Recurrence quantification analysis for fine-scale characterisation of arrhythmic patterns in cardiac tissue.

This paper uses recurrence quantification analysis (RQA) combined with entropy measures and organization indices to characterize arrhythmic patterns and dynamics in computer simulations of cardiac tissue. We performed different simulations of cardiac tissues of sizes comparable to the human heart atrium. In these simulations, we observed four classic arrhythmic patterns: a spiral wave anchored to a highly fibrotic region resulting in sustained re-entry, a meandering spiral wave, fibrillation, and a spiral wave anchored to a scar region that breaks up into wavelets away from the main rotor. A detailed analysis revealed that, within the same simulation, maps of RQA metrics could differentiate regions with regular AP propagation from ones with chaotic activity. In particular, the combination of two RQA metrics, the length of the longest diagonal string of recurrence points and the mean length of diagonal lines, was able to identify the location of rotor tips, which are the active elements that maintain spiral waves and fibrillation. By proposing low-dimensional models based on the mean value and spatial correlation of metrics calculated from membrane potential time series, we identify RQA-based metrics that successfully separate the four different types of cardiac arrhythmia into distinct regions of the feature space, and thus might be used for automatic classification, in particular distinguishing between fibrillation driven by self-sustaining chaos and that created by a persistent rotor and wavebreak. We also discuss the practical applicability of such an approach.

Homogenisation for the monodomain model in the presence of microscopic fibrotic structures.

Computational models in cardiac electrophysiology are notorious for long runtimes, restricting the numbers of nodes and mesh elements in the numerical discretisations used for their solution. This makes it particularly challenging to incorporate structural heterogeneities on small spatial scales, preventing a full understanding of the critical arrhythmogenic effects of conditions such as cardiac fibrosis. In this work, we explore the technique of homogenisation by volume averaging for the inclusion of non-conductive micro-structures into larger-scale cardiac meshes with minor computational overhead. Importantly, our approach is not restricted to periodic patterns, enabling homogenised models to represent, for example, the intricate patterns of collagen deposition present in different types of fibrosis. We first highlight the importance of appropriate boundary condition choice for the closure problems that define the parameters of homogenised models. Then, we demonstrate the technique's ability to correctly upscale the effects of fibrotic patterns with a spatial resolution of 10 µm into much larger numerical mesh sizes of 100- 250 µm . The homogenised models using these coarser meshes correctly predict critical pro-arrhythmic effects of fibrosis, including slowed conduction, source/sink mismatch, and stabilisation of re-entrant activation patterns. As such, this approach to homogenisation represents a significant step towards whole organ simulations that unravel the effects of microscopic cardiac tissue heterogeneities.

Analysis of sloppiness in model simulations: Unveiling parameter uncertainty when mathematical models are fitted to data.

This work introduces a comprehensive approach to assess the sensitivity of model outputs to changes in parameter values, constrained by the combination of prior beliefs and data. This approach identifies stiff parameter combinations strongly affecting the quality of the model-data fit while simultaneously revealing which of these key parameter combinations are informed primarily by the data or are also substantively influenced by the priors. We focus on the very common context in complex systems where the amount and quality of data are low compared to the number of model parameters to be collectively estimated, and showcase the benefits of this technique for applications in biochemistry, ecology, and cardiac electrophysiology. We also show how stiff parameter combinations, once identified, uncover controlling mechanisms underlying the system being modeled and inform which of the model parameters need to be prioritized in future experiments for improved parameter inference from collective model-data fitting.

Graph-based homogenisation for modelling cardiac fibrosis.

Fibrosis, the excess of extracellular matrix, can affect, and even block, propagation of action potential in cardiac tissue. This can result in deleterious effects on heart function, but the nature and severity of these effects depend strongly on the localisation of fibrosis and its by-products in cardiac tissue, such as collagen scar formation. Computer simulation is an important means of understanding the complex effects of fibrosis on activation patterns in the heart, but concerns of computational cost place restrictions on the spatial resolution of these simulations. In this work, we present a novel numerical homogenisation technique that uses both Eikonal and graph approaches to allow fine-scale heterogeneities in conductivity to be incorporated into a coarser mesh. Homogenisation achieves this by deriving effective conductivity tensors so that a coarser mesh can then be used for numerical simulation. By taking a graph-based approach, our homogenisation technique functions naturally on irregular grids and does not rely upon any assumptions of periodicity, even implicitly. We present results of action potential propagation through fibrotic tissue in two dimensions that show the graph-based homogenisation technique is an accurate and effective way to capture fine-scale domain information on coarser meshes in the context of sharp-fronted travelling waves of activation. As test problems, we consider excitation propagation in tissue with diffuse fibrosis and through a tunnel-like structure designed to test homogenisation, interaction of an excitation wave with a scar region, and functional re-entry.

Reducing the rate of negative ureteroscopy: predictive factors and the role of preoperative imaging.

INTRODUCTION: The aim of this study was to investigate factors that may predict a negative ureteroscopy (URS) performed for ureteric calculi in prestented patients and to assess preoperative imaging in reducing the rate of negative URS. METHODS: Data were collected on emergency stent placement for a ureteric calculus from April 2011 to February 2016 (Group A) and October 2016 to October 2019 (Group B). Data included patient demographics, indication for a stent, stone characteristics, baseline bloods, urine culture, readmission, negative URS rate and the use of pre-URS imaging. Multivariate logistic regression was used for statistical analysis. RESULTS: Of 257 patients who underwent emergency stent insertion, 251 underwent deferred URS for a ureteric calculus and 6 avoided URS due to pre-URS imaging. Indications for stent were pain (42%), sepsis (39%) and acute kidney injury (19%). Mean stone size was 7.8mm, mean stone density was 699 Hounsfield units (HU) and the stone locations were upper (62%), mid (13%) and lower ureter (25%). The overall negative URS rate was 12%. The negative URS rate was lower in patients with pre-URS imaging compared with those with none, 6% and 14%, respectively (OR=2.33, 95% CI: 0.69-7.56, p=0.2214). Logistic regression analysis indicated stone size as the only significant predictor of a negative URS, where the greater the size of the stone the less likely URS would be negative (ß=0.75, 95% CI: 0.60-0.94 p=0.011). CONCLUSIONS: Utilising pre-URS imaging can lead to a reduction in negative URS rate. Stone size <5mm appears to be the subgroup most likely to benefit from imaging.

Machine Learning Identification of Pro-arrhythmic Structures in Cardiac Fibrosis.

Cardiac fibrosis and other scarring of the heart, arising from conditions ranging from myocardial infarction to ageing, promotes dangerous arrhythmias by blocking the healthy propagation of cardiac excitation. Owing to the complexity of the dynamics of electrical signalling in the heart, however, the connection between different arrangements of blockage and various arrhythmic consequences remains poorly understood. Where a mechanism defies traditional understanding, machine learning can be invaluable for enabling accurate prediction of quantities of interest (measures of arrhythmic risk) in terms of predictor variables (such as the arrangement or pattern of obstructive scarring). In this study, we simulate the propagation of the action potential (AP) in tissue affected by fibrotic changes and hence detect sites that initiate re-entrant activation patterns. By separately considering multiple different stimulus regimes, we directly observe and quantify the sensitivity of re-entry formation to activation sequence in the fibrotic region. Then, by extracting the fibrotic structures around locations that both do and do not initiate re-entries, we use neural networks to determine to what extent re-entry initiation is predictable, and over what spatial scale conduction heterogeneities appear to act to produce this effect. We find that structural information within about 0.5 mm of a given point is sufficient to predict structures that initiate re-entry with more than 90% accuracy.

Variability in electrophysiological properties and conducting obstacles controls re-entry risk in heterogeneous ischaemic tissue.

Ischaemia, in which inadequate blood supply compromises and eventually kills regions of cardiac tissue, can cause many types of arrhythmia, some life-threatening. A significant component of this is the effects of the resulting hypoxia, and concomitant hyperklaemia and acidosis, on the electrophysiological properties of myocytes. Clinical and experimental data have also shown that regions of structural heterogeneity (fibrosis, necrosis, fibro-fatty infiltration) can act as triggers for arrhythmias under acute ischaemic conditions. Mechanistic models have successfully captured these effects in silico. However, the relative significance of these separate facets of the condition, and how sensitive arrhythmic risk is to the extents of each, is far less explored. In this work, we use partitioned Gaussian process emulation and new metrics for source-sink mismatch that rely on simulations of bifurcating cardiac fibres to interrogate a model of heterogeneous ischaemic tissue. Re-entries were most sensitive to the level of hypoxia and the fraction of non-excitable tissue. In addition, our results reveal both protective and pro-arrhythmic effects of hyperklaemia, and present the levels of hyperklaemia, hypoxia and percentage of non-excitable tissue that pose the highest arrhythmic risks. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Comparison of Traditional and Skin-Sparing Approaches for Surgical Treatment of Necrotizing Soft-Tissue Infections.

Background: A skin-sparing approach for the treatment of necrotizing soft-tissue infections (NSTIs) removes necrotic tissue planes while leaving viable overlying skin. Subsequent closure of the spared skin may decrease the need for graft-based reconstruction, which is associated with contracture, pain, and deformity. This study compared the outcomes of a traditional approach (excision of overlying skin with diseased fascia) with that of a skin-sparing approach for patients with NSTI treated at a major metropolitan medical center. Methods: Demographic, clinical, and operative details for patients treated for NSTI between July 2012 and December 2016 at a single institution were reviewed retrospectively. Pre-operative and post-operative photographs were evaluated independently by three surgeons to determine reconstructive outcomes. Cohen's κ was used to assess inter-rater reliability. Multiple regression and Poisson regression models were used to assess the association between outcomes and the surgical approach. Results: A total of 487 patients were divided into two cohorts: Traditional approach (TA), treated between July 2012 and December 2014 (n = 230), and skin-sparing approach (SS), treated after January 2015 (n = 257). The mortality rate in the two groups was equal at approximately 10%. The median percentage of each wound closed by skin graft was significantly lower for the SS group than for the TA group (20% versus 90%; p < 0.0001) with a correspondingly higher median percentage of primary skin closure for the SS group (50% versus 0; p < 0.0001). Conclusions: Relative to traditional debridement, skin-sparing debridement for source control of NSTI results in significantly more wounds closed completely by delayed primary suture of existing skin flaps and a significantly lower overall wound percentage closed by skin graft, while demonstrating equivalent efficacy of source control and a similar low mortality rate.

Slow Recovery of Excitability Increases Ventricular Fibrillation Risk as Identified by Emulation.

Purpose: Rotor stability and meandering are key mechanisms determining and sustaining cardiac fibrillation, with important implications for anti-arrhythmic drug development. However, little is yet known on how rotor dynamics are modulated by variability in cellular electrophysiology, particularly on kinetic properties of ion channel recovery. Methods: We propose a novel emulation approach, based on Gaussian process regression augmented with machine learning, for data enrichment, automatic detection, classification, and analysis of re-entrant biomarkers in cardiac tissue. More than 5,000 monodomain simulations of long-lasting arrhythmic episodes with Fenton-Karma ionic dynamics, further enriched by emulation to 80 million electrophysiological scenarios, were conducted to investigate the role of variability in ion channel densities and kinetics in modulating rotor-driven arrhythmic behavior. Results: Our methods predicted the class of excitation behavior with classification accuracy up to 96%, and emulation effectively predicted frequency, stability, and spatial biomarkers of functional re-entry. We demonstrate that the excitation wavelength interpretation of re-entrant behavior hides critical information about rotor persistence and devolution into fibrillation. In particular, whereas action potential duration directly modulates rotor frequency and meandering, critical windows of excitability are identified as the main determinants of breakup. Further novel electrophysiological insights of particular relevance for ventricular arrhythmias arise from our multivariate analysis, including the role of incomplete activation of slow inward currents in mediating tissue rate-dependence and dispersion of repolarization, and the emergence of slow recovery of excitability as a significant promoter of this mechanism of dispersion and increased arrhythmic risk. Conclusions: Our results mechanistically explain pro-arrhythmic effects of class Ic anti-arrhythmics in the ventricles despite their established role in the pharmacological management of atrial fibrillation. This is mediated by their slow recovery of excitability mode of action, promoting incomplete activation of slow inward currents and therefore increased dispersion of repolarization, given the larger influence of these currents in modulating the action potential in the ventricles compared to the atria. These results exemplify the potential of emulation techniques in elucidating novel mechanisms of arrhythmia and further application to cardiac electrophysiology.

A Potential Mechanism for Immune Suppression by Beta-Adrenergic Receptor Stimulation following Traumatic Injury.

BACKGROUND: ß-Adrenergic agents suppress inflammation and may play an important role in posttraumatic infections. Mechanisms may include inhibition of MAP kinase signaling. We sought to determine whether MKP-1 contributed to catecholamine suppression of innate immunity and also wanted to know whether early catecholamine treatment after traumatic injury increases the risk of later nosocomial infection. METHODS: We performed experiments using THP-1 cells and peripheral blood mononuclear cells from healthy individuals. We exposed cells to epinephrine and/or LPS and measured inflammatory gene transcription and MAP kinase activation. We inhibited MKP-1 activity to determine its role in catecholamine-induced immune suppression. Finally, we studied injured subjects to determine whether early catecholamine treatment was associated with nosocomial infection. RESULTS: Epinephrine increases MKP-1 transcripts and protein and decreases LPS-induced p38 and JNK phosphorylation and TNF-α gene transcription. RNAi inhibition of MKP-1 at least partially restores LPS-induced TNF-α gene expression (p = 0.024). In the clinical cohort, subjects treated with ß-adrenergic agents had an increased risk of ventilator-associated pneumonia (aOR = 1.9; 95% CI = 1.3-2.6) and bacteremia (aOR = 1.5; 95% CI = 1.1-2.3). CONCLUSIONS: MKP-1 may have a role in catecholamine-induced suppression of innate immunity, and exogenous catecholamines might contribute to nosocomial infection risk.

From ionic to cellular variability in human atrial myocytes: an integrative computational and experimental study.

Variability refers to differences in physiological function between individuals, which may translate into different disease susceptibility and treatment efficacy. Experiments in human cardiomyocytes face wide variability and restricted tissue access; under these conditions, computational models are a useful complementary tool. We conducted a computational and experimental investigation in cardiomyocytes isolated from samples of the right atrial appendage of patients undergoing cardiac surgery to evaluate the impact of variability in action potentials (APs) and subcellular ionic densities on Ca2+ transient dynamics. Results showed that 1) variability in APs and ionic densities is large, even within an apparently homogenous patient cohort, and translates into ±100% variation in ionic conductances; 2) experimentally calibrated populations of models with wide variations in ionic densities yield APs overlapping with those obtained experimentally, even if AP characteristics of the original generic model differed significantly from experimental APs; 3) model calibration with AP recordings restricts the variability in ionic densities affecting upstroke and resting potential, but redundancy in repolarization currents admits substantial variability in ionic densities; and 4) model populations constrained with experimental APs and ionic densities exhibit three Ca2+ transient phenotypes, differing in intracellular Ca2+ handling and Na+/Ca2+ membrane extrusion. These findings advance our understanding of the impact of variability in human atrial electrophysiology. NEW & NOTEWORTHY Variability in human atrial electrophysiology is investigated by integrating for the first time cellular-level and ion channel recordings in computational electrophysiological models. Ion channel calibration restricts current densities but not cellular phenotypic variability. Reduced Na+/Ca2+ exchanger is identified as a primary mechanism underlying diastolic Ca2+ fluctuations in human atrial myocytes.

Unlocking data sets by calibrating populations of models to data density: A study in atrial electrophysiology.

The understanding of complex physical or biological systems nearly always requires a characterization of the variability that underpins these processes. In addition, the data used to calibrate these models may also often exhibit considerable variability. A recent approach to deal with these issues has been to calibrate populations of models (POMs), multiple copies of a single mathematical model but with different parameter values, in response to experimental data. To date, this calibration has been largely limited to selecting models that produce outputs that fall within the ranges of the data set, ignoring any trends that might be present in the data. We present here a novel and general methodology for calibrating POMs to the distributions of a set of measured values in a data set. We demonstrate our technique using a data set from a cardiac electrophysiology study based on the differences in atrial action potential readings between patients exhibiting sinus rhythm (SR) or chronic atrial fibrillation (cAF) and the Courtemanche-Ramirez-Nattel model for human atrial action potentials. Not only does our approach accurately capture the variability inherent in the experimental population, but we also demonstrate how the POMs that it produces may be used to extract additional information from the data used for calibration, including improved identification of the differences underlying stratified data. We also show how our approach allows different hypotheses regarding the variability in complex systems to be quantitatively compared.

Parenteral and enteral nutrition in surgical critical care: Plasma metabolomics demonstrates divergent effects on nitrogen, fatty-acid, ribonucleotide, and oxidative metabolism.

BACKGROUND: Artificial nutrition support is central to the care of critically ill patients and is primarily provided enterally (EN). There are circumstances when parenteral nutrition (PN) is considered necessary. We are uncertain how each of these approaches confer clinical benefits beyond simply providing calories. We sought to better understand how each of these techniques influence metabolism in critically ill patients using a broad-based metabolomics approach. Metabolic responses to EN and PN may differ in ways that could help us understand how to optimize use of these therapies. METHODS: We prospectively enrolled subjects over 7 months in 2015 at an urban, Level I trauma center. Subjects were included before starting either EN or PN during their inpatient admission. Plasma samples were obtained between 1 and 12 hours before initiation of artificial nutrition, and 3 and 7 days later. All samples were analyzed with liquid chromatography/mass spectrometry-based metabolomics. Differences in metabolite concentrations were assessed via principal component analyses and multiple linear regression. RESULTS: We enrolled 30 subjects. Among the critically ill subjects, 10 received EN and 10 received PN. In subjects receiving EN, amino acid and urea cycle metabolites (citrulline, p = 0.04; ornithine, p = 0.05) increased, as did ribonucleic acid metabolites (uridine, p = 0.04; cysteine, 0 = 0.05; oxypurinol, p = 0.04). Oxidative stress decreased over time (increased betaine, p = 0.05; decreased 4-pyridoxic acid, p = 0.04). In subjects receiving PN, amino acid concentrations increased over time (taurine, p = 0.04; phenylalanine, p = 0.05); omega 6 and omega 3 fatty acid concentrations decreased over time (p = 0.05 and 0.03, respectively). CONCLUSION: EN was associated with amino acid repletion, urea cycle upregulation, restoration of antioxidants, and increasing ribonucleic acid synthesis. Parenteral nutrition was associated with increased amino acid concentrations, but did not influence protein metabolism or antioxidant repletion. This suggests that parenteral amino acids are used less effectively than those given enterally. The biomarkers reported in this study may be useful in guiding nutrition therapy for critically ill patients. LEVEL OF EVIDENCE: Therapeutic study, level III; prognostic study, level II.

Space-Limited Mitosis in the Glazier-Graner-Hogeweg Model.

The Glazier-Graner-Hogeweg (GGH) model is a cellular automata framework for representing the time evolution of cellular systems, appealing because unlike many other individual-cell-based models it dynamically simulates changes in cell shape and size. Proliferation has seen some implementation into this modelling framework, but without consensus in the literature as to how this behaviour is best represented. Additionally, the majority of published GGH model implementations which feature proliferation do so in order to simulate a certain biological situation where mitosis is important, but without analysis of how these proliferation routines operate on a fundamental level. Here, a method of proliferation for the GGH model which uses separate cell phenotypes to differentiate cells which have entered or just left the mitotic phase of the cell cycle is presented and demonstrated to correctly predict logistic growth on a macroscopic scale (in accordance with experimental evidence). Comparisons between model simulations and the generalised logistic growth model provide an interpretation of the latter's 'shape parameter', and the proliferation routine used here is shown to offer the modeller somewhat predictable control over the proliferation rate, important for ensuring temporal consistency between different cellular behaviours in the model. All results are found to be insensitive to the inclusion of active cell motility. The implications of these simulated proliferation assays towards problems in cell biology are also discussed.

Melanocortin-1 Receptor Polymorphisms and the Risk of Complicated Sepsis After Trauma: A Candidate Gene Association Study.

OBJECTIVE: The aim of the study was to determine if melanocortin-1 receptor (MC1R) single nucleotide polymorphisms (SNPs) are associated with complicated sepsis after trauma. BACKGROUND: Nosocomial infections are an important cause of morbidity and mortality after trauma. Several SNPs in inflammation-related genes have been associated with sepsis. MC1R is an anti-inflammatory mediator that may be involved in the immune response after trauma. PATIENTS AND METHODS: We genotyped eight common MC1R SNPs in genomic DNA from subjects enrolled in a previously reported prospective cohort study. Subjects were adult trauma patients admitted to the intensive care unit at a Level 1 trauma center (2003-2005). RESULTS: A total of 1,246 subjects were included in the analysis. The majority were male (70%), severely injured (81%), and injured by a blunt mechanism (89%). Forty percent developed sepsis, and 23% developed complicated sepsis, which was defined as sepsis with organ dysfunction. In logistic regression analysis, with adjustments for age, sex, body mass index, injury severity score, red blood cell transfusion requirement, and mechanism of injury, the MC1RR163Q variant (rs885479) was associated with a lower risk of developing complicated sepsis (adjusted odds ratio [ORadj] = 0.48, 95% confidence interval [CI]: 0.28-0.81, P = 0.006). In a subgroup of 511 subjects with genome-wide SNP data, the association between the MC1RR163Q variant and complicated sepsis remained significant after adjusting for genetic substructure (by principal components) and the above clinical factors (ORadj = 0.30, 95% CI: 0.13-0.70, P = 0.005). CONCLUSIONS: MC1RR163Q is associated with a lower risk of complicated sepsis after trauma. Therapeutic targeting of MC1R may be beneficial for trauma patients at risk for complicated sepsis.

Use of Metabolomics to Trend Recovery and Therapy After Injury in Critically Ill Trauma Patients.

IMPORTANCE: Metabolomics is the broad and parallel study of metabolites within an organism and provides a contemporaneous snapshot of physiologic state. Use of metabolomics in the clinical setting may help achieve precision medicine for those who have experienced trauma, where diagnosis and treatment are tailored to the individual patient. OBJECTIVE: To examine whether metabolomics can (1) distinguish healthy volunteers from trauma patients and (2) quantify changes in catabolic metabolites over time after injury. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study with enrollment from September 2014 to May 2015 at an urban, level 1 trauma center. Included in the study were 10 patients with severe blunt trauma admitted within 12 hours of injury with systolic blood pressure less than 90 mm Hg or base deficit greater than 6 mEq/L and 5 healthy volunteers. Plasma samples (n = 35) were obtained on days 1, 3, and 7, and they were analyzed using mass spectrometry. MAIN OUTCOMES AND MEASURES: Principal component analyses, multiple linear regression, and paired t tests were used to select biomarkers of interest. A broad-based metabolite profile comparison between trauma patients and healthy volunteers was performed. Specific biomarkers of interest were oxidative catabolites. RESULTS: Trauma patients had a median age of 45 years and a median injury severity score of 43 (interquartile range, 34-50). Healthy fasting volunteers had a median age of 33 years. Compared with healthy volunteers, trauma patients showed oxidative stress on day 1: niacinamide concentrations were a mean (interquartile range) of 0.95 (0.30-1.45) relative units for trauma patients vs 1.06 (0.96-1.09) relative units for healthy volunteers (P = .02), biotin concentrations, 0.43 (0.27-0.58) relative units for trauma patients vs 1.21 (0.93-1.56) relative units for healthy volunteers (P = .049); and choline concentrations, 0.17 (0.09-0.22) relative units for trauma patients vs 0.21 (0.18-0.22) relative units for healthy volunteers (P = .004). Trauma patients showed lower nucleotide synthesis on day 1: adenylosuccinate concentrations were 0.08 (0.04-0.12) relative units for trauma patients vs 0.15 (0.14-0.17) relative units for healthy volunteers (P = .02) and cytidine concentrations were 1.44 (0.95-1.73) relative units for trauma patients vs 1.74 (1.62-1.98) relative units for healthy volunteers (P = .05). From trauma day 1 to day 7, trauma patients showed increasing muscle catabolism: serine levels increased from 42.03 (31.20-54.95) µM to 79.37 (50.29-106.37) µM (P = .002), leucine levels increased from 69.21 (48.36-99.89) µM to 114.16 (92.89-143.52) µM (P = .004), isoleucine levels increased from 20.43 (10.92-27.41) µM to 48.72 (36.28-64.84) µM (P < .001), and valine levels increased from 122.56 (95.63-140.61) µM to 190.52 (136.68-226.07) µM (P = .004). There was an incomplete reversal of oxidative stress. CONCLUSIONS AND RELEVANCE: Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients.

Safety of minimizing preoperative starvation in critically ill and intubated trauma patients.

BACKGROUND: Cessation of enteral nutrition prior to an operation/procedure is the most common reason for feeding interruption in critically ill trauma patients and contributes to substantial calorie deficits. This study reports on a strategy to increase calorie intake by continuing feeds until transfer for operations/procedures. METHODS: Nutrition guidelines were modified in 2006 to allow continuation of feeding in intubated patients up until transfer to the operating room. Prior to 2006, enteral feeding was stopped at least 6 hours prior to surgery. A retrospective cohort design from 2003 to 2010 compared clinical outcomes in groups of adult trauma subjects before and after guideline changes and in subjects at other centers without guideline changes. RESULTS: During the first week, subjects in the preimplementation cohort (n = 245) received a median of 3,787 kcal per person per week, while subjects in the postimplementation cohort (n = 368) received a median of 6,662 kcal per person per week (p < 0.001). There was no change in calorie intake for subjects at other centers (n = 1,002). The risks of acute respiratory distress syndrome, pneumonia, and mortality were decreased after implementation relative to the preimplementation cohort (acute respiratory distress syndrome: relative risk ratio [RR], 0.69; 95% confidence interval [CI], 0.59-0.81; pneumonia: RR, 0.82; 95% CI, 0.65-1.00; mortality: RR, 0.67; 95% CI, 0.46-0.99). Ventilator-free days increased by 1.4 days (95% CI, 0.1-2.7), while intensive care unit stay and hospital length of stay were unchanged. These outcomes showed similar trends over time at other participating centers. CONCLUSIONS: Allowing intubated trauma patients to continue enteral nutrition until transfer for operations or procedures was associated with increased caloric intake without evidence of increased pulmonary complications. This represents an important strategy to reduce calorie deficits in the trauma intensive care unit. LEVEL OF EVIDENCE: Therapeutic study/care management, level III.

A mathematical model for the induction of the mammalian ureteric bud.

Congenital abnormalities of the kidney and urinary tract collectively form the most common type of prenatally diagnosed malformations. Whilst many of the crucial genes that direct the kidney developmental program are known, the mechanisms by which kidney organogenesis is achieved is still largely unclear. In this paper, we propose a mathematical model for the localisation of the ureteric bud, the precursor to the ureter and collecting duct system of the kidney. The mathematical model presented fundamentally implicates Schnakenberg-like ligand-receptor Turing patterning as the mechanism by which the ureteric bud is localised on the Wolfian duct as proposed by Menshykaul and Iber (2013). This model explores the specific roles of regulatory proteins GREM1 and BMP as well as the domain properties of GDNF production. Our model demonstrates that this proposed pattern formation mechanism is capable of naturally predicting the phenotypical outcomes of many genetic experiments from the literature. Furthermore, we conclude that whilst BMP inhibits GDNF away from the budding site and GREM1 permits GDNF to signal, GREM1 also stabilises the effect of BMP on GDNF signalling from fluctuations in BMP sensitivity but not signal strength.

Characterizing the Morbidity of Postchemotherapy Retroperitoneal Lymph Node Dissection for Testis Cancer in a National Cohort of Privately Insured Patients.

OBJECTIVE: To characterize morbidity of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) for testis cancer, we analyze a contemporary national database. PC-RPLND is the standard for residual radiographic masses ≥1 cm (nonseminoma) and positron emission tomography-avid masses ≥3 cm (seminoma). Morbidity for PC-RPLND is greater than primary RPLND, which may be mitigated by performing surgery at a high-volume cancer center. METHODS: Current Procedural Terminology and International Classification of Diseases, Ninth Edition codes identified men with testis cancer undergoing PC- or primary RPLND in MarketScan (2007-2012). Multivariable logistic regression assessed factors associated with receiving adjunctive procedures (ie, nephrectomy, vascular reconstruction), prolonged hospitalization, and 90-day readmission. Geographic variables assessed regionalization of PC-RPLND. RESULTS: Of 559 men with claims for PC- or primary RPLND (206, 37% PC-RPLND), 19% of PC-RPLND underwent adjunctive procedures (vs 1% among RPLND, P < .01). For PC-RPLND, the nephrectomy rate was 10% and the vascular reconstruction rate was 8%. On multivariable analysis, PC-RPLND was associated with undergoing adjunctive procedures (odds ratio 41.9; 95% confidence interval 11.7, 150) and prolonged hospitalization (odds ratio 3.75; 95% confidence interval 1.68, 8.42) compared to primary RPLND. PC-RPLND was not associated with 90-day readmission. Up to 29% of PC-RPLNDs are performed in centers, billing just a single case through MarketScan in the 6 years studied. CONCLUSION: PC-RPLND is associated with adjunctive procedures and longer hospitalizations. Given the morbidity of PC-RPLND in this young patient population, efforts are needed to establish quality benchmarks for, reduce the morbidity of, and to accurately discriminate risk during patient discussions prior to this complex, specialized surgery.

The relationship between ambient ultraviolet radiation (UVR) and objectively measured personal UVR exposure dose is modified by season and latitude.

Despite the widespread use of ambient ultraviolet radiation (UVR) as a proxy measure of personal exposure to UVR, the relationship between the two is not well-defined. This paper examines the effects of season and latitude on the relationship between ambient UVR and personal UVR exposure. We used data from the AusD Study, a multi-centre cross-sectional study among Australian adults (18-75 years), where personal UVR exposure was objectively measured using polysulphone dosimeters. Data were analysed for 991 participants from 4 Australian cities of different latitude: Townsville (19.3°S), Brisbane (27.5°S), Canberra (35.3°S) and Hobart (42.8°S). Daily personal UVR exposure varied from 0.01 to 21 Standard Erythemal Doses (median = 1.1, IQR: 0.5-2.1), on average accounting for 5% of the total available ambient dose. There was an overall positive correlation between ambient UVR and personal UVR exposure (r = 0.23, p < 0.001). However, the correlations varied according to season and study location: from strong correlations in winter (r = 0.50) and at high latitudes (Hobart, r = 0.50; Canberra, r = 0.39), to null or even slightly negative correlations, in summer (r = 0.01) and at low latitudes (Townsville, r = -0.06; Brisbane, r = -0.16). Multiple regression models showed significant effect modification by season and location. Personal exposure fraction of total available ambient dose was highest in winter (7%) and amongst Hobart participants (7%) and lowest in summer (1%) and in Townsville (4%). These results suggest season and latitude modify the relationship between ambient UVR and personal UVR exposure. Ambient UVR may not be a good indicator for personal exposure dose under some circumstances.