Novel pathogenic GATA6 variant associated with congenital heart disease, diabetes mellitus and necrotizing enterocolitis.

BACKGROUND: Pathogenic GATA6 variants have been associated with congenital heart disease (CHD) and a spectrum of extracardiac abnormalities, including pancreatic agenesis, congenital diaphragmatic hernia, and developmental delay. However, the comprehensive genotype-phenotype correlation of pathogenic GATA6 variation in humans remains to be fully understood. METHODS: Exome sequencing was performed in a family where four members had CHD. In vitro functional analysis of the GATA6 variant was performed using immunofluorescence, western blot, and dual-luciferase reporter assay. RESULTS: A novel, heterozygous missense variant in GATA6 (c.1403 G > A; p.Cys468Tyr) segregated with affected members in a family with CHD, including three with persistent truncus arteriosus. In addition, one member had childhood onset diabetes mellitus (DM), and another had necrotizing enterocolitis (NEC) with intestinal perforation. The p.Cys468Tyr variant was located in the c-terminal zinc finger domain encoded by exon 4. The mutant protein demonstrated an abnormal nuclear localization pattern with protein aggregation and decreased transcriptional activity. CONCLUSIONS: We report a novel, familial GATA6 likely pathogenic variant associated with CHD, DM, and NEC with intestinal perforation. These findings expand the phenotypic spectrum of pathologic GATA6 variation to include intestinal abnormalities. IMPACT: Exome sequencing identified a novel heterozygous GATA6 variant (p.Cys468Tyr) that segregated in a family with CHD including persistent truncus arteriosus, atrial septal defects and bicuspid aortic valve. Additionally, affected members displayed extracardiac findings including childhood-onset diabetes mellitus, and uniquely, necrotizing enterocolitis with intestinal perforation in the first four days of life. In vitro functional assays demonstrated that GATA6 p.Cys468Tyr variant leads to cellular localization defects and decreased transactivation activity. This work supports the importance of GATA6 as a causative gene for CHD and expands the phenotypic spectrum of pathogenic GATA6 variation, highlighting neonatal intestinal perforation as a novel extracardiac phenotype.

Long-Term Outcomes of Exercise Therapy Versus Revascularization in Patients With Intermittent Claudication.

OBJECTIVE: The aim was to analyze the risk of progression to chronic limb-threatening ischemia (CLTI), amputation and subsequent interventions after revascularization versus noninvasive therapy in patients with intermittent claudication (IC). BACKGROUND: Conflicting evidence exists regarding adverse limb outcomes after each treatment strategy. METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. MEDLINE, Web of Science, and Google Scholar were searched aided by a health sciences librarian through August 16, 2022. Randomized control trials (RCTs) comparing invasive (endovascular or surgical revascularization) and noninvasive treatment (exercise and/or medical treatment) were included. PROSPERO registration was completed (CRD42022352831). RESULTS: A total of 9 RCTs comprising 1477 patients (invasive, 765 patients; noninvasive, 712 patients) were eligible. During a mean of 3.6-year follow-up, progression to CLTI after invasive [5 (2-8) per 1000 person-years] and noninvasive treatment [6 (3-10) per 1000 person-years] were not statistically different [rate ratio (RR): 0.77; 95% CI, 0.35-1.69; P =0.51, I2 =0%]. Incidence of amputation (RR: 1.69; 95% CI, 0.54-5.26; P =0.36, I2 =0%) and all-cause mortality (hazard ratio: 1.26; 95% CI, 0.91-1.74; P =0.16, I2 =0%) also did not differ between the groups. However, the invasive treatment group underwent significantly more revascularizations (RR: 4.15; 95% CI, 2.80-6.16; P <0.00001, I2 =83%). The results were not changed by fixed effect or random-effects models, nor by sensitivity analysis. CONCLUSIONS: Although there is equivalent risk of progression to CLTI, major amputation and all-cause mortality compared with noninvasive treatment, invasive treatment for patients with IC led to significantly more revascularization procedures and should be used selectively in patients with major lifestyle limitation. Guideline recommendation of noninvasive treatment for first-line IC therapy is supported.

Genetics of aortic valve disease.

PURPOSE OF REVIEW: Aortic valve disease is a leading global cause of morbidity and mortality, posing an increasing burden on society. Advances in next-generation technologies and disease models over the last decade have further delineated the genetic and molecular factors that might be exploited in development of therapeutics for affected patients. This review describes several advances in the molecular and genetic understanding of AVD, focusing on bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD). RECENT FINDINGS: Genomic studies have identified a myriad of genes implicated in the development of BAV, including NOTCH1 , SMAD6 and ADAMTS19 , along with members of the GATA and ROBO gene families. Similarly, several genes associated with the initiation and progression of CAVD, including NOTCH1 , LPA , PALMD , IL6 and FADS1/2 , serve as the launching point for emerging clinical trials. SUMMARY: These new insights into the genetic contributors of AVD have offered new avenues for translational disease investigation, bridging molecular discoveries to emergent pharmacotherapeutic options. Future studies aimed at uncovering new genetic associations and further defining implicated molecular pathways are fuelling the new wave of drug discovery.

Extracorporeal Membrane Oxygenation in Children With COVID-19: A Systematic Review and Meta-Analysis.

OBJECTIVES: The indication, complications, and outcomes of extracorporeal membrane oxygenation (ECMO) in children with COVID-19-related illnesses remain unelucidated. Our study aimed to investigate the characteristics and outcomes of ECMO in children with COVID-19-related illnesses. DATA SOURCES: We searched PubMed and EMBASE databases in March 2022. STUDY SELECTION: We retrieved all studies involving children (age ≤ 18 yr) with COVID-19-related illnesses who received ECMO. DATA EXTRACTION: Two authors independently extracted data and assessed the risk of bias. Mortality, successful weaning rate, and complications while on ECMO were synthesized by a one-group meta-analysis using a random-effect model. Meta-regression was performed to explore the risk factors for mortality. DATA SYNTHESIS: We included 18 observational studies, four case series, and 22 case reports involving 110 children with COVID-19-related illnesses receiving ECMO. The median age was 8 years (range, 10 d to 18 yr), and the median body mass index was 21.4 kg/m 2 (range, 12.3-56.0 kg/m 2 ). The most common comorbidities were obesity (11% [7/63]) and congenital heart disease (11% [7/63]), whereas 48% (30/63) were previously healthy. The most common indications for ECMO were multisystem inflammatory syndrome in children (52% [47/90]) and severe acute respiratory distress syndrome (40% [36/90]). Seventy-one percent (56/79) received venoarterial-ECMO. The median ECMO runtime was 6 days (range, 3-51 d) for venoarterial ECMO and 11 days (range, 3-71 d) for venovenous ECMO. The mortality was 26.6% (95% CI, 15.9-40.9), and the successful weaning rate was 77.0% (95% CI, 55.4-90.1). Complications were seen in 37.0% (95% CI, 23.1-53.5) while on ECMO, including stroke, acute kidney injury, pulmonary edema, and thromboembolism. Corticosteroids and IV immunoglobulin therapies were associated with lower mortality. CONCLUSIONS: The mortality of children on ECMO for COVID-19 was relatively low. This invasive treatment can be considered as a treatment option for critically ill children with COVID-19.

Longitudinal Cardiac Outcomes of Multisystem Inflammatory Syndrome in Children: A Systematic Review and Meta-Analysis.

There is a paucity of longitudinal data on cardiac outcomes in multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. We aimed to investigate the longitudinal cardiovascular outcomes in MIS-C. PubMed and EMBASE were searched through May 2022. Observational studies were included, reporting mid-term (≥ 3 months) outcomes in children (aged < 21) with MIS-C. Data were extracted by two researchers. Longitudinal outcomes were synthesized by a one-group meta-analysis using a random-effects model. Eleven studies with a follow-up period (3 months to 1 year) were identified, including 547 MIS-C patients. The mortality was 2.5% (95% CI 1.3-4.9). The majority of left ventricular (LV) systolic dysfunction present in 46.8% (95% CI 32.7-61.3) in the acute phase resolved by 3 months, and the prevalence of LV systolic dysfunction was 1.7% (95% CI 0.5-5.7) and 2.1% (95% CI 0.8-5.4) at 3 month and 6 month follow-up, respectively. Additionally, the persistent LV systolic dysfunction in the small population was mild. However, coronary abnormalities such as coronary artery dilatation or aneurysms, seen in 23.7% (95% CI 17.7-31.1) at baseline, persisted in 4.7% (95% CI 1.5-14.3) at 3 months and 5.2% (95% CI 3.0-8.9) at 6 months. Mitral regurgitation (MR), which was observed in 56.6% (95% CI 27.7-81.6) at baseline, also persisted in 7.5% at 6 months. In conclusion, our study demonstrated largely favorable cardiac outcomes, suggesting resolution of LV systolic dysfunction in the majority of cases. However, coronary abnormalities and MR persisted in a subset of patients at mid-term follow-up.

Pulmonary vasodilator therapies in pulmonary arterial hypertension associated with CHD: a systematic review and network meta-analysis.

The optimal treatment strategy using pulmonary vasodilators in pulmonary arterial hypertension associated with CHD (PAH-CHD) remains controversial. We aimed to compare the efficacy and safety of pulmonary vasodilators in PAH-CHD. PubMed and EMBASE databases were searched through May 2022 and a network meta-analysis was conducted. The primary outcomes were mean difference of changes in 6-minute walk distance, NYHA functional class, and N-terminal pro-brain natriuretic peptide. The secondary outcomes included pulmonary vascular resistance, mean pulmonary arterial pressure, and resting oxygen saturation. We identified 14 studies, yielding 807 patients with PAH-CHD. Bosentan and sildenafil were associated with a significant increase in 6-minute walk distance from baseline compared with placebo (MD 48.92 m, 95% CI 0.32 to 97.55 and MD 59.70 m, 95% CI 0.88 to 118.53, respectively). Bosentan, sildenafil, and combination of bosentan and sildenafil were associated with significant improvement in NYHA functional class compared with placebo (MD -0.33, 95% CI -0.51 to -0.14, MD -0.58, 95% CI -0.75 to -0.22 and MD -0.62, 95% CI -0.92 to -0.31, respectively). Bosentan and sildenafil were also associated with significant improvements in secondary outcomes. These findings were largely confirmed in the subgroup analysis. Various adverse events were reported; however, serious adverse event rates were relatively low (4.8-8.7%), including right heart failure, acute kidney injury, respiratory failure, hypotension, and discontinuation of pulmonary vasodilators. In conclusion, bosentan and sildenafil were the most effective in improving prognostic risk factor such as 6-minute walk distance and NYHA class. Overall, pulmonary vasodilators were well tolerated in PAH-CHD.

Meta-analysis finds recurrent infection is more common after endovascular than after open repair of infected abdominal aortic aneurysm.

OBJECTIVE: Controversy has continued regarding the use of endovascular aneurysm repair (EVAR) vs open aneurysm repair (OAR) for infected abdominal aortic aneurysms (AAAs). In the present study, we investigated the comparative outcomes of EVAR and OAR for the treatment of infected AAAs. METHODS: We conducted a systematic review and meta-analysis using the MEDLINE and EMBASE databases through May 2021. We included studies that had described both EVAR and OAR for the treatment of infected AAAs. The primary endpoints were the rates of recurrent infection and related rupture and/or death. Perioperative and 1-year mortality and readmissions and reinterventions were also analyzed. RESULTS: Fourteen observational studies describing a total of 1203 patients (EVAR, 359 [29.8%]; OAR, 844 [70.2%]) were eligible for qualitative analysis. The baseline characteristics included diabetes mellitus (33.2%), fever at presentation (71.6%), rupture at diagnosis (26.1%), and positive blood cultures (52.5%). The mean follow-up period ranged from 12 to 40 months. The use of EVAR became more prevalent in recent years (2016-2020, 32.4%) compared with the former period (2010-2015, 13.8%; P < .0001). Fenestrated, branched, or concomitant visceral debranching EVAR was performed in 6.1% of cases. In OAR, surgical debridement was consistently performed, and in situ reconstruction was applied in 82.2% and an omental flap in 51.5%. In nine studies considered for quantitative analysis, the patients' background (EVAR, n = 264; OAR, n = 274) were statistically balanced. The crude rates of recurrent infection and related rupture or death were 13.6% (95% confidence interval [CI], 8.8%-18.5%) and 4.9% (95% CI 1.8%-8.0%), respectively. The pooled analyses depicted significantly higher rates of recurrent infection after EVAR than after OAR (relative risk [RR], 2.42; 95% CI, 1.80-3.27; P < .0001; I2 = 0%). Recurrent infection-related rupture or death (RR, 1.51; 95% CI, 0.70-3.23; P = .29; I2 = 0%), perioperative death (RR, 0.80; 95% CI, 0.39-1.65; P = .55; I2 = 35%), 1-year mortality (hazard ratio, 1.12; 95% CI, 0.97-1.28; P =.13; I2 = 0%), and readmission or reintervention (RR, 1.16; 95% CI, 0.74-1.82; P =.52; I2 = 0%) were not significantly different statistically between the two groups. Funnel plots showed no evidence of publication bias. Sensitivity analyses of leave-one-out meta-analysis confirmed higher rates of recurrent infection after EVAR. CONCLUSIONS: EVAR has become more prevalent as the initial treatment of infected AAAs. Although operative and 1-year survival were similar between OAR and EVAR groups, recurrent infection was more frequent after EVAR. This limitation should be weighed in selecting patients for EVAR in infected AAAs. Postoperative graft and infection surveillance are critical, especially after EVAR.

Predictability of the Global Limb Anatomic Staging System (GLASS) for Technical and Limb Related Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVE: The newly proposed Global Limb Anatomic Staging System (GLASS), a categorical staging of infrainguinal artery disease complexity, is expected to correlate with clinical outcomes in patients with chronic limb threatening ischaemia (CLTI). This study aimed to verify the relationship between GLASS stages and clinical outcomes after endovascular treatment (EVT) and bypass surgery (BS). DATA SOURCES: MEDLINE, Web of Science Core Collection, and Google Scholar were searched in consultation with a health sciences librarian through June 2021. REVIEW METHODS: This systematic review and meta-analysis was carried out according to the PRISMA guidelines. All studies comparing the outcomes of patients with CLTI stratified by GLASS staging were eligible. Amputation free survival (AFS), limb salvage rate (LSR), major adverse limb event (MALE), overall survival, immediate technical failure (ITF), and limb based patency (LBP) were analysed. Data were pooled and synthesised with a random effects model. RESULTS: Datasets from seven retrospective cohort studies and one randomised control trial with a total of 2 204 patients (2 483 limbs) were identified. Pooled estimates demonstrated statistical differences between GLASS 1+2 and GLASS 3 in LSR (HR 0.61; 95% CI 0.47 - 0.80, p < .001) and MALE (HR 0.66; 95% CI 0.53 - 0.83, p < .001). After stratification, there were statistical differences in AFS, LSR, and MALE between GLASS 1+2 and GLASS 3 in the EVT subgroup but not in BS. In GLASS 2 and 3, MALE was significantly worse after EVT. In GLASS stages 1, 2, and 3, ITF after EVT was 3.9%, 5.3%, and 27.9%, respectively. LBP after EVT was significantly different between GLASS 1+2 and GLASS 3 (HR 0.83; 95% CI 0.71 - 0.97, p = .020). CONCLUSION: GLASS is predictive of LSR and MALE as well as ITF and LBP after EVT. The current meta-analysis suggests advanced GLASS stages favour BS over EVT.

Editor's Choice - Risk of Rupture and All Cause Mortality of Abdominal Aortic Ectasia: A Systematic Review and Meta-Analysis.

OBJECTIVE: To clarify the natural history of abdominal aortic ectasia (AAE) measuring 25 - 29 mm in maximum diameter, and to determine the optimal follow up based on the growth, risk of rupture, and overall mortality of AAE. DATA SOURCES: MEDLINE, Web of Science Core Collection, and Google Scholar. REVIEW METHODS: This was a systematic review and meta-analysis of AAE in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE, Web of Science Core Collection, and Google Scholar were searched, with the help of a health sciences librarian, up to 11 August 2021. Studies with longitudinal outcomes of AAE (prevalence, annual growth rate, aneurysmal enlargement, rupture, aneurysm related death, and all cause mortality) were included. Meta-analyses were conducted with a random effects model RESULTS: Twelve studies describing a total of 8 369 patients were eligible. The prevalence at population based settings was 3.2% (95% confidence interval [CI] 2.4 - 4.0); annual growth rate was 0.82 mm/year (95% CI 0.20 - 1.45). The estimated risks of aortic diameters exceeding 30 mm and 55 mm in five years were 45.0% (95% CI 28.5 - 61.5) and 0.3% (95% CI 0 - 0.6) respectively, while those beyond five years were 70.2% (95% CI 46.9 - 93.6) and 5.2% (95% CI 2.2 - 8.2). The rates of rupture and aneurysm related death were minimal until five years (0.1% and 0.1%, respectively) and beyond (0.4% and 0.2%, respectively). Overall mortality was 7.5% (95% CI 3.9 - 11.0) and 17.3% (95% CI 9.5 - 25.1) up to and beyond five years. Overall mortality from three studies showed no statistical difference between AAE and aneurysms (hazard ratio 0.62, 95% CI 0.32 - 1.21; p = .16). Cancer (35.0%) and cardiovascular diseases (31.9%) were major causes of death. CONCLUSION: AAE carries minimal risk of aneurysm related lethal events during the first five years, but a similar overall mortality risk as abdominal aortic aneurysm. Cancer and cardiovascular diseases are leading causes of death in patients with AAE.

Smaller size is more suitable for pharmacotherapy among undersized abdominal aortic aneurysm: A systematic review and meta-analysis.

Background: Pharmacotherapy for undersized abdominal aortic aneurysm (AAA) is a clinical unmet need. Randomized controlled trials (RCTs) have failed to show effectiveness despite countless promising data in preclinical studies. We aimed to identify the population with undersized AAAs (30-54 mm) who potentially benefit from pharmacotherapy. Methods: In accordance with the PRISMA statement, we conducted a systematic review and meta-analysis of placebo-controlled RCTs. The primary outcome was mean difference (MD) in annual growth rate (< 0 favors pharmacotherapy), and the secondary outcome was aneurysm-related events (diameters ⩾ 55 mm, ruptures, or referral to surgery). Results: Our search strategy identified eight RCTs (six trials on antibiotics [ABx], two on renin-angiotensin system inhibitors [RAS-I]) with a total of 1325 patients. The mean of baseline diameters ranged from 33.1 mm to 43.1 mm. Neither ABx nor RAS-I showed significant differences in MD. Multivariable random-effects restricted maximum likelihood meta-regression revealed a statistically significant linear relationship between baseline diameter and MD (coefficient 0.15 [95% CI 0.0011, 0.30], p = 0.049) but not for the follow-up period (p = 0.28) and duration of treatment (p = 0.11). In line with this result, ABx with baseline diameter < 40 mm significantly reduced MD (-1.03 mm/year [95% CI -1.64, -0.42], p = 0.001) and a borderline significant difference in aneurysm-related events (HR 0.53 [95% CI 0.28, 1.00], p = 0.05), whereas the other groups ⩾ 40 mm never demonstrated effectiveness. Fixed-effect models did not change the results. No evidence of publication bias was detected. Conclusion: Undersized AAAs < 40 mm can potentially benefit from pharmacotherapy. Future RCTs should consider preferentially including undersized AAA with smaller diameters.

Comparison of transcatheter patent ductus arteriosus closure between children and adults.

The data comparing the characteristics and effect of transcatheter patent ductus arteriosus (PDA) closure between children and adults is scarce. We analyzed 54 consecutive patients who underwent transcatheter PDA closures. We divided the patients into 2 groups of < 18 years and ≥ 18 years and compared the hemodynamic changes before and after the PDA closure. Adults had a higher incidence of heart failure on admission, diagnoses by heart failure and incidental echocardiography, PDA calcifications, and procedural complications than children (all P < 0.05). The left ventricular end-diastolic volume index (LVEDVI), left atrial diameter index (LADI), and LV mass index (LVMI) decreased after the PDA closure in children but not in adults. The LV ejection fraction (LVEF) significantly decreased 1 day after the PDA closure in both groups but remained low at 6 months after the procedure in only adults. The percent change in the LVEDVI, LADI, LVMI, and LVEF from baseline to 6 months after the procedure was significantly lesser in adults than children (LVEDVI: - 5.2 ± 29.1% vs. - 34.9 ± 18.9%, LADI: - 7.0 ± 13.2% vs. - 22.1 ± 18.9%, LVMI: - 11.0 ± 16.5% vs. - 34.1 ± 15.7%, LVEF: - 5.9 ± 7.6% vs. 6.1 ± 9.1%, all P < 0.05). Transcatheter PDA closure was not associated with a reduction in the LV and LA volume as well as an improvement in the LV hypertrophy and LV function in adults as compared to children. We suggested that an early diagnosis and transcatheter PDA closure during childhood might provide clinical benefit before progressive LV remodeling and heart failure.

Predictors of Early Postoperative Supraventricular Tachyarrhythmias in Children After the Fontan Procedure.

Postoperative arrhythmias are a frequent and fatal complication after the Fontan operation. However, clinical evidence demonstrating early postoperative arrhythmias in children undergoing the Fontan operation is limited. This study aimed to evaluate the prevalence of arrhythmias and identify the predictors of early postoperative supraventricular tachyarrhythmias (SVTs) after the Fontan procedure.Data were analyzed from 80 pediatric patients who underwent Fontan procedures between April 2000 and December 2017 in a single-center retrospective study. Early postoperative SVTs were defined as arrhythmias within 30 days after the Fontan procedure. We divided the patients into two groups, with or without early postoperative arrhythmias, and the predictors of early postoperative arrhythmias were analyzed. A multivariate logistic regression analysis was performed to determine independent predictors of early postoperative SVTs after the Fontan procedure.Early postoperative SVTs were observed in 21 patients (26.3%). The most common arrhythmia was junctional ectopic tachycardia. After an adjustment, an atrioventricular valve regurgitation (AVVR) grade of ≥2 (odds ratio 10.54, 95% confidence interval 2.52 to 44.17, P = 0.001) and preoperative arrhythmias (odds ratio 26.49, 95% confidence interval 1.64 to 428.62, P = 0.021) were significant predictors of early postoperative SVTs after the Fontan operation.An AVVR grade ≥2 and preoperative arrhythmia were significant predictors associated with early postoperative SVTs. Intervention for AVVR may provide clinical benefit for preventing early postoperative arrhythmias after the Fontan operation.

Pulmonary arterial hypertension associated with tetralogy of Fallot.

Pulmonary arterial hypertension (PAH) is a common postoperative complication in patients with congenital heart disease (CHD). Although the recent clinical classification of pulmonary hypertension divided PAH associated with CHD (PAH-CHD) into several subclasses, the anatomical and hemodynamic features of postoperative PAH-CHD vary enormously. Therefore, it is still difficult to obtain clinical evidence supporting the indication of pulmonary vasodilators for PAH-CHD. We often encounter patients with PAH occurring after surgical treatment of tetralogy of Fallot (TOF), especially patients with major aortopulmonary collateral arteries (MAPCAs). PAH might be caused by pulmonary agenesis, hypoplasia and/or thrombosis, inadequate closure of the ventricular septal defect, relief of the pulmonic stenosis, or an excessively large prior systemic-to-pulmonary shunt. Moreover, patients with TOF and MAPCAs who are diagnosed as inoperable because of the presence of PAH show similar hemodynamic and clinical features to patients with Eisenmenger syndrome. The MAPCAs in these patients usually show hypoplastic and abnormal arborization. Based on our experience, we believe that PAH-targeted therapies are effective in some patients with PAH occurring after surgical treatment of TOF and MAPCAs, especially as an adjunct to percutaneous pulmonary angioplasty. To help classify patients with PAH associated with TOF, especially with MAPCAs, we propose several new subclassifications: "PAH due to hypoplastic pulmonary arterial beds", "PAH due to abnormal pulmonary arborization", or "segmental PAH associated with CHD." A multicenter registry of patients using a unified protocol is essential to explore the indications and efficacy of pulmonary vasodilators for postoperative PAH-CHD.

Primary ciliary dyskinesia diagnosed on nasal mucosal biopsy in two newborns.

Primary ciliary dyskinesia (PCD) is a genetic disease that causes abnormalities in ciliary structure and/or function. Ciliated cells line the upper and lower respiratory tracts and the Eustachian tube. Impairment of mucus clearance at these sites leads to sinusitis, repeated pulmonary infections, bronchiectasis, and chronic otitis media. Situs inversus occurs randomly in approximately 50% of subjects with PCD. The triad of situs inversus, bronchiectasis and sinusitis is known as Kartagener syndrome. PCD is usually an autosomal recessive disease, but occasional instances of X-linked transmission have been reported. Specific diagnosis requires examination of ciliary function or structure on light and electron microscopy. Early diagnosis and respiratory management are important in order to prevent the development of bronchiectasis and deterioration in lung function. We report early diagnosis of PCD on nasal mucosal biopsy in two newborns who presented with prolonged respiratory distress and rhinorrhea.

Multisystem inflammatory syndrome in children associated with COVID-19: from pathophysiology to clinical management and outcomes.

Multisystem inflammatory syndrome in children (MIS-C), also known as pediatric inflammatory multisystem syndrome (PIMS), is a new postinfectious illness associated with COVID-19, affecting children after SARS-CoV-2 exposure. The hallmarks of this disorder are hyperinflammation and multisystem involvement, with gastrointestinal, cardiac, mucocutaneous, and hematologic disturbances seen most commonly. Cardiovascular involvement includes cardiogenic shock, ventricular dysfunction, coronary artery abnormalities, and myocarditis. Now entering the fourth year of the pandemic, clinicians have gained some familiarity with the clinical presentation, initial diagnosis, cardiac evaluation, and treatment of MIS-C. This has led to an updated definition from the Centers for Disease Control and Prevention in the USA driven by increased experience and clinical expertise. Furthermore, the available evidence established expert consensus treatment recommendations supporting a combination of immunoglobulin and steroids. However, the pathophysiology of the disorder and answers to what causes this remain under investigation. Fortunately, long-term outcomes continue to look promising, although continued follow-up is still needed. Recently, COVID-19 mRNA vaccination is reported to be associated with reduced risk of MIS-C, while further studies are warranted to understand the impact of COVID-19 vaccines on MIS-C. We review the findings and current literature on MIS-C, including pathophysiology, clinical features, evaluation, management, and medium- to long-term follow-up outcomes.

Overview of SARS-CoV-2 infection and vaccine associated myocarditis compared to non-COVID-19-associated myocarditis: A systematic review and meta-analysis.

BACKGROUND: Previous literature suggests that both SARS-CoV-2 infection and COVID-19 mRNA vaccine are associated with myocarditis, in which the incidence is higher in the infection group. COVID-19 mRNA vaccine-related myocarditis is noted to have a more benign course. Despite these findings, there is a need for a larger population systematic review that compares the outcomes to pre-pandemic acute myocarditis to better understand the extent of the current post-COVID state. METHODS: We performed a literature search with PubMed and EMBASE and identified studies investigating COVID-19 and its vaccinated population, and the population prior to the pandemic (control group) who had myocarditis. We performed a one-group meta-analysis of the incidence, baseline demographics, and outcomes of myocarditis for each group. RESULTS: The incidence in the SARS-CoV-2 infection group was 2.76 per thousand (95% CI, 0.85-8.92), 19.7 per million (95% CI, 12.3-31.6) in the vaccine group, and 0.861 per million (95% CI, 0.04-16.7) in the control group. The majority of patients were male, with the highest proportion in the vaccine group. The mean age was the youngest in the vaccine group (24.8, 95% CI, 19.1-30.6). The vaccine group had the lowest mortality (2.0%, 95% CI, 1.3-2.7) followed by the control and the SARS-CoV-2 infection group. The vaccine group had the lowest proportion of immunoglobulin and glucocorticoid use, mechanical circulatory support, and cardiogenic shock. CONCLUSION: Our study showed favorable outcomes of myocarditis in patients with COVID-19 mRNA vaccination, despite a higher incidence than pre-COVID controls. Further studies with standardized myocarditis diagnostic criteria assessing long-term outcomes are necessary.

Congenital aortic valve stenosis: from pathophysiology to molecular genetics and the need for novel therapeutics.

Congenital aortic valve stenosis (AVS) is one of the most common valve anomalies and accounts for 3%-6% of cardiac malformations. As congenital AVS is often progressive, many patients, both children and adults, require transcatheter or surgical intervention throughout their lives. While the mechanisms of degenerative aortic valve disease in the adult population are partially described, the pathophysiology of adult AVS is different from congenital AVS in children as epigenetic and environmental risk factors play a significant role in manifestations of aortic valve disease in adults. Despite increased understanding of genetic basis of congenital aortic valve disease such as bicuspid aortic valve, the etiology and underlying mechanisms of congenital AVS in infants and children remain unknown. Herein, we review the pathophysiology of congenitally stenotic aortic valves and their natural history and disease course along with current management strategies. With the rapid expansion of knowledge of genetic origins of congenital heart defects, we also summarize the literature on the genetic contributors to congenital AVS. Further, this increased molecular understanding has led to the expansion of animal models with congenital aortic valve anomalies. Finally, we discuss the potential to develop novel therapeutics for congenital AVS that expand on integration of these molecular and genetic advances.

Assessment of Efficacy and Safety of mRNA COVID-19 Vaccines in Children Aged 5 to 11 Years: A Systematic Review and Meta-analysis.

Importance: Evidence of the efficacy and safety of messenger RNA (mRNA) COVID-19 vaccines in children aged 5 to 11 years has been emerging. Collecting these data will inform clinicians, families, and policy makers. Objective: To evaluate the efficacy and safety of mRNA COVID-19 vaccines in children aged 5 to 11 years in a systematic review and meta-analysis. Data Sources: PubMed and Embase databases were searched on September 29, 2022, without language restrictions. Study Selection: Randomized clinical trials and observational studies comparing vaccinated vs unvaccinated children aged 5 to 11 years and reporting efficacy or safety outcomes were included. Studies reporting safety outcomes in vaccinated children only (ie, no control group) were also included. Data Extraction and Synthesis: Two investigators independently extracted relevant data from each study. Odds ratios (ORs) for efficacy and safety outcomes and incidences of adverse events (AEs) following vaccination were synthesized using a random-effects model. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology reporting guidelines. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infections with or without symptoms. The secondary outcomes included symptomatic SARS-CoV-2 infections, hospitalizations, and multisystem inflammatory syndrome in children. The incidences of each AE following vaccination were also evaluated. Results: Two randomized clinical trials and 15 observational studies involving 10 935 541 vaccinated children (median or mean age range, 8.0-9.5 years) and 2 635 251 unvaccinated children (median or mean age range, 7.0-9.5 years) were included. Two-dose mRNA COVID-19 vaccination compared with no vaccination was associated with lower risks of SARS-CoV-2 infections with or without symptoms (OR, 0.47; 95% CI, 0.35-0.64), symptomatic SARS-CoV-2 infections (OR, 0.53; 95% CI, 0.41-0.70), hospitalizations (OR, 0.32; 95% CI, 0.15-0.68), and multisystem inflammatory syndrome in children (OR, 0.05; 95% CI, 0.02-0.10). Two randomized clinical trials and 5 observational studies investigated AEs among vaccinated children. Most vaccinated children experienced at least 1 local AE following the first injection (32 494 of 55 959 [86.3%]) and second injection (28 135 of 46 447 [86.3%]). Vaccination was associated with a higher risk of any AEs compared with placebo (OR, 1.92; 95% CI, 1.26-2.91). The incidence of AEs that prevented normal daily activities was 8.8% (95% CI, 5.4%-14.2%) and that of myocarditis was estimated to be 1.8 per million (95% CI, 0.000%-0.001%) following the second injection. Conclusions and Relevance: In this systematic review and meta-analysis, COVID-19 mRNA vaccines among children aged 5 to 11 years were associated with measures of efficacy in preventing SARS-CoV-2 infection and severe COVID-19-related illnesses. While most children developed local AEs, severe AEs were rare, and most of AEs resolved within several days. These data provide evidence for future recommendations.

Protective effect of COVID-19 vaccination against long COVID syndrome: A systematic review and meta-analysis.

BACKGROUND: The relationship between coronavirus disease 2019 (COVID-19) vaccination and long COVID has not been firmly established. We conducted a systematic review and meta-analysis to evaluate the association between COVID-19 vaccination and long COVID. METHODS: PubMed and EMBASE databases were searched on September 2022 without language restrictions (CRD42022360399) to identify prospective trials and observational studies comparing patients with and without vaccination before severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. We also included studies reporting symptomatic changes of ongoing long COVID following vaccination among those with a history of SARS-CoV-2 infection. Odds ratios (ORs) for each outcome were synthesized using a random-effects model. Symptomatic changes after vaccination were synthesized by a one-group meta-analysis. RESULTS: Six observational studies involving 536,291 unvaccinated and 84,603 vaccinated (before SARS-CoV-2 infection) patients (mean age, 41.2-66.6; female, 9.0-67.3%) and six observational studies involving 8,199 long COVID patients (mean age, 40.0 to 53.5; female, 22.2-85.9%) who received vaccination after SARS-CoV-2 infection were included. Two-dose vaccination was associated with a lower risk of long COVID compared to no vaccination (OR, 0.64; 95% confidence interval [CI], 0.45-0.92) and one-dose vaccination (OR, 0.60; 95% CI, 0.43-0.83). Two-dose vaccination compared to no vaccination was associated with a lower risk of persistent fatigue (OR, 0.62; 95% CI, 0.41-0.93) and pulmonary disorder (OR, 0.50; 95% CI, 0.47-0.52). Among those with ongoing long COVID symptoms, 54.4% (95% CI, 34.3-73.1%) did not report symptomatic changes following vaccination, while 20.3% (95% CI, 8.1-42.4%) experienced symptomatic improvement after two weeks to six months of COVID-19 vaccination. CONCLUSIONS: COVID-19 vaccination before SARS-CoV-2 infection was associated with a lower risk of long COVID, while most of those with ongoing long COVID did not experience symptomatic changes following vaccination.