−/− mice. mRNA and protein expression of P-selectin and adhesion molecules were reduced in the aorta of the BMP4^Plt−/− mice. In platelets from the BMP4^Plt−/− mice, the expression of P-selectin was reduced, and fewer PLA formations were measured than in the control mice. Loss of platelet BMP-4 further prevented neointima formation after carotid wire injury. Endothelial regeneration after injury was decelerated in the BMP4^Plt−/− mice, and confirmed in-vitro, where the deletion of platelet BMP-4 inhibited endothelial cell proliferation and migration. We demonstrate for the first time that platelet BMP-4 is involved during vascular inflammation and remodeling. This is partially mediated by the inhibition of platelet activation, reduced expression of adhesion molecules and inflammatory responses. Our findings identify platelet BMP-4 as a mediator of vascular inflammation in early atherosclerosis and restenosis.

Circular RNAs (circRNAs) are generated through back-splicing, a process where a backsplice junction (BSJ) is formed, based on the circRNAs’ unique sequence. BSJs are highly conserved and can be mapped to chromosomal coordinates. Current platforms determine these coordinates from bulk RNA sequencing data. We aimed to develop a tool capable of determining backsplice coordinates based on BSJ sequences for any species and genome version. Motivation: circRNAs are emerging as an important regulator of cellular differentiation and other biologically important processes. Common tools for circRNA analyses require a circular RNA’s backsplice coordinates. These can be accessed from public databases. However, the coordinates are specific to a version of a species’ genome, and are unavailable for many model organisms. Results: We have developed a Python-based, command line tool, FindBacksplice, which produces backsplice coordinates for any available genome, based on a circRNA’s BSJ sequence. Implemented in Python, this script is integrated with BLAST for use in existing pipelines. We were able to find valid locations of backsplices for known human BSJs in the rat genome and produce backsplice coordinates for use in existing pipelines. Availability and implementation: FindBacksplice is available at github.com/m-kraljevic/findbacksplice

Many children with congenital surgical anomalies (CSA) face complex, lifelong healthcare challenges. We aimed to evaluate long-term healthcare utilization patterns to guide effective transition-of-care strategies. Our retrospective population study compared CSA patients (n=768) to matched controls (n=7,635). Cox and Poisson regression models assessed time-to-event and frequency of ambulatory visits and hospitalizations, adjusting for sex, socioeconomic status (SEFI), family size and rural/urban residency. CSA survivors had earlier (HR=1.22, 95%CI: 1.12-1.32, p<0.001) and more frequent ambulatory visits (IRR=1.62, 95%CI: 1.61-1.64, p<0.001). CSA cases attended the most annual outpatient visits per child during the first five years post-discharge with esophageal atresia (EA), anorectal malformations (ARM) and Hirschsprung disease having the highest number of contacts. Ambulatory utilization was greater in urban areas and among smaller families, but lower for males. After excluding perinatal hospitalizations, cases were more likely to require hospitalization compared to controls (HR=3.75, 95%CI: 3.42-4.13, p<0.001) and were hospitalized more frequently (IRR=5.63, 95%CI: 5.37-5.89, p<0.001) at all ages. Lower socioeconomic status, rural setting, female sex and larger households increased the frequency of admission. Cox proportional hazard plots showed that patients with ARM, EA/TEF or Hirschsprung disease required particular early re-admission after postnatal discharge compared to other CSAs. Patients with CSA exhibit persistently high healthcare use, with EA, ARM and Hirschsprung disease requiring particularly intensive follow-up beyond adolescence. Healthcare utilization among CSA patients is influenced by biological sex, family structure and sociodemographic factors. These findings underscore the need for personalized follow-up models beyond childhood.