Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (n=187) or enalapril (n=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.

Actomyosin-dependent cell contractility orchestrates Zika virus infection.

Emerging pathogen infections, such as Zika virus (ZIKV), pose an increasing threat to human health, but the role of mechanobiological attributes of host cells during ZIKV infection is largely unknown. Here, we reveal that ZIKV infection leads to increased contractility of host cells. Importantly, we investigated whether host cell contractility contributes to ZIKV infection efficacy, from both the intracellular and extracellular perspective. By performing drug perturbation and gene editing experiments, we confirmed that disruption of contractile actomyosin compromises ZIKV infection efficiency, viral genome replication and viral particle production. By culturing on compliant matrix, we further demonstrate that a softer substrate, leading to less contractility of host cells, compromises ZIKV infection, which resembles the effects of disrupting intracellular actomyosin organization. Together, our work provides evidence to support a positive correlation between host cell contractility and ZIKV infection efficacy, thus unveiling an unprecedented layer of interplay between ZIKV and the host cell.

Postoperative EEG abnormalities in relation to neurodevelopmental outcomes after pediatric cardiac surgery.

BACKGROUND: We had reported that postoperative EEG background including sleep-wake cycle (SWC) and discharge (seizures, spikes/sharp waves) abnormalities were significantly correlated with adverse early outcomes in children after cardiac surgery. We aimed to analyze the relations between these EEG abnormalities and neurodevelopmental outcomes at about 2 years after cardiac surgery. METHODS: We enrolled 121 patients undergoing cardiac surgery at 3.3 months (0.03 ~ 28 months). EEG abnormalities described above during the first postoperative 48 h were evaluated. Griffiths Mental Development Scales-Chinese was used to evaluate the quotients of overall development and 5 subscales of the child's locomotor, language, personal-social, eye-hand coordination and performance skills at 16 ~ 31 months of age. RESULTS: EEG background abnormalities occurred in 59/121 (48.8%) patients and 33 (55.9%) unrecovered to normal by 48 h. Abnormal SWC occurred in 15 (12.4%) patients and 7 (5.8%) unrecovered to normal by 48 h. EEG seizures occurred in 11 (9.1%) patients with frontal lobe seizures in 4. Spikes/sharp waves occurred in 100 (82.6%). EEG background abnormalities, number of spikes/sharp waves and frontal lobe seizures were significantly associated with neurodevelopmental impairment at about 1 ~ 2 year after surgery (Ps ≤ 0.05). CONCLUSIONS: Most parameters of EEG abnormalities were significantly associated with neurodevelopmental impairment after cardiac surgery. IMPACT: Neurodevelopmental impairment in children with congenital heart disease remain poorly understood. Previous studies had reported that either EEG seizures or background abnormalities were associated with worse neurodevelopmental outcomes. Our present study showed that all the EEG background and discharge abnormalities including EEG background, seizures and spikes/sharp waves in the early postoperative period were significantly associated with neurodevelopmental impairment at about 1 ~ 2 years after cardiac surgery. Comprehensive evaluation of early postoperative EEG may provide further insights about postoperative brain injury, its relation with neurodevelopmental impairment, and guide to improve clinical management.

Perioperative EEG background and discharge abnormalities in children undergoing cardiac surgery: a prospective single-centre observational study.

BACKGROUND: We analysed the characteristics of abnormal electroencephalogram (EEG) patterns before, during, and 48 h after cardiac surgery in patients with heterogeneous congenital heart disease to assess their relationship to demographic and perioperative variables and to early patient outcomes. METHODS: In 437 patients enrolled in a single centre, EEG was evaluated for background (including sleep-wake cycle) and discharge (seizures, spikes/sharp waves, pathological delta brushes) abnormalities. Clinical data (arterial blood pressure, doses of inotropic drugs, and serum lactate concentrations) were recorded every 3 h. Postoperative brain MRI was performed before discharge. RESULTS: Preoperative, intraoperative, and postoperative EEG was monitored in 139, 215, and 437 patients, respectively. Patients with a degree of preoperative background abnormalities (n=40) had more severe intraoperative and postoperative EEG abnormalities (P<0.0001). Intraoperatively, 106/215 (49.3%) patients progressed into an isoelectric EEG. Longer durations of isoelectric EEG were associated with more severe postoperative EEG abnormalities and brain injury on MRI (Ps≤0.003). Postoperative background abnormalities occurred in 218/437 (49.9%) patients, and 119 (54.6%) of them had not recovered after surgery. Seizures occurred in 36/437 (8.2%) patients, spikes/sharp waves in 359/437 (82.2%), and pathological delta brushes in 9/437 (2.0%). Postoperative EEG abnormalities correlated with degree of brain injury on MRI (Ps≤0.02). Demographic and perioperative variables were significantly correlated with postoperative EEG abnormalities, which in turn correlated with adverse clinical outcomes. CONCLUSIONS: Perioperative EEG abnormalities occurred frequently and correlated with numerous demographic and perioperative variables and adversely correlated with postoperative EEG abnormalities and early outcomes. The relation of EEG background and discharge abnormalities with long-term neurodevelopmental outcomes remains to be explored.

Reliability and validity of the FFQ and feeding index for 7-to 24-month-old children after congenital heart disease surgery.

BACKGROUND: Congenital heart disease (CHD) is the most common congenital defect in neonates. Infants with CHD often have more nutritional difficulties, but currently, there is no unified Food Frequency Questionnaire (FFQ) for infants and young children aged 7-24 months in China. Therefore, we designed this study to assess the reliability and validity of the FFQ and feeding index for 7-to 24-month-old children after congenital heart disease surgery. METHODS: From July to October 2018, infants and young children aged 7-24 months after congenital heart disease surgery in Guangzhou were selected. Participants were categorized into two groups, in the first group (n = 95), the FFQ was completed twice at intervals of 7-10 days to assess reproducibility. In the second group (n = 98), participants accomplished both the FFQ and the 24-h diet records from 3 consecutive days to assess validity. The score of the Infant and Child Feeding Index (ICFI) and its qualified rate were caculated. Intraclass correlation coefficients (ICC) and Spearman correlation coefficient (SCC) were calculated for reliability and validity, respectively. RESULTS: The average intraclass correlation coefficients and spearman correlation coefficient of the FFQ were 0.536 and 0.318, all with statistical significance except the frequency of meat added. The ICFI of the first group was 8.61 (± 3.20), the qualified rate was 0.06% (6/95). The intraclass correlation coefficients of the ICFI ranged from 0.374 to 0.958; and the spearman correlation of the ICFI was -0.066 to -0.834. CONCLUSIONS: The FFQ possesses satisfactory reliability and moderate validity. The reliability of the ICFI is acceptable, but the validity results are quite different, indicating that the questionnaire is limited in the evaluation of the ICFI.

Extracorporeal membrane oxygenation for congenital diaphragmatic hernia: how to begin?

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is critical for congenital diaphragmatic hernia (CDH), who fails to achieve adequate oxygenation with conventional management. We aim to evaluate initial experiences with ECMO support in a tertiary women and children's medical center in mainland China. METHODS: We retrospectively reviewed the establishment of ECMO for CDH Program in our center and analysis of five CDH neonates, who underwent repair during ECMO between December 2016 and December 2018. RESULTS: The first ECMO for CDH Program in our institution was established and managed by a multidisciplinary team since December 2016. An alert of ECMO was prenatally created for moderate-severe pulmonary hypoplasia. Of sixteen admissions prenatally diagnosed moderate-severe CDH, eight neonates (50%) required ECMO but five (31%) received eventually. Veno-arterial ECMO was established from 3 hours to 41 hours of age (median 20 h). All the five underwent CDH repair after a stabilization period on ECMO, which ranged from 12 h to 122 h (median 58 h). There were no clotting complications, related to coagulating during CDH repair. Bleeding was the most common complication. Cannula malposition was detected in one case. Their median ECMO duration was 437 (range 85-946) hours. Neonatal survival was 80% (4/5) and 3 survived (60%) in the first three months of life. CONCLUSIONS: Multidisciplinary team work, precise prenatal evaluation and skillful cannulation assist the successful beginning of ECMO for CDH. Our preliminary results would encourage other institutions, whose ECMO is not well-established.

Prognostic value of perioperative NT-proBNP after corrective surgery for pediatric congenital heart defects.

BACKGROUND: It is critically important to assess the prognostic value of NT-proBNP in the form of repeated measures among children undergoing surgery for congenital heart defects (CHD). The aim of the present study is to assess the value of repeated perioperative NT-proBNP in evaluating the time dependent and temporal trajectory in prognostics diagnosis during the perioperative period in a large series of children with CHD. METHODS: Repeated measures of NT-proBNP from 329 consecutive children with CHD were obtained before and 1, 12, and 36 h after surgery, respectively. For fully utilizing longitudinal characteristics, we employed parallel cross-sectional logistic regression, a two stage mixed effect model and trajectories over time analysis to mine the predictive value of perioperative NT-proBNP on the binary outcome of prolonged intensive care unit (ICU) stay. RESULTS: The two stage mixed effects model confirmed that both the mean NT-proBNP level (aOR = 1.46, P = 0.001) and the time trends had prognostic value on the prediction of prolonged ICU stay. In the fully adjusted logistic regression analyses based on gaussian distributions, "rapidly rising NT-proBNP" put the subjects at 5.4-times higher risk of prolonged ICU stay compared with "slowly rising" group (aOR = 5.40, P = 0.003). CONCLUSIONS: Comprehensive assessment of the time dependent and temporal trajectory in perioperative NT-proBNP, indicated by repeated measurements, can provide more accurate identification of children with higher risk of prolonged ICU stay after CHD surgery.

Early and mid-term results of the arterial switch operation in patients with intramural coronary artery.

Intramural coronary artery is known to be a risk factor for early death after an arterial switch operation (ASO). We evaluated the early and mid-term results of ASO for patients with intramural coronary artery. From September 2008 to March 2012, seven patients with an intramural coronary artery underwent ASO at our hospital. The mean age at operation was 2.4 months (2 days-1 year), and the mean body weight was 4.3 ± 2.2 kg. The mean follow-up was 35.3 ± 16.5 months (22-63 months). The individual coronary button technique was used in seven patients. The intramural segment was unroofed in one patient; in one patient with myocardial ischemia, the intramural segment was unroofed and enlarged using a patch of autologous pericardium. There was one operative death because of low cardiac output syndrome (14.2% mortality). In the same time period at our hospital, three deaths were reported in 68 ASO patients (4.4% mortality) without an intramural coronary artery. There was no statistical difference between the two groups (P > 0.05). There were no late deaths, and no patients required a coronary intervention. Intramural coronary artery is a well-known risk factor for early death after ASO. To optimize results, the coronary transfer technique should be tailored to each patient's particular anatomy. Intraoperative or postoperative myocardial ischemia should be addressed aggressively by immediately reimplanting the coronary artery. Unroofing the intramural segment, even the distal portion, should restore normal coronary blood flow.

[Surgical treatment of congenital vascular ring].

OBJECTIVE: To discuss the diagnosis and surgical treatment of congenital vascular ring and prognostic factors. METHODS: The clinic data of 42 cases of congenital vascular from January 2010 to December 2013 was analyzed retrospectively (accounting for 1.04% congenital heart operations over the same period ). There were 26 male and 16 female patients, aged at surgery 24 days to 6 years (average 10.7 months). The diagnosis including pulmonary artery sling in 26 cases, double aortic arch in 10 cases, right aortic arch with aberrant left subclavian artery in 3 cases, pulmonary artery sling and right aortic arch with vagus left subclavian artery in 2 cases, pulmonary artery sling and left aortic arch with vagus right subclavian artery in 1 case. In addition to 4 cases the remaining 38 patients were still combined with other cardiovascular malformations. Thirty-six cases of children underwent spiral CT airway remodeling, 23 children underwent fiber- bronchoscopy. In addition to 2 cases of airway abnormalities not seen, the rest of the children were present in varying degrees in different parts of tracheal stenosis or tracheomalacia. All patients underwent surgical correction of congenital vascular ring, concomitant heart deformity correction surgery according to the situation (7 cases of atrial septal defect repair, 3 of ventricular septal defect repair, 1 of mitral valvuloplasty, 1 of bi-Glenn, 1 of coarctation of the aorta correction with ventricular septal defect repair, 1 of trilogy of Fallot correction). One case suffered resection of tracheal stenosis and Slide tracheoplasty simultaneously, another case was implanted tracheal stenting postoperatively after pulmonary artery sling correction. RESULTS: Three patients died in hospital (7.1%), the cause of death were recurrent granuloma formation postoperatively. Remaining 39 patients were successfully discharged. The median time of overall survival of children with mechanical ventilation was 14 h (22 h) (M (Q(R))), median ICU residence time was 5 d (8 d), and the median in-hospital time was 19 d (9 d). Tracheal intubation time and postoperative ICU duration time in children with pulmonary artery sling children were much more than in children with double aortic arch (23 h (123 h) vs. 9 h(9 h), 7 d (13 d) vs. 4 d (2 d)), but the difference were not statistically significant. There was significant difference in the duration of hospitalization between the patient with the pulmonary artery sling and double aortic arch (23 d (9 d) vs. 16 d(6 d)) (χ(2) = 10.157, P = 0.006). CONCLUSIONS: The recent results of surgical treatment of congenital vascular ring is safe and effective. The extent and scope of tracheal stenosis and tracheomalacia is a critical influence prognosis.

Salmonella effector SopB reorganizes cytoskeletal vimentin to maintain replication vacuoles for efficient infection.

A variety of intracellular bacteria modulate the host cytoskeleton to establish subcellular niches for replication. However, the role of intermediate filaments, which are crucial for mechanical strength and resilience of the cell, and in bacterial vacuole preservation remains unclear. Here, we show that Salmonella effector SopB reorganizes the vimentin network to form cage-like structures that surround Salmonella-containing vacuoles (SCVs). Genetic removal of vimentin markedly disrupts SCV organization, significantly reduces bacterial replication and cell death. Mechanistically, SopB uses its N-terminal Cdc42-binding domain to interact with and activate Cdc42 GTPase, which in turn recruits vimentin around SCVs. A high-content imaging-based screening identified that MEK1/2 inhibition led to vimentin dispersion. Our work therefore elucidates the signaling axis SopB-Cdc42-MEK1/2 as mobilizing host vimentin to maintain concrete SCVs and identifies a mechanism contributing to Salmonella replication. Importantly, Trametinib, a clinically-approved MEK1/2 inhibitor identified in the screen, displayed significant anti-infection efficacy against Salmonella both in vitro and in vivo, and may provide a therapeutic option for treating drug-tolerant salmonellosis.

Cerebral Autoregulation Status in Relation to Brain Injury on Electroencephalogram and Magnetic Resonance Imaging in Children Following Cardiac Surgery.

Background Disturbed cerebral autoregulation has been reported in children with congenital heart disease before and during cardiopulmonary bypass surgery, but not after. We sought to characterize the cerebral autoregulation status in the early postoperative period in relation to perioperative variables and brain injuries. Methods and Results A prospective and observational study was conducted in 80 patients in the first 48 hours following cardiac surgery. Cerebral oximetry/pressure index (COPI) was retrospectively calculated as a moving linear correlation coefficient between mean arterial blood pressure and cerebral oxygen saturation. Disturbed autoregulation was defined as COPI >0.3. Correlations of COPI with demographic and perioperative variables as well as brain injuries on electroencephalogram and magnetic resonance imaging and early outcomes were analyzed. Thirty-six (45%) patients had periods of abnormal COPI for 7.81 hours (3.38 hours) either at hypotension (median <45 mm Hg) or hypertension (median >90 mm Hg) or both. Overall, COPI became significantly lower over time, suggesting improved autoregulatory status during the 48 postoperative hours. All of the demographic and perioperative variables were significantly associated with COPI, which in turn was associated with the degree of brain injuries and early outcomes. Conclusions Children with congenital heart disease following cardiac surgery often have disturbed autoregulation. Cerebral autoregulation is at least partly the underlying mechanism of brain injury in those children. Careful clinical management to manipulate the related and modifiable factors, particularly arterial blood pressure, may help to maintain adequate cerebral perfusion and reduce brain injury early after cardiopulmonary bypass surgery. Further studies are warranted to determine the significance of impaired cerebral autoregulation in relation to long-term neurodevelopment outcomes.

Postoperative hypernatremia is associated with worse brain injuries on EEG and MRI following pediatric cardiac surgery.

Objectives: Dysnatremia is a common electrolyte disturbance after cardiopulmonary bypass (CPB) surgery for congenital heart disease (CHD) and a known risk factor for adverse neurological events and clinical outcomes. The objective of this study was to evaluate the association of dysnatremia with worse abnormal EEG patterns, brain injuries detected by magnetic resonance imaging (MRI) and early adverse outcomes. Methods: We monitored continuous EEG in 340 children during the initial 48 h following cardiac surgery. Demographics and clinical characteristics were recorded. Sodium concentrations were measured in the arterial blood gas analysis every 6 h. Hyponatremia and hypernatremia were classified by the average of sodium concentrations over 48 h. Postoperative cerebral MRI was performed before hospital discharge. Results: In our patient cohort, dysnatremia was present in 46 (13.5%) patients. Among them, hyponatremia occurred in 21 (6.2%) and hypernatremia in 25 (7.4%). When compared to patients with normonatremia, hyponatremia was not associated with EEG abnormalities and early adverse outcomes (Ps ≥ .14). In hypernatremia group, the CPB time was significantly longer and more frequent use of DHCA (Ps ≤ .049). After adjusting for time, CPB time and the use of DHCA, hypernatremia was significantly associated with worse EEG abnormalities (including background, seizures and pathological delta brushes), more severe brain injuries on MRI (Ps ≤ .04) and trended to be associated with longer postoperative mechanical ventilation time (P = .06). Conclusion: Hypernatremia and hyponatremia were common in children after cardiac surgery. Hypernatremia, but not hyponatremia, was significantly associated with worse EEG abnormalities and more severe brain injuries on MRI and extended postoperative mechanical ventilation time.

Is the six-minute walk test still reliable compared to cardiopulmonary exercise test for exercise capacity in children with congenital heart disease?

Objectives: We aimed to assess the validity of the six-minute walk test (6MWT) to reflect the functional capacity of children with congenital heart disease (CHD), evaluate a possible correlation between the 6MWT distance with cardiopulmonary exercise test (CPET) variables, as well as to find a cutoff value to stratification the physical fitness in this population. Methods: We enrolled 459 children with CHD, 6-18 years old, who performed a complete CPET and 6MWT on the same day in a cross-sectional observational study. Correlations between variables of CPET and six-minute walking distance (6MWD) were analyzed and cutoff values of 6MWD were identified for the classification of the physical fitness in the population. Results: The mean distance ambulated during the 6MWT was 578 ± 65 m, 590 ± 65 m for boys, and 562 ± 62 m for girls (p < 0.001). Both VO2max and %predicted VO2max showed a correlation with the 6MWT distance (r = 0.35, p < 0.001 and r = 0.51, p < 0.001, respectively), and an inverse correlation was found between VE/VCO2 slope and the 6MWT distance (r = -0.31; p < 0.001). There appeared to be a linear association between 6MWD and VO2max up to a 6MWD of approximately 600 m. We divided the population into 4 subgroups (boys <130 cm; boys ≥130 cm; girls <130 cm; girls ≥130 cm), and get the cutoff values (554 m, 617 m, 549 m, 587 m) respectively equivalent to 80% of predicted VO2max. The 6MWT distances of another 102 patients were applied for external verification of the cutoff values. Conclusions: Our study provided evidence on when a 6MWT should be considered as a convincing complementary test in the pediatric population with CHD and explored the classification of exercise tolerance using a 6MWD value. The cut-off values for 6MWD may be qualified as an intervention target for exercise rehabilitation.

Explainable machine learning model for predicting the occurrence of postoperative malnutrition in children with congenital heart disease.

BACKGROUND & AIMS: Malnutrition is persistent in 50%-75% of children with congenital heart disease (CHD) after surgery, and early prediction is crucial for nutritional intervention. The aim of this study was to develop and validate machine learning (ML) models to predict the malnutrition status of children with CHD. We used explainable ML methods to provide insight into the model's predictions and outcomes. METHODS: This prospective cohort study included consecutive children with CHD admitted to the hospital from December 2017 to May 2020. The cohort data were divided into the training and test data sets based on the follow-up time. The outcome of the study was CHD child malnutrition 1 year after surgery, the primary outcome was an underweight status, and the secondary outcomes were stunted and wasting status. We used five ML algorithms with multiple features to construct prediction models, and the performance of these ML models was measured by an area under the receiver operating characteristic curve (AUC) analysis. We also used the permutation importance and SHapley Additive exPlanations (SHAP) to determine the importance of the selected features and interpret the ML models. RESULTS: We enrolled 536 children with CHD who underwent complete repair. The proportions of children with an underweight, stunted, or wasting status 1 year after surgery were 18.1% (97/536), 12.1% (65/536), and 17.5% (94/536), respectively. All patients contributed to the generation of 115 useable features, which allowed us to build models to predict malnutrition. Five prediction algorithms were used, and the XGBoost model achieved the greatest AUC in all outcomes. The results obtained from the permutation importance and SHAP analyses showed that the 1-month postoperative WAZ-score, discharge WAZ score and preoperative WAZ score were the top 3 important features in predicting an underweight status in the XGBoost algorithm. Regarding the stunted status, the top 3 important features were the 1-month postoperative HAZ score, discharge HAZ score, and aortic clamping time. Regarding the wasting status, the top 3 important features were the hospital length of stay, formula intake, and discharge WHZ-score. We also used a narrative case report as an example to describe the clinical manifestations and predicted the primary outcomes of two children. CONCLUSIONS: We developed an ML model (XGBoost) that provides accurate early predictions of malnutrition 1-year postoperatively in children with CHD. Because the ML model is explainable, it may better enable clinicians to better understand the reasoning underlying the outcome. Our study could aid in determining individual treatment and nutritional follow-up strategies for children with CHD.

Actin nucleator formins regulate the tension-buffering function of caveolin-1.

Both the mechanosensitive actin cytoskeleton and caveolae contribute to active processes such as cell migration, morphogenesis, and vesicular trafficking. Although distinct actin components are well studied, how they contribute to cytoplasmic caveolae, especially in the context of mechano-stress, has remained elusive. Here, we identify two actin-associated mobility stereotypes of caveolin-1 (CAV-1)-marked intracellular vesicles, which are characterized as 'dwelling' and 'go and dwelling'. In order to exploit the reason for their distinct dynamics, elongated actin-associated formin functions are perturbed. We find drastically decreased density, increased clustering, and compromised motility of cytoplasmic CAV-1 vesicles resulting from lacking actin nucleator formins by both chemical treatment and RNA silencing of formin genes. Furthermore, hypo-osmosis-stimulated diminishing of CAV-1 is dramatically intensified upon blocking formins. The clustering of CAV-1 vesicles when cells are cultured on soft substrate is also aggravated under formin inhibition condition. Together, we reveal that actin-associated formins are essential for maintaining the dynamic organization of cytoplasmic CAV-1 and importantly its sensitivity upon mechanical challenge. We conclude that tension-controlled actin formins act as a safety valve dampening excessive tension on CAV-1 and safeguarding CAV-1 against mechanical damage.

Optimal Frequency for Changing Single-Use Enteral Delivery Sets in Infants after Congenital Heart Surgery: A Randomized Controlled Trial.

Objective We aimed to assess the optimal frequency for changing single-use enteral delivery sets during postoperative enteral feeding in infants with congenital heart disease (CHD).Methods We enrolled 120 CHD infants who were fed using an enteral nutrition pump directly connected to a milk bottle with a single-use enteral delivery set in a four-arm randomized controlled trial (ChiCTR2000039544). Patients were randomized into four groups based on the replacement frequency of the enteral delivery set (6 h, 12 h, 18 h, and 24 h groups). The primary outcome was the percentage of contaminated enteral delivery sets (overgrowth of microbiota and colonization of pathogenic bacteria). Secondary outcomes included evidence of infection, gastrointestinal tolerance, intestinal microflora dysbiosis, and healthcare costs.Results The percentages of microbial overgrowth detected in the 6 h, 12 h, 18 h, and 24 h groups were 6.7%, 30.0%, 46.7%, and 80%, respectively (P < 0.001). Significant differences were observed between the 6 h and 18 h groups (P < 0.001), the 6 h and 24 h groups (P < 0.001), and the 18 h and 24 h groups (P = 0.007). Meanwhile, pathogenic bacterial colonization was detected in 0, 4, 6, and 11 delivery sets in the 6 h, 12 h, 18 h, and 24 h groups, respectively (P = 0.002). No difference in clinical symptoms was found among the four groups. The total cost per patient in the 12 h group and the 18 h group was 340.2 RMB and 226.8 RMB, respectively.Conclusion Taking into consideration both microbial overgrowth and cost-effectiveness, the results of this study indicate that for children receiving continuous enteral feeding following CHD surgery, the optimal frequency for changing the single-use enteral delivery set when formula reconstituted from powder is used is 18 hours.

Ultra-high pressure balloon angioplasty for pulmonary artery stenosis in children with congenital heart defects: Short- to mid-term follow-up results from a retrospective cohort in a single tertiary center.

Objective: Balloon angioplasty (BA) has been the treatment of choice for pulmonary artery stenosis (PAS) in children. There remains, however, a significant proportion of resistant lesions. The ultra-high pressure (UHP) balloons might be effective in a subset of these lesions. In this study, we analyzed the safety and efficacy with short- to mid-term follow-up results of UHP BA for PAS in children with congenital heart defects (CHD) in our center. Methods: This is a retrospective cohort study in a single tertiary heart center. Children diagnosed with PAS associated with CHD were referred for UHP BA. All data with these children were collected for analysis with updated follow-up. Results: A total of 37 UHP BAs were performed consecutively in 28 children. The success rate was 78.4%. A significantly (P = 0.005) larger ratio of the balloon to the minimal luminal diameter at the stenotic waist (balloon/waist ratio) was present in the success group (median 3.00, 1.64-8.33) compared to that in the failure group (median 1.94, 1.41 ± 4.00). Stepwise logistic regression analysis further identified that the balloon/waist ratio and the presence of therapeutic tears were two independent predictors of procedural success. The receiver operating characteristic curve revealed a cut-off value of 2.57 for the balloon/waist ratio to best differentiate success from failure cases. Signs of therapeutic tears were present in eight cases, all of whom were in the success group. Perioperative acute adverse events were recorded in 16 patients, including 11 pulmonary artery injuries, three pulmonary hemorrhages, and two pulmonary artery aneurysms. During a median follow-up period of 10.4 (0.1-21.0) months, nine cases experienced restenosis at a median time of 40 (4-325) days after angioplasty. Conclusions: The UHP BA is safe and effective for the primary treatment of PAS in infants and children with CHD. The success rate is high with a low incidence of severe complications. The predictors of success are a larger balloon/waist ratio and the presence of therapeutic tears. The occurrence of restenosis during follow-up, however, remains a problem. A larger number of cases and longer periods of follow-up are needed for further study.

Value of Follow-Up N-Terminal Probrain Natriuretic Peptide (NT-proBNP) after a Modified Fontan Procedure.

OBJECTIVE: To assess the value of N-terminal probrain natriuretic peptide (NT-proBNP) in short-term and long-term follow-up after a modified Fontan procedure. METHODS: We retrospectively enrolled children who had undergone a modified Fontan procedure in the Heart Center of Guangzhou Women and Children's Medical Center from January 2014 to September 2020 and collected data on NT-proBNP values before bidirectional Glenn procedure, before Fontan procedure, and on 1, 3, 7, 30, 90, and 180 days and 1, 2, 3, 4, 5, and 6 year after Fontan procedure. The relationship between changes in NT-proBNP levels and the outcomes in children was analyzed. RESULTS: A total of 108 children (78 boys and 30 girls, mean age: 54.62 ± 29.38 weeks) were included in the analysis. According to one-way analysis of variance, the left ventricular type and biventricular type of single ventricle physiology showed shorter duration on cardiopulmonary bypass during the operation and lower levels of NT-proBNP after the operation than the right ventricular type and univentricular type physiology. CONCLUSION: NT-proBNP is a good indicator for mid and long-term follow-up after a modified Fontan procedure. The left ventricular type and biventricular type of single ventricle physiology show better mid and long-term benefits from the modified Fontan procedure than the right ventricular type and univentricular type physiology.

Assessment of Energy and Protein Requirements in Relation to Nitrogen Kinetics, Nutrition, and Clinical Outcomes in Infants Receiving Early Enteral Nutrition Following Cardiopulmonary Bypass.

BACKGROUND: Nutrition therapies in children with congenital heart disease (CHD) after cardiopulmonary bypass (CPB) is crucial, but energy and protein requirements remain undefined. We assessed energy and protein requirements, with nitrogen kinetics and clinical outcomes, in infants with complex CHD following CPB. METHODS: Infants were randomized to control (1.3 g/kg/d), moderate protein (MP, 2.5 g/kg/d), or high protein (HP, 4 g/kg/d) groups. Resting energy expenditure (REE) was measured 6 hours post-CPB and then at 24-hour intervals, using indirect calorimetry to formulate energy intakes. Enteral formula feeding was initiated 6 hours post-CPB and continued for 5 days. Nitrogen balance (NB); urea nitrogen waste and nitrogen retention; serum prealbumin level; and hepatic, renal, and cardiac function were measured daily. Mid-upper arm circumference and triceps skinfold were measured preoperatively and 5 days after CPB. Adverse outcomes (bacterial infection, reintubation, and cardiac intensive care unit (CICU) stay > 8 days) were recorded. RESULTS: REE was not different across the 3 groups (P = .37). It declined from 62 ± 6 to 57 ± 7 kcal/kg/d over 5 days post-CPB (P = .02). NB and nitrogen retention became positive by day 3 in the HP group but remained negative in the other 2 groups (P = .045-.003), despite higher urea nitrogen waste in the HP group (P < .0001). The HP group had a greater increase in serum prealbumin level and anthropometric measures (P = .009-.03). Other measures were not significantly different across the 3 groups. CONCLUSIONS: In infants with complex CHD in the first 5 days post-CPB, protein and energy intakes of ≈4 g/kg/d and 60 kcal/kg/d, respectively, led to improved nutrition outcomes without increased adverse events.

Multifaceted Function of Myosin-18, an Unconventional Class of the Myosin Superfamily.

Myosin is a diverse superfamily of motor proteins responsible for actin-based motility and contractility in eukaryotic cells. Myosin-18 family, including myosin-18A and myosin-18B, belongs to an unconventional class of myosin, which lacks ATPase motor activity, and the investigations on their functions and molecular mechanisms in vertebrate development and diseases have just been initiated in recent years. Myosin-18A is ubiquitously expressed in mammalian cells, whereas myosin-18B shows strong enrichment in striated muscles. Myosin-18 family is important for cell motility, sarcomere formation, and mechanosensing, mostly by interacting with other cytoskeletal proteins and cellular apparatus. Myosin-18A participates in several intracellular transport processes, such as Golgi trafficking, and has multiple roles in focal adhesions, stress fibers, and lamellipodia formation. Myosin-18B, on the other hand, participates in actomyosin alignment and sarcomere assembly, thus relating to cell migration and muscle contractility. Mutations of either Myo18a or Myo18b cause cardiac developmental defects in mouse, emphasizing their crucial role in muscle development and cardiac diseases. In this review, we revisit the discovery history of myosin-18s and summarize the evolving understanding of the molecular functions of myosin-18A and myosin-18B, with an emphasis on their separate yet closely related functions in cell motility and contraction. Moreover, we discuss the diseases tightly associated with myosin-18s, especially cardiovascular defects and cancer, as well as highlight the unanswered questions and potential future research perspectives on myosin-18s.