Risk Factors for Major Early Adverse Events Related to Cardiac Catheterization in Children and Young Adults With Pulmonary Hypertension: An Analysis of Data From the IMPACT (Improving Adult and Congenital Treatment) Registry.

BACKGROUND: Cardiac catheterization is the gold standard for assessment and follow-up of patients with pulmonary hypertension (PH). To date, there are limited data about the factors that influence the risk of catastrophic adverse events after catheterization in this population. METHODS AND RESULTS: A retrospective multicenter cohort study was performed to measure risk of catastrophic adverse outcomes after catheterization in children and young adults with PH and identify risk factors for these outcomes. All catheterizations in children and young adults, aged 0 to 21 years, with PH at hospitals submitting data to the IMPACT (Improving Adult and Congenital Treatment) registry between January 1, 2011, and December 31, 2015, were studied. Using mixed-effects multivariable regression, we assessed the association between prespecified subject-, procedure-, and center-level covariates and the risk of death, cardiac arrest, or mechanical circulatory support during or after cardiac catheterization. A total of 8111 procedures performed in 7729 subjects at 77 centers were studied. The observed risk of the composite outcome was 1.4%, and the risk of death before discharge was 5.2%. Catheterization in prematurely born neonates and nonpremature infants was associated with increased risk of catastrophic adverse event, as was precatheterization treatment with inotropes and lower systemic arterial saturation. Secondary analyses demonstrated the following: (1) increasing volumes of catheterization in patients with PH were associated with reduced risk of composite outcome (odds ratio, 0.8 per 10 procedures; CONCLUSIONS: Young patients with PH are a high-risk population for diagnostic and interventional cardiac catheterization. Hospital experience with PH is associated with reduced risk, independent of total catheterization case volume

Effect of neoadjuvant chemoradiation on preoperative pulmonary physiology, postoperative respiratory complications and quality of life in patients with oesophageal cancer

Background: It remains controversial whether neoadjuvant chemoradiation (nCRT) for oesophageal cancer influences operative morbidity, in particular pulmonary, and quality of life. This study combined clinical outcome data with systematic evaluation of pulmonary physiology to determine the impact of nCRT on pulmonary physiology and clinical outcomes in locally advanced oesophageal cancer. Methods: Consecutive patients treated between 2010 and 2016 were included. Three-dimensional conformal radiation was standard, with a lung dose–volume histogram of V20 less than 25 per cent, and total radiation between 40 and 41⋅4Gy. Forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO) were assessed at baseline and 1month after nCRT. Radiation-induced lung injury (grade 2 or greater), comprehensive complications index (CCI) and pulmonary complications were monitored prospectively. Health-related quality of life was assessed among disease-free patients in survivorship. Results: Some 228 patients were studied. Comparing pulmonary physiology values before with those after nCRT, FEV1 decreased from mean(s.d.) 96⋅8(17⋅7) to 91⋅5(20⋅4) per cent (–3⋅6(10⋅6) per cent; P \u3c0⋅001), FVC from 104⋅9(15⋅6) to 98⋅1(19⋅8) per cent (–3⋅2(11⋅9) per cent; P =0⋅005) and DLCO from 97⋅6(20⋅7) to 82⋅2(20⋅4) per cent (–14⋅8(14⋅0) per cent; P \u3c0⋅001). Five patients (2⋅2 per cent) developed radiation-induced lung injury precluding surgical resection. Smoking (P =0⋅005) and increased age (P \u3c0⋅001) independently predicted percentage change in DLCO. Carboplatin and paclitaxel with 41⋅4Gy resulted in a greater DLCO decline than cisplatin and 5-fluorouracil with 40Gy (P =0⋅001). On multivariable analysis, post-treatment DLCO predicted CCI (P =0⋅006), respiratory failure (P =0⋅020) and reduced physical function in survivorship (P =0⋅047). Conclusion: These data indicate that modern nCRT alters pulmonary physiology, in particular diffusion capacity, which is linked to short- and longer-term clinical consequences, highlighting a potentially modifiable index of risk

Characterization of the intracellular glutamate decarboxylase system: analysis of its function, transcription, and role in the acid resistance of various strains of listeria monocytogenes

The glutamate decarboxylase (GAD) system is important for the acid resistance of Listeria monocytogenes. We previously showed that under acidic conditions, glutamate (Glt)/gamma-aminobutyrate (GABA) antiport is impaired in minimal media but not in rich ones, like brain heart infusion. Here we demonstrate that this behavior is more complex and it is subject to strain and medium variation. Despite the impaired Glt/GABA antiport, cells accumulate intracellular GABA (GABA(i)) as a standard response against acid in any medium, and this occurs in all strains tested. Since these systems can occur independently of one another, we refer to them as the extracellular (GAD(e)) and intracellular (GAD(i)) systems. We show here that GAD(i) contributes to acid resistance since in a Delta gadD1D2 mutant, reduced GABA(i) accumulation coincided with a 3.2-log-unit reduction in survival at pH 3.0 compared to that of wild-type strain LO28. Among 20 different strains, the GAD(i) system was found to remove 23.11% +/- 18.87% of the protons removed by the overall GAD system. Furthermore, the GAD(i) system is activated at milder pH values (4.5 to 5.0) than the GAD(e) system (pH 4.0 to 4.5), suggesting that GAD, is the more responsive of the two and the first line of defense against acid. Through functional genomics, we found a major role for GadD2 in the function of GAD(i), while that of GadD1 was minor. Furthermore, the transcription of the gad genes in three common reference strains (10403S, LO28, and EGD-e) during an acid challenge correlated well with their relative acid sensitivity. No transcriptional upregulation of the gadT2D2 operon, which is the most important component of the GAD system, was observed, while gadD3 transcription was the highest among all gad genes in all strains. In this study, we present a revised model for the function of the GAD system and highlight the important role of GAD(i) in the acid resistance of L. monocytogenes

Homocysteine toxicity in escherichia coli is caused by a perturbation of branched-chain amino acid biosynthesis

In Escherichia coli the sulfur-containing amino acid homocysteine (Hcy) is the last intermediate on the methionine hiosynthetic pathway. Supplementation of a glucose-based minimal medium with Hcy at concentrations greater than 0.2 mM causes the growth of E. coli Frag1 to be inhibited. Supplementation of Hcy-treated cultures with combinations of branched-chain amino acids containing isoleucine or with isoleucine alone reversed the inhibitory effects of Hcy on growth. The last intermediate of the isoleucine biosynthetic pathway, a-keto-p-methylvalerate, could also alleviate the growth inhibition caused by Hcy. Analysis of amino acid pools in Hcy-treated cells revealed that alanine, valine, and glutamate levels are depleted. Isoleucine could reverse the effects of Hcy on the cytoplasmic pools of valine and alanine. Supplementation of the culture medium with alanine gave partial relief from the inhibitory effects of Hcy. Enzyme assays revealed that the first step of the isoleucine biosynthetic pathway, catalyzed by threonine deaminase, was sensitive to inhibition by Hcy. The gene encoding threonine deaminase, ilvA, was found to be transcribed at higher levels in the presence of Hcy. Overexpression of the ilvA gene from a plasmid could overcome Hcy-mediated growth inhibition. Together, these data indicate that in E. coli Hcy toxicity is caused by a perturbation of branched-chain amino acid biosynthesis that is caused, at least in part, by the inhibition of threonine deaminase

Outcomes of Patients with Pulmonary Atresia and Major Aortopulmonary Collaterals Without Intervention in Infancy.

INTRODUCTION: Treatment of pulmonary atresia with major aortopulmonary collaterals (PA MAPCA’s) remains a challenge. Despite variations in surgical technique, contemporary strategies all include initial intervention in the first year of life. However, a subset of patients presents later in life, and contemporary outcomes of this group have not been reported previously. METHODS: We performed a retrospective case series of consecutive cases of PA MAPCA’s who did not undergo surgery before the age of 1 year from 1/2001 and 2/2016. We describe their presenting characteristics, operative and transcatheter interventions, and outcomes. RESULTS: A total of 8 cases were identified from 76 children with PA MAPCA’s treated over the study period. Median age at presentation was 5.9 years. 75% had confluent pulmonary arteries with a median Nakata index of 113 mm(2)/m(2). Operative intervention was performed in 5/6 cases. Two are awaiting intervention. The combination of operative and transcatheter interventions allowed for ventricular septal defect closure in 60% of cases, all of whom had sub-systemic right ventricular pressures. CONCLUSION: Operative intervention is possible in some older cases with PA and MAPCA’s. Though multiple operations and transcatheter therapies are necessary some can achieve operative correction of serial circulation with tolerable physiology. Subjects with ventricular hypoplasia and those without confluent pulmonary arteries are more challenging

Relationship Between Habitual Exercise and Performance on Cardiopulmonary Exercise Testing Differs Between Children With Single and Biventricular Circulations.

BACKGROUND: Increasing habitual exercise has been associated with improved cardiopulmonary exercise testing (CPET) performance, specifically maximal oxygen consumption in children with operatively corrected congenital heart disease. This has not been studied in children following Fontan palliation, a population in whom CPET performance is dramatically diminished. METHODS: A single-center cross-sectional study with prospective and retrospective data collection was performed that assessed habitual exercise preceding a clinically indicated CPET in children and adolescents with Fontan palliation, transposition of the great arteries following arterial switch operation (TGA), and normal cardiac anatomy without prior operation. Data from contemporaneous clinical reports and imaging studies were collected. The association between percent predicted VO2max and habitual exercise duration adjusted for known covariates was tested. RESULTS: A total of 175 subjects (75 post Fontan, 20 with TGA, and 80 with normal cardiac anatomy) were enrolled. VO2max was lower in the Fontan group than patients with normal cardiac anatomy (p<0.0001) or TGA (p<0.0001). In Fontan subjects, both univariate and multivariate analysis failed to demonstrate a significant association between habitual exercise and VO2max (p=0.6), in sharp contrast to cardiac normal subjects. In multivariate analysis, increasing age was the only independent risk factor associated with decreasing VO2max in the Fontan group (p=0.003). DISCUSSION: Habitual exercise was not associated with VO2max in subjects with a Fontan as compared to biventricular circulation. Further research is necessary to understand why their habitual exercise is ineffective and/or what aspects of the Fontan circulation disrupt this association