Patterns of mucosal inflammation in pediatric inflammatory bowel disease: striking overexpression of IL-17A in children with ulcerative colitis.

BACKGROUND: Aberrant immune responses play a key role in the pathogenesis of inflammatory bowel disease (IBD). Most studies conducted to delineate the underlying molecular mechanisms focus on adults; an understanding of these mechanisms in children remains to be determined. Here, cytokines and transcription factors produced by immune cells within the intestinal mucosa of pediatric patients stricken with ulcerative colitis (UC) and Crohn's disease (CD) are characterized; potential diagnostic and therapeutic targets are identified. METHODS: Fifty-two pediatric IBD and non-IBD patients were enrolled in the study. Specimens were taken during ileocolonoscopy. Expression of 16 genes that encode cytokines or transcription molecules was determined by quantitative polymerase chain reaction. Clinical data were collected via retrospective chart review. RESULTS: Overexpression of interleukin-17A (IL-17A) was evident in children with UC compared to both non-IBD and CD patients. IL-22 was strongly increased in UC patients only. Typical proinflammatory and immunoregulatory cytokines were pronounced in IBD patients, although to a lower extent in the latter case. Clustered gene expression enabled differentiation between UC and non-IBD patients. CONCLUSION: Our findings highlight the crucial involvement of IL-17A immunity in the early course of IBD, particularly UC, and the potential value of gene panels in diagnosing pediatric IBD.

Growth Rate of Plasmodium falciparum: Analysis of Parasite Growth Data From Malaria Volunteer Infection Studies.

BACKGROUND: Growth rate of malaria parasites in the blood of infected subjects is an important measure of efficacy of drugs and vaccines. METHODS: We used log-linear and sine-wave models to estimate the parasite growth rate of the 3D7 strain of Plasmodium falciparum using data from 177 subjects from 14 induced blood stage malaria (IBSM) studies conducted at QIMR Berghofer. We estimated parasite multiplication rate per 48 hours (PMR48), PMR per life-cycle (PMRLC), and parasite life-cycle duration. We compared these parameters to those from studies conducted elsewhere with infections induced by IBSM (n = 66), sporozoites via mosquito bite (n = 336), or injection (n = 51). RESULTS: The parasite growth rate of 3D7 in QIMR Berghofer studies was 0.75/day (95% confidence interval [CI], .73-.77/day), PMR48 was 31.9 (95% CI, 28.7-35.4), PMRLC was 16.4 (95% CI, 15.1-17.8), and parasite life-cycle was 38.8 hours (95% CI, 38.3-39.2 hours). These parameters were similar to estimates from IBSM studies elsewhere (0.71/day, 95% CI, .67-.75/day; PMR48 26.6, 95% CI, 22.2-31.8) but significantly higher (P < .001) than in sporozoite studies (0.47/day, 95% CI, .43-.50/day; PMR48 8.6, 95% CI, 7.3-10.1). CONCLUSIONS: Parasite growth rates were similar across different IBSM studies and higher than infections induced by sporozoite.

Integrative Genome-Scale DNA Methylation Analysis of a Large and Unselected Cohort Reveals 5 Distinct Subtypes of Colorectal Adenocarcinomas.

BACKGROUND & AIMS: Colorectal cancer is an epigenetically heterogeneous disease, however, the extent and spectrum of the CpG island methylator phenotype (CIMP) is not clear. METHODS: Genome-scale methylation and transcript expression were measured by DNA Methylation and RNA expression microarray in 216 unselected colorectal cancers, and findings were validated using The Cancer Genome Atlas 450K and RNA sequencing data. Mutations in epigenetic regulators were assessed using CIMP-subtyped Cancer Genome Atlas exomes. RESULTS: CIMP-high cancers dichotomized into CIMP-H1 and CIMP-H2 based on methylation profile. KRAS mutation was associated significantly with CIMP-H2 cancers, but not CIMP-H1 cancers. Congruent with increasing methylation, there was a stepwise increase in patient age from 62 years in the CIMP-negative subgroup to 75 years in the CIMP-H1 subgroup (P < .0001). CIMP-H1 predominantly comprised consensus molecular subtype 1 cancers (70%) whereas consensus molecular subtype 3 was over-represented in the CIMP-H2 subgroup (55%). Polycomb Repressive Complex-2 (PRC2)-marked loci were subjected to significant gene body methylation in CIMP cancers (P < 1.6 × 10-78). We identified oncogenes susceptible to gene body methylation and Wnt pathway antagonists resistant to gene body methylation. CIMP cluster-specific mutations were observed in chromatin remodeling genes, such as in the SWItch/Sucrose Non-Fermentable and Chromodomain Helicase DNA-Binding gene families. CONCLUSIONS: There are 5 clinically and molecularly distinct subgroups of colorectal cancer. We show a striking association between CIMP and age, sex, and tumor location, and identify a role for gene body methylation in the progression of serrated neoplasia. These data support our recent findings that CIMP is uncommon in young patients and that BRAF mutant polyps in young patients may have limited potential for malignant progression.

Mental health problems and school performance in first graders: results of the prospective cohort study ikidS.

We aimed to estimate unbiased effects of mental health problems (MHPs) on school performance in first graders, with an emphasis on rigorous adjustment for potential confounders. A population-based prospective cohort study was performed in the area of Mainz-Bingen (Germany). In 2015, all preschoolers were approached, and the presence and type of MHP (externalising/internalising) and other physical chronic health conditions were identified by the preschool health examination and study-specific questionnaires. At the end of the first grade, school performance (reading, writing, numeracy, and science) was assessed by the class teacher and rated on a four-item scale ranging from - 8 to + 8. Of 3683 children approached, 2003 (54%) were enrolled. School performance was available for 1462 children (51% boys, mean age 7.3 years). Of these, 41% had signs of at least one MHP. Compared to children without indications of mental and physical chronic health conditions, children with MHPs had lower school performance scores [adjusted mean difference - 0.98, 95% CI (- 1.35; - 0.61); P < 0.001]. Regarding the type of MHP, externalising MHPs were associated with poor school performance [adjusted mean difference - 1.44, 95% CI (- 1.83; - 1.05); P < 0.001], while internalising MHPs were not. Children with hyperactivity inattention problems were most affected [adjusted mean difference - 1.96, 95% CI (- 2.36; - 1.56); P < 0.001]. Externalising MHPs and in particular hyperactivity inattention problems may already affect school performance in early primary school. Identification of children with externalising MHPs prior to school entry may help to prevent impaired academic achievement in affected children.

Chronic health conditions and school performance in first graders: A prospective cohort study.

OBJECTIVE: Children with chronic health conditions may perform poorer at school. Associations may be confounded by numerous social factors. We aimed to estimate the effects of a chronic health condition on overall school performance in first graders with an emphasis on rigorous adjustment for potential confounders. METHODS: A population-based cohort study was performed in the area of Mainz-Bingen (Germany). In 2015 all preschoolers were approached and the presence of a chronic health condition was assessed by parental questionnaires and preschool health examination data. The identification of a chronic health condition was based on special health care needs and presence of a doctor's diagnosis out of 24 school-relevant diseases. At the end of the first school year, overall school performance was assessed by teachers and rated on a 5-item scale ranging from -10 to +10. RESULTS: Of 3683 children approached, 2003 were enrolled. Overall school performance was available for 1462 children (51% boys). Of these, 52% suffered from a chronic health condition. Compared to children without a chronic health condition, children with special health care needs (15%) performed worse at school (adjusted mean difference: -0.95, 95% CI: [-1.55; -0.35], P = 0.002). Children with a doctor's diagnosis but without special health care needs (37%) did not perform worse at school. The effect was further analysed considering the extent of special health care needed. CONCLUSIONS: Chronic health conditions affect overall school performance early in primary school. To identify academically at-risk children, a chronic health condition identification based on special health care needs may be used.

Construct Validity and Population-Based Norms of the German Brief Resilience Scale (BRS).

The Brief Resilience Scale (BRS) measures the ability to recover from stress. To provide further evidence for construct validity of the German BRS and to determine population-based norms, a large sample (N = 1,128) representative of the German adult population completed a survey including the BRS and instruments measuring perceived stress and the resilience factors optimism, self-efficacy, and locus of control. Confirmatory factor analyses showed best model fit for a five-factor model differentiating the ability to recover from stress from the three resilience factors. On the basis of latent and manifest correlations, convergent and discriminant validity of the BRS were fair to good. Female sex, older age, lower weekly working time, higher perceived stress, lower optimism, and self-efficacy as well as higher external locus of control predicted lower BRS scores, that is, lower ability to recover from stress.

Comparison of statistical models to estimate parasite growth rate in the induced blood stage malaria model.

BACKGROUND: The efficacy of vaccines aimed at inhibiting the growth of malaria parasites in the blood can be assessed by comparing the growth rate of parasitaemia in the blood of subjects treated with a test vaccine compared to controls. In studies using induced blood stage malaria (IBSM), a type of controlled human malaria infection, parasite growth rate has been measured using models with the intercept on the y-axis fixed to the inoculum size. A set of statistical models was evaluated to determine an optimal methodology to estimate parasite growth rate in IBSM studies. METHODS: Parasite growth rates were estimated using data from 40 subjects published in three IBSM studies. Data was fitted using 12 statistical models: log-linear, sine-wave with the period either fixed to 48 h or not fixed; these models were fitted with the intercept either fixed to the inoculum size or not fixed. All models were fitted by individual, and overall by study using a mixed effects model with a random effect for the individual. RESULTS: Log-linear models and sine-wave models, with the period fixed or not fixed, resulted in similar parasite growth rate estimates (within 0.05 log10 parasites per mL/day). Average parasite growth rate estimates for models fitted by individual with the intercept fixed to the inoculum size were substantially lower by an average of 0.17 log10 parasites per mL/day (range 0.06-0.24) compared with non-fixed intercept models. Variability of parasite growth rate estimates across the three studies analysed was substantially higher (3.5 times) for fixed-intercept models compared with non-fixed intercept models. The same tendency was observed in models fitted overall by study. Modelling data by individual or overall by study had minimal effect on parasite growth estimates. CONCLUSIONS: The analyses presented in this report confirm that fixing the intercept to the inoculum size influences parasite growth estimates. The most appropriate statistical model to estimate the growth rate of blood-stage parasites in IBSM studies appears to be a log-linear model fitted by individual and with the intercept estimated in the log-linear regression. Future studies should use this model to estimate parasite growth rates.

Effects of stepped psychooncological care on referral to psychosocial services and emotional well-being in cancer patients: A cluster-randomized phase III trial.

OBJECTIVE: Emotional distress in cancer patients often goes unnoticed in daily routine; therefore, distress screening is now recommended in many national guidelines. However, screening alone does not necessarily translate into better well-being. We examined whether stepped psychooncological care improves referral to consultation-liaison (CL) services and improves well-being. METHODS: In a cluster-randomized trial, wards were randomly allocated to stepped versus standard care. Stepped care comprised screening for distress, consultation between doctor and patient about the patient's need for CL services, and provision of CL service. Primary outcomes were referral to psychosocial services and emotional well-being half a year after baseline, measured with the Hospital Anxiety and Depression Scale. A secondary endpoint was uptake of outpatient health care. Analysis employed mixed-effects multivariate regression modeling. RESULTS: Thirteen wards were randomized; 1012 patients participated. With stepped care (N = 570; 7 wards), 22% of the patients were referred to CL services and 3% with standard care (N = 442; 6 wards; odds ratio [OR] 10.0; P < .001). Well-being 6 months after baseline was 9.5 after stepped care (N = 341) and 9.4 after standard care (N = 234, ß -0.3; P = .71). After stepped care, patients with psychiatric comorbidity went more often to psychotherapists (OR 4.0, P = .05) and to psychiatrists (OR 2.3, P = .12), whereas patients without comorbidity used psychiatrists less often (OR 0.4, P = .04) than in standard care. CONCLUSIONS: Stepped care resulted in better referral to CL services. The patients' emotional well-being was not improved, but uptake of outpatient psychiatric help was increased in patients with psychiatric comorbidity and decreased in patients without.

Multiplex Serum Protein Analysis Identifies Novel Biomarkers of Advanced Fibrosis in Patients with Chronic Liver Disease with the Potential to Improve Diagnostic Accuracy of Established Biomarkers.

BACKGROUND AND AIMS: Non-invasive markers of liver fibrosis are urgently required, especially for use in non-specialist settings. The aim of this study was to identify novel serum biomarkers of advanced fibrosis. METHODS: We performed an unbiased screen of 120 serum analytes including cytokines, chemokines and proteases in 70 patients (35 without fibrosis, 35 with cirrhosis on biopsy), and selected a panel of 44 candidate biomarkers, which were subsequently measured in a mixed-etiology cohort of 432 patients with known serum HA, PIIINP and TIMP1 (which comprise the validated Enhanced Liver Fibrosis (ELF) test). Multivariate logistic regression modelling was used to generate models for the prediction of advanced or significant fibrosis (METAVIR ≥F3 and ≥F2, respectively); in addition to identifying biomarkers of disease activity and steatohepatitis. RESULTS: Seventeen analytes were significantly differentially expressed between patients with no advanced fibrosis and patients with advanced fibrosis, the most significant being hyaluronic acid (HA) and matrix metalloproteinase (MMP) 7 (p = 2.9E-41 and p = 1.0E-26, respectively). The optimal model for the prediction of advanced fibrosis comprised HA, MMP7, MMP1, alphafetoprotein (AFP) and the AST to platelet ratio index (APRI). We demonstrate enhanced diagnostic accuracy (AUROC = 0.938) compared to a model comprising HA, PIIINP and TIMP1 alone (ELF) (AUROC = 0.898, p<0.0001, De Long's test). CONCLUSIONS: We have identified novel serum biomarkers of advanced liver fibrosis, which have the potential to enhance the diagnostic accuracy of established biomarkers. Our data suggest MMP7 is a valuable indicator of advanced fibrosis and may play a role in liver fibrogenesis.

In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer-predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error-prone DNA double-strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelial-mesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence-based test system, we analyzed the error-prone DSB repair pathway microhomology-mediated end joining in these tumor-derived cell types and peripheral blood lymphocytes. In parallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP-ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology-mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high-risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair-dysfunctional tumors.-Deniz, M., Kaufmann, J., Stahl, A., Gundelach, T., Janni, W., Hoffmann, I., Keimling, M., Hampp, S., Ihle, M., Wiesmüller, L. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

The count of tender rather than swollen joints correlates with aortic stiffness in patients with rheumatoid arthritis.

BACKGROUND: Patients with rheumatoid arthritis (RA) are at a higher cardiovascular (CV) risk in comparison to the general population. CV risk associates closely with aortic stiffness. Aim of this exploration was therefore to evaluate aortic stiffness in patients with RA and to examine its association with various RA associated parameters as well as with traditional CV risk factors. METHODS: Measurements of carotid-femoral pulse wave velocity (cfPWV) were analyzed retrospectively in 38 RA patients and 25 controls. We investigated the statistical difference between cfPWV values in the two groups. Furthermore, we analyzed the associations of cfPWV with laboratory and clinical RA parameters including Disease Activity Score 28 and its components, rheumatoid factor, cyclic citrullinated peptide antibodies, antinuclear antibodies and RA duration. Finally, we explored the relationship of cfPWV with traditional CV risk factors in the RA group. RESULTS: cfPWV was not significantly higher in RA patients in comparison to controls in an adjusted statistical model for confounding factors [-0.587 95 % CI (-1.38 to 0.201), p = 0.144]. Among RA patients there was a statistically significant correlation of cfPWV with age (rho = 0.544, p = 0.001) and the count of tender joints [0.051 95 % CI (0.008-0.207), p = 0.034]. Finally, C-reactive protein associated only marginally with cfPWV [0.105 95 % CI (-0.410 to 0.003), p = 0.053]. CONCLUSIONS: In RA patients the number of tender, rather than swollen joints correlates with stiffness of the aorta, as measured through cfPWV. Therefore, RA associated joint pain might play a role in the development of aortic stiffness and thus increase CV risk.

Disease Burden of Rotavirus Gastroenteritis in Children Residing in Germany: A Retrospective, Hospital-based Surveillance.

BACKGROUND: Representative, population-based epidemiologic data for gastroenteritis caused by rotavirus (RV) are rare. RV vaccines were first licensed in Europe in 2006 and recommended in 5 western federal states in 2008 or thereafter. This study establishes a baseline for assessing the impact of vaccination and delineates the RV disease burden in Germany today. METHODS: Nationwide data obtained from hospitals for children 0 to 10 years of age and transferred to the Federal Statistical Office were analyzed retrospectively. Acute gastroenteritis cases because of RV were identified by the International Classification of Diseases code (ICD-10) combined with the referring diagnosis-related group code. Coding quality was validated by random sampling the patient records (n=1003). Crude and age-standardized rates per 100,000 person-years were calculated. The rate ratios of seasonal effects and recommended immunization adjusted for year, federal state and age were estimated using Poisson regression. RESULTS: Between 2005 and 2010, 5,843,730 children were hospitalized; 520,606 cases were hospitalized because of acute gastroenteritis. RV caused 152,636 of these cases or an age-standardized rate of 302 hospitalizations per 100,000 person-years. Rates were slightly higher in boys than girls, decreased with age, and differed by federal state, year and season. Rate ratios decreased in those western federal states that recommended immunization and were inversely associated with vaccine doses sold. CONCLUSIONS: With an average of 25,440 children hospitalized yearly, RV infection has a great impact on the German healthcare system. Our findings indicate that RV immunization will lead to a decline in in-patient treatment and associated costs.

Mortality in patients with acute aortic dissection type A: analysis of pre- and intraoperative risk factors from the German Registry for Acute Aortic Dissection Type A (GERAADA).

OBJECTIVES: Acute aortic dissection type A (AADA) is an emergency with excessive mortality if surgery is delayed. Knowledge about independent predictors of mortality on surgically treated AADA patients is scarce. Therefore, this study was conducted to identify pre- and intraoperative risk factors for death. METHODS: Between July 2006 and June 2010, 2137 surgically treated patients with AADA were enrolled in a multicentre, prospective German Registry for Acute Aortic Dissection type A (GERAADA), presenting perioperative status, operative strategies, postoperative outcomes and AADA-related risk factors for death. Multiple logistic regression analysis was performed to identify the influence of different parameters on 30-day mortality. RESULTS: Overall 30-day mortality (16.9%) increased with age [adjusted odds ratio (OR) = 1.121] and among patients who were comatose (adjusted OR = 3.501) or those who underwent cardiopulmonary resuscitation (adjusted OR = 3.751; all P < 0.0001). The higher the number of organs that were malperfused, the risk for death was (adjusted OR for one organ = 1.651, two organs = 2.440, three organs or more = 3.393, P < 0.0001). Mortality increased with longer operating times (total, cardiopulmonary bypass, cardiac ischaemia and circulatory arrest; all P < 0.02). Arterial cannulation site for extracorporeal circulation, operative techniques and arch interventions had no significant impact on 30-day mortality (all P > 0.1). No significant risk factors, but relevant increases in mortality, were determined in patients suffering from hemiparesis pre- and postoperatively (each P < 0.01), and in patients experiencing paraparesis after surgery (P < 0.02). CONCLUSIONS: GERAADA could detect significant disease- and surgery-related risk factors for death in AADA, influencing the outcome of surgically treated AADA patients. Comatose and resuscitated patients have the poorest outcome. Cannulation sites and operative techniques did not seem to affect mortality. Short operative times are associated with better outcomes.

The Impact of Pre-Operative Malperfusion on Outcome in Acute Type A Aortic Dissection: Results From the GERAADA Registry.

BACKGROUND: Malperfusion adversely affects outcomes in patients with acute type A aortic dissection, but reliable quantitative data are lacking. OBJECTIVES: The aim of this study was to analyze the impact of various forms of malperfusion on early outcome. METHODS: A total of 2,137 consecutive patients enrolled in GERAADA (German Registry for Acute Aortic Dissection Type A) who underwent surgery between 2006 and 2010, of whom 717 (33.6%) had any kind of pre-operative malperfusion, were retrospectively analyzed. RESULTS: All-cause 30-day mortality was 16.9% and varied substantially according to the number of organ systems affected by malperfusion (none, 12.6%; 1 system, 21.3%; 2 systems, 30.9%; 3 systems, 43.4%; p < 0.001). Pre-operative cerebral malperfusion, comatose state, peripheral malperfusion, visceral malperfusion, involvement of supra-aortic branches, coronary malperfusion, and renal malperfusion were all independent predictors of developing any post-operative malperfusion syndrome. When survival was considered, age, peripheral malperfusion, involvement of supra-aortic branches, coronary malperfusion, spinal malperfusion, a primary entry in the descending aorta, and pre-operative comatose state were independent predictors, again with increasing significance. CONCLUSIONS: Malperfusion remains a severe clinical condition with strong potential for adverse outcomes in patients undergoing surgery for acute type A aortic dissection. The GERAADA registry suggests that the impact of the number of organs involved and the type of malperfusion on outcome differs substantially. Introducing an appropriate classification system, such as "complicated" and uncomplicated" acute type A aortic dissection, might help predict individual risk as well as select a surgical strategy that may quickly resolve malperfusion.

Determination of reference limits: statistical concepts and tools for sample size calculation.

Reference limits are estimators for 'extreme' percentiles of the distribution of a quantitative diagnostic marker in the healthy population. In most cases, interest will be in the 90% or 95% reference intervals. The standard parametric method of determining reference limits consists of computing quantities of the form X̅±c·S. The proportion of covered values in the underlying population coincides with the specificity obtained when a measurement value falling outside the corresponding reference region is classified as diagnostically suspect. Nonparametrically, reference limits are estimated by means of so-called order statistics. In both approaches, the precision of the estimate depends on the sample size. We present computational procedures for calculating minimally required numbers of subjects to be enrolled in a reference study. The much more sophisticated concept of reference bands replacing statistical reference intervals in case of age-dependent diagnostic markers is also discussed.

Combining techniques for screening and evaluating interaction terms on high-dimensional time-to-event data.

BACKGROUND: Molecular data, e.g. arising from microarray technology, is often used for predicting survival probabilities of patients. For multivariate risk prediction models on such high-dimensional data, there are established techniques that combine parameter estimation and variable selection. One big challenge is to incorporate interactions into such prediction models. In this feasibility study, we present building blocks for evaluating and incorporating interactions terms in high-dimensional time-to-event settings, especially for settings in which it is computationally too expensive to check all possible interactions. RESULTS: We use a boosting technique for estimation of effects and the following building blocks for pre-selecting interactions: (1) resampling, (2) random forests and (3) orthogonalization as a data pre-processing step. In a simulation study, the strategy that uses all building blocks is able to detect true main effects and interactions with high sensitivity in different kinds of scenarios. The main challenge are interactions composed of variables that do not represent main effects, but our findings are also promising in this regard. Results on real world data illustrate that effect sizes of interactions frequently may not be large enough to improve prediction performance, even though the interactions are potentially of biological relevance. CONCLUSION: Screening interactions through random forests is feasible and useful, when one is interested in finding relevant two-way interactions. The other building blocks also contribute considerably to an enhanced pre-selection of interactions. We determined the limits of interaction detection in terms of necessary effect sizes. Our study emphasizes the importance of making full use of existing methods in addition to establishing new ones.

Acute aortic dissection type A: age-related management and outcomes reported in the German Registry for Acute Aortic Dissection Type A (GERAADA) of over 2000 patients.

OBJECTIVE: To determine the association between age and clinical presentation, management and surgical outcomes in a large contemporary, prospective cohort of patients with acute aortic dissection type A (AADA). BACKGROUND: AADA is one of the most life-threatening cardiovascular diseases, and delayed surgery or overly conservative management can result in sudden death. METHODS: The perioperative and intraoperative conditions of 2137 patients prospectively reported to the multicenter German Registry for Acute Aortic Dissection Type A were analyzed. RESULTS: Of all patients with AADA, 640 (30%) were 70 years or older and 160 patients (7%) were younger than 40 years. The probability of aortic dissection extension to the supra-aortic vessels and abdominal aorta decreased with age (P < 0.0001 and P = 0.0017, respectively). In 1447 patients (69%), the aortic root was preserved and supracoronary replacement of the ascending aorta was done. The probability of this procedure increased with age (P < 0.0001). The incidence of new postoperative neurological disorders was not influenced by age. The lowest probability of 30-day mortality was noted in the youngest patients (11%-14% for patients aged between 20 and 40 years) and rose progressively with age, peaking at 25% in octogenarians. CONCLUSIONS: This study reflects current results after surgical treatment of AADA in relation to patient age. Current survival rates are acceptable, even in very elderly patients. The contemporary surgical mortality rate among young patients is lower than that previously reported in the literature. The postoperative stroke incidence does not increase with age.

Controlled type II diabetes mellitus has no major influence on platelet micro-RNA expression. Results from micro-array profiling in a cohort of 60 patients.

Diabetes mellitus as a major contributor to cardiovascular disease burden induces dysfunctional platelets. Platelets contain abundant miRNAs, which are linked to inflammatory responses and, thus, may play a role in atherogenesis. While diabetes mellitus affects plasma miRNAs, no data exist on platelet miRNA profiles in this disease. Therefore, this study sought to explore the miRNA profile of platelets in patients with diabetes mellitus that is unrelated to the presence or absence of coronary artery disease (CAD). Platelet miRNA profiles were assessed in stable diabetic and non-diabetic patients (each n=30); 15 patients in each group had CAD. Platelet miRNA was isolated from leucocyte-depleted platelet-rich plasma, and miRNA profiling was performed using LNA micro-array technology (miRBase18.0, containing 1,917 human miRNAs). Effects of diabetes mellitus were explored by univariate statistical tests for each miRNA, adjusted for potential confounders, and by developing a multivariable signature; evaluated by resampling techniques. Platelets in non-diabetic patients demonstrated miRNA expression profiles comparable to previous data. The miRNA profiles of platelets in diabetics were similar. Statistical analysis unveiled three miRNAs (miR-377-5p, miR-628-3p, miR-3137) with high reselection probabilities in resampling techniques, corresponding to signatures with modest discriminatory performance. Functional annotation of predicted targets for these miRNAs pointed towards an influence of diabetes mellitus on mRNA processing. We did not find major differences in platelet miRNA profiles between diabetics and non-diabetics. Minor differences pertained to miRNAs associated with mRNA processing. Thus, described differences in plasma miRNAs between diabetic and non-diabetic patients cannot be explained by plain changes in platelet miRNA profile.