In acute lung injury, inhaled nitric oxide improves ventilation-perfusion matching, pulmonary vascular mechanics, and transpulmonary vascular efficiency

AbstractAcute respiratory distress syndrome continues to be associated with significant morbidity and mortality related to ventilation-perfusion mismatch, pulmonary hypertension, and right ventricular failure. It has been suggested that inhaled nitric oxide, which is a selective pulmonary vasodilator, may be effective in the treatment of acute respiratory distress syndrome; however, the effects of nitric oxide on cardiopulmonary interactions are poorly understood. We therefore developed a model of acute lung injury that mimics the clinical syndrome of acute respiratory distress syndrome. In our model, inhaled nitric oxide significantly reduced pulmonary artery pressure, pulmonary vascular resistance, and pulmonary vascular impedance. In addition, inhaled nitric oxide improved transpulmonary vascular efficiency and ventilation-perfusion matching, which resulted in increased arterial oxygen tension. Although arterial oxygen tension increased, oxygen delivery did not improve significantly. These data suggest that by improving ventilation-perfusion matching and arterial oxygen tension while lowering pulmonary vascular resistance and impedance, nitric oxide may be beneficial in patients with acute respiratory distress syndrome. However, additional measures to enhance cardiac performance may be required. ( J THORAC CARDIOVASC SURG 1995;110: 593-600

Soluble α2-macroglobulin receptor is increased in endotracheal aspirates from infants and children after cardiopulmonary bypass

ObjectiveCytokine dysregulation contributes to the systemic inflammatory response after cardiopulmonary bypass. Clearance of cytokine binding proteins may be important in the resolution of inflammation. Our aim was to determine whether the cytokine binding protein α2-macroglobulin and its soluble receptor were upregulated in endotracheal aspirates from infants and children undergoing cardiopulmonary bypass.MethodsSeventy tracheal aspirates were collected before and after cardiopulmonary bypass from 35 infants and children undergoing surgical correction of congenital heart defects. α2-Macroglobulin and the soluble α2-macroglobulin receptor were identified by Western blot. With the use of multi-analyte cytokine profiling, pro-inflammatory and anti-inflammatory cytokines were quantified, normalized to total protein, and expressed as ratios. Paired t tests and Wilcoxon signed-rank tests were performed between prebypass and postbypass samples. Correlations were examined among α2-macroglobulin, soluble α2-macroglobulin receptor, cytokine ratios, and the clinical variables of cardiopulmonary bypass, aortic crossclamp, and circulatory arrest times.Resultsα2-Macroglobulin increased by 50% (mean densitometry increase 82,683 ± 184,594, P = .012), and soluble α2-macroglobulin receptor increased by 17% (mean densitometry increase 506,148 ± 687,037, P = .0001) after cardiopulmonary bypass. The ratio of interleukin-8/interleukin-4 increased by 136% (P = .0001), and interleukin-8/interleukin-10 increased by 102% (P = .001). The increase in soluble α2-macroglobulin receptor was positively correlated with the ratios of interleukin-8/interleukin-4 and interleukin-8/interleukin-10. There were no statistically significant positive correlations between the increase in α2-macroglobulin or soluble α2-macroglobulin receptor and measured clinical variables.ConclusionsWe report for the first time the upregulation of α2-macroglobulin and soluble α2-macroglobulin receptor in tracheal aspirates after cardiopulmonary bypass in infants and children. Soluble α2-macroglobulin receptor correlates with increased α2-macroglobulin and a disproportionate increase in pro-inflammatory to anti-inflammatory cytokine ratios

Risk factors for 1-year mortality after thoracic endovascular aortic repair

ObjectiveThoracic endovascular aortic repair, although physiologically well tolerated, may fail to confer significant survival benefit in some high-risk patients. In an effort to identify patients most likely to benefit from intervention, the present study sought to determine the risk factors for 1-year mortality after thoracic endovascular aortic repair.MethodsA retrospective review was performed on prospectively collected data from all patients undergoing thoracic endovascular aortic repair from 2002 to 2010 at a single institution. Univariate analysis and multivariate Cox proportional hazards regression analysis were used to identify risk factors associated with mortality within 1 year after thoracic endovascular aortic repair.ResultsDuring the study period, 282 patients underwent at least 1 thoracic endovascular aortic repair; index procedures included descending aortic repair (n = 189), hybrid arch repair (n = 55), and hybrid thoracoabdominal repair (n = 38). The 30-day/in-hospital mortality was 7.4% (n = 21) and the overall 1-year mortality was 19% (n = 54). Cardiopulmonary pathologies were the most common cause of nonperioperative 1-year mortality (22%, n = 12). Multivariate modeling demonstrated 3 variables independently associated with 1-year mortality: age older than 75 years (hazard ratio, 2.26; P = .005), aortic diameter greater than 6.5 cm (hazard ratio, 2.20; P = .007), and American Society of Anesthesiologists class 4 (hazard ratio, 1.85; P = .049). A baseline creatinine greater than 1.5 mg/dL (hazard ratio, 1.79; P = .05) and congestive heart failure (hazard ratio, 1.87; P = .08) were also retained in the final model. These 5 variables explained a large proportion of the risk of 1-year mortality (C statistic = 0.74).ConclusionsAge older than 75 years, aortic diameter greater than 6.5 cm, and American Society of Anesthesiologists class 4 are independently associated with 1-year mortality after thoracic endovascular aortic repair. These clinical characteristics may help risk-stratify patients undergoing thoracic endovascular aortic repair and identify those unlikely to derive a long-term survival benefit from the procedure

The genome-wide distribution of non-B DNA motifs is shaped by operon structure and suggests the transcriptional importance of non-B DNA structures in Escherichia coli

Although the right-handed double helical B-form DNA is most common under physiological conditions, DNA is dynamic and can adopt a number of alternative structures, such as the four-stranded G-quadruplex, left-handed Z-DNA, cruciform and others. Active transcription necessitates strand separation and can induce such non-canonical forms at susceptible genomic sequences. Therefore, it has been speculated that these non-B DNA motifs can play regulatory roles in gene transcription. Such conjecture has been supported in higher eukaryotes by direct studies of several individual genes, as well as a number of large-scale analyses. However, the role of non-B DNA structures in many lower organisms, in particular proteobacteria, remains poorly understood and incompletely documented. In this study, we performed the first comprehensive study of the occurrence of B DNA–non-B DNA transition-susceptible sites (non-B DNA motifs) within the context of the operon structure of the Escherichia coli genome. We compared the distributions of non-B DNA motifs in the regulatory regions of operons with those from internal regions. We found an enrichment of some non-B DNA motifs in regulatory regions, and we show that this enrichment cannot be simply explained by base composition bias in these regions. We also showed that the distribution of several non-B DNA motifs within intergenic regions separating divergently oriented operons differs from the distribution found between convergent ones. In particular, we found a strong enrichment of cruciforms in the termination region of operons; this enrichment was observed for operons with Rho-dependent, as well as Rho-independent terminators. Finally, a preference for some non-B DNA motifs was observed near transcription factor-binding sites. Overall, the conspicuous enrichment of transition-susceptible sites in these specific regulatory regions suggests that non-B DNA structures may have roles in the transcriptional regulation of specific operons within the E. coli genome

Inhaled nitric oxide, right ventricular efficiency, and pulmonary vascular mechanics: Selective vasodilation of small pulmonary vessels during hypoxic pulmonary vasoconstriction

AbstractObjective: In the setting of acute pulmonary artery hypertension, techniques to reduce right ventricular energy requirements may ameliorate cardiac failure and reduce morbidity and mortality. Inhaled nitric oxide, a selective pulmonary vasodilator, may be effective in the treatment of pulmonary artery hypertension, but its effects on cardiopulmonary interactions are poorly understood. Methods: We therefore developed a model of hypoxic pulmonary vasoconstriction that mimics the clinical syndrome of acute pulmonary hypertension. Inhaled nitric oxide was administered in concentrations of 20, 40, and 80 ppm. Results: During hypoxic pulmonary vasoconstriction, the administration of nitric oxide resulted in a significant improvement in pulmonary vascular mechanics and a reduction in right ventricular afterload. These improvements were a result of selective vasodilation of small pulmonary vessels and more efficient blood flow through the pulmonary vascular bed (improved transpulmonary vascular efficiency). The right ventricular total power output diminished during the inhalation of nitric oxide, indicating a reduction in right ventricular energy requirements. The net result of nitric oxide administration was an increase in right ventricular efficiency. Conclusion: These data suggest that nitric oxide may be beneficial to the failing right ventricle by improving pulmonary vascular mechanics and right ventricular efficiency. (J Thorac Cardiovasc Surg 1997;113:1006-13

Atherogenic Lipoprotein Determinants of Cardiovascular Disease and Residual Risk Among Individuals With Low Low‐Density Lipoprotein Cholesterol

Background: Levels of LDL (low‐density lipoprotein) cholesterol in the population are declining, and increasing attention is being focused on residual lipid‐related pathways of atherosclerotic cardiovascular disease risk beyond LDL cholesterol. Among individuals with low (<130 mg/dL) LDL cholesterol, we undertook detailed profiling of circulating atherogenic lipoproteins in relation to incident cardiovascular disease in 2 populations. Methods and Results: We performed proton nuclear magnetic resonance spectroscopy to quantify concentrations of LDL and VLDL (very low‐density lipoprotein) particle subclasses in 11 984 JUPITER trial participants (NCT00239681). Adjusted Cox models examined cardiovascular disease risk associated with lipoprotein measures according to treatment allocation. Risk (adjusted hazard ratio [95%CI] per SD increment) among placebo‐allocated participants was associated with total LDL particles (1.19 [1.02, 1.38]) and total VLDL particles (1.21 [1.04, 1.41]), as well as apolipoprotein B, non–high‐density lipoprotein cholesterol, and triglycerides, but not LDL‐c. Rosuvastatin reduced LDL measures but had variable effects on triglyceride and VLDL measures. On‐statin levels of the smallest VLDL particle subclass were associated with a 68% per‐SD (adjusted hazard ratio 1.68 [1.28, 2.22]) increase in residual risk—this risk was related to VLDL cholesterol and not triglyceride or larger VLDL particles. There was evidence that residual risk prediction during statin therapy could be significantly improved through the inclusion of key VLDL measures (Harrell C‐index 0.780 versus 0.712; P<0.0001). In an independent, prospective cohort of 4721 individuals referred for cardiac catheterization (CATHGEN), similar patterns of lipoprotein‐related risk were observed. Conclusions: Atherogenic lipoprotein particle concentrations were associated with cardiovascular disease risk when LDL cholesterol was low. VLDL lipoproteins, particularly the smallest remnant subclass, may represent unused targets for risk prediction and potential therapeutic intervention for reducing residual risk. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681

Are vaccination programmes delivered by lay health workers cost-effective? A systematic review

<p>Abstract</p> <p>Background</p> <p>A recently updated Cochrane systematic review on the effects of lay or community health workers (LHWs) in primary and community health care concluded that LHW interventions could lead to promising benefits in the promotion of childhood vaccination uptake. However, understanding of the costs and cost-effectiveness of involving LHWs in vaccination programmes remains poor. This paper reviews the costs and cost-effectiveness of vaccination programme interventions involving LHWs.</p> <p>Methods</p> <p>Articles were retrieved if the title, keywords or abstract included terms related to 'lay health workers', 'vaccination' and 'economics'. Reference lists of studies assessed for inclusion were also searched and attempts were made to contact authors of all studies included in the Cochrane review. Studies were included after assessing eligibility of the full-text article. The included studies were then reviewed against a set of background and technical characteristics.</p> <p>Results</p> <p>Of the 2616 records identified, only three studies fully met the inclusion criteria, while an additional 11 were retained as they included some cost data. Methodologically, the studies were strong but did not adequately address affordability and sustainability and were also highly heterogeneous in terms of settings and LHW outcomes, limiting their comparability. There were insufficient data to allow any conclusions to be drawn regarding the cost-effectiveness of LHW interventions to promote vaccination uptake. Studies focused largely on health outcomes and did illustrate to some extent how the institutional characteristics of communities, such as governance and sources of financial support, influence sustainability.</p> <p>Conclusion</p> <p>The included studies suggest that conventional economic evaluations, particularly cost-effectiveness analyses, generally focus too narrowly on health outcomes, especially in the context of vaccination promotion and delivery at the primary health care level by LHWs. Further studies on the costs and cost-effectiveness of vaccination programmes involving LHWs should be conducted, and these studies should adopt a broader and more holistic approach.</p

International perspective on research priorities and outcome measures of importance in the care of children with acute exacerbations of asthma: A qualitative interview study

Background: Acute exacerbations of asthma are common in children, however, treatment decisions for severe exacerbations are challenging due to a lack of robust evidence. In order to create more robust research, a core set of outcome measures needs to be developed. In developing these outcomes, it is important to understand the views of clinicians who care for these children in particular, views that relate to outcome measures and research priorities. Methods: To determine the views of clinicians, a total of 26 semistructured interviews based on the theoretical domains framework were conducted. These included experienced clinicians from emergency, intensive care and inpatient paediatrics across 17 countries. The interviews were recorded, and later transcribed. All data analyses were conducted in Nvivo by using thematic analysis. Results: The length of stay in hospital and patient-focused parameters, such as timing to return to school and normal activity, were the most frequently highlighted outcome measures, with clinicians identifying the need to achieve a consensus on key core outcome measure sets. Most research questions focused on understanding the best treatment options, including the role of novel therapies and respiratory support. Conclusion: Our study provides an insight into what research questions and outcome measures clinicians view as important. In addition, information on how clinicians define asthma severity and measure treatment success will assist with methodological design in future trials. The current findings will be used in parallel with a further Paediatric Emergency Research Network study focusing on the child and family perspectives and will contribute to develop a core outcome set for future research

Acute severe paediatric asthma: Study protocol for the development of a core outcome set, a Pediatric Emergency Research Networks (PERN) study

BackgroundAcute severe childhood asthma is an infrequent, but potentially life-threatening emergency condition. There is a wide range of different approaches to this condition, with very little supporting evidence, leading to significant variation in practice. To improve knowledge in this area, there must first be consensus on how to conduct clinical trials, so that valid comparisons can be made between future studies. We have formed an international working group comprising paediatricians and emergency physicians from North America, Europe, Asia, the Middle East, Africa, South America, Central America, Australasia and the United Kingdom.Methods/designA 5-stage approach will be used: (1) a comprehensive list of outcomes relevant to stakeholders will be compiled through systematic reviews and qualitative interviews with patients, families, and clinicians; (2) Delphi methodology will be applied to reduce the comprehensive list to a core outcome set; (3) we will review current clinical practice guidelines, existing clinical trials, and literature on bedside assessment of asthma severity. We will then identify practice differences in tne clinical assessment of asthma severity, and determine whether further prospective work is needed to achieve agreement on inclusion criteria for clinical trials in acute paediatric asthma in the emergency department (ED) setting; (4) a retrospective chart review in Australia and New Zealand will identify the incidence of serious clinical complications such as intubation, ICU admission, and death in children hospitalized with acute severe asthma. Understanding the incidence of such outcomes will allow us to understand how common (and therefore how feasible) particular outcomes are in asthma in the ED setting; and finally (5) a meeting of the Pediatric Emergency Research Networks (PERN) asthma working group will be held, with invitation of other clinicians interested in acute asthma research, and patients/families. The group will be asked to achieve consensus on a core set of outcomes and to make recommendations for the conduct of clinical trials in acute severe asthma. If this is not possible, the group will agree on a series of prioritized steps to achieve this aim.DiscussionThe development of an international consensus on core outcomes is an important first step towards the development of consensus guidelines and standardised protocols for randomized controlled trials (RCTs) in this population. This will enable us to better interpret and compare future studies, reduce risks of study heterogeneity and outcome reporting bias, and improve the evidence base for the management of this important condition

Modeling denitrification in aquatic sediments

Author Posting. © The Author(s), 2008. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Biogeochemistry 93 (2009): 159-178, doi:10.1007/s10533-008-9270-z.Sediment denitrification is a major pathway of fixed nitrogen loss from aquatic systems. Due to technical difficulties in measuring this process and its spatial and temporal variability, estimates of local, regional and global denitrification have to rely on a combination of measurements and models. Here we review approaches to describing denitrification in aquatic sediments, ranging from mechanistic diagenetic models to empirical parameterizations of nitrogen fluxes across the sediment-water interface. We also present a compilation of denitrification measurements and ancillary data for different aquatic systems, ranging from freshwater to marine. Based on this data compilation we reevaluate published parameterizations of denitrification. We recommend that future models of denitrification use (1) a combination of mechanistic diagenetic models and measurements where bottom waters are temporally hypoxic or anoxic, and (2) the much simpler correlations between denitrification and sediment oxygen consumption for oxic bottom waters. For our data set, inclusion of bottom water oxygen and nitrate concentrations in a multivariate regression did not improve the statistical fit.Financial support for AEG to work on the manuscript came from NSF NSF-DEB-0423565. KF, DB and DDT acknowledge support from NOAA CHRP grant NA07NOS4780191