European Cardiovascular Magnetic Resonance (EuroCMR) registry--multi national results from 57 centers in 15 countries.

BACKGROUND: The EuroCMR registry sought to evaluate indications, image quality, safety and impact on patient management of clinical routine CMR in a multi-national European setting. Furthermore, interim analysis of the specific protocols should underscore the prognostic potential of CMR. METHODS: Multi-center registry with consecutive enrolment of patients in 57 centers in 15 countries. More than 27000 consecutive patients were enrolled. RESULTS: The most important indications were risk stratification in suspected CAD/Ischemia (34.2%), workup of myocarditis/cardiomyopathies (32.2%), as well as assessment of viability (14.6%). Image quality was diagnostic in more than 98% of cases. Severe complications occurred in 0.026%, always associated with stress testing. No patient died during or due to CMR. In 61.8% CMR findings impacted on patient management. Importantly, in nearly 8.7% the final diagnosis based on CMR was different to the diagnosis before CMR, leading to a complete change in management. Interim analysis of suspected CAD and risk stratification in HCM specific protocols revealed a low rate of adverse events for suspected CAD patients with normal stress CMR (1.0% per year), and for HCM patients without LGE (2.7% per year). CONCLUSION: The most important indications in Europe are risk stratification in suspected CAD/Ischemia, work-up of myocarditis and cardiomyopathies, as well as assessment of viability. CMR imaging is a safe procedure, has diagnostic image quality in more than 98% of cases, and its results have strong impact on patient management. Interim analyses of the specific protocols underscore the prognostic value of clinical routine CMR in CAD and HCM.

A new perspective on the evolutionary history of western European Sorex araneus group revealed by paternal and maternal molecular markers.

The species of the common shrew (Sorex araneus) group are morphologically very similar, but have undergone a spectacular chromosomal evolution. We investigate here the evolutionary history of the Sorex araneus group distributed in western Europe. In particular, we clarify the position of a difficult species, S. granarius, using sex-specific (mtDNA and Y-chromosome) markers. The karyotype of S. granarius is generally considered similar to the common ancestor of the restricted group considered here. The mtDNA data (1.4 kb) confirms the close relationship between S. granarius and S. araneus sensu stricto (hereafter S. araneus s.s.), but the Y-chromosome (3.4 kb) produces a quite different picture: S. granarius is closely related to another species, S. coronatus. Comparison of mtDNA and Y-chromosome phylogenies suggests that the genetic and chromosomal evolution in this group are disconnected processes. The evolutionary history of the south-western European populations of the S. araneus group can only be understood considering secondary contacts between taxa after their divergence, implying genetic exchanges by means of hybridization and/or introgression.

Interactions of dietary whole-grain intake with fasting glucose- and insulin-related genetic loci in individuals of European descent: a meta-analysis of 14 cohort studies.

Whole-grain foods are touted for multiple health benefits, including enhancing insulin sensitivity and reducing type 2 diabetes risk. Recent genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) associated with fasting glucose and insulin concentrations in individuals free of diabetes. We tested the hypothesis that whole-grain food intake and genetic variation interact to influence concentrations of fasting glucose and insulin. Via meta-analysis of data from 14 cohorts comprising ∼ 48,000 participants of European descent, we studied interactions of whole-grain intake with loci previously associated in GWAS with fasting glucose (16 loci) and/or insulin (2 loci) concentrations. For tests of interaction, we considered a P value <0.0028 (0.05 of 18 tests) as statistically significant. Greater whole-grain food intake was associated with lower fasting glucose and insulin concentrations independent of demographics, other dietary and lifestyle factors, and BMI (β [95% CI] per 1-serving-greater whole-grain intake: -0.009 mmol/l glucose [-0.013 to -0.005], P < 0.0001 and -0.011 pmol/l [ln] insulin [-0.015 to -0.007], P = 0.0003). No interactions met our multiple testing-adjusted statistical significance threshold. The strongest SNP interaction with whole-grain intake was rs780094 (GCKR) for fasting insulin (P = 0.006), where greater whole-grain intake was associated with a smaller reduction in fasting insulin concentrations in those with the insulin-raising allele. Our results support the favorable association of whole-grain intake with fasting glucose and insulin and suggest a potential interaction between variation in GCKR and whole-grain intake in influencing fasting insulin concentrations.

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program.

Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30-40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.

Retrograde ascending aortic dissection during or after thoracic aortic stent graft placement: insight from the European registry on endovascular aortic repair complications.

BACKGROUND: Single-center reports have identified retrograde ascending aortic dissection (rAAD) as a potentially lethal complication of thoracic endovascular aortic repair (TEVAR). METHODS AND RESULTS: Between 1995 and 2008, 28 centers participating in the European Registry on Endovascular Aortic Repair Complications reported a total of 63 rAAD cases (incidence, 1.33%; 95% CI, 0.75 to 2.40). Eighty-one percent of patients underwent TEVAR for acute (n=26, 54%) or chronic type B dissection (n=13, 27%). Stent grafts with proximal bare springs were used in majority of patients (83%). Only 7 (15%) patients had intraoperative rAAD, with the remaining occurring during the index hospitalization (n=10, 21%) and during follow-up (n=31, 64%). Presenting symptoms included acute chest pain (n=16, 33%), syncope (n=12, 25%), and sudden death (n=9, 19%) whereas one fourth of patients were asymptomatic (n=12, 25%). Most patients underwent emergency (n=25) or elective (n=5) surgical repair. Outcome was fatal in 20 of 48 patients (42%). Causes of rAAD included the stent graft itself (60%), manipulation of guide wires/sheaths (15%), and progression of underlying aortic disease (15%). CONCLUSIONS: The incidence of rAAD was low (1.33%) in the present analysis with high mortality (42%). Patients undergoing TEVAR for type B dissection appeared to be most prone for the occurrence of rAAD. This complication occurred not only during the index hospitalization but after discharge up to 1050 days after TEVAR. Importantly, the majority of rAAD cases were associated with the use of proximal bare spring stent grafts with direct evidence of stent graft-induced injury at surgery or necropsy in half of the patients.

European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3--2009 update.

In 2005, several groups, including the European Group for Blood and Marrow Transplantation, the European Organization for Treatment and Research of Cancer, the European Leukemia Net and the Immunocompromised Host Society created the European Conference on Infections in Leukemia (ECIL). The main goal of ECIL is to elaborate guidelines, or recommendations, for the management of infections in leukemia and stem cell transplant patients. The first sets of ECIL slides about the management of invasive fungal disease were made available on the web in 2006 and the papers were published in 2007. The third meeting of the group (ECIL 3) was held in September 2009 and the group updated its previous recommendations. The goal of this paper is to summarize the new proposals from ECIL 3, based on the results of studies published after the ECIL 2 meeting: (1) the prophylactic recommendations for hematopoietic stem cell transplant recipients were formulated differently, by splitting the neutropenic and the GVHD phases and taking into account recent data on voriconazole; (2) micafungin was introduced as an alternative drug for empirical antifungal therapy; (3) although several studies were published on preemptive antifungal approaches in neutropenic patients, the group decided not to propose any recommendation, as the only randomized study comparing an empirical versus a preemptive approach showed a significant excess of fungal disease in the preemptive group.

Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882).

BACKGROUND: In a previous randomised EORTC study on adjuvant dibromodulcitol (DBD) and bichloroethylnitrosourea (BCNU) in adults with glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA), a clinically significant trend towards a longer overall survival (OS) and a progression-free survival (PFS) was observed in the subgroup of AA. The aim of the present study was to test this adjuvant regimen in a larger number of AA patients. METHODS: Continuation of the previous phase III trial for newly diagnosed AA according to the local pathologist. Patients were randomised to either radiotherapy only or to radiotherapy in combination with BCNU on day 2 and weekly DBD, followed by adjuvant DBD and BCNU in cycles of six weeks for a maximum total treatment duration of one year. OS was the primary end-point. RESULTS: Patients (193 ) with newly diagnosed AA according to local pathological assessment were randomised to radiotherapy (RT) alone (n=99), or to RT plus DBD/BCNU (n=94); 12 patients were considered not eligible. At central pathology review, over half (53%) of the locally diagnosed AA cases could not be confirmed. On intent-to-treat analysis, no statistically significant differences in OS (p=0.111) and PFS (p=0.087) were observed, median OS after RT was only 23.9 months 95% confidence interval (CI), [18.4-34.0] after RT plus DBD/BCNU 27.3 months 95% CI [21.4-46.8]. CONCLUSION: No statistically significant improvement in survival was observed after BCNU/DBD adjuvant chemotherapy in AA patients. The trend towards improved survival is consistent with previous reports. Central pathology review of grade 3 tumours remains crucial.

Impact, challenges and perspectives of Euromelanoma, a pan-European campaign of skin cancer prevention.

The serotonin-2A receptor (5-HT(2A)R) has been implicated in the pathogenesis of schizophrenia and related inhibitory gating and behavioral inhibition deficits of schizophrenia patients. The hallucinogen psilocybin disrupts automatic forms of sensorimotor gating and response inhibition in humans, but it is unclear so far whether the 5-HT(2A)R or 5-HT(1A)R agonist properties of its bioactive metabolite psilocin account for these effects. Thus, we investigated whether psilocybin-induced deficits in automatic and controlled inhibition in healthy humans could be attenuated by the 5-HT(2A/2C)R antagonist ketanserin. A total of 16 healthy participants received placebo, ketanserin (40 mg p.o.), psilocybin (260 μg/kg p.o.), or psilocybin plus ketanserin in a double-blind, randomized, and counterbalanced order. Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response. The effects on psychopathological core dimensions and behavioral inhibition were assessed by the altered states of consciousness questionnaire (5D-ASC), and the Color-Word Stroop Test. Psilocybin decreased PPI at short lead intervals (30 ms), increased all 5D-ASC scores, and selectively increased errors in the interference condition of the Stroop Test. Stroop interference and Stroop effect of the response latencies were increased under psilocybin as well. Psilocybin-induced alterations were attenuated by ketanserin pretreatment, whereas ketanserin alone had no significant effects. These findings suggest that the disrupting effects of psilocybin on automatic and controlled inhibition processes are attributable to 5-HT(2A)R stimulation. Sensorimotor gating and attentional control deficits of schizophrenia patients might be due to changes within the 5-HT(2A)R system.

The costs of disorders of the brain in Switzerland: an update from the European Brain Council Study for 2010.

BACKGROUND: In 2005, findings of the first "cost of disorders of the brain in Europe" study of the European Brain Council (EBC) showed that these costs cause a substantial economic burden to the Swiss society. In 2010 an improved update with a broader range of disorders has been analysed. This report shows the new findings for Switzerland and discusses changes. METHODS: Data are derived from the EBC 2010 census study that estimates 12-month prevalence of 12 groups of disorders of the brain and calculates costs (direct health-care costs, direct non-medical costs and indirect costs) by combining top-down and bottom up cost approaches using existing data. RESULTS: The most frequent disorder was headache (2.3 million). Anxiety disorders were found in 1 million persons and sleep disorders in 700,000 persons. Annual costs for all assessed disorders total to 14.5 billion Euro corresponding to about 1,900 EUR per inhabitant per year. Mood, psychotic disorders and dementias (appr. 2 billion EUR each) were most costly. Costs per person were highest for neurological/neurosurgery-relevant disorders, e.g. neuromuscular disorders, brain tumour and multiple sclerosis (38,000 to 24,000 EUR). CONCLUSION: The estimates of the EBC 2010 study for Switzerland provide a basis for health care planning. Increase in size and costs compared to 2005 are mostly due to the inclusion of new disorders (e.g., sleep disorders), or the re-definition of others (e.g., headache) and to an increase in younger cohorts. We suggest coordinated research and preventive measures coordinated between governmental bodies, private health-care and pharmaceutical companies.

Paper 5: Surveillance of multiple congenital anomalies: implementation of a computer algorithm in European registers for classification of cases.

BACKGROUND: Surveillance of multiple congenital anomalies is considered to be more sensitive for the detection of new teratogens than surveillance of all or isolated congenital anomalies. Current literature proposes the manual review of all cases for classification into isolated or multiple congenital anomalies. METHODS: Multiple anomalies were defined as two or more major congenital anomalies, excluding sequences and syndromes. A computer algorithm for classification of major congenital anomaly cases in the EUROCAT database according to International Classification of Diseases (ICD)v10 codes was programmed, further developed, and implemented for 1 year's data (2004) from 25 registries. The group of cases classified with potential multiple congenital anomalies were manually reviewed by three geneticists to reach a final agreement of classification as "multiple congenital anomaly" cases. RESULTS: A total of 17,733 cases with major congenital anomalies were reported giving an overall prevalence of major congenital anomalies at 2.17%. The computer algorithm classified 10.5% of all cases as "potentially multiple congenital anomalies". After manual review of these cases, 7% were agreed to have true multiple congenital anomalies. Furthermore, the algorithm classified 15% of all cases as having chromosomal anomalies, 2% as monogenic syndromes, and 76% as isolated congenital anomalies. The proportion of multiple anomalies varies by congenital anomaly subgroup with up to 35% of cases with bilateral renal agenesis. CONCLUSIONS: The implementation of the EUROCAT computer algorithm is a feasible, efficient, and transparent way to improve classification of congenital anomalies for surveillance and research.

An Analysis of the Benefit of Using HEV Genotype 3 Antigens in Detecting Anti-HEV IgG in a European Population

Introduction Quatre génotypes pathogènes de l'hépatite E (HEV) sont actuellement connus. Ils présentent des caractéristiques épidémiologiques différentes. Les génotypes 1 et 2 infectent uniquement l'homme et sont à l'origine d'épidémies dans des pays en voie de développement. Les génotypes 3 et 4 se présentent sous forme de zoonose, endémiques chez des cochons et autres mammifères dans des pays industrialisés. Ces derniers génotypes sont à l'origine de cas sporadiques d'hépatite E autochtones. La majorité des tests de sérologie actuellement commercialisés se basent sur des virus de génotype 1 et 2. Le bénéfice de l'utilisation d'un test sérologique basé sur le génotype 3 dans des pays industrialisés n'a pas été étudié jusqu'à présent. Dans cette étude, les performances de tests sérologiques basés sur des antigènes de plusieurs génotypes de l'HEV ont été comparées. Méthode Les tests ont été appliqués à deux populations distinctes: une population de 20 patients, chez qui une infection aiguë d'hépatite E, génotype 3, a été documentée par PCR sanguine, et une population de 550 donneurs de sang de la région de Lausanne. Le dépistage des IgGs anti-HEV a été effectué dans le sérum des deux populations par trois «Enzyme Immuno Assays» (EIA) à savoir MP Diagnostics, Dia.Pro et Fortress. Les échantillons positifs avec au moins un des EIA ont été testés par un «Immunodot Assay», le recomLine HEV IgG/IgM. Tous les EIA sont basés sur des antigènes des génotypes 1 et 2, alors que l'immunodot se base sur des antigènes des génotypes 1 et 3. Résultats Tous les échantillons des cas d'hépatite E documentés et 124 sur 550 échantillons des donneurs de sang étaient positifs avec au moins un des tests sérologique. Parmi les cas confirmés par PCR, 45 %, 65 %, 95 % et 55 % étaient respectivement positifs avec le test de MP Diagnostics, Dia.Pro, Fortress et recomLine. Parmi les échantillons positifs des donneurs de sang avec au moins un des tests, 120/124 (97 %) étaient positifs avec le test Fortress, 19/124 (15 %) étaient positifs avec tous les EIA et 51/124 (41 %) étaient positifs avec le recomLine. Parmi les cas d'hépatite E confirmés, 11/20 (55 %) étaient positifs avec le recomLine et parmi ceux-ci, une réactivité plus forte pour le génotype 3 était observée dans 1/11 (9 %) et une réactivité identique dans 5/11 (45.5 %) cas. Conclusions Même si le recomLine contient des protéines dérivées de l'HEV génotype 3, sa sensibilité est inférieure à l'EIA de Fortress dans les cas d'hépatite E aiguë de génotype 3. De plus, chez environ 45 % des patients, le recomLine ne parvient pas à identifier une infection comme étant causé par un virus du génotype 3. Dans la population de donneurs de sang, nous avons observe de grandes variations dans les séroprévalences mesurées, allant de 4.2 % à 21.8 % selon les tests sérologiques employés.