Candida albicans Scavenges Host Zinc via Pra1 during Endothelial Invasion

The ability of pathogenic microorganisms to assimilate essential nutrients from their hosts is critical for pathogenesis. Here we report endothelial zinc sequestration by the major human fungal pathogen, Candida albicans. We hypothesised that, analogous to siderophore-mediated iron acquisition, C. albicans utilises an extracellular zinc scavenger for acquiring this essential metal. We postulated that such a “zincophore” system would consist of a secreted factor with zinc-binding properties, which can specifically reassociate with the fungal cell surface. In silico analysis of the C. albicans secretome for proteins with zinc binding motifs identified the pH-regulated antigen 1 (Pra1). Three-dimensional modelling of Pra1 indicated the presence of at least two zinc coordination sites. Indeed, recombinantly expressed Pra1 exhibited zinc binding properties in vitro. Deletion of PRA1 in C. albicans prevented fungal sequestration and utilisation of host zinc, and specifically blocked host cell damage in the absence of exogenous zinc. Phylogenetic analysis revealed that PRA1 arose in an ancient fungal lineage and developed synteny with ZRT1 (encoding a zinc transporter) before divergence of the Ascomycota and Basidiomycota. Structural modelling indicated physical interaction between Pra1 and Zrt1 and we confirmed this experimentally by demonstrating that Zrt1 was essential for binding of soluble Pra1 to the cell surface of C. albicans. Therefore, we have identified a novel metal acquisition system consisting of a secreted zinc scavenger (“zincophore”), which reassociates with the fungal cell. Furthermore, functional similarities with phylogenetically unrelated prokaryotic systems indicate that syntenic zinc acquisition loci have been independently selected during evolution

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Deformation analysis of 3D tagged cardiac images using an optical flow method

Abstract Background This study proposes and validates a method of measuring 3D strain in myocardium using a 3D Cardiovascular Magnetic Resonance (CMR) tissue-tagging sequence and a 3D optical flow method (OFM). Methods Initially, a 3D tag MR sequence was developed and the parameters of the sequence and 3D OFM were optimized using phantom images with simulated deformation. This method then was validated in-vivo and utilized to quantify normal sheep left ventricular functions. Results Optimizing imaging and OFM parameters in the phantom study produced sub-pixel root-mean square error (RMS) between the estimated and known displacements in the x (RMSx = 0.62 pixels (0.43 mm)), y (RMSy = 0.64 pixels (0.45 mm)) and z (RMSz = 0.68 pixels (1 mm)) direction, respectively. In-vivo validation demonstrated excellent correlation between the displacement measured by manually tracking tag intersections and that generated by 3D OFM (R ≥ 0.98). Technique performance was maintained even with 20% Gaussian noise added to the phantom images. Furthermore, 3D tracking of 3D cardiac motions resulted in a 51% decrease in in-plane tracking error as compared to 2D tracking. The in-vivo function studies showed that maximum wall thickening was greatest in the lateral wall, and increased from both apex and base towards the mid-ventricular region. Regional deformation patterns are in agreement with previous studies on LV function. Conclusion A novel method was developed to measure 3D LV wall deformation rapidly with high in-plane and through-plane resolution from one 3D cine acquisition.</p

Early postinfarction ventricular restraint improves borderzone wall thickening dynamics during remodeling.

BACKGROUND: Early infarct expansion impairs function of normally perfused borderzone myocardium (BZM), initiates adverse remodeling, and portends a poor long-term outcome. Early ventricular restraint has been demonstrated to improve global remodeling but its effect on BZM function has not been assessed. Using an ovine model of infarct induced remodeling and MRI, we tested the hypothesis that ventricular restraint early after MI preserves BZM function and reduces remodeling. METHODS: Six sheep had a large anterior infarction after ligation of all diagonal branches. One week after infarction 3 sheep had placement of a cardiac support device (CSD) to restrain infarct expansion. Global remodeling and borderzone wall thickening strain were assessed using tagged MRI before and 8 weeks after infarction. RESULTS: Global remodeling was greatly reduced in the CSD group compared with control. The BZM systolic wall thickening was similar in both groups at baseline (13.5% +/- 2.0%, control; 12.8% +/- 2.0%, CSD, p = 0.8). After 8 weeks of infarction-induced remodeling, systolic wall thickening strain decreased significantly to 4.9% +/- 0.7% in the control group (p = 0.03). In contrast, systolic wall thickening was preserved in the CSD group at 8 weeks (11.0% +/- 1.6%, p = 0.3). In the control group all thickening occurred during isovolemic contraction, plateauing during ejection. The CSD improved late systolic borderzone wall thickening, although dynamics remained perturbed. CONCLUSIONS: Ventricular restraint early after MI improves both contractile function of the BZM and global ventricular remodeling. The dynamics of BZM wall thickening are impaired during remodeling. The CSD significantly improves but does not completely maintain baseline BZM wall thickening dynamics

Passive ventricular constraint to improve left ventricular function and mechanics in an ovine model of heart failure secondary to acute myocardial infarction

AbstractObjectiveThis study investigated the effects on global cardiac function and myocardial energetics of limiting progressive dilatation after infarction by means of a woven polyester jacket cardiac support device. We hypothesized that placement of the cardiac support device results in a decrease in myocardial wall stress and improvement in cardiac function and myocardial energetics.MethodsTo investigate the effect of passive constraint on left ventricular function and mechanics, a total of 10 sheep were studied with pressure-volume analysis and magnetic resonance imaging. A baseline study was followed by the creation of an anterior infarct. After 1 week, the animals underwent a second study. The cardiac support device was then placed over the epicardium in 5 sheep; the remaining animals served as controls. A terminal study was performed at 2 months after the infarct.ResultsThe cardiac support device group at the terminal study exhibited a decrease in end-diastolic volume (control 110.3 ± 19.8 mL vs cardiac support device 67.6 ± 4.7 mL, P = .006) and an improved ejection fraction (control 15.5% ± 5.7% vs cardiac support device 29.46% ± 4.42%, P = .008) relative to the control group. Myocardial energetics were also enhanced in the cardiac support device group, as evidenced by the significant improvements in potential energy (control 2015 ± 503 mL · mm Hg/beat vs cardiac support device 885 ± 220 mL · mm Hg/beat, P = .006), efficiency (control 39.4% ± 13.6% vs cardiac support device 59.8% ± 8.5%, P = .044), and oxygen consumption (control 0.072 ± 0.013 mL O2/beat vs cardiac support device 0.052 ± 0.007 mL O2/beat, P = .034).ConclusionPassive constraint with the cardiac support device after infarct prevents further remodeling and may stimulate reverse remodeling in heart failure secondary to acute myocardial infarction. These results suggest that in human beings placement of the cardiac support device after a large anterior myocardial infarction may be effective in halting the remodeling process that often leads to end-stage heart failure. If proved effective, placement of a cardiac support device after large heart attacks has the potential to decrease the incidence of heart failure that results after large myocardial infarctions