Evaluation and optimal utilisation of the international linear type classification schemes

End of project reportThe authors would like to acknowledge the Irish Cattle Breeding Federation for access to their excellent database for use in this study and to the Irish Holstein-Friesian Association for financial support of this studyThe main objectives of this study were: 1) to evaluate the phenotypic associations between linear type traits and survival in New Zealand and identify potential new traits for inclusion in the type classification scheme in Ireland, and 2) to quantify the potential of linear type traits scored in Ireland as early predictors of genetic merit for fertility and survival in Ireland

A multicenter comparison between Child Pugh and ALBI scores in patients treated with sorafenib for hepatocellular carcinoma

Background & aims: The ALBI grade was proposed as an objective means to evaluate liver function in patients with Hepatocellular Carcinoma (HCC). ALBI grade 1 vs 2 were proposed as stratification factors within the Child Pugh (CP) A class. However, the original publication did not provide comparison with the sub-classification by points (5 to 15) within the CP classification. Methods: We retrospectively analyzed data from patients treated with sorafenib for HCC from 17 centers in United Kingdom and France. Overall survival (OS) was analyzed with the Kaplan-Meier method and a Cox regression model. Discriminatory abilities of the classifications were assessed with the log likelihood ratio, Harrell’s C statistics and Akaike information criterion. Results: Data from 1,019 patients were collected, of which 905 could be assessed for both scores. 92% of ALBI grade 1 were CP A5 while ALBI 2 included a broad range of CP scores of which 44% were CP A6. Median OS was 10.2, 7.0 and 3.6 months for CP scores A5, A6 and >A6, respectively (P<0.001), Hazard Ratio (HR)=1.60 (95%CI: 1.35-1.89, P<0.001) for A6 vs A5. Median OS was 10.9, 6.6 and 3.0 months for ALBI grade 1, 2 and 3, respectively (P<0.001), HR=1.68 (1.43-1.97, P<0.001) for grade 2 vs 1. Discriminatory abilities of CP and ALBI were similar in the CP A population, but better for CP in the overall population. Conclusions: Our findings support the use CP class A as an inclusion criterion, and ALBI as a stratification factor in trials of systemic therapy

Intrarenal Resistance Index as a Prognostic Parameter in Patients with Liver Cirrhosis Compared with Other Hepatic Scoring Systems

Background and Aims: Patients with advanced liver cirrhosis who develop renal dysfunction have a poor prognosis. Elevated intrarenal resistance indices (RIs) due to renal vascular constriction have been described before in cirrhotic patients. In the current study, we prospectively investigated the course of intrarenal RIs and compared their prognostic impact with those of the Model for End-Stage Liver Disease (MELD) and the Child-Pugh scores. Methods: Sixty-three patients with liver cirrhosis underwent a baseline visit which included a sonographic examination and laboratory tests. Forty-four patients were prospectively monitored. The end points were death or survival at the day of the follow-up visit. Results: In 28 patients, a follow-up visit was performed after 22 8 months (group 1). Sixteen patients died during follow-up after 12 8 months (group 2). Group 2 patients showed a significantly higher baseline RI (0.76 +/- 0.05) than group 1 patients (RI = 0.72 +/- 0.06; p < 0.05). As shown by receiver operating characteristic analysis, the RI and the MELD score achieved similar sensitivity and specificity {[}area under the curve (AUC): 0.722; 95% confidence interval (95% CI): 0.575-0.873 vs. AUC: 0.724; 95% CI: 0.575-0.873, z = 0.029, n.s.] in predicting survival and were superior to the Child-Pugh score (AUC: 0.677; 96% Cl: 0.518-0.837). Conclusion: The RI is not inferior in sensitivity and specificity to the MELD score. Cirrhotic patients with elevated RIs have impaired short- and long-term survival. The RI may help identify high-risk patients that require special therapeutic care. Copyright (C) 2012 S. Karger AG, Base

Clinical Severity Score System in Dogs with Degenerative Mitral Valve Disease

BACKGROUND: Several risk factors already have been determined for dogs with degenerative mitral valve disease (DMVD). Risk factors often have been considered in isolation and have not always taken into account additional information provided by the history and physical examination (PE). HYPOTHESIS/OBJECTIVES: Data obtained from history and PE of dogs with DMVD provide prognostic information and can be used for risk stratification. ANIMALS: Client‐owned dogs (n = 244) with DMVD recruited from first opinion practice. METHODS: Prospective longitudinal follow‐up of dogs with DMVD. History and PE data were obtained at 6‐month intervals and analyzed with time‐dependent Cox models to derive relative risk of cardiac death. Independent hazard ratios were used to derive a clinical severity score (CSS), the prognostic value of which was evaluated by analyzing the median survival times for different risk groups and ROC analysis. Analysis of the progression of CSS over time also was undertaken. RESULTS: History of cough, exercise intolerance, decreased appetite, breathlessness (difficulty breathing) and syncope with PE findings of heart murmur intensity louder than III/VI and absence of respiratory sinus arrhythmia were independently associated with outcome and allowed development of the CSS. Clinical severity score distinguished groups of dogs with significantly different outcomes. CONCLUSIONS AND CLINICAL IMPORTANCE: Routinely obtained clinical findings allow risk stratification of dogs with DMVD. Results of ancillary diagnostic tests may be complementary to history and PE findings and always should be interpreted in conjunction with these findings

Conditional Transformation Models

The ultimate goal of regression analysis is to obtain information about the conditional distribution of a response given a set of explanatory variables. This goal is, however, seldom achieved because most established regression models only estimate the conditional mean as a function of the explanatory variables and assume that higher moments are not affected by the regressors. The underlying reason for such a restriction is the assumption of additivity of signal and noise. We propose to relax this common assumption in the framework of transformation models. The novel class of semiparametric regression models proposed herein allows transformation functions to depend on explanatory variables. These transformation functions are estimated by regularised optimisation of scoring rules for probabilistic forecasts, e.g. the continuous ranked probability score. The corresponding estimated conditional distribution functions are consistent. Conditional transformation models are potentially useful for describing possible heteroscedasticity, comparing spatially varying distributions, identifying extreme events, deriving prediction intervals and selecting variables beyond mean regression effects. An empirical investigation based on a heteroscedastic varying coefficient simulation model demonstrates that semiparametric estimation of conditional distribution functions can be more beneficial than kernel-based non-parametric approaches or parametric generalised additive models for location, scale and shape

A Novel Long-term, Multi-Channel and Non-invasive Electrophysiology Platform for Zebrafish.

Zebrafish are a popular vertebrate model for human neurological disorders and drug discovery. Although fecundity, breeding convenience, genetic homology and optical transparency have been key advantages, laborious and invasive procedures are required for electrophysiological studies. Using an electrode-integrated microfluidic system, here we demonstrate a novel multichannel electrophysiology unit to record multiple zebrafish. This platform allows spontaneous alignment of zebrafish and maintains, over days, close contact between head and multiple surface electrodes, enabling non-invasive long-term electroencephalographic recording. First, we demonstrate that electrographic seizure events, induced by pentylenetetrazole, can be reliably distinguished from eye or tail movement artifacts, and quantifiably identified with our unique algorithm. Second, we show long-term monitoring during epileptogenic progression in a scn1lab mutant recapitulating human Dravet syndrome. Third, we provide an example of cross-over pharmacology antiepileptic drug testing. Such promising features of this integrated microfluidic platform will greatly facilitate high-throughput drug screening and electrophysiological characterization of epileptic zebrafish

Prognostic relevance of MMP-2 (72-kD collagenase IV) in gastric cancer

The association of MMP-2 (matrix metalloproteinase 2, 72-kD collagenase IV) with invasive and metastatic capacity of tumor cells has implicated a potential role in the prognosis for cancer patients. However, no larger study has been done to prove this hypothesis. The present study was therefore designed to investigate the prognostic impact of MMP-2 in a prospective series of 203 gastric cancer patients. MMP-2 expression was measured immunohistochemically and scored semiquantitatively (score 0-3) in carcinoma cells, and results were correlated with clinicopathological tumor parameters and parameters of the urokinase-type plasminogen activator (uPA) system. Survival analyses were done using the Kaplan-Meier method (log-rank statistics) and multivariate Cox analysis. Significant correlations were found for MMP-2 and Lauren's classification, M stage and proteases/inhibitors of the uPA system in the primary tumor. Kaplan-Meier analysis revealed an association of increasing MMP-2 expression with worse prognosis. This was especially seen in patients with a parallel high expression of uPA receptor. However, differences in survival probabilities between low and high MMP-2 levels were not significant. In a separate analysis of diffuse-type cancers, MMP-2 was significantly associated with disease-free (p = 0.0056) and overall survival (p = 0.0426). Multivariately, MMP-2 was not an independent parameter. Our results demonstrate that there is an association of immunohistochemical detection of MMP-2 with prognosis of cancer patients. For diffuse gastric cancers, it is a significant prognostic parameter, however, not of independent impact. The study further suggests that consideration of interrelated tumor-associated proteases like uPA receptor in combination with MMP-2 may improve its prognostic power