Neurological Prognostication after Cardiac Arrest and Therapeutic Hypothermia: a Prospective Validation Study

Introduction: Clinical examination and electroencephalography study (EEG) have been recommended to predict functional recovery in comatose survivors of cardiac arrest (CA), however their prognostic value in patients treated with induced hypothermia (IH) has not been evaluated. Hypothesis: We aimed to validate the prognostic ability of clinical examination and EEG in predicting outcome of patients with coma after CA treated with IH and sought to derive a score with high predictive value for poor functional outcome in this setting. Methods: We prospectively studied 100 consecutive comatose survivors of CA treated with IH. Repeated neurological examination and EEG were performed early after passive rewarming and off sedation. Mortality was assessed at hospital discharge, and functional outcome at 3 to 6 months with Cerebral Performance Categories (CPC), and was dichotomized as good (CPC 1-2) vs. poor (CPC 3-5). Independent predictors of outcome were identified by multivariable logistic regression and used to assess the prognostic value of a Reproducible Electro-clinical Prognosticators of Outcome Score (REPOS). Results: Patients (20/100) with good outcome had all a reactive EEG background. Incomplete recovery of brainstem reflexes, myoclonus, time to return of spontaneous circulation (ROSC) > 25 min, and unreactive EEG background were all independent predictors of death and severe disability, and were added to construct the REPOS. Using a cut-off of 0 or 1 variables for good vs. 2 to 4 for poor outcome, the REPOS had a positive predictive value of 1.00 (95% CI: 0.92-1.00), a negative predictive value of 0.43 (95% CI: 0.29-0.58) and an accuracy of 0.81 for poor functional recovery at 3 to 6 months. Conclusions: In comatose survivors of CA treated with IH, a prognostic score, including clinical and EEG examination, was highly predictive of death and poor functional outcome at 3 to 6 months. Lack of EEG background reactivity strongly predicted poor neurological recovery after CA. Our findings show that clinical and electrophysiological studies are effective in predicting long-term outcome of comatose survivors after CA and IH, and suggest that EEG improves early prognostic assessment in the setting of therapeutic cooling.

Ruling out coronary artery disease in primary care: development and validation of a simple prediction rule.

BACKGROUND: Chest pain can be caused by various conditions, with life-threatening cardiac disease being of greatest concern. Prediction scores to rule out coronary artery disease have been developed for use in emergency settings. We developed and validated a simple prediction rule for use in primary care. METHODS: We conducted a cross-sectional diagnostic study in 74 primary care practices in Germany. Primary care physicians recruited all consecutive patients who presented with chest pain (n = 1249) and recorded symptoms and findings for each patient (derivation cohort). An independent expert panel reviewed follow-up data obtained at six weeks and six months on symptoms, investigations, hospital admissions and medications to determine the presence or absence of coronary artery disease. Adjusted odds ratios of relevant variables were used to develop a prediction rule. We calculated measures of diagnostic accuracy for different cut-off values for the prediction scores using data derived from another prospective primary care study (validation cohort). RESULTS: The prediction rule contained five determinants (age/sex, known vascular disease, patient assumes pain is of cardiac origin, pain is worse during exercise, and pain is not reproducible by palpation), with the score ranging from 0 to 5 points. The area under the curve (receiver operating characteristic curve) was 0.87 (95% confidence interval [CI] 0.83-0.91) for the derivation cohort and 0.90 (95% CI 0.87-0.93) for the validation cohort. The best overall discrimination was with a cut-off value of 3 (positive result 3-5 points; negative result <or= 2 points), which had a sensitivity of 87.1% (95% CI 79.9%-94.2%) and a specificity of 80.8% (77.6%-83.9%). INTERPRETATION: The prediction rule for coronary artery disease in primary care proved to be robust in the validation cohort. It can help to rule out coronary artery disease in patients presenting with chest pain in primary care.

Identification and validation of copy number variants using SNP genotyping arrays from a large clinical cohort.

BACKGROUND: Genotypes obtained with commercial SNP arrays have been extensively used in many large case-control or population-based cohorts for SNP-based genome-wide association studies for a multitude of traits. Yet, these genotypes capture only a small fraction of the variance of the studied traits. Genomic structural variants (GSV) such as Copy Number Variation (CNV) may account for part of the missing heritability, but their comprehensive detection requires either next-generation arrays or sequencing. Sophisticated algorithms that infer CNVs by combining the intensities from SNP-probes for the two alleles can already be used to extract a partial view of such GSV from existing data sets. RESULTS: Here we present several advances to facilitate the latter approach. First, we introduce a novel CNV detection method based on a Gaussian Mixture Model. Second, we propose a new algorithm, PCA merge, for combining copy-number profiles from many individuals into consensus regions. We applied both our new methods as well as existing ones to data from 5612 individuals from the CoLaus study who were genotyped on Affymetrix 500K arrays. We developed a number of procedures in order to evaluate the performance of the different methods. This includes comparison with previously published CNVs as well as using a replication sample of 239 individuals, genotyped with Illumina 550K arrays. We also established a new evaluation procedure that employs the fact that related individuals are expected to share their CNVs more frequently than randomly selected individuals. The ability to detect both rare and common CNVs provides a valuable resource that will facilitate association studies exploring potential phenotypic associations with CNVs. CONCLUSION: Our new methodologies for CNV detection and their evaluation will help in extracting additional information from the large amount of SNP-genotyping data on various cohorts and use this to explore structural variants and their impact on complex traits.

Ruling out coronary heart disease in primary care: external validation of a clinical prediction rule.

BACKGROUND: The Marburg Heart Score (MHS) aims to assist GPs in safely ruling out coronary heart disease (CHD) in patients presenting with chest pain, and to guide management decisions. AIM: To investigate the diagnostic accuracy of the MHS in an independent sample and to evaluate the generalisability to new patients. DESIGN AND SETTING: Cross-sectional diagnostic study with delayed-type reference standard in general practice in Hesse, Germany. METHOD: Fifty-six German GPs recruited 844 males and females aged ≥ 35 years, presenting between July 2009 and February 2010 with chest pain. Baseline data included the items of the MHS. Data on the subsequent course of chest pain, investigations, hospitalisations, and medication were collected over 6 months and were reviewed by an independent expert panel. CHD was the reference condition. Measures of diagnostic accuracy included the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, likelihood ratios, and predictive values. RESULTS: The AUC was 0.84 (95% confidence interval [CI] = 0.80 to 0.88). For a cut-off value of 3, the MHS showed a sensitivity of 89.1% (95% CI = 81.1% to 94.0%), a specificity of 63.5% (95% CI = 60.0% to 66.9%), a positive predictive value of 23.3% (95% CI = 19.2% to 28.0%), and a negative predictive value of 97.9% (95% CI = 96.2% to 98.9%). CONCLUSION: Considering the diagnostic accuracy of the MHS, its generalisability, and ease of application, its use in clinical practice is recommended.

La validation des techniques en chirurgie laparoscopique [Validation of laparoscopic surgical techniques].

The use of laparoscopic surgery has increased rapidly. However, a technically feasible procedure is not automatically recommendable. Thus, if cholecystectomy and fundoplication are currently fully validated techniques, this does not hold true for gastroplasty and kidney harvesting for transplantation: these operations are feasible indeed but their efficacy remains to be proved. Laparoscopic oncology has been shown to be feasible too, but its efficacy has not been documented yet.

Validation of two echocardiographic indexes to improve the diagnosis of complex coarctations.

OBJECTIVES: Coarctation of the aorta is one of the most common congenital heart defects. Its diagnosis may be difficult in the presence of a patent ductus arteriosus, of other complex defects or of a poor echocardiographic window. We sought to demonstrate that the carotid-subclavian artery index (CSA index) and the isthmus-descending aorta ratio (I/D ratio), two recently described echocardiographic indexes, are effective in detection of isolated and complex aortic coarctations in children younger and older than 3 months of age. The CSA index is the ratio of the distal aortic arch diameter to the distance between the left carotid artery and the left subclavian artery. It is highly suggestive of a coarctation when it is <1.5. The I/D ratio defined as the diameter of the isthmus to the diameter of the descending aorta, suggests an aortic coarctation when it is less than 0.64. METHODS: This is a retrospective cohort study in a tertiary care children's hospital. Review of all echocardiograms in children aged 0-18 years with a diagnosis of coarctation seen at the author's institution between 1996 and 2006. An age- and sex-matched control group without coarctation was constituted. Offline echocardiographic measurements of the aortic arch were performed in order to calculate the CSA index and I/D ratio. RESULTS: Sixty-eight patients were included in the coarctation group, 24 in the control group. Patients with coarctation had a significantly lower CSA index (0.84+/-0.39 vs 2.65+/-0.82, p<0.0001) and I/D ratio (0.58+/-0.18 vs 0.98+/-0.19, p<0.0001) than patients in the control group. Associated cardiac defects and age of the child did not significantly alter the CSA index or the I/D ratio. CONCLUSIONS: A CSA index less than 1.5 is highly suggestive of coarctation independent of age and of the presence of other cardiac defects. I/D ratio alone is less specific than CSA alone at any age and for any associated cardiac lesion. The association of both indexes improves sensitivity and permits diagnosis of coarctation in all patients based solely on a bedside echocardiographic measurement.

Etude de validation du "Michigan alcoholism screening test" (MAST) en langue française

Le but de cette étude est de répondre aux 3 questions suivantes: - 1) Le test de MAST est-il applicable, dans sa traduction française, à la population d'un service de médecine interne d'un hôpital universitaire en Suisse romande ? - 2) Le test de MAST apporte-t-il des résultats concordants avec le diagnostic clinique d'une part, et avec les résultats tirés de la littérature d'autre part ? - 3) De quelles façons peut-on définir et choisir deux valeurs critiques du test afin d'optimaliser l'utilisation du test de MAST dans l'étude comparative projetée ? ANNEXE: Traduction littérale en langue française du : "Michigan Alcoholism Screening Test" (MAST); etc.

Translation and validation of the Ten-Item-Personality Inventory into spanish and catalan

In response to an increasing need for ever-shorter personality instruments, Gosling, Rentfrow, and Swann (2003) developed the Ten-Item-Personality Inventory (TIPI), which measures the dimensions of the Five Factor Model (FFM) using 10 items (two for each dimension) and can be administered in about one minute. In two studies and using a multi-judge (self and observer) and multi-instrument design, we develop Spanish (Castilian) and Catalan versions of the TIPI and evaluate them in terms of internal consistency, test-retest reliability, convergent, discriminant, and content validity, as well as self-observer correlations. Test-retest correlations were strong, and convergence with the NEO-PI-R factors was significant. There were also strong correlations between observer ratings and the participants’ self-ratings. Despite some inconsistencies with respect to the Agreeableness scale, the Catalan translation and both translations into Spanish of the original TIPI demonstrated sufficient psychometric properties to warrant use as a Five Factor personality measure when the use of longer instruments is not convenient or possible. Furthermore, as the first translation of a brief standard Big Five Instrument into Catalan, this work should facilitate future research on personality in the Catalan-speaking population.

Development process and initial validation of the ethical conflict in nursing questionnaire-critical care version

Background: Ethical conflicts are arising as a result of the growing complexity of clinical care, coupled with technological advances. Most studies that have developed instruments for measuring ethical conflict base their measures on the variables"frequency" and"degree of conflict". In our view, however, these variables are insufficient for explaining the root of ethical conflicts. Consequently, the present study formulates a conceptual model that also includes the variable"exposure to conflict", as well as considering six"types of ethical conflict". An instrument was then designed to measure the ethical conflicts experienced by nurses who work with critical care patients. The paper describes the development process and validation of this instrument, the Ethical Conflict in Nursing Questionnaire Critical Care Version (ECNQ-CCV). Methods: The sample comprised 205 nursing professionals from the critical care units of two hospitals in Barcelona (Spain). The ECNQ-CCV presents 19 nursing scenarios with the potential to produce ethical conflict in the critical care setting. Exposure to ethical conflict was assessed by means of the Index of Exposure to Ethical Conflict (IEEC), a specific index developed to provide a reference value for each respondent by combining the intensity and frequency of occurrence of each scenario featured in the ECNQ-CCV. Following content validity, construct validity was assessed by means of Exploratory Factor Analysis (EFA), while Cronbach"s alpha was used to evaluate the instrument"s reliability. All analyses were performed using the statistical software PASW v19. Results: Cronbach"s alpha for the ECNQ-CCV as a whole was 0.882, which is higher than the values reported for certain other related instruments. The EFA suggested a unidimensional structure, with one component accounting for 33.41% of the explained variance. Conclusions: The ECNQ-CCV is shown to a valid and reliable instrument for use in critical care units. Its structure is such that the four variables on which our model of ethical conflict is based may be studied separately or in combination. The critical care nurses in this sample present moderate levels of exposure to ethical conflict. This study represents the first evaluation of the ECNQ-CCV.

Development process and initial validation of the ethical conflict in nursing questionnaire-critical care version

Background: Ethical conflicts are arising as a result of the growing complexity of clinical care, coupled with technological advances. Most studies that have developed instruments for measuring ethical conflict base their measures on the variables"frequency" and"degree of conflict". In our view, however, these variables are insufficient for explaining the root of ethical conflicts. Consequently, the present study formulates a conceptual model that also includes the variable"exposure to conflict", as well as considering six"types of ethical conflict". An instrument was then designed to measure the ethical conflicts experienced by nurses who work with critical care patients. The paper describes the development process and validation of this instrument, the Ethical Conflict in Nursing Questionnaire Critical Care Version (ECNQ-CCV). Methods: The sample comprised 205 nursing professionals from the critical care units of two hospitals in Barcelona (Spain). The ECNQ-CCV presents 19 nursing scenarios with the potential to produce ethical conflict in the critical care setting. Exposure to ethical conflict was assessed by means of the Index of Exposure to Ethical Conflict (IEEC), a specific index developed to provide a reference value for each respondent by combining the intensity and frequency of occurrence of each scenario featured in the ECNQ-CCV. Following content validity, construct validity was assessed by means of Exploratory Factor Analysis (EFA), while Cronbach"s alpha was used to evaluate the instrument"s reliability. All analyses were performed using the statistical software PASW v19. Results: Cronbach"s alpha for the ECNQ-CCV as a whole was 0.882, which is higher than the values reported for certain other related instruments. The EFA suggested a unidimensional structure, with one component accounting for 33.41% of the explained variance. Conclusions: The ECNQ-CCV is shown to a valid and reliable instrument for use in critical care units. Its structure is such that the four variables on which our model of ethical conflict is based may be studied separately or in combination. The critical care nurses in this sample present moderate levels of exposure to ethical conflict. This study represents the first evaluation of the ECNQ-CCV.

Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies

Background: Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics. Objective: To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias. Design, Setting, and Participants: A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArrayH NT Cycler. Outcome Measurements and Statistical Analysis: Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer. Results and Limitations: We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics. Conclusion: Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.

Quantitative multi-parameter mapping of R1, PD(*), MT, and R2(*) at 3T: a multi-center validation.

Multi-center studies using magnetic resonance imaging facilitate studying small effect sizes, global population variance and rare diseases. The reliability and sensitivity of these multi-center studies crucially depend on the comparability of the data generated at different sites and time points. The level of inter-site comparability is still controversial for conventional anatomical T1-weighted MRI data. Quantitative multi-parameter mapping (MPM) was designed to provide MR parameter measures that are comparable across sites and time points, i.e., 1 mm high-resolution maps of the longitudinal relaxation rate (R1 = 1/T1), effective proton density (PD(*)), magnetization transfer saturation (MT) and effective transverse relaxation rate (R2(*) = 1/T2(*)). MPM was validated at 3T for use in multi-center studies by scanning five volunteers at three different sites. We determined the inter-site bias, inter-site and intra-site coefficient of variation (CoV) for typical morphometric measures [i.e., gray matter (GM) probability maps used in voxel-based morphometry] and the four quantitative parameters. The inter-site bias and CoV were smaller than 3.1 and 8%, respectively, except for the inter-site CoV of R2(*) (<20%). The GM probability maps based on the MT parameter maps had a 14% higher inter-site reproducibility than maps based on conventional T1-weighted images. The low inter-site bias and variance in the parameters and derived GM probability maps confirm the high comparability of the quantitative maps across sites and time points. The reliability, short acquisition time, high resolution and the detailed insights into the brain microstructure provided by MPM makes it an efficient tool for multi-center imaging studies.

Computational analysis of the genetic and environmental contributions to disease-related human phenotypes: From predicting adverse lipid response of HIV patients receiving antiretroviral therapy to genome-wide association studies of cardiovascular and lipid related disorders

Genetic variants influence the risk to develop certain diseases or give rise to differences in drug response. Recent progresses in cost-effective, high-throughput genome-wide techniques, such as microarrays measuring Single Nucleotide Polymorphisms (SNPs), have facilitated genotyping of large clinical and population cohorts. Combining the massive genotypic data with measurements of phenotypic traits allows for the determination of genetic differences that explain, at least in part, the phenotypic variations within a population. So far, models combining the most significant variants can only explain a small fraction of the variance, indicating the limitations of current models. In particular, researchers have only begun to address the possibility of interactions between genotypes and the environment. Elucidating the contributions of such interactions is a difficult task because of the large number of genetic as well as possible environmental factors.In this thesis, I worked on several projects within this context. My first and main project was the identification of possible SNP-environment interactions, where the phenotypes were serum lipid levels of patients from the Swiss HIV Cohort Study (SHCS) treated with antiretroviral therapy. Here the genotypes consisted of a limited set of SNPs in candidate genes relevant for lipid transport and metabolism. The environmental variables were the specific combinations of drugs given to each patient over the treatment period. My work explored bioinformatic and statistical approaches to relate patients' lipid responses to these SNPs, drugs and, importantly, their interactions. The goal of this project was to improve our understanding and to explore the possibility of predicting dyslipidemia, a well-known adverse drug reaction of antiretroviral therapy. Specifically, I quantified how much of the variance in lipid profiles could be explained by the host genetic variants, the administered drugs and SNP-drug interactions and assessed the predictive power of these features on lipid responses. Using cross-validation stratified by patients, we could not validate our hypothesis that models that select a subset of SNP-drug interactions in a principled way have better predictive power than the control models using "random" subsets. Nevertheless, all models tested containing SNP and/or drug terms, exhibited significant predictive power (as compared to a random predictor) and explained a sizable proportion of variance, in the patient stratified cross-validation context. Importantly, the model containing stepwise selected SNP terms showed higher capacity to predict triglyceride levels than a model containing randomly selected SNPs. Dyslipidemia is a complex trait for which many factors remain to be discovered, thus missing from the data, and possibly explaining the limitations of our analysis. In particular, the interactions of drugs with SNPs selected from the set of candidate genes likely have small effect sizes which we were unable to detect in a sample of the present size (<800 patients).In the second part of my thesis, I performed genome-wide association studies within the Cohorte Lausannoise (CoLaus). I have been involved in several international projects to identify SNPs that are associated with various traits, such as serum calcium, body mass index, two-hour glucose levels, as well as metabolic syndrome and its components. These phenotypes are all related to major human health issues, such as cardiovascular disease. I applied statistical methods to detect new variants associated with these phenotypes, contributing to the identification of new genetic loci that may lead to new insights into the genetic basis of these traits. This kind of research will lead to a better understanding of the mechanisms underlying these pathologies, a better evaluation of disease risk, the identification of new therapeutic leads and may ultimately lead to the realization of "personalized" medicine.

Experimental thermal hydraulic studies on the enhancement of safety of LWRs

The safe use of nuclear power plants (NPPs) requires a deep understanding of the functioning of physical processes and systems involved. Studies on thermal hydraulics have been carried out in various separate effects and integral test facilities at Lappeenranta University of Technology (LUT) either to ensure the functioning of safety systems of light water reactors (LWR) or to produce validation data for the computer codes used in safety analyses of NPPs. Several examples of safety studies on thermal hydraulics of the nuclear power plants are discussed. Studies are related to the physical phenomena existing in different processes in NPPs, such as rewetting of the fuel rods, emergency core cooling (ECC), natural circulation, small break loss-of-coolant accidents (SBLOCA), non-condensable gas release and transport, and passive safety systems. Studies on both VVER and advanced light water reactor (ALWR) systems are included. The set of cases include separate effects tests for understanding and modeling a single physical phenomenon, separate effects tests to study the behavior of a NPP component or a single system, and integral tests to study the behavior of the whole system. In the studies following steps can be found, not necessarily in the same study. Experimental studies as such have provided solutions to existing design problems. Experimental data have been created to validate a single model in a computer code. Validated models are used in various transient analyses of scaled facilities or NPPs. Integral test data are used to validate the computer codes as whole, to see how the implemented models work together in a code. In the final stage test results from the facilities are transferred to the NPP scale using computer codes. Some of the experiments have confirmed the expected behavior of the system or procedure to be studied; in some experiments there have been certain unexpected phenomena that have caused changes to the original design to avoid the recognized problems. This is the main motivation for experimental studies on thermal hydraulics of the NPP safety systems. Naturally the behavior of the new system designs have to be checked with experiments, but also the existing designs, if they are applied in the conditions that differ from what they were originally designed for. New procedures for existing reactors and new safety related systems have been developed for new nuclear power plant concepts. New experiments have been continuously needed.

Evaluation of a piezoelectric system as an alternative to electroencephalogram/ electromyogram recordings in mouse sleep studies.

STUDY OBJECTIVES: Traditionally, sleep studies in mammals are performed using electroencephalogram/electromyogram (EEG/EMG) recordings to determine sleep-wake state. In laboratory animals, this requires surgery and recovery time and causes discomfort to the animal. In this study, we evaluated the performance of an alternative, noninvasive approach utilizing piezoelectric films to determine sleep and wakefulness in mice by simultaneous EEG/EMG recordings. The piezoelectric films detect the animal's movements with high sensitivity and the regularity of the piezo output signal, related to the regular breathing movements characteristic of sleep, serves to automatically determine sleep. Although the system is commercially available (Signal Solutions LLC, Lexington, KY), this is the first statistical validation of various aspects of sleep. DESIGN: EEG/EMG and piezo signals were recorded simultaneously during 48 h. SETTING: Mouse sleep laboratory. PARTICIPANTS: Nine male and nine female CFW outbred mice. INTERVENTIONS: EEG/EMG surgery. MEASUREMENTS AND RESULTS: The results showed a high correspondence between EEG/EMG-determined and piezo-determined total sleep time and the distribution of sleep over a 48-h baseline recording with 18 mice. Moreover, the piezo system was capable of assessing sleep quality (i.e., sleep consolidation) and interesting observations at transitions to and from rapid eye movement sleep were made that could be exploited in the future to also distinguish the two sleep states. CONCLUSIONS: The piezo system proved to be a reliable alternative to electroencephalogram/electromyogram recording in the mouse and will be useful for first-pass, large-scale sleep screens for genetic or pharmacological studies. CITATION: Mang GM, Nicod J, Emmenegger Y, Donohue KD, O'Hara BF, Franken P. Evaluation of a piezoelectric system as an alternative to electroencephalogram/electromyogram recordings in mouse sleep studies.