Ventricular Arrhythmia in the Fontan Circulation:Prevalence,Risk Factors and Clinical Implications

Objective:Sudden cardiac death(SCD)and malignant ventricular arrhythmia(VA)are increasingly recognized as important issues for people living with a Fontan circulation,but data are lacking.We sought to characterize the cohort who had sudden cardiac death,most likely related to VA and/or documented VA in the Australia and New Zealand Fontan Registry including risk factors and clinical outcomes.Methods:A retrospective cohort study was performed.Inclusion criteria were documented non-sustained ventricular tachycardia,sustained ventricular tachycardia,ventricular fibrillation,resuscitated cardiac arrest or SCD>30 days post-Fontan completion.Results:Of 1611 patients,20(1.2%)had VA;14(1.0%)had VA without SCD and 6(<1%)had SCD(6%of all deaths recorded in Registry;5 of those had documented VA at the time of arrest and 1 was presumed to be VA-associated).The median age at first VA was 20.5(14–32)years,10(50%)were females,and the median age at Fontan operation was 8(4–17)years.On univariable analysis,hypoplastic left heart syndrome(p=0.03)and older age Fontan operation(p<0.001)were associated with VA.Earlier Fontan era(p<0.003),atriopulmonary Fontan(p<0.001),pre-Fontan atrioventricular valve repair(p=0.013)pre-or post-Fontan atrial arrhythmia(p=0.010)were associated with SCD.Patients with VA had a 3 times higher risk of death or heart transplant(HR 3.27(1.19,8.98),p=0.02).Conclusions:A proportion of people living with a Fontan circulation have malignant VA.Routine VA screening in this cohort is essential.More data are needed to aid risk stratification.

Exploration of the shared pathophysiological mechanisms of gestational diabetes and large for gestational age offspring

Gestational diabetes mellitus (GDM) and large for gestational age (LGA) offspring are two common pregnancy complications. Connections also exist between the two conditions, including mutual maternal risk factors for the conditions and an increased prevalence of LGA offspring amongst pregnancies affected by GDM. Thus, it is important to elucidate potential shared underlying mechanisms of both LGA and GDM. One potential mechanistic link relates to macronutrient metabolism. Indeed, derangement of carbohydrate and lipid metabolism is present in GDM, and maternal biomarkers of glucose and lipid control are associated with LGA neonates in such pregnancies. The aim of this paper is therefore to reflect on the existing nutritional guidelines for GDM in light of our understanding of the pathophysiological mechanisms of GDM and LGA offspring. Lifestyle modification is first line treatment for GDM, and while there is some promise that nutritional interventions may favourably impact outcomes, there is a lack of definitive evidence that changing the macronutrient composition of the diet reduces the incidence of either GDM or LGA offspring. The quality of the available evidence is a major issue, and rigorous trials are needed to inform evidence-based treatment guidelines.

Diagnostic utility of faecal biomarkers in patients with irritable bowel syndrome

Irritable bowel syndrome(IBS)is a common functional gastrointestinal(GI)disorder characterized by unspecific symptoms.In clinical practice it is crucial to distinguish between non-inflammatory functional problems and inflammatory,malignant or infectious diseases of the GI tract.Differentiation between these involves the use of clinical,radiological,endoscopic,histological and serological techniques,which are invasive,expensive,time-consuming and/or hindered by inaccuracies arising from subjective components.A range of faecal markers now appears to have the potential to greatly assist in the differentiation of inflammatory bowel disease(IBD)and IBS.Faecal markers of neutrophil influx into the mucosa are reliable indicators of intestinal inflammation and their role has been mainly studied in discriminating IBD from non-IBD conditions(including IBS)rather than organic from non-organic diseases.Phagocytespecific proteins of the S100 family(S100A12,calprotectin)are amongst the most promising faecal biomarkers of inflammation.Faecal leukocyte degranulation markers(lactoferrin,polymorphonuclear elastase and myeloperoxidase)have also been suggested as diagnostic tools for the differentiation of IBD and IBS.More recently,additional proteins,including granins,defensins and matrix-metalloproteases,have been discussed as differential diagnostic markers in IBD and IBS.In this review,some of the most promising faecal markers,which have the potential to differentiate IBD and IBS and to advance diagnostic practices,will be discussed.

Associations between Bodyweight and Clinical Outcome in Patients Post-Fontan Procedure: A Systematic Review

Background: Patients born with a single ventricle circulation commonly experience growth failure in early life,which is associated with adverse outcomes in infancy. However, associations between bodyweight or weight trajectoryand clinical outcome post-Fontan procedure are yet to be determined. Methods: On the 1st of July 2021, asystematic review was performed in MEDLINE, EMBASE, the Cochrane Library, and Scopus of studies of patientswith clinical outcome data post-Fontan procedure and association with bodyweight. Quality of studies was evaluatedby Newcastle–Ottawa scale for cohort studies and Joanna Briggs Institute tool for cross-sectional studies.Results: Of 527 studies that underwent title and abstract screening, 15 were selected for final review. An increasedrisk of adverse post-Fontan outcomes was found for low weight patients, consistent with findings in infants.Whilst there is some evidence to suggest increased mortality in overweight adult patients, studies are conflictingas to whether overweight status is associated with increased heart failure. Increased BMI is associated with diminishedexercise capacity and deceased physiological functioning. Negative weight trajectory is associated withadverse outcomes in the peri-Fontan period, whereas a positive weight trajectory is associated with increased Fontanfailure in adulthood. Abnormal BMI (high or low) is associated with increased heart failure and poorer performancein quality-of-life scores. Conclusions: Bodyweight is a modifiable risk factor for poor clinical outcomein patients with a single ventricle circulation. Recognizing associations between bodyweight and Fontan pathophysiologymay help to define patient-centered exercise and diet interventions that minimize patient morbidityand mortality.

CTLA4 protects against maladaptive cytotoxicity during the differentiation of effector and follicular CD4^(+)T cells

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects.CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation.Indeed,while circulating CD57^(+)CD4^(+)T cells are normally rare,we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade.We performed single-cell RNA-seq analysis of matched CD57^(+)CD4^(+)T cells from blood and tonsil samples.Circulating CD57^(+)CD4^(+)T cells(CD4cyt)exhibited a cytotoxic transcriptome similar to that of CD8^(+)effector cells,could kill B cells,and inhibited B-cell responses.CTLA4 restrained the formation of CD4cyt.While CD57 also marked an abundant subset of follicular helper T cells,which is consistent with their antigen-driven differentiation,this subset had a preexhaustion transcriptomic signature marked by TCF7,TOX,and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition.Thus,CD57^(+)CD4^(+)T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers.CTLA4 is a key modifier of CD4^(+)T-cell cytotoxicity,and the pathological CD4cyt phenotype is accentuated by infection.

Absence of human papillomavirus in nasopharyngeal swabs from infants in a population at high risk of human papillomavirus infection

Maternal urogenital human papillomavirus(HPV)infection may place neonates at risk of HPV acquisition and subsequently lower respiratory infections as HPV can influence development of immunity.The respiratory HPV prevalence is not known in remote-dwelling Aboriginal infants,who are at high risk of respiratory infection and where the population prevalence of urogenital HPV in women is high.These data are necessary to inform HPV vaccination regimens.A retrospective analysis using PCR specific for HPV was performed on 64 stored nasopharyngeal swabs from remote-dwelling Aboriginal infants<6 months of age,with and without hospitalised pneumonia.HPV DNA was not detected in any specimen.Despite the negative result,we cannot exclude a role for HPV in respiratory infections affecting infants in this population;however,our data do not support HPV as an important contributor to acute respiratory infection in remote-dwelling Aboriginal children.

Neonatal neuroimaging after repair of congenital diaphragmatic hernia and long-term neurodevelopmental outcome

Objective Previous outcome reports of congenital diaphragmatic hernia(CDH)have described neuroimaging anomalies and neurodevelopmental impairment.However,the link between imaging and outcome has not been described.We aimed to determine whether routine postoperative neonatal neuroimaging in infants with CDH detects later neurodevelopmental impairment.Methods In a prospective cohort study within a clinical service in The Royal Children’s Hospital Newborn Intensive Care.Cerebral ultrasound was performed in 81 children and MRI in 57 children who subsequently underwent neurodevelopmental follow-up after surgery for CDH.MRI scans were analyzed using a scoring system designed to identify injury,maturation and volume loss.Neurodevelopmental assessment occurred at 2 years(48)and neurocognitive assessment at 5 years(26)and/or 8 years(27).Brain imaging scores corrected for gestational age at scan time were correlated with outcome measures,adjusting for known clinical confounders.results Clinically significant findings were identified on MRI of 16(28%)infants.Mean scores were in the normal range for all domains assessed at each age.Language impairment was seen in 23%at 2 years and verbal intellectual impairment in 25%at 8 years.Mean cognitive scores were lower in 2-year-old children with white matter injury on MRI(p=0.03).Mean motor scores were lower in 2-year-old children with brain immaturity(p=0.01).Associations between MRI and 5-year and 8-year assessments were no longer significant when adjusting for known clinical confounders.Conclusions Neuroimaging abnormalities were associated with worse neurodevelopment at 2 years,but not with later neurocognitive outcomes,after accounting for clinical risk factors.