Risk Stratification in Post-MI Patients Based on Left Ventricular Ejection Fraction and Heart-Rate Turbulence

Objectives: Development of risk stratification criteria for predicting mortality in post-infarction patients taking into account LVEF and heart-rate turbulence (HRT). Methods: Based on previous results the two parameters LVEF (continuously) and turbulence slope (TS) as an indicator of the HRT were combined for risk stratification. The method has been applied within two independent data sets (the MPIP-trial and the EMIAT-study). Results: The criteria were defined in order to match the outcome of applying LVEF ( 30 % in sensitivity. In the MPIP trial the optimal criteria selected are TS normal and LVEF ( 21 % or TS abnormal and LVEF ( 40 %. Within the placebo group of the EMIAT-study the corresponding criteria are: TS normal and LVEF ( 23 % or TS abnormal and LVEF ( 40 %. Combining both studies the following criteria could be obtained: TS normal and LVEF ( 20 % or TS abnormal and LVEF ( 40 %. In the MPIP study 83 out of the 581 patients (= 14.3 %) are fulfilling these criteria. Within this group 30 patients have died during the follow-up. In the EMIAT-trial 218 out of the 591 patients (= 37.9 %) are classified as high risk patients with 53 deaths. Combining both studies the high risk group contains 301 patients with 83 deaths (ppv = 27.7 %). Using the MADIT-criterion as classification rule (LVEF ( 30 %) a sample of 375 patients with 85 deaths (ppv = 24 %) can be selected. Conclusions: The stratification rule based on LVEF and TS is able to select high risk patients suitable for implanting an ICD. The rule performs better than the classical one with LVEF alone. The high risk group applying the new criteria is smaller with about the same number of deaths and therefor with a higher positive predictive value. The classification criteria have been validated within a bootstrap study with 100 replications. In all samples the rule based on TS and LVEF (= NEW) was superior to LVEV alone, the high risk group has been smaller (( s: 301 ( 14.5 (NEW) vs. 375 ( 14.5 (LVEF)) and the positive predictive value was larger (( s: 27.2 ( 2.6 % (NEW) vs. 23.3 ( 2.2 % (LVEF)). The new criteria are less expensive due to a reduced number of high risk patients selected

Boon or Bane? Advance Tax Rulings as a Measure to Mitigate Tax Uncertainty and Foster Investment

Politicians and tax practitioners often claim that tax uncertainty negatively affects investment. In many countries, firms can request fee-based Advance Tax Rulings (ATRs) to mitigate tax uncertainty. We analyze theoretically the circumstances under which investors request ATRs, how tax authorities should price them and how they can affect investment. We assume that tax authorities integrate investors' reasoning into their decisions. We find that it is often optimal for tax authorities to charge prohibitively high fees to discourage firms from requesting an ATR. However, we find that revenue-maximizing tax authorities offer ATRs if the ruling enables them either to significantly reduce their tax audit costs or to increase the probability of detecting ambiguous tax issues. Under certain circumstances, ATRs may effectively foster investment and potentially benefit both the tax authorities and taxpayers. Our results provide new explanations for why taxpayers that face high levels of tax uncertainty often do not request ATRs, even when the fee is rather low. Our results also hold when the tax authority maximizes social wealth instead of its revenues. Regulatory changes in ATR requirements might serve as a natural quasi-experiment for an empirical study of our predictions regarding investment decisions. (authors' abstract)Series: WU International Taxation Research Paper Serie

A Statistical Model for Risk Stratification on the Basis of Left Ventricular Ejection Fraction and Heart-Rate Turbulence

The MPIP data set was used to obtain a model for mortality risk stratification of acute myocardial infarction patients. The predictors heart rate turbulence (HRT) and left-ventricular ejection fraction (LVEF) were employed. HRT was a categorical variable of three levels; LVEF was continuous and its influence on the relative risk was explained by the natural logarithm function (found using fractional polynomials). Cox - PH model with HRT and lnLVEF was constructed and used for risk stratification. The model can be used to divide the patients into two or more groups according to mortality risk. It also describes the relationship between risk and predictors by a (continuous) function, which allows the calculation of individual mortality risk

Variable Outcomes of Hepatitis E Infections in Patients with Hemato-Oncologic Diseases

IntroductionThe hepatitis E virus (HEV) represents an important cause of viral hepatitis and could cause chronic infections in immunocompromised patients. However, data about immunocompromised patients other than solid organ transplant recipients are limited.MethodsWe identified patients from a laboratory database and retrospectively compiled and analyzed clinical as well as laboratory data in detail.ResultsOverall, 22 severely immunosuppressed patients, excluding solid organ transplant recipients, were identified. Four patients did not experience viral clearance (one without and three despite ribavirin therapy). Three patients acquired the infection after allogeneic hematopoietic stem cell transplantation (alloHSCT) and recovered spontaneously, whereas another patient, infected prior to alloHSCT, developed a chronic infection. Four patients failed to clear HEV, resulting in fatal liver failure in two patients. The CD4+ cell counts increased in all but one patient attaining a sustained virological response (SVR), as compared to patients with clinical failure. Severe immunoglobulin deficiency did not appear to obviate the control of HEV. Six of ten (60%) patients with and nine of twelve (75%) patients without ribavirin therapy achieved a SVR.ConclusionsUpfront ribavirin therapy does not appear mandatory in patients without CD4+ lymphopenia, but a prolonged HEV-replication carries the risk of liver failure. Our data suggest that chronic HEV-infections could cause T-cell exhaustion, which might be overruled with ribavirin therapy

Metabolism of remimazolam in primary human hepatocytes during continuous long-term infusion in a 3-D bioreactor system

Background: Remimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. It is hydrolyzed by CES1 to an inactive metabolite (CNS7054). Purpose: In this study, the effect of continuous remimazolam exposure on its metabolism and on CES1 expression was investigated in a dynamic 3-D bioreactor culture model inoculated with primary human hepatocytes. Methods: Remimazolam was continuously infused into bioreactors for 5 days at a final concentration of 3,000 ng/ml (6.8 μM). In parallel, 2-D cultures were run with cells from the same donors, but with discontinuous exposure to remimazolam. Results: Daily measurement of clinical chemistry parameters (glucose, lactate, urea, ammonia, and liver enzymes) in culture supernatants indicated no noxious effect of remimazolam on hepatocyte integrity as compared to untreated controls. Concentrations of remimazolam reached steady-state values of around 250 ng/ml within 8 hours in 3-D bioreactors whereas in 2-D cultures remimazolam concentrations declined to almost zero within the same time frame. Levels of CNS7054 showed an inverse time-course reaching average values of 1,350 ng/ml in perfused 3-D bioreactors resp. 2,800 ng/ml in static 2-D cultures. Analysis of mRNA expression levels of CES1 indicated no changes in gene expression over the culture period. Conclusion: The results indicated a stable metabolism of remimazolam during 5 days of continuous exposure to clinically relevant concentrations of the drug. Moreover, there was no evidence for a harmful effect of remimazolam exposure on the integrity and metabolic activity of in vitro cultivated primary human hepatocytes

TEMPUS - A microgravity electromagnetic levitation facility for parabolic flights

During the ~22s lasting free fall phase in an aircraft flying a parabola, the aboard installed electromagnetic levitation facility TEMPUS is used to investigate contactlessly and undisturbed of gravity induced convection thermophysical properties and microstructure formations of hot and highly reactive metal or semiconductor melts. The completely contactless handling and measurement of a liquid by the levitation technique keeps the melt free of contamination and enables the extension of the accessible sample temperature range far into the undercooled liquid state below the melting point. Additionally, the state of reduced weight during parabolic flights allows us to considerably decrease the strongly disturbing electromagnetic levitation forces acting in ground-based facilities on the suspended liquids. The present paper explains in detail the basic principle and the technical realization of the TEMPUS levitation facility and its attached measurement devices. Furthermore, it presents some typical experiments performed in TEMPUS, which also show the advantages resulting from the combination of reduced weight, electromagnetic levitation and contactless measurement techniques. The control and data recording, as well as the planning, preparation, and operation of the TEMPUS experiments within the parabolic flight campaign, are another aspect outlined in the following

Substance Abuse-Related Self-Stigma in Women with Substance Use Disorder and Comorbid Posttraumatic Stress Disorder

Background: Self-stigma is a result of internalizing negative stereotypes by the affected person. Research on self-stigma in substance use disorders (SUD) is still scarce, especially regarding the role of childhood trauma and subsequent posttraumatic disorders. Objectives: The present study investigated the progressive model of self-stigma in women with SUD and posttraumatic stress disorder (PTSD), and the predictive value of PTSD severity and childhood trauma experiences on self-stigma. Method: In a cross-sectional study with 343 women with SUD and PTSD, we used the Self-Stigma in Alcohol Dependency Scale, the Childhood Trauma Questionnaire (CTQ), the PTSD Symptom Scale Interview (PSS-I), and to control for SUD severity and depression, the Addiction Severity Index Lite and the Beck Depression Inventory-II. Hierarchical regression analyses were conducted for each stage of self-stigma (aware-agree-apply-harm). Results: The interrelated successive stages of self-stigma were largely confirmed. In the regression models, no significant effects of the PSS-I- and the CTQ-scores were observed at any stage of self-stigma. Agreeing with negative stereotypes was solely predicted by younger age, applying these stereotypes to oneself was higher in women with younger age, higher depression and SUD severity, and suffering from the application (harm) was only predicted by depression. Conclusions: The progressive model of self-stigma could be confirmed in women with SUD and PTSD, but PTSD severity and childhood trauma did not directly affect this process. Self-stigma appears to be related to depression in a stronger way than PTSD is related to women with SUD and PTSD

Recombinant expression and characterization of the endochitinase Chit36-TA from Trichoderma asperellum in Komagataella phaffii for chitin degradation of black soldier fly exuviae

The natural polymer chitin is an abundant source for valuable N-acetylchitooligosaccharides and N-acetylglucosamine applicable in several industries. The endochitinase Chit36-TA from Trichoderma asperellum was recombinantly expressed in Komagataella phaffii for the enzymatic degradation of chitin from unused insect exuviae into N-acetylchitooligosaccharides. Chit36-TA was purified by Ni–NTA affinity chromatography and subsequently biochemically characterized. After deglycosylation, the endochitinase had a molecular weight of 36 kDa. The optimum pH for Chit36-TA was 4.5. The temperature maximum of Chit36-TA was determined to be 50 °C, while it maintained > 93% activity up to 60 °C. The chitinase was thermostable up to 45 °C and exhibited ~ 50% activity after a 15 min incubation at 57 °C. Chit36-TA had a maximum specific enzyme activity of 50 nkat/mg with a Km value of 289 µM with 4-methylumbelliferyl-N,N′,N″-triacetyl-β-chitotrioside as substrate. Most tested cations, organic solvents and reagents were well-tolerated by the endochitinase, except for SDS (1 mM), Cu2+ (10 mM) and Mn2+ (10 mM), which had stronger inhibitory effects with residual activities of 3, 41 and 28%, respectively. With a degree of hydrolysis of 32% applying colloidal shrimp chitin (1% (w/v)) and 12% on insect larvae (1% (w/v)) after 24 h, the endochitinase was found to be suitable for the conversion of colloidal chitin as well as chitin from black soldier fly larvae into water-soluble N-acetylchitooligosaccharides. To prove scalability, a bioreactor process was developed in which a 55-fold higher enzyme activity of 49 µkat/l and a tenfold higher protein expression of 1258 mg/l were achieved

Host taxon-derived Sarcoptes mite in European wild animals revealed by microsatellite markers

Ten markers specific to Sarcoptes mites were used in applying microsatellite genotyping to individual Sarcoptes mites collected in three European countries from 15 wild mammal populations belonging to 10 host species. The results showed that geographical separation had real biological significance for the definition of mite sub-populations, and that the degree of genetic exchange occurring between mites from different localities was apparently related to the geographical distance between locations. Wild host-derived mite populations were found to be clustered into three main groups: herbivore-, carnivore- and omnivore-derived Sarcoptes populations, with the omnivore-derived group located halfway between the herbivore- and carnivore-derived Sarcoptes populations. The separation between these three mite groups was better supported than the geographical separations; nevertheless, a kind of sub-clustering was detected within each of these three groups that separates mite populations into their geographical localities (countries). The lack of gene flow between Sarcoptes populations may have improved parasitic adaptations and led to what we refer to as a host-taxon-derived (carnivore host-, herbivore host- and omnivore host-derived) Sarcoptes mite found on European wild animals. Our results demonstrate that Sarcoptes is not a single panmictic population, even within each geographical location. This finding will have important ramifications for the study of the genetic structure of populations, life cycles, diagnosis and the monitoring protocols of the ubiquitous Sarcoptes mite, and could thus contribute to a better understanding of its associated epidemiology, which is of pivotal interest for wildlife biological conservation. © 2010 Elsevier Ltd. All rights reserved.Peer Reviewe

Vedolizumab use after failure of TNF- antagonists in children and adolescents with inflammatory bowel disease

BACKGROUND: Vedolizumab is safe and effective in adult patients with Crohn's disease (CD) and ulcerative colitis (UC); however, data in children with inflammatory bowel disease (IBD) are scarce. Therefore, we evaluated vedolizumab use in a cohort of Austrian paediatric patients with IBD. METHODS: Twelve patients (7 female; 7 CD; 5 UC), aged 8-17 years (median, 15 years), with severe IBD who received vedolizumab after tumour necrosis factor antagonist treatment were retrospectively analysed. Clinical activity scores, relevant laboratory parameters, and auxological measures were obtained at infusion visits. RESULTS: In the CD group, 1/7 patient discontinued therapy due to a severe systemic allergic reaction; 1/7 and 2/7 patients achieved complete and partial response, respectively, at week 14; and 3/7 patients discontinued therapy due to a primary non-response or loss of response. In the UC group, complete clinical remission was achieved at weeks 2, 6, and 14 in 2/5, 1/5 and 1/5 patients respectively; partial response was observed in one patient at week 2. CD activity scores did not significantly change from baseline to week 38 (median 47.5 vs. 40 points, p=1,0), while median UC activity scores changed from 70 to 5 points (p<0,001). Substantial weight gain and increased albumin and haemoglobin levels were observed in both groups. CONCLUSION: These results demonstrate that vedolizumab can be an effective treatment for individual paediatric patients with IBD who are unresponsive, intolerant, or experience a loss of efficacy in other therapies. However, vedolizumab appears to be more effective in paediatric UC than in paediatric CD.(VLID)286504