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Expanding indications for defibrillators after myocardial infarction: risk stratification and cost effectiveness.

Practice guidelines have expanded to include a new Class IIa recommendation for implantable cardiac defibrillator (ICD) use in patients post-myocardial infarction (MI) with a left ventricular ejection fraction (LVEF) </=30% on the basis of the results of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II). Given that over 3 million patients in North America meet these criteria and over 400,000 additional patients will meet these criteria every year, the potential costs to the healthcare system are substantial and possibly prohibitive. The results of MADIT II must be interpreted in the context of other studies. The benefits of ICD therapy may vary substantially across subgroups of MADIT II patients. Studies of amiodarone suggest that it may be useful if used in addition to beta-blockers, and the relative value of this therapy compared to ICD therapy remains to be elucidated. Subgroups of MADIT II patients with QRS duration >0.12 seconds or LVEF </=25% appear to derive the greatest benefit from ICD therapy. Cost-effectiveness depends on the magnitude of benefit expected and will differ across subgroups of patients with different levels of risk. Better risk stratification strategies are needed to predict which patients will benefit most. Results of ongoing studies will be crucial in determining the relative effectiveness of ICD compared to optimal medical therapy including the use of amiodarone and beta-blockers. Predictors of subsets of MADIT II patients most likely to benefit from ICD therapy are urgently needed in order to prioritize allocation of healthcare resources.

Canada↗

[Practice based evaluation and risk stratification of arterial hypertension. Focus on ECG].

Risk stratification and treatment decision of arterial hypertension is influenced by blood pressure grade, concomitant cardiovascular risk factors, associated clinical conditions and the presence of target organ damage. The general practitioner can completely evaluate many patients without referring them for special investigations. ECG is among the routine practice methods. The sensitivity in detecting left ventricular hypertrophy is low but the specificity is very high. The new ECG parameter Cornell Strain Index with higher sensitivity is presented.

Adult↗

Increased thermohaline stratification as a possible cause for an ocean anoxic event in the Cretaceous period.

Ocean anoxic events were periods of high carbon burial that led to drawdown of atmospheric carbon dioxide, lowering of bottom-water oxygen concentrations and, in many cases, significant biological extinction. Most ocean anoxic events are thought to be caused by high productivity and export of carbon from surface waters which is then preserved in organic-rich sediments, known as black shales. But the factors that triggered some of these events remain uncertain. Here we present stable isotope data from a mid-Cretaceous ocean anoxic event that occurred 112 Myr ago, and that point to increased thermohaline stratification as the probable cause. Ocean anoxic event 1b is associated with an increase in surface-water temperatures and runoff that led to decreased bottom-water formation and elevated carbon burial in the restricted basins of the western Tethys and North Atlantic. This event is in many ways similar to that which led to the more recent Plio-Pleistocene Mediterranean sapropels, but the greater geographical extent and longer duration (approximately 46 kyr) of ocean anoxic event 1b suggest that processes leading to such ocean anoxic events in the North Atlantic and western Tethys were able to act over a much larger region, and sequester far more carbon, than any of the Quaternary sapropels.

Animals↗

Single-substrate liquid-crystal displays by photo-enforced stratification.

Data visualization plays a crucial role in our society, as illustrated by the many displays that surround us. In the future, displays may become even more pervasive, ranging from individually addressable image-rendering wall hangings to data displays integrated in clothes. Liquid-crystal displays (LCDs) provide most of the flat-panel displays currently used. To keep pace with the ever-increasing possibilities afforded by developments in information technology, we need to develop manufacturing processes that will make LCDs cheaper and larger, with more freedom in design. Existing batch processes for making and filling LCD cells are relatively expensive, with size and shape limitations. Here we report a cost-effective, single-substrate technique in which a coated film is transformed into a polymer-covered liquid-crystal layer. This approach is based on photo-enforced stratification: a two-step photopolymerization-induced phase separation of a liquid-crystal blend and a polymer precursor. The process leads to the formation of micrometre-sized containers filled with a switchable liquid-crystal phase. In this way, displays can be produced on a variety of substrates using current coating technology. The developed process may be an important step towards new technologies such as 'display-on-anything' and 'paintable displays'.

Journal Article↗

Serum beta 2-microglobulin in myelomatosis: potential value in stratification and monitoring.

In a longitudinal study of the evolution of serum beta 2-microglobulin (beta 2-m) levels in 37 patients with myelomatosis, those patients with a level of < 4 mg/l at first presentation had a median survival of 46 months, whereas those with an initial level of > mg/l had a median survival of 15 months. THe beta 2-m appeared to be independent of the level of the paraprotein and its class, as seen in a vertical study of 129 patients. Analysis of the influence of a rising serum creatinine on the serum beta 2-m indicates that beta 2-m production is excessive in advanced disease with or without renal failure. Practical application of the measurement of serum beta 2-m in the stratification and monitoring of patients is suggested.

Beta-Globulins↗

Locus-specific stratification and prioritization unveil genetic risk mechanism underlying complex diseases.

Although genome-wide association studies have identified thousands of disease-associated loci, the mechanistic understanding and drug target discovery remain challenging, particularly for complex diseases. The multi-signal architecture of complex diseases complicates the interpretation of genetic contributions. To address this challenge, we develop an approach comprising locus-specific stratification (LSS) and gene regulatory prioritization score (GRPS), which uniquely considers multi-signals during fine-mapping and target gene identification. LSS significantly enhances the interpretability of genetic risk associated with complex diseases. For loci associated with serum urate levels, the method identifies candidate causal genes in 34.43% of loci, surpassing the performance of other methods by 5.47% to 25.14%. GRPS considers the regulatory network of LSS-variants comprehensively and successfully nominates under-explored drug targets for hyperuricemia with high confidence such as SLC17A4, which is further validated using epigenetic activation and phenotypic assays. This study introduces an approach to efficiently and comprehensively address the multi-signal challenges in complex diseases.

Humans↗

Genetic stratification of pathogen-response-related and other variants within a homogeneous Caucasian Irish population.

Selection pressures from pathogens impact on the worldwide geographic distribution of polymorphisms in certain pathogen-response-associated genes. Such gene-specific effects could lead to confounding by geographic disease associations. We wished to determine if such constraints impinge on the genetic structure of a population of Irish patients and whether variants associated with responses to pathogens showed greater stratification. The counties of origin of each subject's grandparents were used as the geographic variable. F(st), proportional to the extent of population structure, was low (mean F(st)=0.004 across 25 SNPs, range 0.001-0.008) and it was not significantly higher for pathogen response SNPs (F(st)=0.004) than for other SNPs (F(st)=0.003, P=0.21). Correspondence analysis revealed weak trends primarily in approximately northeast to southwest and secondarily in northwest to southeast directions. One-dimensional spatial autocorrelation analysis revealed a weak (Moran's I autocorrelation of -0.10) tendency for SNP frequencies to diverge with greater distance. Two-dimensional autocorrelation indicated a northeast to southwest gradient that was similar for both the pathogen response and other SNPs. The southeastern county, Wexford, showed a distinctive pattern, perhaps consistent with Anglo-Norman settlements. In conclusion, these results indicate that pathogen response SNPs do not exhibit significantly more population structure than other SNPs within this Caucasian population. This suggests that the specific population structure of particular genes may not typically be a cause of strong confounding in genetic studies where population structure is controlled.

Arylsulfotransferase↗

Usefulness of QT-interval parameters for cardiovascular risk stratification in type 2 diabetic patients with arterial hypertension.

QT-interval parameters are potential indicators of increased cardiovascular risk. We evaluated prospectively their prognostic value, in relation to other risk markers, for cardiovascular fatal and nonfatal events in a cohort of 271 hypertensive type 2 diabetic outpatients. QT intervals were measured from 12-lead standard ECGs obtained on admission and maximum rate-corrected QT-interval duration and QT-interval dispersion (QTd) calculated. Clinical and laboratory data and 2-D echocardiograms (available in 126 patients) were recorded. Survival analyses included Kaplan-Meier survival curves, uni and multivariate Cox proportional-hazards models. After a median follow-up of 55 months (range 2-84), 68 total fatal or nonfatal cardiovascular events and 34 cardiovascular deaths (24 of them from cardiac causes) were observed. In multivariate Cox analysis, QTd was an independent predictor for total cardiovascular events (HR: 1.16, 95% CI: 1.01-1.34, for each 10 ms increments) and for cardiac deaths (HR: 1.28, 95% CI: 1.01-1.60). Other independent risk indicators for cardiovascular morbidity and mortality were echocardiographic left ventricular hypertrophy (Echo-LVH), serum triglycerides, presence of pre-existing cardiac and peripheral arterial disease, age, diabetes duration, heart rate and the presence of frequent ventricular premature contractions on ECG. The combination of QTd and Echo-LVH improved cardiovascular risk stratification compared with either alone, the presence of both prolonged QTd (>65 ms) and Echo-LVH was associated with a 3.2-fold (95% CI: 1.7-6.1) increased risk of a first cardiovascular event and a 5.9-fold (95% CI: 2.1-16.4) increased risk of cardiovascular death. Thus, QT provided additive prognostic information for cardiovascular morbidity and mortality beyond that obtained from conventional risk markers, including Echo-LVH, in type 2 diabetic patients with arterial hypertension.

Adult↗

Influence of target organ lesion detection (assessment of microalbuminuria and echocardiogram) in cardiovascular risk stratification and treatment of untreated hypertensive patients.

European guidelines indicate the importance of the evaluation of global cardiovascular risk (CVR) to determine the management of the hypertensive patients (EH). However, in primary care, the diagnostic work-up (PCD) only includes the metabolic risk factors. The aim of this study was to assess the importance of microalbuminuria (MA) and echocardiogram (ECHO) in the process of risk stratification, and the number of patients to be treated with drugs at diagnosis. In total, 155 nontreated EH were included in the study. Blood pressure, a lipid profile and plasma glucose (LG) were determined after an overnight fast. MA was evaluated with dipstick MICRALTEST, and in those patients with two positive results, it was measured again in two 24-h urine samples and was considered positive (MA+) if the average was >30 mg/24 h. Left ventricular mass index was calculated and values>125 g/m2 were considered as LV hypertrophy (LVH+). When the patients were stratified according to PCD, 22 had to be treated with drugs. When MA, ECHO and both tests used together were added to the risk evaluation, the number of patients to be treated were 42, 51 and 64, respectively (P<0.001 vs PCD). It is mainly in patients who have moderate cardiovascular risk that risk changes, whereas risk hardly changes in those having low and very high risk. In conclusion, in EH with moderate risk, measurement of MA, due to its easy availability and low cost, seems to be a cost effective screening test to avoid the underestimation of the CVR.

Albuminuria↗

Mortality after acute renal failure: models for prognostic stratification and risk adjustment.

To adjust adequately for comorbidity and severity of illness in quality improvement efforts and prospective clinical trials, predictors of death after acute renal failure (ARF) must be accurately identified. Most epidemiological studies of ARF in the critically ill have been based at single centers, or have examined exposures at single time points using discrete outcomes (e.g., in-hospital mortality). We analyzed data from the Program to Improve Care in Acute Renal Disease (PICARD), a multi-center observational study of ARF. We determined correlates of mortality in 618 patients with ARF in intensive care units using three distinct analytic approaches. The predictive power of models using information obtained on the day of ARF diagnosis was extremely low. At the time of consultation, advanced age, oliguria, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality. Upon initiation of dialysis for ARF, advanced age, hepatic failure, respiratory failure, sepsis, and thrombocytopenia were associated with mortality; higher blood urea nitrogen and lower serum creatinine were also associated with mortality in logistic regression models. Models incorporating time-varying covariates enhanced predictive power by reducing misclassification and incorporating day-to-day changes in extra-renal organ system failure and the provision of dialysis during the course of ARF. Using data from the PICARD multi-center cohort study of ARF in critically ill patients, we developed several predictive models for prognostic stratification and risk-adjustment. By incorporating exposures over time, the discriminatory power of predictive models in ARF can be significantly improved.

APACHE↗

Genetic heterogeneity in schizophrenia: stratification of genome scan data using co-segregating related phenotypes.

Despite considerable effort to identify susceptibility loci for schizophrenia, none have been localized. Multiple genome scans and collaborative efforts have shown evidence for linkage to regions on chromosomes 1q, 5q, 6q, 8p, 13q, 10p and 22q.(1-9) Heterogeneity is likely. We previously mapped schizophrenia susceptibility loci (SSL) to chromosomes 13q32 (P = 0.00002) and 8p21-22 (P= 0.0001) using 54 multiplex pedigrees and suggested linkage heterogeneity. We have now stratified these families based on co-segregating phenotypes in non-schizophrenic first degree relatives (schizophrenia spectrum personality disorders (SSPD); psychotic affective disorders (PAD)). Genome scans were conducted for these phenotypic subgroups of families and broadened affected phenotypes were tested. The SSPD group provided its strongest genome-wide linkage support for the chromosome 8p21 region (D8S1771) using either narrow (non-parametric lod (NPL) P= 0.000002) or broadened phenotypes (NPL P = 0.0000008) and a new region of interest on 1p was identified (P = 0.006). For PAD families, the peak NPL in the genome scan occurred on chromosome 3p26-p24 (P = 0.008). The identification of multiple susceptibility loci for schizophrenia may be enhanced by stratification of families using psychiatric diagnoses of the non-schizophrenic relatives.

Family Health↗

Arrhythmic risk stratification after myocardial infarction using ambulatory electrocardiography signal averaging.

Ambulatory ECG had been proposed to examine the amplified high resolution signal-averaged electrocardiogram (SAECG). Clinical investigations are required to confirm the predictive value of such a high resolution technique in arrhythmic risk stratification. The prognostic value of ambulatory Holter SAECG was evaluated in 108 postinfarction patients for the purpose of predicting the occurrence of serious arrhythmic (SARR) events (sudden cardiac death [SCD], VT, or VF) in comparison with classical real-time SAECG. During the 42+/-8 months of follow-up, the sudden cardiac death mortality was 4.6% (five deaths), six (5.6%) patients had VT, and one (0.9%) VF. QRSd was found to be the most predictive parameter using ROC curves analysis for SAAR + outcome (W = 0.833 and W = 0.803 for 25-250 Hz and 40-250 Hz filters, respectively) followed by RMS (W = 0.766 and W = 0.721) and LAS (W = 0.759, W = 0.709) (all P < 0.01). Abnormal Holter SAECG for 25 and 40-Hz LP filter were significant predictors of SARR+ by log-rank test (P < 0.01, P < 0.05, respectively). This study confirms that valuable prognostic information can be obtained from the ambulatory high resolution ECG technique and that Holter SAECG may predict arrhythmic risk in a postinfarction population.

Action Potentials↗

Stratification and seasonal stability of diverse bacterial communities in a Pinus merkusii (pine) forest soil in central Java, Indonesia.

In Java, Indonesia, many nutrient-poor soils are intensively reforested with Pinus merkusii (pine). Information on nutrient cycles and microorganisms involved in these cycles will benefit the management of these important forests. Here, seasonal effects on the stratification of bacterial community structure in the soil profile of a tropical pine forest are described, and differences in bacterial communities are related to chemical and physical soil parameters. Culture-independent community profiles of litter, fragmented litter and mineral soil layers were made by denaturing gradient gel electrophoresis (DGGE) of 16S rDNA-specific polymerase chain reaction (PCR) fragments. The community profiles of the different soil layers clustered separately, correlating with significant differences in organic matter content between the three layers. The bacterial communities appeared to be stable during the wet season of 1998. The drought in 1997, caused by the El Niño climatic effect, did not influence the bacterial communities in fragmentation and mineral soil, although moisture content and other soil parameters were markedly lower than in the wet season. However, communities in litter were influenced by drought. In the litter layer, the moisture content was significantly lower than in the fragmentation and mineral layers during the dry season. A clone library was made from a litter sample taken during the wet season. Partial sequencing of 74 clones and linking the DGGE banding positions of these clones to bands in the DGGE profile of the sample from which the clone library was derived showed considerable bacterial diversity. Alpha-proteobacteria (40.5% of the clones, of which 57% belonged to the Rhizobium-Agrobacterium group) and high-G+C content, Gram-positive bacteria (36.5%) dominated the clone library.

Bacteria↗

Differential expression of connexins during stratification of human keratinocytes.

To assess whether gap junctions and connexins change during keratinocyte differentiation, we have studied epidermal equivalents obtained in organotypic cultures of keratinocytes from the outer root sheath of human hair follicles. These reconstituted tissues exhibit a number of differentiation and proliferation markers of human epidermis, including gap junctions, connexins, and K6 and Ki67 proteins. Immunostaining and northern blots showed that gap junctions of the epidermal equivalents were made of Cx26 and Cx43. Cx26 was expressed in all keratinocyte layers, throughout the development of the epidermal equivalents. In contrast, Cx43 was initially observed only in the basal layer of keratinocytes and became detectable in the stratum spinosum and granulosum only after the epidermal equivalents had thickened. The levels of Cx26 and its transcript markedly increased as a function of stratification of the epidermal equivalents, whereas those of Cx43 remained almost constant. Microinjection of Lucifer Yellow into individual keratinocytes showed that gap junctions were similarly permeable at all stages of development of the epidermal equivalents. The data show that epidermal equivalents (i) feature a pattern of connexins typical of an actively renewing human interfollicular epidermis, and (ii) provide a model that reproduces the tridimensional organization of intact epidermis and that is amenable for experimentally testing the function of junctional communication between human keratinocytes.

Cell Differentiation↗

Long-term prognosis in unstable angina. The importance of early risk stratification using continuous ST segment monitoring.

AIMS: To assess the ability of clinical characteristics, admission ECG and continuous ST segment monitoring in determining long-term prognosis in unstable angina. METHODS: Two hundred and twelve patients with unstable angina (mean age 59 years), presenting within 24 h of an acute episode of angina were recruited at three hospitals and treated with standardized medical therapy. All patients kept chest pain charts and underwent ST segment monitoring for 48 h. The occurrence of death, myocardial infarction, and need for revascularization was assessed over a median follow-up of 2.6 years. RESULTS: The risk of death of myocardial infarction was greatest in the first 6-8 weeks after admission. Admission ECG ST depression and the presence of transient ischaemia predicted increased risk of subsequent death or myocardial infarction, whereas a normal ECG predicted a good prognosis. In 14 patients, ST segment monitoring provided the only evidence of recurrent ischaemia, and 72% of this group suffered an adverse event. Transient ischaemia and a history of hypertension were the most powerful independent predictors of death or myocardial infarction. CONCLUSIONS: Adverse events in unstable angina occur early after admission and can be predicted by clinical and ECG characteristics, and by the presence of transient ischaemia during ST segment monitoring. Risk stratification by these simple assessments can identify patients with unstable angina at high risk.

Adult↗

Early symptom-limited exercise test for risk stratification in post menopausal women with unstable coronary artery disease. FRISC study group. Fragmin during Instability in Coronary Artery Disease.

AIMS: The exercise test is considered less reliable in women than in men both for diagnostic and prognostic purposes. The value, however, of the exercise test might vary with the population that is examined, the way the test is performed and which exercise test variables are taken into consideration in the analysis. The aim of the study was to evaluate an early symptom-limited exercise test as a tool for risk stratification in women with unstable coronary artery disease admitted to the coronary care unit. METHODS AND RESULTS: Of the 543 women in the FRISC I study, 395 stabilized on medical treatment and performed a symptom-limited exercise test 5-8 days after inclusion. Sixteen patients with a cardiac event before the scheduled exercise test were excluded. During the 6 months follow-up 17% of the women who did not perform the exercise test and 9% of the 395 women who did, died or had a myocardial infarction (P<0.01). Multivariate stepwise logistic regression analysis was performed to assess the value of clinical variables and findings at the predischarge exercise test to predict cardiac events. Based on the exercise test results three risk groups were identified with an event rate of 19%, 9% and 1%, respectively. The exercise test was better than any of the tested clinical variables in predicting cardiac events. CONCLUSION: Women with unstable coronary artery disease who do not stabilize within a few days have a high event rate early during follow-up. For women who are medically stabilized, considering not only variables like ST depression and chest pain but also parameters reflecting the cardiac performance such as maximal workload and increase in rate-pressure product, an early symptom-limited exercise test is a good predictor of future cardiac events.

Aged↗

The combination of a continuous 12-lead ECG and troponin T; a valuable tool for risk stratification during the first 6 hours in patients with chest pain and a non-diagnostic ECG.

AIMS: The aim was to examine the early prognostic value of a combination of a continuous 12-lead ECG and troponin T in patients with chest pain and an ECG non-diagnostic for acute myocardial infarction. METHODS AND RESULTS: ST monitoring was performed and samples for analysis of troponin T were collected from admission for 12 h from 598 patients. After 6 h, the peak value of troponin T in 27% was > or = 0.10 microg.l(- 1), while 15% had had ST episodes, defined as transient ST deviations of at least 0.1 mV. Both a troponin T > or = 0.10 microg. l(-1) and ST episodes predicted worsening outcome. After 30 days, there were 6.8% and 1.4% (P<0.01) cardiac deaths or myocardial infarctions in the group with and without troponin T > or = 0.10 microg.l(-1), respectively. The corresponding event rates in patients with and without ST episodes were 10% and 1.6% (P<0.001). In a multivariate analysis both troponin T and ST episodes were independent predictors of cardiac death or myocardial infarction. When ST monitoring and troponin T status were combined, patients could be divided into low-, intermediate-, and high-risk groups. CONCLUSIONS: A combination of continuous 12-lead monitoring and troponin T seems to be a valuable tool for risk stratification during the first 6 h in this population.

Aged↗

Risk stratification in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) follows an extremely variable clinical course with survival ranging from months to decades. Available treatments can often induce remissions, but eventually all patients relapse. Recently, there has been major progress in the identification of molecular and cellular markers that may predict the tendency for disease progression in patients with CLL. Genomic aberrations, the mutational profile of IgVH genes and its surrogate marker ZAP-70 expression, and serum markers like B2-microglobulin (beta2-MG) and thymidine kinase (TK) provide prognostic information for individual patients independently of clinical disease characteristics. These molecular markers are about to enter the stage of risk stratification for individual patients in clinical trials.

Biomarkers, Tumor↗