Prediction of sepsis in the burn intensive care unit patient

Sepsis is a significant cause for multiple organ failure and death in the burn patient, yet identification in this population is confounded by chronic hypermetabolism and impaired immune function. The purpose of this study was twofold: 1) determine the ability of the systemic inflammatory response syndrome (SIRS) and American Burn Association (ABA) criteria to predict sepsis in the burn patient; and 2) develop a model representing the best combination of clinical predictors associated with sepsis in the same population. A retrospective, case-controlled, within-patient comparison of burn patients admitted to a single intensive care unit (ICU) was conducted for the period January 2005 to September 2010. Blood culture results were paired with clinical condition: "positive-sick"; "negative-sick", and "screening-not sick". Data were collected for the 72 hours prior to each blood culture. The most significant predictors were evaluated using logistic regression, Generalized Estimating Equations (GEE) and ROC area under the curve (AUC) analyses to assess model predictive ability. Bootstrapping methods were employed to evaluate potential model over-fitting. Fifty-nine subjects were included, representing 177 culture periods. SIRS criteria were not found to be associated with culture type, with an average of 98% of subjects meeting criteria in the 3 days prior. ABA sepsis criteria were significantly different among culture type only on the day prior (p = 0.004). The variables identified for the model included: heart rate>130 beats/min, mean blood pressure<60 mmHg, base deficit<-6 mEq/L, temperature>36°C, use of vasoactive medications, and glucose>150 mg/d1. The model was significant in predicting "positive culture-sick" and sepsis state, with AUC of 0.775 (p < 0.001) and 0.714 (p < .001), respectively; comparatively, the ABA criteria AUC was 0.619 (p = 0.028) and 0.597 (p = .035), respectively. SIRS criteria are not appropriate for identifying sepsis in the burn population. The ABA criteria perform better, but only for the day prior to positive blood culture results. The time period useful to diagnose sepsis using clinical criteria may be limited to 24 hours. A combination of predictors is superior to individual variable trends, yet algorithms or computer support will be necessary for the clinician to find such models useful. ^

Trastuzumab use and risk of congestive heart failure in older breast cancer patients

Trastuzumab is a humanized-monoclonal antibody, developed specifically for HER2-neu over-expressed breast cancer patients. Although highly effective and well tolerated, it was reported associated with Congestive Heart Failure (CHF) in clinical trial settings (up to 27%). This leaves a gap where, Trastuzumab-related CHF rate in general population, especially older breast cancer patients with long term treatment of Trastuzumab remains unknown. This thesis examined the rates and risk factors associated with Trastuzumab-related CHF in a large population of older breast cancer patients. A retrospective cohort study using the existing Surveillance, Epidemiology and End Results (SEER) and Medicare linked de-identified database was performed. Breast cancer patients ≥ 66 years old, stage I-IV, diagnosed in 1998-2007, fully covered by Medicare but no HMO within 1-year before and after first diagnosis month, received 1st chemotherapy no earlier than 30 days prior to diagnosis were selected as study cohort. The primary outcome of this study is a diagnosis of CHF after starting chemotherapy but none CHF claims on or before cancer diagnosis date. ICD-9 and HCPCS codes were used to pool the claims for Trastuzumab use, chemotherapy, comorbidities and CHF claims. Statistical analysis including comparison of characteristics, Kaplan-Meier survival estimates of CHF rates for long term follow up, and Multivariable Cox regression model using Trastuzumab as a time-dependent variable were performed. Out of 17,684 selected cohort, 2,037 (12%) received Trastuzumab. Among them, 35% (714 out of 2037) were diagnosed with CHF, compared to 31% (4784 of 15647) of CHF rate in other chemotherapy recipients (p<.0001). After 10 years of follow-up, 65% of Trastuzumab users developed CHF, compared to 47% in their counterparts. After adjusting for patient demographic, tumor and clinical characteristics, older breast cancer patients who used Trastuzumab showed a significantly higher risk in developing CHF than other chemotherapy recipients (HR 1.69, 95% CI 1.54 - 1.85). And this risk is increased along with the increment of age (p-value < .0001). Among Trastuzumab users, these covariates also significantly increased the risk of CHF: older age, stage IV, Non-Hispanic black race, unmarried, comorbidities, Anthracyclin use, Taxane use, and lower educational level. It is concluded that, Trastuzumab users in older breast cancer patients had 69% higher risk in developing CHF than non-Trastuzumab users, much higher than the 27% increase reported in younger clinical trial patients. Older age, Non-Hispanic black race, unmarried, comorbidity, combined use with Anthracycline or Taxane also significantly increase the risk of CHF development in older patients treated with Trastuzumab. ^

Elevated cystatin C & heart failure prognosis a systematic review

Renal insufficiency is one of the most common co-morbidities present in heart failure (HF) patients. It has significant impact on mortality and adverse outcomes. Cystatin C has been shown as a promising marker of renal function. A systematic review of all the published studies evaluating the prognostic role of cystatin C in both acute and chronic HF was undertaken. A comprehensive literature search was conducted involving various terms of 'cystatin C' and 'heart failure' in Pubmed medline and Embase libraries using Scopus database. A total of twelve observational studies were selected in this review for detailed assessment. Six studies were performed in acute HF patients and six were performed in chronic HF patients. Cystatin C was used as a continuous variable, as quartiles/tertiles or as a categorical variable in these studies. Different mortality endpoints were reported in these studies. All twelve studies demonstrated a significant association of cystatin C with mortality. This association was found to be independent of other baseline risk factors that are known to impact HF outcomes. In both acute and chronic HF, cystatin C was not only a strong predictor of outcomes but also a better prognostic marker than creatinine and estimated glomerular filtration rate (eGFR). A combination of cystatin C with other biomarkers such as N terminal pro B- type natriuretic peptide (NT-proBNP) or creatinine also improved the risk stratification. The plausible mechanisms are renal dysfunction, inflammation or a direct effect of cystatin C on ventricular remodeling. Either alone or in combination, cystatin C is a better, accurate and a reliable biomarker for HF prognosis. ^

Regression with autocorrelated data: A study of time trend of global infant mortality rate

The infant mortality rate (IMR) is considered to be one of the most important indices of a country's well-being. Countries around the world and other health organizations like the World Health Organization are dedicating their resources, knowledge and energy to reduce the infant mortality rates. The well-known Millennium Development Goal 4 (MDG 4), whose aim is to archive a two thirds reduction of the under-five mortality rate between 1990 and 2015, is an example of the commitment. ^ In this study our goal is to model the trends of IMR between the 1950s to 2010s for selected countries. We would like to know how the IMR is changing overtime and how it differs across countries. ^ IMR data collected over time forms a time series. The repeated observations of IMR time series are not statistically independent. So in modeling the trend of IMR, it is necessary to account for these correlations. We proposed to use the generalized least squares method in general linear models setting to deal with the variance-covariance structure in our model. In order to estimate the variance-covariance matrix, we referred to the time-series models, especially the autoregressive and moving average models. Furthermore, we will compared results from general linear model with correlation structure to that from ordinary least squares method without taking into account the correlation structure to check how significantly the estimates change.^

Effect of the temperature, strain rate and microstructure on flow and fracture characteristics of Ti-45Al-2Nb-2Mn+0.8vol.% TiB2 XD alloy

A series of quasi-static and dynamic tensile tests at varying temperatures were carried out to determine the mechanical behaviour of Ti-45Al-2Nb-2Mn+0.8vol.% TiB2 XD as-HIPed alloy. The temperature for the tests ranged from room temperature to 850  ∘C. The effect of the temperature on the ultimate tensile strength, as expected, was almost negligible within the selected temperature range. Nevertheless, the plastic flow suffered some softening because of the temperature. This alloy presents a relatively low ductility; thus, a low tensile strain to failure. The dynamic tests were performed in a Split Hopkinson Tension Bar, showing an increase of the ultimate tensile strength due to the strain rate hardening effect. Johnson-Cook constitutive relation was used to model the plastic flow. A post-testing microstructural of the specimens revealed an inhomogeneous structure, consisting of lamellar α2 + γ structure and γ phase equiaxed grains in the centre, and a fully lamellar structure on the rest. The assessment of the duplex-fully lamellar area ratio showed a clear relationship between the microstructure and the fracture behaviour.

Mechanical behavior and deformation micromechanisms of polypropylene nonwoven fabrics as a function of temperature and strain rate

The mechanical behavior and the deformation and failure micromechanisms of a thermally-bonded polypropylene nonwoven fabric were studied as a function of temperature and strain rate. Mechanical tests were carried out from 248 K (below the glass transition temperature) up to 383 K at strain rates in the range ≈10−3 s−1 to 10−1 s−1. In addition, individual fibers extracted from the nonwoven fabric were tested under the same conditions. Micromechanisms of deformation and failure at the fiber level were ascertained by means of mechanical tests within the scanning electron microscope while the strain distribution at the macroscopic level upon loading was determined by means of digital image correlation. It was found that the nonwoven behavior was mainly controlled by the properties of the fibers and of the interfiber bonds. Fiber properties determined the nonlinear behavior before the peak load while the interfiber bonds controlled the localization of damage after the peak load. The influence of these properties on the strength, ductility and energy absorbed during deformation is discussed from the experimental observations.

Strain rate effect on semi‐crystalline plla mechanical properties measured by instrumented indentation tests

Poly(L‐lactide) is a widely studied biomaterial, currently approved for use in a range of medical devices. Its mechanical properties can be tailored giving the material different crystallinity degrees. PLLA presents a complex non‐linear behaviour that depends not only on structural parameters such as crystallinity degree but also on external parameters such as strain rate and temperature. Failure of polymeric implants is attributed to their intrinsic time‐dependent performance under static loading conditions.

Virulence of a Mycobacterium tuberculosis clinical isolate in mice is determined by failure to induce Th1 type immunity and is associated with induction of IFN-α/β

To understand how virulent mycobacteria subvert host immunity and establish disease, we examined the differential response of mice to infection with various human outbreak Mycobacterium tuberculosis clinical isolates. One clinical isolate, HN878, was found to be hypervirulent, as demonstrated by unusually early death of infected immune-competent mice, compared with infection with other clinical isolates. The differential effect on survival required lymphocyte function because severe combined immunodeficiency (SCID) mice infected with HN878 or other clinical isolates all died at the same rate. The hypervirulence of HN878 was associated with failure to induce M. tuberculosis-specific proliferation and IFN-γ production by spleen and lymph node cells from infected mice. In addition, 2- to 4-fold lower levels of tumor necrosis factor-α (TNF-α), IL-6, IL-12, and IFN-γ mRNAs were observed in lungs of HN878-infected mice. IL-10, IL-4, and IL-5 mRNA levels were not significantly elevated in lungs of HN878 infected mice. In contrast, IFN-α mRNA levels were significantly higher in lungs of these mice. To further investigate the role of Type 1 IFNs, mice infected with HN878 were treated intranasally with purified IFN-α/β. The treatment resulted in increased lung bacillary loads and even further reduced survival. These results suggest that the hypervirulence of HN878 may be due to failure of this strain to stimulate Th1 type immunity. In addition, the lack of development of Th1 immunity in response to HN878 appears to be associated with increased induction of Type 1 IFNs.

Cardiac βARK1 inhibition prolongs survival and augments β blocker therapy in a mouse model of severe heart failure

Chronic human heart failure is characterized by abnormalities in β-adrenergic receptor (βAR) signaling, including increased levels of βAR kinase 1 (βARK1), which seems critical to the pathogenesis of the disease. To determine whether inhibition of βARK1 is sufficient to rescue a model of severe heart failure, we mated transgenic mice overexpressing a peptide inhibitor of βARK1 (βARKct) with transgenic mice overexpressing the sarcoplasmic reticulum Ca2+-binding protein, calsequestrin (CSQ). CSQ mice have a severe cardiomyopathy and markedly shortened survival (9 ± 1 weeks). In contrast, CSQ/βARKct mice exhibited a significant increase in mean survival age (15 ± 1 weeks; P < 0.0001) and showed less cardiac dilation, and cardiac function was significantly improved (CSQ vs. CSQ/βARKct, left ventricular end diastolic dimension 5.60 ± 0.17 mm vs. 4.19 ± 0.09 mm, P < 0.005; % fractional shortening, 15 ± 2 vs. 36 ± 2, P < 0.005). The enhancement of the survival rate in CSQ/βARKct mice was substantially potentiated by chronic treatment with the βAR antagonist metoprolol (CSQ/βARKct nontreated vs. CSQ/βARKct metoprolol treated, 15 ± 1 weeks vs. 25 ± 2 weeks, P < 0.0001). Thus, overexpression of the βARKct resulted in a marked prolongation in survival and improved cardiac function in a mouse model of severe cardiomyopathy that can be potentiated with β-blocker therapy. These data demonstrate a significant synergy between an established heart-failure treatment and the strategy of βARK1 inhibition.

Atrial-like phenotype is associated with embryonic ventricular failure in retinoid X receptor alpha -/- mice.

We have recently characterized a cardiac model of ventricular chamber defects in retinoid X receptor alpha (RXR alpha) homozygous mutant (-/-) gene-targeted mice. These mice display generalized edema, ventricular chamber hypoplasia, and muscular septal defects, and they die at embryonic day 15. To substantiate our hypothesis that the embryos are dying of cardiac pump failure, we have used digital bright-field and fluorescent video microscopy and in vivo microinjection of fluorescein-labeled albumin to analyze cardiac function. The affected embryos showed depressed ventricular function (average left ventricular area ejection fraction, 14%), ventricular septal defects, and various degrees of atrioventricular block not seen in the RXR alpha wild-type (+/+) and heterozygous (+/-) littermates (average left ventricular area ejection fraction, 50%). The molecular mechanisms involved in these ventricular defects were studied by evaluating expression of cardiac-specific genes known to be developmentally regulated. By in situ hybridization, aberrant, persistent expression of the atrial isoform of myosin light chain 2 was identified in the ventricles. We hypothesize that retinoic acid provides a critical signal mediated through the RXR alpha pathway that is required to allow progression of development of the ventricular region of the heart from its early atrial-like form to the thick-walled adult ventricle. The conduction system disturbances found in the RXR alpha -/- embryos may reflect a requirement of the developing conduction system for the RXR alpha signaling pathway, or it may be secondary to the failure of septal development.

Estimating and forecasting generalized fractional Long memory stochastic volatility models

In recent years fractionally differenced processes have received a great deal of attention due to its flexibility in financial applications with long memory. This paper considers a class of models generated by Gegenbauer polynomials, incorporating the long memory in stochastic volatility (SV) components in order to develop the General Long Memory SV (GLMSV) model. We examine the statistical properties of the new model, suggest using the spectral likelihood estimation for long memory processes, and investigate the finite sample properties via Monte Carlo experiments. We apply the model to three exchange rate return series. Overall, the results of the out-of-sample forecasts show the adequacy of the new GLMSV model.

Unit graph and loss rate optimization : Hydrologic Engineering Center computer program 23-J2-L211.

At head of title : Generalized computer program.

Mollusca Non-Grata: The influence of top-down control and residence time on the abundance, distribution, and behavior of non-native marine snails in Washington State

Thesis (Ph.D.)--University of Washington, 2016-06

Expression of the HPV16E7 oncoprotein by thymic epithelium is accompanied by disrupted T cell maturation and a failure of the thymus to involute with age

Transgenic mice expressing the E7 protein of HPV16 from the keratin 14 promoter demonstrate increasing thymic hypertrophy with age. This hypertrophy is associated with increased absolute numbers of all thymocyte types, and with increased cortical and medullary cellularity. In the thymic medulla, increased compartmentalization of the major thymic stromal cell types and expansion of thymic epithelial cell population is observed. Neither an increased rate of immature thymocyte division nor a decreased rate of immature thymocyte death was able to account for the observed hypertrophy. Thymocytes with reduced levels of expression of CD4 and/or CD8 were more abundant in transgenic (tg) mice and became increasingly more so with age. These thymic SP and DP populations with reduced levels of CD4 and/or CD8 markers had a lower rate of apoptosis in the tg than in the non-tg mice. The rate of export of mature thymocytes to peripheral lymphoid organs was less in tg animals relative to the pool of available mature cells, particularly for the increasingly abundant CD4lo population. We therefore suggest that mature thymocytes that would normally die in the thymus gradually accumulated in E7 transgenic animals, perhaps as a consequence of exposure to a hypertrophied E7-expressing thymic epithelium or to factors secreted by this expanded thymic stromal cell population. The K14E7 transgenic mouse thus provides a unique model to study effects of the thymic epithelial cell compartment on thymus development and involution.

Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure

Background - Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results - Thirty medically treated ambulatory hypertensive patients (19 women, age 62 +/- 6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31 +/- 5 kg/m(2)) with reduced treadmill exercise capacity (6.7 +/- 2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133 +/- 17/80 +/- 7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57 +/- 0.46 s(-1) versus 6-months: -1.91 +/- 0.36 s(-1), P < 0.01), peak systolic strain (-20.3 &PLUSMN; 5.0% versus -26.9 &PLUSMN; 4.3%, P < 0.001), and CVIB (7.4 +/- 1.7dB versus 8.6 +/- 1.7 dB, P = 0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P = 0.05, P = 0.02, and P = 0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P = 0.04) and a trend to reduced left atrial area (P = 0.09). Conclusions - Aldosterone antagonism improves myocardial function in hypertensive heart disease.