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Augmented Reality in education can support students in a wide range of cognitive tasks–fostering understanding, remembering, applying, analysing, evaluating, and creating learning-relevant information more easily. It can help keep up engagement, and it can render learning more fun. Within the framework of a multi-year investigation encompassing primary and secondary schools across Europe, the ARETE project developed several Augmented Reality applications, providing tools for user interaction and data collection in the education sector. The project developed innovative AR learning technology and methodology, validating these in four comprehensive pilot studies, in total involving more than 2,900 students and teachers. Each pilot made use of a different Augmented Reality application covering specific subjects (English literacy skills, Mathematics and Geography, Positive Behaviour, plus, additionally, an Augmented Reality authoring tool applied in a wide range of subjects). In this paper, we introduce the datasets collected during the pilots, describe how the data enabled the validation of the technology, and how the approach chosen could enhance existing augmented reality applications in data exploration and modelling. [ABSTRACT FROM AUTHOR]

Comparative studies of genetic diversity and population structure can shed light on the ecological and evolutionary factors governing host–parasite interactions. Even though invasive parasites are considered of major biological importance, little is known about their adaptative potential when infesting the new hosts. Here, the genetic diversification of Varroa destructor, a novel parasite of Apis mellifera originating from Asia, was investigated using population genetics to determine how the genetic structure of the parasite changed in distinct European populations of its new host. To do so, mites infesting two categories of hosts in four European regions were compared: (a) adapted hosts surviving through means of natural selection, thereby expected to impose strong selective pressure on the mites, and (b) treated host populations, surviving mite infestations because acaricides are applied, therefore characterized by a relaxed selection imposed by the host on the mites. Significant genetic divergence was found across regions, partially reflecting the invasion pattern of V. destructor throughout Europe and indicating local adaptation of the mite to the host populations. Additionally, varying degrees of genotypic changes were found between mites from adapted and treated colonies. Altogether, these results indicate that V. destructor managed to overcome the genetic bottlenecks following its introduction in Europe and that host‐mediated selection fostered changes in the genetic structure of this mite at diverse geographic scales. These findings highlight the potential of parasites to adapt to their local host populations and confirm that adaptations developed within coevolutionary dynamics are a major determinant of population genetic changes. [ABSTRACT FROM AUTHOR]

Hydroclimate extremes in North America, Europe, and the Mediterranean are linked to ocean and atmospheric circulation anomalies in the Atlantic, but the limited length of the instrumental record prevents complete identification and characterization of these patterns of covariability especially at decadal to centennial time scales. Here we analyze the coupled patterns of drought variability on either sides of the North Atlantic Ocean basin using independent climate field reconstructions spanning the last millennium in order to detect and attribute epochs of coherent basin‐wide moisture anomalies to ocean and atmosphere processes. A leading mode of broad‐scale moisture variability is characterized by distinct patterns of North Atlantic atmosphere circulation and sea surface temperatures. We infer a negative phase of the North Atlantic Oscillation and colder Atlantic sea surface temperatures in the middle of the fifteenth century, coincident with weaker solar irradiance and prior to strong volcanic forcing associated with the early Little Ice Age. Key Points: Atlantic ocean‐atmosphere circulation links drought in North America, Europe, and the MediterraneanCoupled modes of drought variability can be used to infer atmospheric circulation and ocean temperature anomaliesCoupled terrestrial drought patterns reveal the start of the Little Ice Age to be characterized by a negative NAO and cold Atlantic SSTs [ABSTRACT FROM AUTHOR]

Aims: Several clinical conditions may precipitate acute heart failure (AHF) and influence clinical outcome. In this study we hypothesized that precipitating factors are independently associated with 90-day risk of death in AHF.Methods and Results: The study population consisted of 15 828 AHF patients from Europe and Asia. The primary outcome was 90-day all-cause mortality according to identified precipitating factors of AHF [acute coronary syndrome (ACS), infection, atrial fibrillation (AF), hypertension, and non-compliance]. Mortality at 90 days was 15.8%. AHF precipitated by ACS or by infection showed increased 90-day risk of death compared with AHF without identified precipitants [hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.44-1.97, P < 0.001; and HR 1.51, 95% CI 1.18-1.92, P = 0.001), while AHF precipitated by AF showed lower 90-day risk of death (HR 0.56, 95% CI 0.42-0.75, P < 0.001), after multivariable adjustment. The risk of death in AHF precipitated by ACS was the highest during the first week after admission, while in AHF precipitated by infection the risk of death had a delayed peak at week 3. In AHF precipitated by AF, a trend toward reduced risk of death during the first weeks was shown. At weeks 5-6, AHF precipitated by ACS, infection, or AF showed similar risk of death to that of AHF without identified precipitants.Conclusions: Precipitating factors are independently associated with 90-day mortality in AHF. AHF precipitated by ACS or infection is independently associated with higher, while AHF precipitated by AF is associated with lower 90-day risk of death. [ABSTRACT FROM AUTHOR]

Objectives: Our goal was to provide data on the economic burden and health-related quality of life (HRQOL) of patients with cystic fibrosis (CF) and their caregivers in Europe.Methods: A cross-sectional study was carried out on adults and children with CF in eight European countries. Patients completed an anonymous questionnaire regarding their socio-demographic characteristics, use of healthcare services and presence of a caregiver. Costs were calculated with a bottom-up approach using unit costs from each participating country, and HRQOL was assessed using EQ-5D. The principal caregiver also answered a questionnaire on their characteristics, HRQOL and burden.Results: A total of 905 patients with CF was included (399 adults and 506 children). The total average annual cost per patient varied from €21,144 in Bulgaria to €53,256 in Germany. Adults had higher direct healthcare costs than children, but children had much higher informal care costs (P < 0.0001). Total costs increased with patients' level of dependence. In adults, mean utility fell between 0.640 and 0.870, and the visual analogue scale ranged from 46.0 to 69.7. There was no difference in caregiver HRQOL regardless of whether they cared for an adult or a child. However, caregivers who looked after a child had a significantly higher burden (P = 0.0013).Conclusions: Our study highlights the burden of CF in terms of costs and decreased HRQOL for both patients and their caregivers throughout Europe. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with Duchenne muscular dystrophy (DMD) in Europe.Methods: We conducted a cross-sectional study of patients with DMD from Bulgaria, France, Germany, Hungary, Italy, Spain, Sweden, and the UK. Data on demographic characteristics, healthcare resource utilization, informal care, labor productivity losses, and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. Costs have been estimated from a societal perspective adopting a bottom-up approach.Results: A total of 422 questionnaires were included in the study; 268 of which were collected from patients with DMD and 154 from caregivers. The average annual cost per person in 2012 ranged from €7657 in Hungary to €58,704 in France. Direct non-healthcare costs are the main component of whole costs and informal care is the main driver of non-healthcare costs. Costs are also shown to differ between children and adults. With regard to HRQOL of adult patients, the EQ-5D VAS score and EQ-5D index scores were 50.5 and 0.24, respectively. The corresponding EQ-5D VAS and EQ-5D index scores for caregivers were 74.7 and 0.71, respectively.Conclusions: We have estimated the average annual cost per patient with DMD in eight European countries adopting a social perspective, and to our knowledge this is the first study with such a wide perspective. The results on costs show a considerable gap between Eastern and Western European countries. Non-healthcare costs range from 64 to 89 % of overall costs and informal care is to a great extent the main driver of this cost category. The HRQOL of people with DMD is much lower than that of the general population. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to determine the social/economic costs and health-related quality of life (HRQOL) of patients with epidermolysis bullosa (EB) in eight EU member states.Methods: We conducted a cross-sectional study of patients with EB from Bulgaria, France, Germany, Hungary, Italy, Spain, Sweden and the United Kingdom. Data on demographic characteristics, health resource utilisation, informal care, labour productivity losses, and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire.Results: A total of 204 patients completed the questionnaire. Average annual costs varied from country to country, and ranged from €9509 to €49,233 (reference year 2012). Estimated direct healthcare costs ranged from €419 to €10,688; direct non-healthcare costs ranged from €7449 to €37,451 and labour productivity losses ranged from €0 to €7259. The average annual cost per patient across all countries was estimated at €31,390, out of which €5646 accounted for direct health costs (18.0 %), €23,483 accounted for direct non-healthcare costs (74.8 %), and €2261 accounted for indirect costs (7.2 %). Costs were shown to vary across patients with different disability but also between children and adults. The mean EQ-5D score for adult EB patients was estimated at between 0.49 and 0.71 and the mean EQ-5D visual analogue scale score was estimated at between 62 and 77.Conclusion: In addition to its negative impact on patient HRQOL, our study indicates the substantial social/economic burden of EB in Europe, attributable mostly to high direct non-healthcare costs. [ABSTRACT FROM AUTHOR]

Objective: To estimate the social/economic costs of fragile X syndrome (FXS) in Europe and to assess the health-related quality of life (HRQOL) of patients and caregivers.Methods: A cross-sectional study was conducted in a sample of European countries. Patients were recruited through patients' associations. Data on their resource use and absence from the labour market were retrospectively obtained from an online questionnaire. Costs were estimated by a bottom-up approach and the EuroQol-5 Domain (EQ-5D) questionnaire was used to measure patients' and caregivers' HRQOL.Results: Five countries were included in the analysis. The mean annual cost of FXS per patient varied from €4951 in Hungary to €58,862 in Sweden. Direct non-healthcare costs represented the majority of costs in all countries but there were differences in the share incurred by formal and informal care among those costs. Costs were also shown to differ between children and adults. Mean EQ-5D utility score for adult patients varied from 0.52 in France (n = 42) to 0.73 in Hungary (n = 2), while for caregivers this score was consistently inferior to 0.87.Conclusion: Our findings underline that, although its prevalence is low, FXS is costly from a societal perspective. They support the development of tailored policies to reduce the consequences of FXS on both patients and their relatives. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with haemophilia in Europe.Methods: We conducted a cross-sectional study of patients with haemophilia from Bulgaria, France, Germany, Hungary, Italy, Spain Sweden and the UK. Data on demographic characteristics, health resource utilisation, informal care, loss of labour productivity and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. The costs have been estimated from a societal perspective adopting a bottom-up approach.Results: A total of 401 questionnaires were included in the study, of which 339 were collected from patients with haemophilia and 62 from caregivers. The lowest average annual cost per person was reported in Bulgaria (€6,660) and the highest in Germany (€194,490). Our results demonstrate both a large difference from country to country in the average annual cost per patient in 2012 and the driving role of drugs in costs. Drugs represent nearly 90 % of direct healthcare costs in a majority of the countries analysed (Hungary, Italy, Spain and Germany). In Bulgaria, France and Sweden, however, healthcare services (visits, tests and hospitalisations) prevail. Costs are also shown to differ between children and adults. The mean EQ-5D index score for adult patients was 0.69 and mean EQ-5D VAS was 66.6. The mean EQ-5D index score for carers was 0.87 and mean EQ-5D VAS was 75.5. In the disability score, 60 % showed no disability and measuring caregiver burden with the Zarit Index produced an overall mean score of 25.3.Conclusion: We have shown that haemophilia is associated with a substantial economic burden and impaired HRQOL. Studies on cost of illness and HRQOL are important for haemophilia as the future of this disease is likely to change with the development of new innovative treatments. The introduction of these treatments will most likely impact future costs related to haemophilia. [ABSTRACT FROM AUTHOR]

Objectives: To assess the health-related quality of life (HRQOL) of patients with mucopolysaccharidosis (MPS) and their caregivers and to quantify the disease-related costs from a societal perspective.Methods: In the context of a multi-country study of rare diseases (BURQOL-RD project), a cross-sectional survey was performed among MPS patients in seven European countries. Data on demographic characteristics, health resource utilization, informal care, and loss of labor productivity were collected. The EQ-5D, Barthel index (BI), and Zarit burden interview (ZBI) questionnaires were used to assess patients' and their informal caregivers' quality of life, patients' functional ability, and caregivers' burden, respectively.Results: Altogether, 120 patients (children 62 %, females 40 %) and 66 caregivers completed the questionnaire. Patients' mean age was 16.5 years and median age at diagnosis was 3 years. Adult patients' average EQ-5D and EQ VAS scores varied across countries from 0.13 to 0.43 and 30.0 to 62.2, respectively, mean BI was 46.7, and ZBI was 32.7. Mean informal care time was 51.3 h/week. The mean total annual cost per patient (reference year 2012) was €24,520 in Hungary, €25,993 in France, €84,921 in Italy, €94,384 in Spain, and €209,420 in Germany. Costs are also shown to differ between children and adults. Direct costs accounted for most of the costs in all five countries (80, 100, 99, 98, and 93 %, respectively).Conclusions: MPS patients experience substantial loss of HRQOL and their families take a remarkable part in their care. Although utilization of health and social care resources varies significantly across countries, MPS incurs considerable societal costs in all the countries studied. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the economic burden from a societal perspective and health-related quality of life (HRQOL) of patients with Prader-Willi syndrome (PWS) in Europe.Methods: We conducted a cross-sectional study of patients with PWS from Spain, Bulgaria, Hungary, Germany, Italy, the UK, Sweden and France. Data on demographic characteristics, healthcare resource utilisation, informal care, labour productivity losses and HRQOL were collected from questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire.Results: A total of 261 patients completed the questionnaire. The average annual costs ranged from € 3937 to € 67,484 between countries; the reference year for unit prices was 2012. Direct healthcare costs ranged from € 311 to € 18,760, direct non-healthcare costs ranged from € 1269 to € 44,035, and loss of labour productivity ranged from € 0 to € 2255. Costs were also shown to differ between children and adults. The mean EQ-5D index score for adult PWS patients ranged between 0.40 and 0.81 and the mean EQ-5D visual analogue scale score ranged between 51.25 and 90.00.Conclusion: The main strengths of this study lie in our bottom-up approach to costing and in the evaluation of PWS patients from a broad societal perspective. This type of analysis is very scarce in the international literature on rare diseases in comparison with other illnesses. We conclude that PWS patients incur considerable societal costs and experience substantial deterioration in HRQOL. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with systemic sclerosis (SSc; scleroderma) in Europe.Methods: We conducted a cross-sectional study of patients with SSc (involving both localised and systemic sclerosis) from Germany, Italy, Spain, France, the UK, Hungary and Sweden. Data on demographic characteristics, healthcare resource utilisation, informal care, labour productivity losses and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire.Results: A total of 589 patients completed the questionnaire. The rate of patients with localised scleroderma, limited cutan and diffuse cutan SSc were 28, 68 and 4 %, respectively. Average annual costs varied from country to country and ranged from € 4607 to € 30,797 (reference year: 2012). Estimated direct healthcare costs ranged from € 1413 to € 17,300; direct non-healthcare costs ranged from € 1875 to € 4684 and labour productivity losses ranged from € 1701 to € 14,444. The mean EQ-5D index score for adult SSc patients varied from 0.49 to 0.75 and the mean EQ-5D visual analogue scale score was between 58.72 and 65.86.Conclusion: The main strengths of this study lie in our bottom-up approach to costing and our evaluation of SSs patients from a broad societal perspective. This type of analysis is very unusual in the international literature on rare diseases in comparison with other illnesses. We concluded that SSc patients incur considerable societal costs and experience substantial deterioration in HRQOL. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine the economic burden from a societal perspective and the health-related quality of life (HRQOL) of patients with histiocytosis in Europe.Methods: We conducted a cross-sectional study of patients with histiocytosis from France, Germany, Italy, Spain, Bulgaria, the UK, and Sweden. Data on demographic characteristics, health resource utilisation, informal care, loss of labour productivity and HRQOL were collected from the questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire.Results: A total of 134 patients (35 France, 32 Germany, 30 Italy, 24 Spain, 7 Bulgaria, 4 UK and 2 Sweden) completed the questionnaire. The average annual costs ranged from € 6832 to € 33,283 between countries, the year of reference being 2012. Estimated direct healthcare costs ranged from € 1698 to € 18,213; direct nonhealthcare costs ranged from € 2936 to € 17,622 and labour productivity losses ranged from € 1 to € 8855. The mean EQ-5D score for adult histiocytosis patients was estimated at between 0.32 and 0.85, and the mean EQ-5D visual analogue scale score was estimated at between 50.00 and 66.50.Conclusion: The main strengths of this study lie in our bottom-up approach to costing and in the evaluation of histiocytosis patients from a broad perspective (societal costs). This type of analysis is very scarce in international literature for rare diseases in comparison with other illnesses. We conclude that histiocytosis patients incur considerable societal costs and experience substantial deterioration in HRQOL. [ABSTRACT FROM AUTHOR]

Infrastructure is widely recognized as a key ingredient in a country's economic success. However many issues surrounding infrastructure management are not well analysed. This paper assesses the performance of rail infrastructures management. Focusing on key European countries this study monitors the factors directly related to the effective allocation of resources. Results suggest that the outperforming system is the Swedish, characterised by reduced cost, and the German, marked by significant scale economics. The Italian case follows these two. The expenses for running the Spanish infrastructure are relatively low but this advantage is outweighed by weak traffic. If on one hand the cost of the British network appears to be above the average, on the other hand it is compensated by the intensive use of the network. The French infrastructure presents an average production cost along with moderate productivity; a remarkable average loading makes up for this performance gap. Main limitations stem from the fact that the railway industries and their development greatly differ across European countries since the infrastructure were built on national bases. This study serves as an entry point to further assessments and evaluation of the efficacy of policies regarding the management of rail infrastructures in Europe. [ABSTRACT FROM AUTHOR]

This paper examines the pricing models for the use of the railway infrastructure in some European countries. A regulatory environment shall guarantee fair access to essential facilities, specifically in presence of vertically related markets and the existence of an essential facility provided only by one firm. This paper considers two pricing models classified according different principles: the model of marginal cost and the model of full cost. Given that the effective traffic does not influence the relevant fixed costs of the networks, managers will have expected curves of marginal cost firmly under the curves of average cost, and as a result, the current trade-off between the optimal use of the network and the optimal coverage of the costs. This paper states that countries where a marginal cost model is in use, the railway system has a smaller impact on public spending. [ABSTRACT FROM AUTHOR]

This paper focuses on the use of mobile technologies in relation to the aims of the European Union's Lifelong Learning programme. First, we explain the background to the notion of mobile lifelong learning. We then present a methodological framework to analyse and identify good practices in mobile lifelong learning, based on the outcomes of the MOTILL project ('Mobile Technologies in Lifelong Learning: Best Practices'). In particular, we give an account of the methodology adopted to carry out meta-analyses of published literature and accounts of mobile learning experiences. Furthermore, we present the results of an implementation of our Evaluation Grid and the implications arising from it in terms of management, pedagogy, policies and ethical issues. Finally, we discuss lessons learnt and future work. [ABSTRACT FROM AUTHOR]

Aim To predict the fate of alpine interactions involving specialized species, using a monophagous beetle and its host plant as a case study. Location The Alps. Methods We investigated genetic structuring of the herbivorous beetle Oreina gloriosa and its specific host-plant Peucedanum ostruthium. We used genome fingerprinting (in the insect and the plant) and sequence data (in the insect) to compare the distribution of the main gene pools in the two associated species and to estimate divergence time in the insect, a proxy for the temporal origin of the interaction. We quantified the similarity in spatial genetic structures by performing a Procrustes analysis, a tool from shape theory. Finally, we simulated recolonization of an empty space analogous to the deglaciated Alps just after ice retreat by two lineages from two species showing unbalanced dependence, to examine how timing of the recolonization process, as well as dispersal capacities of associated species, could explain the observed pattern. Results Contrasting with expectations based on their asymmetrical dependence, patterns in the beetle and plant were congruent at a large scale. Exceptions occurred at a regional scale in areas of admixture, matching known suture zones in Alpine plants. Simulations using a lattice-based model suggested these empirical patterns arose during or soon after recolonization, long after the estimated origin of the interaction c. 0.5 million years ago. Main conclusions Species-specific interactions are scarce in alpine habitats because glacial cycles have limited the opportunities for co-evolution. Their fate, however, remains uncertain under climate change. Here we show that whereas most dispersal routes are paralleled at a large scale, regional incongruence implies that the destinies of the species might differ under changing climate. This may be a consequence of the host dependence of the beetle, which locally limits the establishment of dispersing insects. [ABSTRACT FROM AUTHOR]

Aims: Bleeding and thrombotic complications compromise outcomes in patients undergoing percutaneous mechanical circulatory support (pMCS) with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and/or microaxial flow pumps like Impella™. Antithrombotic practices are an important determinant of the coagulopathic risk, but standardization in the antithrombotic management during pMCS is lacking. This survey outlines European practices in antithrombotic management in adults on pMCS, making an initial effort to standardize practices, inform future trials, and enhance outcomes., Methods and Results: This online cross-sectional survey was distributed through digital newsletters and social media platforms by the Association of Acute Cardiovascular Care and the European branch of the Extracorporeal Life Support Organization. The survey was available from 17 April 2023 to 23 May 2023. The target population were European clinicians involved in care for adults on pMCS. We included 105 responses from 26 European countries. Notably, 72.4% of the respondents adhered to locally established anticoagulation protocols, with unfractionated heparin (UFH) being the predominant anticoagulant (Impella™: 97.0% and V-A ECMO: 96.1%). A minority of the respondents, 10.8 and 14.5%, respectively, utilized the anti-factor-Xa assay in parallel with activated partial thromboplastin time for UFH monitoring during Impella™ and V-A ECMO support. Anticoagulant targets varied across institutions. Following acute coronary syndrome without percutaneous coronary intervention (PCI), 54.0 and 42.7% were administered dual antiplatelet therapy during Impella™ and V-A ECMO support, increasing to 93.7 and 84.0% after PCI., Conclusion: Substantial heterogeneity in antithrombotic practices emerged from participants' responses, potentially contributing to variable device-associated bleeding and thrombotic complications., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Adding ibrutinib to standard immunochemotherapy might improve outcomes and challenge autologous stem-cell transplantation (ASCT) in younger (aged 65 years or younger) mantle cell lymphoma patients. This trial aimed to investigate whether the addition of ibrutinib results in a superior clinical outcome compared with the pre-trial immunochemotherapy standard with ASCT or an ibrutinib-containing treatment without ASCT. We also investigated whether standard treatment with ASCT is superior to a treatment adding ibrutinib but without ASCT., Methods: The open-label, randomised, three-arm, parallel-group, superiority TRIANGLE trial was performed in 165 secondary or tertiary clinical centres in 13 European countries and Israel. Patients with previously untreated, stage II-IV mantle cell lymphoma, aged 18-65 years and suitable for ASCT were randomly assigned 1:1:1 to control group A or experimental groups A+I or I, stratified by study group and mantle cell lymphoma international prognostic index risk groups. Treatment in group A consisted of six alternating cycles of R-CHOP (intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous cyclophosphamide 750 mg/m 2 on day 1, intravenous doxorubicin 50 mg/m 2 on day 1, intravenous vincristine 1·4 mg/m 2 on day 1, and oral prednisone 100 mg on days 1-5) and R-DHAP (or R-DHAOx, intravenous rituximab 375 mg/m 2 on day 0 or 1, intravenous or oral dexamethasone 40 mg on days 1-4, intravenous cytarabine 2 × 2 g/m 2 for 3 h every 12 h on day 2, and intravenous cisplatin 100 mg/m 2 over 24 h on day 1 or alternatively intravenous oxaliplatin 130 mg/m 2 on day 1) followed by ASCT. In group A+I, ibrutinib (560 mg orally each day) was added on days 1-19 of R-CHOP cycles and as fixed-duration maintenance (560 mg orally each day for 2 years) after ASCT. In group I, ibrutinib was given the same way as in group A+I, but ASCT was omitted. Three pairwise one-sided log-rank tests for the primary outcome of failure-free survival were statistically monitored. The primary analysis was done by intention-to-treat. Adverse events were evaluated by treatment period among patients who started the respective treatment. This ongoing trial is registered with ClinicalTrials.gov, NCT02858258., Findings: Between July 29, 2016 and Dec 28, 2020, 870 patients (662 men, 208 women) were randomly assigned to group A (n=288), group A+I (n=292), and group I (n=290). After 31 months median follow-up, group A+I was superior to group A with 3-year failure-free survival of 88% (95% CI 84-92) versus 72% (67-79; hazard ratio 0·52 [one-sided 98·3% CI 0-0·86]; one-sided p=0·0008). Superiority of group A over group I was not shown with 3-year failure-free survival 72% (67-79) versus 86% (82-91; hazard ratio 1·77 [one-sided 98·3% CI 0-3·76]; one-sided p=0·9979). The comparison of group A+I versus group I is ongoing. There were no relevant differences in grade 3-5 adverse events during induction or ASCT between patients treated with R-CHOP/R-DHAP or ibrutinib combined with R-CHOP/R-DHAP. During maintenance or follow-up, substantially more grade 3-5 haematological adverse events and infections were reported after ASCT plus ibrutinib (group A+I; haematological: 114 [50%] of 231 patients; infections: 58 [25%] of 231; fatal infections: two [1%] of 231) compared with ibrutinib only (group I; haematological: 74 [28%] of 269; infections: 52 [19%] of 269; fatal infections: two [1%] of 269) or after ASCT (group A; haematological: 51 [21%] of 238; infections: 32 [13%] of 238; fatal infections: three [1%] of 238)., Interpretation: Adding ibrutinib to first-line treatment resulted in superior efficacy in younger mantle cell lymphoma patients with increased toxicity when given after ASCT. Adding ibrutinib during induction and as maintenance should be part of first-line treatment of younger mantle cell lymphoma patients. Whether ASCT adds to an ibrutinib-containing regimen is not yet determined., Funding: Janssen and Leukemia & Lymphoma Society., Competing Interests: Declaration of interests MD reports research grants for clinical studies from AbbVie, Bayer, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Roche; speakers' honoraria from AstraZeneca, BeiGene, Gilead/Kite, Janssen, Lilly, Novartis, and Roche; travel support from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, Lilly/Loxo Oncology, Novartis, and Roche. JDo reports payment for expert testimony (once Advisory Board) from Lilly. EG reports grants from Janssen; honoraria (educational lecture) from Genmab, Gilead, Janssen, and Lilly; support for attending meetings or travel from Janssen and Roche; and participation on a Data Safety Monitoring Board or Advisory Board for Gilead/Kite and Miltenyi Biotec. MJ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Gilead/Kite, and Roche; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Gilead/Kite, Janssen, and Pierre Fabre. JW reports grants to his institution from GlaxoSmithKline/Novartis and Roche; honoraria for lectures from AbbVie, Amgen, Gilead, Novartis, Roche, Servier, and Takeda; participation on an Advisory Board from AbbVie, Gilead, Novartis, Roche, and Takeda. MHu reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, Roche, and Takeda. UM reports travel support from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Janssen-Cilag, and Roche; Advisory Board role for Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Novartis, Pfizer, Roche, Sanofi, and Takeda; participation in national Guideline committee for the German-Swiss-Austrian Guideline for Mantle Cell Lymphoma. JR reports participation on an Advisory Board for AstraZeneca. VV reports consulting fees from AbbVie, BeiGene, Gilead, Lilly, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Janssen; payment for expert testimony from Gilead and Roche; support for attending meetings or travel from AbbVie and Gilead. MGdS reports a research grant from AstraZeneca; payment for Advisory Boards from AbbVie, Gilead, Janssen-Cilag, Roche, and Takeda; payment or honoraria for educational events from Gilead and Janssen-Cilag; support for attending meetings or travel from AbbVie, Janssen-Cilag, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for Roche; leadership in a scientific society (Sociedade Portuguesa de Hematologia); administration board on a patient advocacy group (Associação Portuguesa Contra a Leucemia). SL reports grants or contracts to her institution from Bristol-Myers Squibb/Celgene, Genmab, HUTCHMED, Novartis, and Roche; consulting fees from AbbVie, Genmab, Gilead, Novartis, ORION Pharma, Roche, and Swedish Orphan Biovitrum (sobi); payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Gilead, Incyte, and Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Incyte. StS reports grants or contracts from any entity from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; consulting fees from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; support for attending meetings or travel from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem; receipt of equipment, materials, drugs, medical writing, gifts, or other services from AbbVie, Acerta Pharma, Amgen, AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Roche, Gilead, GlaxoSmithKline, Infinity Pharmaceuticals, Janssen, Novartis, Sunesis Pharmaceuticals, and Verastem. AK reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, Bristol-Myers Squibb/Celgene, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; support for attending meetings or travel from AbbVie, BeiGene, EUSA Pharma, Swedish Orphan Biovitrum (sobi), and Takeda. RJ reports travel support for meeting attendance from BeiGene; meeting fee from Janssen. GH reports grants or contracts for clinical research from AbbVie, Gilead/Kite, Incyte, Janssen, MorphoSys, Pfizer, and Roche; consulting fees from AbbVie, ADC Therapeutics, AstraZeneca, Bristol-Myers Squibb, Genmab, Gilead/Kite, Incyte, Janssen, Lilly, Miltenyi Biotec, Novartis, and Roche; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Genmab, Gilead, Incyte, Janssen, Lilly, and Roche; support for attending meetings or travel from Gilead/Kite and Janssen; participation on a Data Safety Monitoring Board or Advisory Board for Miltenyi Biotec. CV reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AbbVie, AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead/Kite, Incyte, Istituto Gentili, Janssen, Lilly, Novartis, Pfizer, Roche, and Servier; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Bristol-Myers Squibb, Incyte, Janssen, Lilly, Pfizer, and Roche. TvM reports payment or honoraria for educational lectures from Bristol-Myers Squibb/Celgene, Gilead/Kite, Janssen, and Lilly; participation on a Data Safety Monitoring Board or Advisory Board for GE HealthCare and Gilead/Kite. SW reports payment to his institution from AbbVie, Stemline Therapeutics, and Takeda; payment for expert testimony from Stemline Therapeutics; support for attending meetings or travel from AbbVie and BeiGene; participation on a Data Safety Monitoring Board or Advisory Board for AbbVie, Astra Zeneca, Roche, and Stemline Therapeutics. PLZ reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb, Gilead, Incyte, Janssen, Kyowa Kirin, Merck Sharp and Dohme, Novartis, Roche, Swedish Orphan Biovitrum (sobi), and Takeda. UN reports consulting fees to his institution from AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to his institution from Bristol-Myers Squibb/Celgene, Gilead, Novartis, and Takeda; support for attending meetings or travel from Janssen, Gilead, Roche, and Takeda; participation on a Data Safety Monitoring Board or Advisory Board for AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen-Cilag, Kyowa Kirin, Novartis, Pierre Fabre, Roche, and Takeda. CH reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol-Myers Squibb, Janssen, and Pfizer; support for attending meetings or travel from AbbVie and Janssen. MHa reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Falk Foundation, Gilead, Novartis, and Swedish Orphan Biovitrum (sobi); payment for expert testimony from Amgen, Bristol-Myers Squibb/Celgene, Gilead, Incyte, Janssen, Novartis, Pizer, Roche, Sanofi-Aventis, and Swedish Orphan Biovitrum (sobi). WK reports research grants provided to his institution from Amgen, Janssen, Roche, and Takeda. DG reports support for attending meetings and travel from Janssen. CS reports consulting fees from Bristol-Myers Squibb and Janssen; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca and Bristol-Myers Squibb; support for attending meetings or travel from Gilead/Kite. MU reports institutional funding of the TRIANGLE trial from Janssen. ML reports consulting fees from AstraZeneca, BeiGene, Janssen, and Lilly; honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from AstraZeneca, BeiGene, Janssen, and Lilly; participation on a Data Safety Monitoring Board with Acerta. All other authors (MT, OS, LJ, MC, LA, PH, FB, KS, JDi, CP, and EH) declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In patients with ST-segment elevation myocardial infarction (STEMI) with multivessel coronary artery disease, the time at which complete revascularization of nonculprit lesions should be performed remains unknown., Methods: We performed an international, open-label, randomized, noninferiority trial at 37 sites in Europe. Patients in a hemodynamically stable condition who had STEMI and multivessel coronary artery disease were randomly assigned to undergo immediate multivessel percutaneous coronary intervention (PCI; immediate group) or PCI of the culprit lesion followed by staged multivessel PCI of nonculprit lesions within 19 to 45 days after the index procedure (staged group). The primary end point was a composite of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year after randomization. The percentages of patients with a primary or secondary end-point event are provided as Kaplan-Meier estimates at 6 months and at 1 year., Results: We assigned 418 patients to undergo immediate multivessel PCI and 422 to undergo staged multivessel PCI. A primary end-point event occurred in 35 patients (8.5%) in the immediate group as compared with 68 patients (16.3%) in the staged group (risk ratio, 0.52; 95% confidence interval, 0.38 to 0.72; P<0.001 for noninferiority and P<0.001 for superiority). Nonfatal myocardial infarction and unplanned ischemia-driven revascularization occurred in 8 patients (2.0%) and 17 patients (4.1%), respectively, in the immediate group and in 22 patients (5.3%) and 39 patients (9.3%), respectively, in the staged group. The risk of death from any cause, the risk of stroke, and the risk of hospitalization for heart failure appeared to be similar in the two groups. A total of 104 patients in the immediate group and 145 patients in the staged group had a serious adverse event., Conclusions: Among patients in hemodynamically stable condition with STEMI and multivessel coronary artery disease, immediate multivessel PCI was noninferior to staged multivessel PCI with respect to the risk of death from any cause, nonfatal myocardial infarction, stroke, unplanned ischemia-driven revascularization, or hospitalization for heart failure at 1 year. (Supported by Boston Scientific; MULTISTARS AMI ClinicalTrials.gov number, NCT03135275.)., (Copyright © 2023 Massachusetts Medical Society.)

Introduction: Molnupiravir and nirmatrelvir/ritonavir are antivirals used to prevent progression to severe SARS-CoV-2 infections and decrease hospitalisation and mortality rates. Nirmatrelvir/ritonavir was authorised in Europe in December 2021, whereas molnupiravir is not yet licensed in Europe as of February 2022. Molnupiravir may be an alternative to nirmatrelvir/ritonavir because it is associated with fewer drug-drug interactions and contraindications. A caveat for molnupiravir is the mode of action induces viral mutations. Mortality rate reduction with molnupiravir was less pronounced than that with nirmatrelvir/ritonavir in patients without haematological malignancy. Little is known about the comparative efficacy of the two drugs in patients with haematological malignancy at high-risk of severe COVID-19. Thus, molnupiravir and nirmatrelvir/ritonavir were compared in a cohort of patients with haematological malignancies., Methods: Clinical data from patients treated with molnupiravir or nirmatrelvir/ritonavir monotherapy for COVID-19 were retrieved from the EPICOVIDEHA registry. Patients treated with molnupiravir were matched by sex, age (±10 years), and severity of baseline haematological malignancy to controls treated with nirmatrelvir/ritonavir., Results: A total of 116 patients receiving molnupiravir for the clinical management of COVID-19 were matched to an equal number of controls receiving nirmatrelvir/ritonavir. In each of the groups, 68 (59%) patients were male; with a median age of 64 years (interquartile range [IQR] 53-74) for molnupiravir recipients and 64 years (IQR 54-73) for nirmatrelvir/ritonavir recipients; 56.9% (n=66) of the patients had controlled baseline haematological malignancy, 12.9% (n=15) had stable disease, and 30.2% (n=35) had active disease at COVID-19 onset in each group. During COVID-19 infection, one third of patients from each group were admitted to hospital. Although a similar proportion of patients in the two groups were vaccinated (molnupiravir n=77, 66% vs. nirmatrelvir/ritonavir n=87, 75%), more of those treated with nirmatrelvir/ritonavir had received four vaccine doses (n=27, 23%) compared with those treated with molnupiravir (n=5, 4%) (P<0.001). No differences were detected in COVID-19 severity (P=0.39) or hospitalisation (P=1.0). No statistically significant differences were identified in overall mortality rate (P=0.78) or survival probability (d30 P=0.19, d60 P=0.67, d90 P=0.68, last day of follow up P=0.68). Deaths were either attributed to COVID-19, or the infection was judged by the treating physician to have contributed to death., Conclusions: Hospitalisation and mortality rates with molnupiravir were comparable to those with nirmatrelvir/ritonavir in high-risk patients with haematological malignancies and COVID-19. Molnupiravir is a plausible alternative to nirmatrelvir/ritonavir for COVID-19 treatment in patients with haematological malignancy., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Mushrooms and derivates are well known to the scientific community for having different health benefits and exhibit a wide range of pharmacological activities, including lipid-lowering, antihypertensive, antidiabetic, antimicrobic, antiallergic, anti-inflammatory, anticancer, immunomodulating, neuroprotective and osteoprotective actions. In Europe, medical mushrooms are mainly marketed in the form of food supplements as single components or combined with other nutraceuticals. In this context, the first peculiarity that distinguishes it is the safety established through the "history of consumption" that characterizes that mushroom. However, the cultivation of medicinal mushrooms on a large scale is performed mainly in China, where most of the production facilities do not have internationally recognized good manufacturing practices, despite that many European companies that sell myotherapies are supplied by Chinese manufacturers. This is particularly evident in Italy, where an arsenal of mushroom products is marketed in the form of powders and extracts not always of ascertained origin and sometimes of doubtful taxonomic identification, and thus not meeting the quality criteria required. The growing interest in mycotherapy involves a strong commitment from the scientific community to propose supplements of safe origin and genetic purity as well as to promote clinical trials to evaluate its real effects on humans. The purpose of this research is to analyze different mushroom-based dietary supplements used in medicine as monotherapy on the Italian market and to evaluate their composition and quality. The molecular identification of the sequences with those deposited in GenBank allowed for identifying 6 out of 19 samples, matching with those deposited belonging to the species indicated in the label, i.e., Lentinula edodes (samples 1, 4, 12 and 18) and Ganoderma lucidum (samples 5 and 10). Samples containing Ganoderma, labeled in the commercial product as G. lucidum , showed sequences that showed homology of 100% and 99% with G. resinaceum and G. sichuanense . An additional investigation was carried out in order to determine the active fungal ingredients, such as ergosterol, aflatoxins, heavy metals, nicotine and total glucan. The results obtained and shown in the manuscript highlight how the data were not only in line with what is expected with respect to what is indicated in the labels.

Background: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe., Methods: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing., Findings: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57-77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19-0·61) and 28 days (0·34 [0·16-0·79]), complications due to COVID-19 (0·26 [0·17-0·46]), and hospitalisation due to COVID-19 (0·17 [0·09-0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15-0·34]) and oxygen therapy (0·24 [0·14-0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase., Interpretation: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19., Funding: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust., Competing Interests: Declaration of interests DJP has received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, and Falk Foundation; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, Eisai, Roche, DaVolterra, and Astra Zeneca; and research funding (to their institution) from MSD and BMS. MLa has acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen, and Gilead; and has received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen, Libbs, Knight, and Sandoz. FM has received consulting fees from Eli Lilly, MSD, Takeda, and Roche; and travel support from Sanofi. SP reported that their spouse is employed by AstraZeneca. ASa has received consulting fees from Arqule, Sanofi, and Incyte; speaker's fees from Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Eli Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD; and participation on data monitoring committees for BMS, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD. FG has received consulting fees from Novocure, BMS, PharmaMar, and Novartis; speaker's fees from Novocure; travel support from MSD, Novocure, BMS, Boehringer Ingelheim, PharmaMar, Novartis, and Pierre Fabre; and participation on a data safety monitoring board for MSD, BMS, PharmaMar and Novartis. JH has a leadership role with Blood Cancer UK. NS-G has received speakers' fees from Amgen. GG has received consulting fees or had an advisory role for Janssen, AbbVie, AstraZeneca, Roche, Incyte, and BeiGene, and reported speaker fees from Janssen and AbbVie. LRi has received consulting fees from Taiho Oncology, Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, and Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks. JT reports consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; speaker's fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and institutional research support from Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA, Spanish Association Against Cancer Scientific Foundation, and Cancer Research UK. MB has received speakers' fee from Eisai pharma, Gilead Sciences, Merck, and ViiV; and has had leadership roles in the European AIDS Clinical Society, UNAIDS, WHO, and The European Hematology Association/ European Society of Medical Oncology. AC has received consulting fees from MSD, BMS, AstraZeneca, and Roche; and speakers' fee from AstraZeneca, MSD, Novartis, and Eisai. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality., Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020., Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases., Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases., (© 2021. The Author(s).)

Background and Purpose: Acute ischemic stroke and large vessel occlusion can be concurrent with the coronavirus disease 2019 (COVID-19) infection. Outcomes after mechanical thrombectomy (MT) for large vessel occlusion in patients with COVID-19 are substantially unknown. Our aim was to study early outcomes after MT in patients with COVID-19., Methods: Multicenter, European, cohort study involving 34 stroke centers in France, Italy, Spain, and Belgium. Data were collected between March 1, 2020 and May 5, 2020. Consecutive laboratory-confirmed COVID-19 cases with large vessel occlusion, who were treated with MT, were included. Primary investigated outcome: 30-day mortality., Secondary Outcomes: early neurological improvement (National Institutes of Health Stroke Scale improvement ≥8 points or 24 hours National Institutes of Health Stroke Scale 0-1), successful reperfusion (modified Thrombolysis in Cerebral Infarction grade ≥2b), and symptomatic intracranial hemorrhage., Results: We evaluated 93 patients with COVID-19 with large vessel occlusion who underwent MT (median age, 71 years [interquartile range, 59-79]; 63 men [67.7%]). Median pretreatment National Institutes of Health Stroke Scale and Alberta Stroke Program Early CT Score were 17 (interquartile range, 11-21) and 8 (interquartile range, 7-9), respectively. Anterior circulation acute ischemic stroke represented 93.5% of cases. The rate modified Thrombolysis in Cerebral Infarction 2b to 3 was 79.6% (74 patients [95% CI, 71.3-87.8]). Thirty-day mortality was 29% (27 patients [95% CI, 20-39.4]). Early neurological improvement was 19.5% (17 patients [95% CI, 11.8-29.5]), and symptomatic intracranial hemorrhage was 5.4% (5 patients [95% CI, 1.7-12.1]). Patients who died at 30 days exhibited significantly lower lymphocyte count, higher levels of aspartate, and LDH (lactate dehydrogenase). After adjustment for age, initial National Institutes of Health Stroke Scale, Alberta Stroke Program Early CT Score, and successful reperfusion, these biological markers remained associated with increased odds of 30-day mortality (adjusted odds ratio of 2.70 [95% CI, 1.21-5.98] per SD-log decrease in lymphocyte count, 2.66 [95% CI, 1.22-5.77] per SD-log increase in aspartate, and 4.30 [95% CI, 1.43-12.91] per SD-log increase in LDH)., Conclusions: The 29% rate of 30-day mortality after MT among patients with COVID-19 is not negligible. Abnormalities of lymphocyte count, LDH and aspartate may depict a patient's profiles with poorer outcomes after MT. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT04406090.

Background: The RESTORE study, a multi-national randomized, placebo-controlled study, showed that erdosteine - a muco-active antioxidant that modulates bacterial adhesiveness - reduced the rate and duration of exacerbations in moderate and severe COPD with a history of exacerbations. How much benefit patients with less severe disease experience when taking this drug remains unclear., Methods: This post hoc analysis of the 254 RESTORE participants with spirometrically-defined moderate COPD (post-bronchodilator forced expiratory volume in 1 second [FEV 1 ] 50‒79% predicted) examined exacerbation rate and duration, time to first exacerbation, and exacerbation-free time. Data were analyzed using descriptive statistics and comparisons between treatment groups used Wilcoxon rank-sum tests, Mann-Whitney U -tests, or log rank tests., Results: Patients with moderate COPD received erdosteine 300 mg twice daily (n=126) or placebo (n=128) added to usual COPD therapy for 12 months. During this time, there were 53 exacerbations in the erdosteine group and 74 in the placebo group, with 42.1% and 57.8% of patients, respectively, experiencing an exacerbation. There was a 47% reduction in the mean exacerbation rate with erdosteine compared to placebo (0.27 vs 0.51 exacerbations per-patient per-year, respectively, P =0.003), and a 58.3% reduction in the mild exacerbation rate (0.23 vs 0.53 mild exacerbations per-patient per-year, P =0.001). Mean duration of exacerbations was 26% shorter in erdosteine-treated patients (9.1 vs 12.3 days for placebo, P =0.022), with significant reductions in the duration of mild and moderate-to-severe exacerbations. Mean time to first exacerbation was prolonged by 7.7% (182 days for erdosteine vs 169 days for placebo, P <0.001) and the mean exacerbation-free time was increased by 51 days (279 days for erdosteine vs 228 days for placebo; P <0.001)., Conclusion: These results indicate that adding erdosteine to usual COPD maintenance therapy reduces the number of mild, and duration of all, exacerbations in patients with moderate COPD and a history of exacerbations., Competing Interests: EP is employed by Edmond Pharma. PC, CP, RDN, GF, MC, and AC report personal fees from Edmond Pharma. The authors report no other conflicts of interest in this work., (© 2019 Calverley et al.)

Background: Calcific coronary lesions can be so resistant to prevent symmetric stent dilatation with high risk of ISR/thrombosis. The aim of the current study is to evaluate the safety and efficacy of super high-pressure dilatation (>30-to-45Atm) using a dedicated NC-balloon (OPN, SIS-Medical-AG, Winterthur-Switzerland)., Methods: We retrospectively evaluated 326 consecutive undilatable lesions in which conventional NC-balloons failed to achieve adequate post-dilatation luminal gain. After the failed attempt an OPN-balloon was inflated up to achieve a uniform balloon expansion (maximal dilatation pressure of 45-50 Atm). Lesions were divided into two groups according to the final inflation pressure: Group-I: lesion responsive to 30-40Atm and Group-2:>40 Atm. Angiographic success was defined as residual angiographic stenosis<30% assessed by visual estimation with TIMI3-flow. Procedural success was defined as the achievement of angiographic success without any MACE., Results: Angiographic success was achieved in 97.5%, procedural success in 96.6%; 53% of the lesions were responsive to a slower inflation pressure (Group I) while in the remaining 47%, the optimal expansion required a pressure > 40ATM (Group II). In 3 patients coronary rupture occurred after balloon inflation and was successfully treated with stent implantation with a final TIMI3-flow. The OPN alone was able to achieve adequate expansion in >90%. 0.9% days MACE were reported., Conclusion: The OPN-dedicated high-pressure balloon provides an effective and safe strategy for treatment of severe resistant coronary lesions., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In the recent years percutaneous treatment of the left main stem (LM) has gained a precise role as a result of consistent scientific evidence vs. coronary artery bypass. A self-apposing stent offers an improved adaptation to the vessel wall, especially in case of tapered vessels; aim of this study was to investigate the role of a novel self-apposing, sirolimus-eluting stent (Stentys, France) for the treatment of LM coronary artery disease., Methods and Results: MATISSE is a retrospective, multicenter registry, which enrolled 151 patients treated with the device at 17 international centers. Primary study endpoint was the occurrence of major adverse cardiovascular events (MACE), a composite endpoint of cardiac death, target lesion revascularization (TLR) and target-vessel myocardial infarction, at 9months clinical follow-up. Secondary endpoints included procedural success, the single determinants of MACE and stent thrombosis. Lesions were located in distal LM bifurcation in 84% of the patients. Procedural success was achieved in 150 patients. The average follow-up length was 348±52days. MACE occurred in 14 (9.3%) patients with 2 (1.3%) cardiac deaths. TLR occurred in 8 patients (5.3%). There were 2 cases of definite stent thrombosis, 1 acute and 1 very late., Conclusions: A self-apposing stent, when used for LM PCI in a real world, high risk population, showed good immediate procedural results with low rates of adverse events at mid-term follow-up., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The European Society for Medical Oncology (ESMO) consensus conference on malignant lymphoma was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the questions devised by their group. These recommendations were then presented to the entire multidisciplinary panel and a consensus was reached. This manuscript presents recommendations regarding the management of the following 'ultra-high-risk' situations: (1) early central nervous system relapse of diffuse large B-cell lymphoma, (2) primary refractory Hodgkin lymphoma and (3) plasmablastic lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. All expert panel members approved this final article.

Background: Antecedent hypertension represents a risk factor for adverse outcomes in survivors of acute myocardial infarction (AMI). Prognosis of such patients might be greatly improved by drugs enhancing blood pressure control. In the present retrospective analysis of the randomized, double-blind, parallel-group, SMILE-4 study we compared the efficacy of zofenopril 60 mg and acetylsalicylic acid (ASA) 100 mg versus ramipril 10 mg and ASA in patients with AMI complicated by left ventricular dysfunction, classified according to a history of hypertension., Methods: The primary study end-point was 1-year combined occurrence of death or hospitalization for cardiovascular causes. Hypertension was defined according to medical history and current blood pressure values at entry and could be determined in 682 of 716 patients of the intention-to-treat analysis., Results: One hundred and fifty-seven patients (23%) were normotensives and 525 (77%) hypertensives. In the normotensive population the primary end-point occurred in 19 of 76 zofenopril-treated patients (25%) and in 23 of 81 ramipril-treated patients (28%) [odds ratio (95% confidence interval): 0.84 (0.41-1.71), P = 0.631]. In the hypertensive population, major cardiovascular outcomes were reported in 84 of 273 zofenopril-treated patients (31%) and in 99 of 252 ramipril-treated patients (39%), with a 31% significantly (P = 0.041) lower risk with zofenopril [0.69 (0.48-0.99)]. The superiority of zofenopril versus ramipril was particularly evident in patients with isolated systolic hypertension [n = 131, 0.48 (0.23-0.99), P = 0.045]., Conclusion: This retrospective analysis of the SMILE-4 study confirmed the good efficacy of zofenopril and ASA in the prevention of long-term cardiovascular outcomes also in the subgroup of patients with hypertension.

The European genus Ophrys (Orchidaceae) is famous for its insect-like floral morphology, an adaptation for a pseudocopulatory pollination strategy involving Hymenoptera males. A large number of endemic Ophrys species have recently been described, especially within the Mediterranean Basin, which is one of the major species diversity hotspots. Subtle morphological variation and specific pollinator dependence are the two main perceptible criteria for describing numerous endemic taxa. However, the degree to which endemics differ genetically remains a challenging question. Additionally, knowledge regarding the factors underlying the emergence of such endemic entities is limited. To achieve new insights regarding speciation processes in Ophrys, we have investigated species boundaries in the Fly Orchid group (Ophrys insectifera sensu lato) by examining morphological, ecological and genetic evidence. Classically, authors have recognized one widespread taxon (O. insectifera) and two endemics (O. aymoninii from France and O. subinsectifera from Spain). Our research has identified clear morphological and ecological factors segregating among these taxa; however, genetic differences were more ambiguous. Insights from cpDNA sequencing and amplified fragment length polymorphisms genotyping indicated a recent diversification in the three extant Fly Orchid species, which may have been further obscured by active migration and admixture across the European continent. Our genetic results still indicate weak but noticeable phylogeographic clustering that partially correlates with the described species. Particularly, we report several isolated haplotypes and genetic clusters in central and southeastern Europe. With regard to the morphological, ecological and genetic aspects, we discuss the endemism status within the Fly Orchid group from evolutionary, taxonomical and conservation perspectives., (© 2013 Blackwell Publishing Ltd.)

Objectives: The BURQOL-RD project is intended to develop a disease based model capable of quantifying the socio-economic burden and health-related quality of life for patients with rare diseases (RDs) and their caregivers in Europe. We described the methodology used to select a set of 10 RDs to be approached in a pilot study., Methods: BURQOL-RD project includes 23 partners from 8 European countries: Spain, UK, France, Germany, Sweden, Italy, Hungary and Bulgaria. A two-round Delphi panels in combination with Carroll diagram was used to generate consensus in the selection of the 10 RDs among the project participants., Results: The two Delphi rounds yielded a prioritised list, to which the Carroll diagram was applied, taking into account three determinants: prevalence, availability of effective treatment and need for carer. The final set of RD to be studied was obtained: cystic fibrosis, Prader-Willi syndrome, haemophilia, duchenne muscular dystrophy, epidermolysis bullosa, fragile X syndrome, scleroderma, mucopolysaccharidosis, juvenile idiopathic arthritis and histiocytosis., Conclusions: This methodology permitted the generation of an equilibrated set of RDs for the pilot study of BURQOL-RD project. The model will be suitable for application in a wide range of RDs., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: In order to facilitate multinational clinical research, regulatory requirements need to become international and harmonised. The EU introduced the Directive 2001/20/EC in 2004, regulating investigational medicinal products in Europe., Methods: We conducted a survey in order to identify the national regulatory requirements for major categories of clinical research in ten European Clinical Research Infrastructures Network (ECRIN) countries-Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and United Kingdom-covering approximately 70% of the EU population. Here we describe the results for regulatory requirements for typical investigational medicinal products, in the ten countries., Results: Our results show that the ten countries have fairly harmonised definitions of typical investigational medicinal products. Clinical trials assessing typical investigational medicinal products require authorisation from a national competent authority in each of the countries surveyed. The opinion of the competent authorities is communicated to the trial sponsor within the same timelines, i.e., no more than 60 days, in all ten countries. The authority to which the application has to be sent to in the different countries is not fully harmonised., Conclusion: The Directive 2001/20/EC defined the term 'investigational medicinal product' and all regulatory requirements described therein are applicable to investigational medicinal products. Our survey showed, however, that those requirements had been adopted in ten European countries, not for investigational medicinal products overall, but rather a narrower category which we term 'typical' investigational medicinal products. The result is partial EU harmonisation of requirements and a relatively navigable landscape for the sponsor regarding typical investigational medicinal products.

Diesel soot (Euro IV and Euro VI) was investigated with spectroscopic methods such as near-edge X-ray absorption fine structure (NEXAFS) spectroscopy and X-ray photoemission spectroscopy (XPS). C and O K-edge NEXAFS show that structural disorder on the surface is accompanied by a higher amount of oxygen functional groups. O K-edge NEXAFS and O1s XPS results are discussed with the aim to elucidate the nature of the oxygen surface species. The analysis of the data presented here allows the postulation of a hypothetical structure for soot samples emitted by diesel engines.

Patients with rare diseases are awaiting an answer to their needs. Traditionally, however, research on rare diseases has been limited by the idea that it was too difficult to do and too little rewarding in terms of return of profit. This attitude has actually changed during the last decade, because it was realized that research on rare diseases may help finding solutions valid also for common conditions. Indeed, while we all invoke translational research as the way to adapt results of laboratory studies into therapeutic interventions for patients, rare diseases often need the opposite path: we observe rare patients in the clinical practice, then we find out that they have a genetic defect, and finally we reproduce the defect in an animal model to extend the observation further beyond the clinic. In the process we also learn a lot about the physiology and the pathology and have insight into the mechanisms of common diseases. In other words, studying a rare condition may enlighten the path to other discoveries and to break the boundaries between disciplines and specialities to provide solutions for the sake of the patients.

Aquatic plants, and especially the emblematic genus Baldellia (Alismataceae), are among the most threatened organisms, due to unprecedented human-driven habitat destructions. Therefore protection plans are crucially needed and call for thoroughly documenting the genetic diversity and clarifying the taxonomy of this endangered genus. Our sampling included 282 individuals from 42 natural populations and covered the whole geographical range of the genus, across Europe and the Mediterranean. We combined sequencing of nuclear internal transcribed spacer (ITS) and chloroplastic trnL-ndhF regions with amplified fragment length polymorphism (AFLP) genotyping to investigate the Alismataceae phylogeny, and produce a phylogeography of Baldellia. Our phylogeny strongly supported the monophyly of Baldellia and placed it as the sister clade to Luronium and Alisma, therefore excluding, as previously supposed, a close genetic relatedness to the predominantly neotropical genus Echinodorus. The phylogeography of Baldellia outlined patterns consistent with a hypothesis considering glacial refugia located in the Iberian Peninsula and the Italy/Balkan region from which two distinct genetic lineages re-colonized Europe. These two lineages corresponded respectively to Baldellia ranunculoides (Italy/Balkan derived populations) and Baldellia repens (populations recovered from the Iberian Peninsula refuge), therefore supporting differences outlined between the two taxa in previous ecological and morphological studies. These results allowed clarifying taxonomic uncertainties by confirming the genetic distinctness of B. repens according to B. ranunculoides. A third lineage, Baldellia alpestris, originated and remained endemic to the mountainous regions of the Iberian Peninsula. Unexpectedly, B. repens populations collected in northern Africa, appeared to be genetically distinct from their European counterparts, this calls for further investigation to fully address their genetic and conservation status. Finally, we detected a large hybridization zone in northwestern Europe between B. repens and B. ranunculoides. These results were discussed in light of conservation approaches for Baldellia populations., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: 'Compassionate use' programmes allow medicinal products that are not authorised, but are in the development process, to be made available to patients with a severe disease who have no other satisfactory treatment available to them. We sought to understand how such programmes are regulated in ten European Union countries., Methods: The European Clinical Research Infrastructures Network (ECRIN) conducted a comprehensive survey on clinical research regulatory requirements, including questions on regulations of 'compassionate use' programmes. Ten European countries, covering approximately 70% of the EU population, were included in the survey (Austria, Denmark, France, Germany, Hungary, Ireland, Italy, Spain, Sweden, and the UK)., Results: European Regulation 726/2004/EC is clear on the intentions of 'compassionate use' programmes and aimed to harmonise them in the European Union. The survey reveals that different countries have adopted different requirements and that 'compassionate use' is not interpreted in the same way across Europe. Four of the ten countries surveyed have no formal regulatory system for the programmes. We discuss the need for 'compassionate use' programmes and their regulation where protection of patients is paramount., Conclusions: 'Compassionate use' is a misleading term and should be replaced with 'expanded access'. There is a need for expanded access programmes in order to serve the interests of seriously ill patients who have no other treatment options. To protect these patients, European legislation needs to be more explicit and informative with regard to the regulatory requirements, restrictions, and responsibilities in expanded access programmes.

Background: Thorough knowledge of the regulatory requirements is a challenging prerequisite for conducting multinational clinical studies in Europe given their complexity and heterogeneity in regulation and perception across the EU member states., Methods: In order to summarise the current situation in relation to the wide spectrum of clinical research, the European Clinical Research Infrastructures Network (ECRIN) developed a multinational survey in ten European countries. However a lack of common classification framework for major categories of clinical research was identified, and therefore reaching an agreement on a common classification was the initial step in the development of the survey., Results: The ECRIN transnational working group on regulation, composed of experts in the field of clinical research from ten European countries, defined seven major categories of clinical research that seem relevant from both the regulatory and the scientific points of view, and correspond to congruent definitions in all countries: clinical trials on medicinal products; clinical trials on medical devices; other therapeutic trials (including surgery trials, transplantation trials, transfusion trials, trials with cell therapy, etc.); diagnostic studies; clinical research on nutrition; other interventional clinical research (including trials in complementary and alternative medicine, trials with collection of blood or tissue samples, physiology studies, etc.); and epidemiology studies. Our classification was essential to develop a survey focused on protocol submission to ethics committees and competent authorities, procedures for amendments, requirements for sponsor and insurance, and adverse event reporting following five main phases: drafting, consensus, data collection, validation, and finalising., Conclusion: The list of clinical research categories as used for the survey could serve as a contribution to the, much needed, task of harmonisation and simplification of the regulatory requirements for clinical research in Europe.

The alpine white-flowered buttercup, Ranunculus kuepferi Greuter & Burdet, is a polyploid complex with diploids endemic to the southwestern Alps and polyploids - which have been previously described as apomictic - widespread throughout European mountains. Due to the polymorphic status of both its ploidy level and its reproductive mode, R. kuepferi represents a key species for understanding the evolution of polyploid lineages in alpine habitats. To disentangle the phylogeography of this polyploid taxon, we used cpDNA sequences and AFLP (amplified fragment length polymorphism) markers in 33 populations of R. kuepferi representative of its ploidy level and distribution area. Polyploid individuals were shown to be the result of at least two polyploidization events that may have taken place in the southwestern Alps. From this region, one single main migration of tetraploids colonized the entire Alpine range, the Apennines and Corsica. Genetic recombination among tetraploids was also observed, revealing the facultative nature of the apomictic reproductive mode in R. kuepferi polyploids. Our study shows the contrasting role played by diploid lineages mostly restricted to persistent refugia and by tetraploids, whose dispersal abilities have permitted their range extension all over the previously glaciated Alpine area and throughout neighbouring mountain massifs.

The genus Vitis is represented by several coexisting species in Europe. Our study focuses on naturalised rootstocks that originate in viticulture. The consequences of their presence to the landscape and to native European species (Vitis vinifera ssp. silvestris) are evaluated. This study compares ecological traits (seven qualitative and quantitative descriptors) and the genetic diversity (10 SSR markers) of populations of naturalised rootstocks and native wild grapevines. 18 large naturalised rootstock populations were studied in the Rhône watershed. Wild European grapevines are present in four main habitats (screes, alluvial forests, hedges, and streamside hedges). In contrast, naturalised rootstock populations are mainly located in alluvial forests, but they clearly take advantage of alluvial system dynamics and connectivity at the landscape level. These latter populations appear to reproduce sexually, and show a higher genetic diversity than Vitis vinifera ssp. silvestris. The regrouping of naturalised rootstocks in interconnected populations tends to create active hybrid swarms of rootstocks. The rootstocks show characters of invasive plants. The spread of naturalised rootstocks in the environment, the acceleration of the decline of the European wild grapevine, and the propagation of genes of viticultural interest in natural populations are potential consequences that should be kept in mind when undertaking appropriate management measures.

Background & Aims: Inherited colorectal polyposis has been linked to constitutive mutations of the APC tumor suppressor gene. Recently, germline mutations in the base excision repair gene MYH have been associated with a recessively inherited form of the disease. The aim of this study was to evaluate germline mutation frequencies of both MYH and APC susceptibility genes in Italian patients with attenuated familial adenomatous polyposis., Methods: The analysis was performed in 14 unrelated patients by using the protein truncation test for APC and genomic DNA sequencing for MYH., Results: Overall, we identified 7 of 14 (50%) mutation carriers. Two patients were heterozygotes for an APC truncating mutation (2 of 14 [14%]), whereas 5 proved to be homozygotes or compound heterozygotes for MYH gene alterations (5 of 14 [36%]). Two MYH missense mutations, Y165C and G382D, already found to be frequent among patients from northern Europe, were also preponderant in our survey. Individuals with APC-associated syndrome showed a dominant family history of polyposis, whereas patients with MYH-associated disease were either apparently sporadic cases or had a family history consistent with recessive inheritance. MYH biallelic mutation carriers were up to 60% (5 of 8) among patients showing at least 30 adenomas and a family history with no vertical transmission of polyposis., Conclusions: On the basis of our data, patients with attenuated familial adenomatous polyposis with >30 adenomas and no obvious vertical transmission of the disease should be considered for MYH gene testing.

In Italy and Europe, strokes are the third most common cause of death and resulting invalidity. In the ever-increasing 80-years-old-and-over population, strokes become more serious due to the clinical presentation during the acute phase and the ten times higher mortality, but also in relation to the twice as high resulting disability as for younger subjects. With the growing number of ailing and not-self-sufficient elderly, other resources will have to be relocated to this field of public health. Then, the dependence index and the ensuing equivalence based on estimates for the first decades of 2000 will create more difficulties in retrieving the funds for social policies. However, stroke prevention is possible both through correct behavioural habits and pharmacological means. Besides the well-known preventive effects of an adequate antihypertensive, antidiabetic and/or antiaggregant/anticoagulant therapy, there is increasing evidence of the effectiveness of statin therapy in stroke prevention. Subjects with a personal history of cerebrovascular events have an increased coronary risk and vice versa. The greatest part of the risk factors for the cerebrovascular disease coincides with those for cardiovascular disease, for which the correction of the former automatically involves a reduction in incidence of both pathologies. In this context, a statin's rational use can therefore represent an important tool for the combined prevention of the two pathologies. Finally, different hypotheses link the origin of Alzheimer's disease to that of progressive cerebrovascular dementia caused by cerebral microcirculation damage. The aim of this review is to resume the actual knowledge about the epidemiology of cerebrovascular disease in Italy and Europe, and about the means available to prevent this phenomenon., (Copyright 2003 S. Karger AG, Basel)

In Italy and Europe, strokes are the third most common cause of death and resulting invalidity. In the ever-increasing 80-years-old-and-over people, strokes become more serious due to the clinical presentation during the acute phase and the ten-times higher mortality, but also in relation to the twice as high resulting disability as for younger subjects. However, stroke prevention is possible both through correct behavioural habits and pharmacological means. Besides the well-known preventive effects of an adequate anti-hypertensive, anti-diabetic and/or anti-aggregant/anti-coagulant therapy, there are increasing evidences of the effectiveness of the anti-hypercholesterolemic therapy in stroke prevention. Moreover, a great part of the risk factors for the cerebrovascular disease coincides with those for cardiovascular disease, for which the correction of the former automatically involves a reduction in incidence of both pathologies. In this context, a statin's rational use can therefore represent an important tool for the combined prevention of the two pathologies. Finally, different hypotheses link the origin of Alzheimer's disease to that of progressive cerebrovascular dementia caused by cerebral microcirculation damage. It is plausible that the application of a suitable early prevention of the cerebrovascular pathology could bring to a more late slatentisation and less serious demonstrations of Alzheimer's disease, when this is destined to develop.

The Physician Data Query (PDQ) is a computerised medical database aimed at communicating cancer-related information through computer technology. PDQ has been distributed in Europe since 1988 and in the U.S. since 1985. A study aimed at evaluating whether PDQ had reached a wide medical community was conducted among European PDQ distributors in 1992 as part of an evaluation of PDQ use and impact. Results indicate that PDQ promotion was limited and that several countries were underserved. A preference was expressed for on-line systems. It was found that PDQ access was limited by the requirement of special equipment, by subscription costs and by language barriers. Subscribers were found mainly in the countries with the highest number of distributors. Among a total 12,205 reported subscribers, only 20% were physicians. The proportion of physicians subscribing to the system was, therefore, low (range 4-39.7/10,000). Altogether 453 searches (range 0-213) and 84.5 h of connection time (range 0-52.5) were reported per month for Europe. It is obvious that additional investigation is needed to further evaluate the impact of PDQ on clinical practice.