Transcatheter Palliation With Pulmonary Artery Flow Restrictors in Neonates With Congenital Heart Disease: Feasibility, Outcomes, and Comparison With a Historical Hybrid Stage 1 Cohort.

BACKGROUND: Neonates with complex congenital heart disease and pulmonary overcirculation have been historically treated surgically. However, subcohorts may benefit from less invasive procedures. Data on transcatheter palliation are limited. METHODS: We present our experience with pulmonary flow restrictors (PFRs) for palliation of neonates with congenital heart disease, including procedural feasibility, technical details, and outcomes. We then compared our subcohort of high-risk single ventricle neonates palliated with PFRs with a similar historical cohort who underwent a hybrid Stage 1. Cox regression was used to evaluate the association between palliation strategy and 6-month mortality. RESULTS: From 2021 to 2023, 17 patients (median age, 4 days; interquartile range [IQR], 2-8; median weight, 2.5 kilograms [IQR, 2.1-3.3]) underwent a PFR procedure; 15 (88%) had single ventricle physiology; 15 (88%) were high-risk surgical candidates. All procedures were technically successful. At a median follow-up of 6.2 months (IQR, 4.0-10.8), 13 patients (76%) were successfully bridged to surgery (median time since PFR procedure, 2.6 months [IQR, 1.1-4.4]; median weight, 4.9 kilograms [IQR, 3.4-5.8]). Pulmonary arteries grew adequately for age, and devices were easily removed without complications. The all-cause mortality rate before target surgery was 24% (n=4). Compared with the historical hybrid stage 1 cohort (n=23), after adjustment for main confounding (age, weight, intact/severely restrictive atrial septum or left ventricle to coronary fistulae), the PFR procedure was associated with a significantly lower all-cause 6-month mortality risk (adjusted hazard ratio, 0.26 [95% CI, 0.08-0.82]). CONCLUSIONS: Transcatheter palliation with PFR is feasible, safe, and represents an effective strategy for bridging high-risk neonates with congenital heart disease to surgical palliation, complete repair, or transplant while allowing for clinical stabilization and somatic growth.

Reduction of infant mortality from congenital heart defects in a middle-income country: Costa Rican experience.

BACKGROUND: We aimed to analyze recent infant and neonatal mortality from congenital heart defects (CHD) in Costa Rica, a middle-income country where CHD mortality was above expectations. METHODS: A descriptive analysis of infant and neonatal mortality rates from CHD (IMR-CHD and NMR-CHD) during 2000-2019 was performed, according to province, sex, specific CHD, and sub-period, using data from the National Institute of Statistics and Censuses. We used joinpoint regression to identify any calendar-year where a significant change in trend occurred; the average annual percent change (AAPC) was determined. Using Poisson regression, marginal means and mortality ratios (MR) for IMR-CHD and NMR-CHD by sub-period (2000-2006-referent-, 2007-2013, 2014-2019) were estimated and compared using Wald's chi-square tests (α ≤ .05). RESULTS: During 2000-2019, CHD accounted for 12% of overall infant mortality. IMR-CHD and NMR-CHD decreased linearly over the study period (AAPC = -3.4; p < .01). IMR-CHD decreased by 41%, from 13.6 per 10,000 in 2000-2006 (13.4% of infant mortality) to 8.1 per 10,000 in 2014-2019 (10% of infant mortality) (MR = 0.59; 95% confidence intervals [CI] = 0.52-0.68). NMR-CHD decreased by 38%, from 7.9 per 10,000 in 2000-2006 (11.1% of neonatal mortality) to 4.9 per 10,000 in 2014-2019 (7.9% of infant mortality) (MR = 0.59; 95% CI = 0.52-0.68). Male presented significantly higher NMR-CHD. The main causes of mortality (2014-2019) were total anomalous pulmonary venous connections, hypoplastic left heart syndrome, and double inlet ventricle. CONCLUSIONS: IMR-CHD, NMR-CHD, and their proportional contribution to mortality by all causes and by birth defects decreased significantly, demonstrating that all improvements implemented in the last decades have yielded favorable results.

Ameloblastoma Differential Radiographic Findings in Children and Adolescents

ABSTRACT: The aim of this research was to investigate the radiographic, clinical, and histological features of cases of ameloblastoma from a period of 17 years in a Brazilian center and to explore potential differences in children and adolescen ts in relation to adults. Seventy-five patients diagnosed with ameloblastoma from 2001 to 2018 were included. Data from each patient including gender, age, histologic type, location, and radiographic characteristics were reviewed and analyzed retrospectively. The association between the clinical, radiographic, and histologic findings was investigated. No differences regarding the histological pattern of the lesions were observed between groups. Children and adolescents presented well- defined lesions associated with an unerupted tooth compared to adults (p<0.05). The presence of an unerupted tooth was associated with cortical erosion and expansion and MC displacement (p<0.05). Despite similar histologic characteristics, differential radiographic appearance was observed between young patients and adults.

RESUMEN: El objetivo de este trabajo fue investigar las características radiográficas, clínicas e histológicas de casos de ameloblastoma en un período de 17 años, en un centro brasileño y explorar las posibles diferencias en niños y adolescentes en relación con los adultos. Se incluyeron 75 pacientes diagnosticados con ameloblastoma desde 2001 hasta 2018. Los datos de cada paciente, incluyendo el sexo, la edad, el tipo histológico, la ubicación y las características radiográficas, se revisaron y analizaron retrospectivamente. Se investigó la asociación entre los hallazgos clínicos, radiográficos e histológicos. No se observaron diferencias en cuanto al patrón histológico de las lesiones entre los grupos. Los niños y adolescentes presentaron lesiones bien definidas asociadas a un diente no erupcionado en comparación con los adultos (p<0,05). La presencia de un diente no erupcionado se asoció con erosión y expansión cortical y desplazamiento de MC (p<0,05). A pesar de las características histológicas similares, se observó una apariencia radiográfica diferente entre pacientes jóvenes y adultos.

Factors Associated With Initiation of Extracorporeal Cardiopulmonary Resuscitation in the Pediatric Population: An International Survey.

Although extracorporeal cardiopulmonary resuscitation (ECPR) is increasingly utilized in the pediatric critical care environment, our understanding regarding pediatric candidacy for ECPR remains unknown. Our objective is to explore current practice and indications for pediatric ECPR. Scenario-based, self-administered, online survey, evaluating clinical determinants that may impact pediatric ECPR initiation with respect to four scenarios: postoperative cardiac surgery, cardiac failure secondary to myocarditis, septic shock, and chronic respiratory failure in a former preterm child. Responders are pediatric critical care physicians from four societies. 249 physicians, mostly from North America, answered the survey. In cardiac scenarios, 40% of the responders would initiate ECPR, irrespective of CPR duration, compared with less than 20% in noncardiac scenarios. Nearly 33% of responders would consider ECPR if CPR duration was less than 60 minutes in noncardiac scenarios. Factors strongly decreasing the likelihood to initiate ECPR were out-of-hospital unwitnessed cardiac arrest and blood pH <6.60. Additional factors reducing this likelihood were multiple organ failure, pre-existing neurologic delay, >10 doses of adrenaline, poor CPR quality, and lactate >18 mmol/l. Pediatric intensive care unit location for cardiac arrest, good CPR quality, 24/7 in-house extracorporeal membrane oxygenation (ECMO) team moderately increase the likelihood of initiating ECPR. This international survey of pediatric ECPR initiation practices reveals significant differences regarding ECPR candidacy based on patient category, location of arrest, duration of CPR, witness status, and last blood pH. Further research identifying prognostic factors measurable before ECMO initiation should help define the optimal ECPR initiation strategy.

Primary Intraosseous Synovial Sarcoma in the Mandible.

Synovial sarcoma (SS) is a rare malignant mesenchymal tumor that mainly occurs in body extremities, being uncommon in the head and neck region. In the present study, we described a case of primary intraosseous SS arising in the mandible of a 22-year-old young male. The patient reported a painful swelling on the left side of the mandible for the last 7 months. Imaging exams showed the presence of an expansive and multilocular radiolucent lesion, extending from the left condyle to the mandibular body. The clinic diagnostic hypotheses were ameloblastoma or malignant neoplasm. Histologically, the lesion was characterized by a proliferation of spindle cells exhibiting vesicular nuclei and evident nucleolus. Neoplastic cells were positive for AE1/AE3, cytokeratin 7, vimentin, CD-99, and TLE-1 and negative for CD-34, S-100, SMA, and HHF-35. A combination of clinical, histologic, and immunohistochemical characteristics supported the diagnosis of SS. The patient was referred for treatment, and preoperative exams did not reveal any other tumor foci in the body of the patient. The final diagnosis was of a primary intraosseous SS of the mandible.

International Survey on the Use of Arginine Vasopressin in the Postoperative Management of Single Ventricle Patients.

Management of patients with single ventricle physiology after surgical palliation is challenging. Arginine vasopressin has gained popularity in recent years as a non-catecholamine vasoactive medication due to its unique properties. However, data regarding its use in the pediatric population is limited. Therefore, we designed a survey to explore whether and how clinicians use this medication in intensive care units for the postoperative management of single ventricle patients. This international survey aimed to assess usage, practices, and concepts related to arginine vasopressin in pediatric intensive care units worldwide. Directors of pediatric intensive care units who are members of the following international professional societies: European Society of Pediatric Neonatal Intensive Care, Association for European Pediatric and Congenital Cardiology, and Pediatric Cardiac Intensive Care Society were invited to participate in this survey. Of the 62 intensive care unit directors who responded, nearly half use arginine vasopressin in the postoperative management of neonatal single ventricle patients, and 90% also use the drug in subsequent surgical palliation. The primary indications are vasoplegia, hemodynamic instability, and refractory shock, although it is still considered a second-line medication. Conceptual benefits include improved hemodynamics and end-organ perfusion and decreased incidence of low cardiac output syndrome. Those practitioners who do not use arginine vasopressin cite lack of availability, fear of potential adverse effects, unclear indication for use, and lack of evidence suggesting improved outcomes. Both users and non-users described increased myocardial afterload and extreme vasoconstriction as potential disadvantages of the medication. Despite the lack of conclusive data demonstrating enhanced clinical outcomes, our study found arginine vasopressin is used widely in the care of infants and children with single ventricle physiology after the first stage and subsequent palliative surgeries. While many intensive care units use this medication, few had protocols, offering an area for further growth and development.

Antifungal activity of ß-lapachone against azole-resistant Candida spp. and its aspects upon biofilm formation.

Aim: The purpose of this study was to assess the antifungal effect of ß-lapachone (ß-lap) on azole-resistant strains of Candida spp. in both planktonic and biofilm form. Materials & methods: The antifungal activity of ß-lap was evaluated by broth microdilution, flow cytometry and the comet assay. The cell viability of the biofilms was assessed using the MTT assay. Results: ß-lap showed antifungal activity against resistant strains of Candida spp. in planktonic form. In addition, ß-lap decreased the viability of mature biofilms and inhibited the formation of biofilms in vitro. Conclusion: ß-lap showed antifungal activity against Candida spp., suggesting that the compound can be utilized as an adjunct agent in the treatment of candidiasis.

Recommendations for hemodynamic monitoring for critically ill children-expert consensus statement issued by the cardiovascular dynamics section of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC).

BACKGROUND: Cardiovascular instability is common in critically ill children. There is a scarcity of published high-quality studies to develop meaningful evidence-based hemodynamic monitoring guidelines and hence, with the exception of management of shock, currently there are no published guidelines for hemodynamic monitoring in children. The European Society of Paediatric and Neonatal Intensive Care (ESPNIC) Cardiovascular Dynamics section aimed to provide expert consensus recommendations on hemodynamic monitoring in critically ill children. METHODS: Creation of a panel of experts in cardiovascular hemodynamic assessment and hemodynamic monitoring and review of relevant literature-a literature search was performed, and recommendations were developed through discussions managed following a Quaker-based consensus technique and evaluating appropriateness using a modified blind RAND/UCLA voting method. The AGREE statement was followed to prepare this document. RESULTS: Of 100 suggested recommendations across 12 subgroups concerning hemodynamic monitoring in critically ill children, 72 reached "strong agreement," 20 "weak agreement," and 2 had "no agreement." Six statements were considered as redundant after rephrasing of statements following the first round of voting. The agreed 72 recommendations were then coalesced into 36 detailing four key areas of hemodynamic monitoring in the main manuscript. Due to a lack of published evidence to develop evidence-based guidelines, most of the recommendations are based upon expert consensus. CONCLUSIONS: These expert consensus-based recommendations may be used to guide clinical practice for hemodynamic monitoring in critically ill children, and they may serve as a basis for highlighting gaps in the knowledge base to guide further research in hemodynamic monitoring.

International evidence-based guidelines on Point of Care Ultrasound (POCUS) for critically ill neonates and children issued by the POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC).

BACKGROUND: Point-of-care ultrasound (POCUS) is nowadays an essential tool in critical care. Its role seems more important in neonates and children where other monitoring techniques may be unavailable. POCUS Working Group of the European Society of Paediatric and Neonatal Intensive Care (ESPNIC) aimed to provide evidence-based clinical guidelines for the use of POCUS in critically ill neonates and children. METHODS: Creation of an international Euro-American panel of paediatric and neonatal intensivists expert in POCUS and systematic review of relevant literature. A literature search was performed, and the level of evidence was assessed according to a GRADE method. Recommendations were developed through discussions managed following a Quaker-based consensus technique and evaluating appropriateness using a modified blind RAND/UCLA voting method. AGREE statement was followed to prepare this document. RESULTS: Panellists agreed on 39 out of 41 recommendations for the use of cardiac, lung, vascular, cerebral and abdominal POCUS in critically ill neonates and children. Recommendations were mostly (28 out of 39) based on moderate quality of evidence (B and C). CONCLUSIONS: Evidence-based guidelines for the use of POCUS in critically ill neonates and children are now available. They will be useful to optimise the use of POCUS, training programs and further research, which are urgently needed given the weak quality of evidence available.

The Role of Echocardiography in Neonates and Pediatric Patients on Extracorporeal Membrane Oxygenation.

Indications for extracorporeal membrane oxygenation (ECMO) and extracorporeal cardiopulmonary resuscitation (ECPR) are expanding, and echocardiography is a tool of utmost importance to assess safety, effectiveness and readiness for circuit initiation and separation. Echocardiography is key to anticipating complications and improving outcomes. Understanding the patient's as well as the ECMO circuit's anatomy and physiology is crucial prior to any ECMO echocardiographic evaluation. It is also vital to acknowledge that the utility of echocardiography in ECMO patients is not limited to the evaluation of cardiac function, and that clinical decisions should not be made exclusively upon echocardiographic findings. Though echocardiography has specific indications and applications, it also has limitations, characterized as: prior to and during cannulation, throughout the ECMO run, upon separation and after separation from the circuit. The use of specific and consistent echocardiographic protocols for patients on ECMO is recommended.

Antiplatelet Effect of Ketorolac in Children After Congenital Cardiac Surgery.

BACKGROUND: Ketorolac is used for pediatric analgesia after surgery despite its known platelet inhibition via the arachidonic acid (AA) pathway. The degree of platelet inhibitory effect after cardiac surgery is not well characterized. Thromboelastography with platelet mapping (TEG-PM) is emerging as a frequently used test to evaluate platelet inhibition via the AA pathway. METHODS: Post hoc analysis of a data set collected in a prospective observational cohort study evaluating platelet inhibition in children after congenital heart surgery with cardiopulmonary bypass (CPB). Categorization into two groups: (1) received ketorolac and (2) did not receive ketorolac for analgesia after surgery. The TEG-PM was evaluated at two time points (prior to surgery and 12-48 hours after CPB). RESULTS: Fifty-three children were studied; mean age was 6.6 (range: 0.07-16.7) years and 45% (n = 24) were female. Participants were distributed into two groups by ketorolac use, 41 within the ketorolac group and 12 in the no ketorolac group. All 41 participants who received ketorolac had platelet inhibition and 11 (91.7%) of 12 participants who did not receive ketorolac had normal platelet function after surgery ( P < .0001). There was no difference in patient characteristics or clinical data between the two groups. CONCLUSIONS: Ketorolac use in a cohort of children after congenital cardiac surgery was associated with platelet inhibition via the AA pathway when evaluated by TEG-PM.

Machine intelligence decrypts ß-lapachone as an allosteric 5-lipoxygenase inhibitor.

Using machine learning, targets were identified for ß-lapachone. Resorting to biochemical assays, ß-lapachone was validated as a potent, ligand efficient, allosteric and reversible modulator of 5-lipoxygenase (5-LO). Moreover, we provide a rationale for 5-LO modulation and show that inhibition of 5-LO is relevant for the anticancer activity of ß-lapachone. This work demonstrates the power of machine intelligence to deconvolute complex phenotypes, as an alternative and/or complement to chemoproteomics and as a viable general approach for systems pharmacology studies.

Morphine Pharmacokinetics in Children With Down Syndrome Following Cardiac Surgery.

OBJECTIVES: To assess if morphine pharmacokinetics are different in children with Down syndrome when compared with children without Down syndrome. DESIGN: Prospective single-center study including subjects with Down syndrome undergoing cardiac surgery (neonate to 18 yr old) matched by age and cardiac lesion with non-Down syndrome controls. Subjects were placed on a postoperative morphine infusion that was adjusted as clinically necessary, and blood was sampled to measure morphine and its metabolites concentrations. Morphine bolus dosing was used as needed, and total dose was tracked. Infusions were continued for 24 hours or until patients were extubated, whichever came first. Postinfusion, blood samples were continued for 24 hours for further evaluation of kinetics. If patients continued to require opioid, a nonmorphine alternative was used. Morphine concentrations were determined using a unique validated liquid chromatography tandem-mass spectrometry assay using dried blood spotting as opposed to large whole blood samples. Morphine concentration versus time data was modeled using population pharmacokinetics. SETTING: A 16-bed cardiac ICU at an university-affiliated hospital. PATIENTS: Forty-two patients (20 Down syndrome, 22 controls) were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of morphine in pediatric patients with and without Down syndrome following cardiac surgery were analyzed. No significant difference was found in the patient characteristics or variables assessed including morphine total dose or time on infusion. Time mechanically ventilated was longer in children with Down syndrome, and regarding morphine pharmacokinetics, the covariates analyzed were age, weight, presence of Down syndrome, and gender. Only age was found to be significant. CONCLUSIONS: This study did not detect a significant difference in morphine pharmacokinetics between Down syndrome and non-Down syndrome children with congenital heart disease.

Enteral Feeding Practices in Infants With Congenital Heart Disease Across European PICUs: A European Society of Pediatric and Neonatal Intensive Care Survey.

OBJECTIVES: To describe enteral feeding practices in pre and postoperative infants with congenital heart disease in European PICUs. DESIGN: Cross-sectional electronic survey. SETTING: European PICUs that admit infants with congenital heart disease pre- and postoperatively. PARTICIPANTS: One senior PICU physician or designated person per unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Fifty-nine PICUs from 18 European countries responded to the survey. PICU physicians were involved in the nutritional care of children with congenital heart disease in most (76%) PICUs, but less than 60% of units had a dedicated dietician. Infants with congenital heart disease were routinely fed preoperatively in only 63% of the PICUs, due to ongoing concerns around prostaglandin E1 infusion, the presence of umbilical venous and/or arterial catheters, and the use of vasoactive drugs. In three quarters of the PICUs (76%), infants were routinely fed during the first 24 hours postoperatively. Units cited, the most common feeding method, both pre and postoperatively, was intermittent bolus feeds via the gastric route. Importantly, 69% of European PICUs still did not have written guidelines for feeding, but this varied for pre and postoperative patients. CONCLUSIONS: Wide variations in practices exist in the nutritional care between European PICUs, which reflects the absence of local protocols and scientific society-endorsed guidelines. This is likely to contribute to suboptimal energy delivery in this particularly vulnerable group.

Synthesis of Selenium-Quinone Hybrid Compounds with Potential Antitumor Activity via Rh-Catalyzed C-H Bond Activation and Click Reactions.

In continuation of our quest for new redox-modulating catalytic antitumor molecules, selenium-containing quinone-based 1,2,3-triazoles were synthesized using rhodium-catalyzed C-H bond activation and click reactions. All compounds were evaluated against five types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), SF295 (human glioblastoma cells), NCIH-460 (human lung cells) and PC3 (human prostate cancer cells). Some compounds showed good activity with IC50 values below 1 µM. The cytotoxic potential of the naphthoquinoidal derivatives was also evaluated in non-tumor cells, exemplified by L929 cells. Overall, these compounds represent promising new lead derivatives and stand for a new class of chalcogenium-containing derivatives with potential antitumor activity.

Clinical Associations of Early Dysnatremias in Critically Ill Neonates and Infants Undergoing Cardiac Surgery.

Dysnatremias (DN) are common electrolyte disturbances in cardiac critical illness and are known risk factors for adverse outcomes in certain populations. Little information exists on DN in children with cardiac disease admitted to the cardiac intensive care unit (CICU) after undergoing cardiac surgery, either corrective or palliative. The aim was to determine the incidence and adverse outcomes associated with DN in neonates and infants undergoing cardiac surgery. Retrospective cohort and single center study performed at Children's Hospital Colorado from May 2013 to May 2014, in children under 1 year old admitted to the CICU after undergoing surgery for congenital or acquired cardiac disease. 183 subjects were analyzed. EXCLUSIONS: subjects that demonstrated DN before surgery. Serum sodium levels were recorded for the first 72 h post-operatively. DN was present in 54% of the subjects (98/183): hypernatremia in 60 (33%), hyponatremia in 38 (21%). Multivariate analysis revealed that mild hypernatremia (146-150 mmol/dl) and moderate hypernatremia (151-155 mmol/dl) were associated with longer hospital length of stay (LOS, p < 0.05) and ventilation times (p < 0.05). No association was shown between mild/moderate hyponatremia (125-134 mmol/dl) with either outcome. Hours to DN were significantly lower in hypernatremic (median = 5.8 h) than hyponatremic (median = 43.8 h) patients (p < 0.001). Children younger than 30 days presented DN at an earlier stage than those 31 days-1 year old (median +2.2 vs. 17.3 h). No associations present between DN and the class of diuretic (loop vs. thiazide) administered, or the route of administration (intravenous bolus vs. constant infusion). Total median sodium bicarbonate administration was associated with hypernatremia, as was exposure to vasopressin within the first 72 h post-operatively. Dysnatremias are common in the early post-operative period in neonates and infants undergoing cardiac surgery. Mild to moderate hypernatremia, but not hyponatremia, is associated with longer LOS and longer ventilation time in infants undergoing cardiovascular surgery. Hypernatremia is also associated with younger infants, a higher surgical complexity, administration of bicarbonate and exposure to vasopressin. Diuretic type or interval timing of intravenous delivery did not demonstrate any effect. Prospective studies are needed in this population, in order to determine how DN, particularly hypernatremia, contributes to adverse outcomes, whether this association is independent of illness severity, and what may be safe treatments and interventions for these disorders.

Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and their mechanistic insights.

Selenium-containing quinone-based 1,2,3-triazoles were synthesized using click chemistry, the copper catalyzed azide-alkyne 1,3-dipolar cycloaddition, and evaluated against six types of cancer cell lines: HL-60 (human promyelocytic leukemia cells), HCT-116 (human colon carcinoma cells), PC3 (human prostate cells), SF295 (human glioblastoma cells), MDA-MB-435 (melanoma cells) and OVCAR-8 (human ovarian carcinoma cells). Some compounds showed IC50 values < 0.3 µM. The cytotoxic potential of the quinones evaluated was also assayed using non-tumor cells, exemplified by peripheral blood mononuclear (PBMC), V79 and L929 cells. Mechanistic role for NAD(P)H: Quinone Oxidoreductase 1 (NQO1) was also elucidated. These compounds could provide promising new lead derivatives for more potent anticancer drug development and delivery, and represent one of the most active classes of lapachones reported.