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Pharmaceutical care was proposed to address morbidity and mortality associated with medicine-related problems. It utilises the pharmacist's expertise in medicines, their relationship with the patient and cooperation with other healthcare professionals to optimise the use of medicines. The European Directorate for the Quality of Medicines & HealthCare (EDQM), part of the Council of Europe, found significant variation in the acceptance of pharmaceutical care and in the implementation of pharmaceutical care in Europe. A multidisciplinary group was established to draft a statement of principles and recommendations concerning pharmaceutical care. Through face-to-face meetings, circulation of draft texts and informal consultation with stakeholders, the group produced a resolution. On 11 March 2020, the resolution was adopted by the Committee of Ministers of the Council of Europe. It explains pharmaceutical care and illustrates pharmacists' contribution to medicine optimisation in different care settings. Pharmaceutical care's value to health services and its place in health policy were emphasised by addressing the risks and harms from suboptimal use of medicines. Pharmaceutical care can improve medicine use, promote rational use of healthcare resources and reduce inequalities in healthcare by realigning the roles and responsibilities of pharmacists and healthcare professionals. EDQM will promote and advocate for the implementation of pharmaceutical care by enacting practice Resolution CM/Res(2020)3. [ABSTRACT FROM AUTHOR]

One year since the emergence of the COVID-19 pandemic, rapid response measures have been implemented internationally to mitigate the spread of the virus. Following rapid and successful pre-clinical and human trials, several vaccines have been authorised for use across Europe through the European Medicines Agency and national regulatory authorities. Clinical trials have shown promising results including important reductions in disease severity, hospitalisation and mortality. In order to maximise the public health benefit of available vaccines, there is a pressing need to vaccinate a large proportion of the population. Internationally, this has prompted coordination of existing services at enormous scale, and development and implementation of novel vaccination strategies to ensure maximum inoculation over the shortest possible timeframe. Pharmacists are being promoted as healthcare professionals that enhance roll-out of COVID-19 vaccination programmes. This paper aims to summarise current policy and practice in relation to pharmacists' involvement in COVID-19 vaccination in 13 countries across Europe. [ABSTRACT FROM AUTHOR]

Expansion of quinolone-resistant Neisseria meningitidis clone ChinaCC4821-R1-C/B from sequence type (ST) 4821 clonal complex (CC4821) caused a serogroup shift from serogroup A to serogroup C invasive meningococcal disease (IMD) in China. To determine the relationship among globally distributed CC4821 meningococci, we analyzed whole-genome sequence data from 173 CC4821 meningococci isolated from 4 continents during 1972-2019. These meningococci clustered into 4 sublineages (1-4); sublineage 1 primarily comprised of IMD isolates (41/50, 82%). Most isolates from outside China (40/49, 81.6%) formed a distinct sublineage, the Europe-USA cluster, with the typical strain designation B:P1.17-6,23:F3-36:ST-3200(CC4821), harboring mutations in penicillin-binding protein 2. These data show that the quinolone-resistant clone ChinaCC4821-R1-C/B has expanded to other countries. The increasing distribution worldwide of serogroup B CC4821 raises the concern that CC4821 has the potential to cause a pandemic that would be challenging to control, despite indirect evidence that the Trumenba vaccine might afford some protection. [ABSTRACT FROM AUTHOR]

Lung and heart & lung transplantations in neonates and infants are extreme treatments offered for some life-threatening conditions especially in some North-American centers with promising results. These transplantations are rarely performed in Europe, and we set up a continent-based survey to describe the attitude of European neonatologists and pediatric intensivists on the subject and identify the main indications for this transplantation and the obstacles for the realization of a European lung transplantation program. Conclusion: The main indications for lung transplantation program for neonates and infants are represented by congenital disorders, and physicians indicate as main obstacles the donors' availability. European neonatologists and pediatric intensivists are interested to create a European network to overcome this problem and realize a lung transplantation program for neonates and infants. What is Known: • Lung transplantation in neonates and infants seems to slowly increase, and some North-American centers accumulated a relevant experience. What is New: • European neonatologists and pediatric intensivists are interested in creating a European network for a lung transplantation program for neonates and infants. • The main indications for lung transplantation program for neonates and infants are represented by congenital disorders and main obstacle to lung transplantation is the donors' availability [ABSTRACT FROM AUTHOR]

Despite continued efforts to improve biosecurity protocols, Campylobacter continues to be detected in the majority of commercial chicken flocks across Europe. Using an extensive data set of Campylobacter prevalence within a chicken breeder flock for over a year, multiple Bayesian models are presented to explore the dynamics of the spread of Campylobacter in response to seasonal variation, species-specificity, bird health, and total colonization prevalence. These models indicated that birds within the flock varied greatly in their response to bacterial challenge, and that this phenomenon had a large impact on the overall prevalence of different species of Campylobacter. Campylobacter jejuni appeared more frequently in the summer, while Campylobacter coli persisted for a longer duration, amplified by the most susceptible birds in the flock. Our study suggests that strains of Campylobacter that appear most frequently likely possess no demographic advantage, but are instead amplified due to the health of the birds that ingest it. [ABSTRACT FROM AUTHOR]

The number of diabetic patients in Europe and world-wide is growing. Diabetes confers a 2-fold higher risk for vascular disease. Lack of insulin production (Type 1 diabetes, T1D) or lack of insulin responsiveness (Type 2 diabetes, T2D) causes systemic metabolic changes such as hyperglycemia (HG) which contribute to the pathology of diabetes. Monocytes and macrophages are key innate immune cells that control inflammatory reactions associated with diabetic vascular complications. Inflammatory programming of macrophages is regulated and maintained by epigenetic mechanisms, in particular histone modifications. The aim of our study was to identify the epigenetic mechanisms involved in the hyperglycemia-mediated macrophage activation. Using Affymetrix microarray profiling and RT-qPCR we identified that hyperglycemia increased the expression of S100A9 and S100A12 in primary human macrophages. Expression of S100A12 was sustained after glucose levels were normalized. Glucose augmented the response of macrophages to Toll-like receptor (TLR)-ligands Palmatic acid (PA) and Lipopolysaccharide (LPS) i.e., pro-inflammatory stimulation. The abundance of activating histone Histone 3 Lysine 4 methylation marks (H3K4me1, H3K4me3) and general acetylation on histone 3 (AceH3) with the promoters of these genes was analyzed by chromatin immunoprecipitation. Hyperglycemia increased acetylation of histones bound to the promoters of S100A9 and S100A12 in M1 macrophages. In contrast, hyperglycemia caused a reduction in total H3 which correlated with the increased expression of both S100 genes. The inhibition of histone methyltransferases SET domain-containing protein (SET)7/9 and SET and MYND domain-containing protein (SMYD)3 showed that these specifically regulated S100A12 expression. We conclude that hyperglycemia upregulates expression of S100A9, S100A12 via epigenetic regulation and induces an activating histone code on the respective gene promoters in M1 macrophages. Mechanistically, this regulation relies on action of histone methyltransferases SMYD3 and SET7/9. The results define an important role for epigenetic regulation in macrophage mediated inflammation in diabetic conditions. [ABSTRACT FROM AUTHOR]

Introduction and aims: Since 2013 MenC and MenW disease incidence and associated mortality rates have increased in the Republic of Ireland. From 2002/2003 to 2012/2013, the average annual MenC incidence was 0.08/100,000, which increased to 0.34/100,000 during 2013/2014 to 2017/18, peaking in 2016/17 (0.72/100,000) with an associated case fatality rate (CFR) of 14.7%. MenW disease incidence has increased each year from 0.02/100,000 in 2013/2014, to 0.29/100,000 in 2017/18, with an associated CFR of 28.6%. We aimed to characterise and relate recent MenC isolates to the previously prevalent MenC:cc11 ET-15 clones, and also characterise and relate recent MenW isolates to the novel ‘Hajj’ clones. Methods: Using WGS we characterised invasive (n = 74, 1997/98 to 2016/17) and carried (n = 16, 2016/17) MenC isolates, and invasive (n = 18, 2010/11 to 2016/17) and carried (n = 15, 2016/17) MenW isolates. Genomes were assembled using VelvethOptimiser and stored on the PubMLST Neisseria Bacterial Isolate Genome Sequence Database. Isolates were compared using the cgMLST approach. Results: Most MenC and MenW isolates identified were cc11. A single MenC:cc11 sub-lineage contained the majority (68%, n = 19/28) of recent MenC:cc11 disease isolates and all carried MenC:cc11 isolates, which were interspersed and distinct from the historically significant ET-15 clones. MenW:cc11 study isolates clustered among international examples of both the original UK 2009 MenW:cc11, and novel 2013 MenW:cc11clones. Conclusions: We have shown that the majority of recent MenC disease incidence was caused by strain types distinct from the MenC:cc11 ET-15 clone of the late 1990s, which still circulate but have caused only sporadic disease in recent years. We have identified that the same aggressive MenW clone now established in several other European countries, is endemic in the RoI and responsible for the recent MenW incidence increases. This data informed the National immunisation Advisory Committee, who are currently deliberating a vaccine policy change to protect teenagers. [ABSTRACT FROM AUTHOR]

Background. The global emergence of infections caused by Enterobacteriaceae resistant to expanded-spectrum cephalosporins (ESCs) in intensive care units (ICUs) is, at least partly, driven by cross-transmission. Yet, individual transmission capacities of bacterial species have not been quantified. Methods. In this post hoc analysis of a multicenter study in 13 European ICUs, prospective surveillance data and a mathematical model were used to estimate transmission capacities and single-admission reproduction numbers (RA) of Escherichia coli and non-E. coli Enterobacteriaceae (non-EcE), all being ESC resistant. Surveillance was based on a chromogenic selective medium for ESC-resistant Enterobacteriaceae, allowing identification of E. coli and of Klebsiella, Enterobacter, Serratia, and Citrobacter species, grouped as non-EcE. Results. Among 11 420 patients included, the admission prevalence was 3.8% for non-EcE (74% being Klebsiella pneumoniae) and 3.3% for E. coli. Acquisition rates were 7.4 and 2.6 per 100 admissions at risk for non-EcE and E. coli, respectively. The estimated transmission capacity of non-EcE was 3.7 (95% credibility interval [CrI], 1.4-11.3) times higher than that of E. coli, yielding single-admission reproduction numbers (RA) of 0.17 (95% CrI, .094-.29) for non-EcE and 0.047 (95% CrI, .018-.098) for E. coli. Conclusions. In ICUs, non-EcE, mainly K. pneumoniae, are 3.7 times more transmissible than E. coli. Estimated RA values of these bacteria were below the critical threshold of 1, suggesting that in these ICUs outbreaks typically remain small with current infection control policies. [ABSTRACT FROM AUTHOR]

Five tyrosine kinase inhibitors (TKIs) are currently approved in the European Union for treatment of chronic myeloid leukemia (CML) and all have considerable overlap in their indications. While disease-specific factors such as CML phase, mutational status, and line of treatment are key to TKI selection, other important features must be considered, such as patient-specific comorbidities and TKI safety profiles. Ponatinib, the TKI most recently approved, has demonstrated efficacy in patients with refractory CML, but is associated with an increased risk of arterial hypertension, sometimes severe, and serious arterial occlusive and venous thromboembolic events. A panel of European experts convened to discuss their clinical experience in managing patients with CML. Based on the panel discussions, scenarios in which a CML patient may be an appropriate candidate for ponatinib therapy are described, including presence of the T315I mutation, resistance to other TKIs without the T315I mutation, and intolerance to other TKIs. [ABSTRACT FROM AUTHOR]

The Dublin Declaration on Partnership to fight HIV/AIDS in Europe and Central Asia is the key policy document on HIV/AIDS in the European Region as a whole Among the Declaration's 33 actions for governments are many that apply to prison populations. Based upon an analysis of these commitments, and a review of the current status of states in meeting those targets, it is clear that the scale-up of HIV/AIDS prevention and treatment programmes and services in prisons lags far behind what is needed, what is available outside of prisons, and what is mandated within the Declaration itself. [ABSTRACT FROM AUTHOR]

The middle and lower sections of most large rivers have fine-grained bed sediments, which may have a strong influence on the functional and taxonomical structure of benthic invertebrates. Based on results from several studies by the authors on the faunal assemblages and habitat structures of the Paraguay–Paraná River system (Brazil, Paraguay, Argentina), from European (Rhine, Loire) River systems, and data from the literature, this review identifies general patterns which appear to have a global character. On one hand, the invertebrate assemblages largely differed between the main channel (MC) and the corresponding floodplain habitats in different sections, and also the floodplain habitats along the river channel revealed great differences in their biodiversity. On the other hand, there was a remarkable homogeneity among the main-channel sections within and even between river systems. We consider physical habitat features as the crucial variables responsible for these patterns. In cross-sections from the MC towards the floodplain habitats, grain size, organic matter content and oxygen supply change dramatically, and different floodplain habitats along the same river system may have different successional stages even at small geographical distances. The sandy structure of potamal habitats (including underwater dunes), however, provides a set of habitat features characterized by continuously changing sediment structures with well-defined grain sizes, low organic matter contents and good oxygenation, which force a set of adaptations by the invertebrates that limits but stabilizes the diversity of invertebrates in these large river sections. A better understanding of the ecohydrological interactions between habitat dynamics and benthic invertebrates is needed to improve sustainable river ecosystem management. We discuss the non-recovery of large benthic invertebrate species in the lower section of large rivers after improvement of the water quality in the context of these ecohydrological features. Conclusions are drawn for river restoration. [ABSTRACT FROM AUTHOR]

Objectives To assess the efficacy and safety of flexible-dose fesoterodine in elderly adults with overactive bladder ( OAB). Design Twelve-week, randomized, double-blind, placebo-controlled trial. Setting Sixty-one outpatient clinics in Europe, Israel, and Turkey. Participants Seven hundred ninety-four individuals aged 65 and older (47% male) with OAB symptoms for 3 months or longer, mean of eight or more micturitions and three or more urgency episodes per 24 hours, at least some moderate problems on Patient Perception of Bladder Condition ( PPBC), and Mini- Mental State Examination ( MMSE) score of 20 or greater. Interventions Participants were randomized to fesoterodine or placebo for 12 weeks, with stratification according to age (>75 vs ≤75) and dosing time (morning vs evening). Participants receiving fesoterodine started on 4 mg and could increase to 8 mg at week 4 or 8 and de-escalate to 4 mg at week 8 (sham escalation for placebo). Measurements Changes from baseline in bladder-diary variables (primary endpoint, urgency episodes) and patient-reported outcomes including OAB Questionnaire, Treatment Benefit Scale ( TBS), PPBC, Urgency Perception Scale ( UPS), and OAB Satisfaction Questionnaire ( OAB- S); all observed or reported adverse events. Results By week 8, 64% of fesoterodine-treated and 71% of placebo-treated participants opted for dose escalation. At week 12, the fesoterodine group had statistically significantly greater improvement than the placebo group in urgency episodes, micturitions, nocturnal micturitions, incontinence pad use, and OAB Questionnaire scores but not urgency urinary incontinence episodes. Responder rates on TBS, PPBC, UPS, and OAB-S were statistically significantly higher with fesoterodine. Improvements in most diary variables and participant-reported outcomes were greater with fesoterodine than placebo in participants in both age groups and when administered in the morning and evening. Rates of dry mouth and constipation were 34% and 9% with fesoterodine and 5% and 3% with placebo, respectively. Rates of adverse events and discontinuations were generally similar in participants in both age groups. There was no change in MMSE score. Conclusion Fesoterodine was associated with significantly greater improvements in most diary variables and participant-reported outcomes than placebo and was generally well tolerated in older people. [ABSTRACT FROM AUTHOR]

Objective To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. Methods STAGE was a phase III randomized, double-blind, parallel-group international study to evaluate the safety and efficacy of ocrelizumab compared with placebo in patients with active RA continuing MTX treatment. Patients receiving stable doses of MTX were randomized to receive 2 infusions of placebo (n = 320), ocrelizumab 200 mg (n = 343), or ocrelizumab 500 mg (n = 343) on days 1 and 15 as well as weeks 24 and 26. Coprimary end points were the proportion of patients with an American College of Rheumatology 20% improvement criteria (ACR20) response at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. Results The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks ( P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3-fold as compared with placebo and showed a statistically significant ( P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200-mg and 500-mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient-years) and ocrelizumab 200 mg (3.54 per 100 patient-years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient-years). Conclusion With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression of joint damage. A higher rate of serious infections was observed with 500 mg of ocrelizumab as compared with ocrelizumab 200 mg or placebo. [ABSTRACT FROM AUTHOR]

The distribution of biota from the temperate regions changed considerably during the climatic fluctuations of the Quaternary. This is especially true for many bat species that depend on warm roosts to install their nursery colonies. Surveys of genetic variation among European bats have shown that the southern peninsulas (Iberia and the Balkans) harbour endemic diversity, but to date, no such surveys have been conducted in the third potential glacial refuge area, the Apennine peninsula. We report here the phylogeographical analysis of 115 greater mouse-eared bats ( Myotis myotis) sampled throughout Italy, and show that 15 of the 18 different haplotypes found in the mitochondrial control region of these bats were unique to the Apennine peninsula. Colonies within this region also showed substantial genetic structure at both mitochondrial ( ΦST = 0.47, P<0.001) and nuclear markers ( FST = 0.039, P<0.001). Based on a comprehensive survey of 575 bats from Europe, these genetic markers further indicate that central Italian populations of M. myotis are more closely related to Greek samples from across the Adriatic Sea, than to other Italian bats. Mouse-eared bat populations from the Apennine peninsula thus represent a complex mixture of several endemic lineages, which evolved in situ, with others that colonized this region more recently along an Adriatic route. Our broad survey also confirms that the Alps represent a relatively impermeable barrier to gene flow for Apennine lineages, even for vagile animals such as bats. These results underline the conservation value of bats from this region and the need to include the Apennine peninsula in phylogeographical surveys in order to provide a more accurate view of the evolution of bats in Europe. [ABSTRACT FROM AUTHOR]

Physics experiments in space will permit us to investigate natural phenomena that cannot be observed on the ground, such as low-frequency gravitational waves, and to reach uncharted realms of accuracy — accessible only through experiments carried out in space — where current foundations of physics can be further tested and potentially falsified. Such projects require technologies that have not been in hand for a long time but are available now. To avoid conflict of interest, the merit of space projects in physics, from the proposal stage through development, ought to be judged by experts in physics, rather than by space scientists from other fields. It is time now to set aside some funding to let missions in fundamental physics compete fairly with the established space sciences, thereby enriching and deepening the space enterprise — and broadening its advocacy base. We look, in the context of the European space scene, at the measures and events that resurrected the initially suppressed planetary sciences and brought solar physics to blooming after a long drought; and derive ideas on how to increase the number of flight opportunities for fundamental physics in space. [ABSTRACT FROM AUTHOR]

Abstract: Providing equitable access to highly active antiretroviral treatment (HAART) to injecting drug users (IDUs) is both feasible and desirable. Given the evidence that IDUs can adhere to HAART as well as non-IDUs and the imperative to provide universal and equitable access to HIV/AIDS treatment for all who need it, here we examine whether IDUs in the 52 countries in the WHO European Region have equitable access to HAART and whether that access has changed over time between 2002 and 2004. We consider regional and country differences in IDU HAART access; examine preliminary data regarding the injecting status of those initiating HAART and the use of opioid substitution therapy among HAART patients, and discuss how HAART might be better delivered to injecting drug users. Our data adds to the evidence that IDUs in Europe have poor and inequitable access to HAART, with only a relatively small improvement in access between 2002 and 2004. Regional and country comparisons reveal that inequities in IDU access to HAART are worst in eastern European countries. [Copyright &y& Elsevier]

Objective To estimate access, activity and coverage of needle and syringe programmes (NSP) in Central and Eastern Europe and Central Asia. Methods Two data sets (‘regional’ and ‘high-coverage sites’) were used to estimate NSP provision (availability/number of sites), NSP utilization (syringes distributed/year), needle and syringe distribution (needles/syringes distributed/IDU/year), IDU reached (number/percentage of IDU contacted/year), regular reach (five or more contacts/month) and syringe coverage (percentage of injections/IDU/year administrable with new injecting equipment). Results Regional data set: results from 213 sites in 25 countries suggested that Czech Republic, Poland, Russia and Ukraine had > 10 NSP during 2001/2. Czech Republic, Kazakhstan, Latvia, Russia, Slovakia and Ukraine had ≥ 10 000 IDU in contact with NSP. Ten countries reached ≥ 10% of the estimated IDU population. The 25 countries distributed ∼ 17 million syringes/needles. Eight countries distributed > 0.5 million syringes/year. Syringe coverage (assuming 400 injections/IDU/year) was < 5% in 19 countries, 5–15% in five and > 15% in Macedonia. Overall syringe coverage was 1.2% and when assuming 700 injections/IDU/year it decreased to 0.7%. Syringe coverage for the IDU population in contact with NSP was ≤ 15% in 10 countries, 15–60% in 11 and > 60% in Croatia, Macedonia, Moldova and Tajikistan. Overall syringe coverage for the population in contact with NSP was 9.8%. High-coverage data set: Soligorsk, Pskov and Sumy's NSP reached 92.3%, 92.2% and 73.3% of their estimated IDU population, respectively (regular reach: 0.2%, 1.8% and 22.7%). The distribution levels were 47.2, 51.7 and 94.2 syringes/IDU/year, respectively. Conclusion The evidence suggests suboptimal levels of NSP implementation, programme activity and coverage. This paper provides a baseline for development of indicators that could be used to monitor NSP. Strategies to increase coverage that may go beyond NSP are urgently required, as is research into understanding how NSP can contribute to better syringe coverage among IDU. [ABSTRACT FROM AUTHOR]

Members of the Burkholderia cepacia complex (Bcc), found in many environments, are associated with clinical infections. Examining diverse species and strains from different environments with multilocus sequence typing, we identified > 20% of 381 clinical isolates as indistinguishable from those in the environment. This finding links the natural environment with the emergence of many Bcc infections. [ABSTRACT FROM AUTHOR]

Between 1999 and 2004, the European Union Invasive Bacterial Infections Surveillance Network (EU-IBIS) received c. 50 000 reports of meningococcal disease from 27 participating countries. Analysis has demonstrated a major decline in the incidence of invasive disease in those countries that have introduced routine vaccination against serogroup C infection. The establishment of rapid reporting of W135 and B2a/B2b strains has been able to provide early reassurance that these strains are not emerging as major public health problems in Europe. Between September 2001 and February 2005, the EU-MenNet project offered further opportunities for enhancing this data resource. Collaborative projects included: improving the EU-IBIS website; reviewing case ascertainment in Europe; reviewing cost-effectiveness studies for meningococcal serogroup C conjugate (MCC) vaccination; international comparisons of MCC vaccine efficacy; and mathematical modelling studies. In addition, linking of data from the European Meningococcal Multi-locus Sequence Type Centre to epidemiological data was performed. Particular clonal complexes were found to be preferentially associated with certain serogroups. Case fatality was also found to vary with clonal complex, suggesting that genotype can be a marker for hypervirulence. The importance of close collaboration between networks of epidemiologists, microbiologists, and the wider scientific and public health community is demonstrated. [ABSTRACT FROM AUTHOR]

Predicted species lists are generated from regional species pools, coupled to codified habitat, microhabitat and biological trait data for the species. At site level, habitat association data are used to tailor the predicted list to site conditions and comparison between predicted and observed species lists is used to explore elements of site quality and site management options involving microhabitat and trait data for the species in the process. It is pointed out that this approach makes possible the interpretation of insect species lists by non-specialist site managers. At larger geographic scales, attributes of regional lists are identified. Throughout, the approach is considered in the context of its potential to contribute to resolution of issues relating to maintenance of biodiversity in Europe and the taxonomic group employed is the Syrphidae (Diptera). [ABSTRACT FROM AUTHOR]

This article argues that privatization of state-owned industries in Eastern Europe and Russia may not be the solution for development in the region. Since the fall of communism, most Western economists and international agencies have advised East and Central European countries to privatize their state-owned industry without prior restructuring or deconcentration. What international agencies mean by privatization is turning state-owned enterprises into joint-stock companies with a nongovernmental board of directors. By 1995, privatization of large state-owned enterprises had been accomplished through voucher auctions in the Czech Republic and Russia. From a business point of view, the successful privatization of medium-sized and larger factories almost always requires new management and physical restructuring, layoffs and large net investments. The main bar to rapid privatization is financial weakness and over manning of the firms to be sold. However, privatization can be a source of consulting and legal fees. Advisors to the privatization agencies have a natural tendency to promote the success of their advisees and hide the remaining deficiencies. Rapid privatization threatens jobs, social and political stability.

The article focuses on the economic advantages and disadvantages if a state or nation is a constituent or part of a multinational imperial system explicitly European countries. Being a constituent or part of a system has its own favorable and unfavorable effects but rarely beneficial factors outweigh the unfavorable outcome and it applies to nations or states who was once been a member of a multinational system. It has been considered as an opportunity when a country or the nation's natural resources are unharnessed and its supply of technology were considered obsolete because these multinationals can help augment their country's economic conditions.

Aims: To assess changes in access to highly active antiretroviral therapy (HAART) between the end of 2002 and the end of 2005, and to review the capacity for further HAART scale-up in the then 52 Member States of the WHO European Region. Methods: Analysis of data from four surveys evaluating access to HAART, supplemented by regional estimates of the number of people receiving HAART. Changes in access to HAART are evaluated in terms of changes in the number of people receiving HAART over time and changes in country-level HAART coverage. Results: During 2003-2005, the total number of individuals receiving HAART increased by an estimated 101,000, from 242,000 to 343,000 (a 42% increase); 85,000 were in the west region (a 36% increase) and 16,000 in the centre and east regions (a 229% increase). The number of countries providing "high'' coverage with HAART (>75% of those in need receiving it) increased from 29 to 38, and the number of countries providing no HAART declined from eight to four. Conclusions: Despite high and increasing coverage in many European countries, access to HAART remained inequitable in terms of geographical location. By the end of 2005, all countries in the west provided "high'' HAART coverage as compared with half of countries in the centre and east. Six east countries still provided poor or no HAART coverage. Countries must address how to further equitably increase the number of people receiving HAART. [ABSTRACT FROM AUTHOR]

Background: Tyrosine kinase inhibitors (TKIs) have improved the survival of patients with chronic myeloid leukaemia. Many patients have deep molecular responses, a prerequisite for TKI therapy discontinuation. We aimed to define precise conditions for stopping treatment.Methods: In this prospective, non-randomised trial, we enrolled patients with chronic myeloid leukaemia at 61 European centres in 11 countries. Eligible patients had chronic-phase chronic myeloid leukaemia, had received any TKI for at least 3 years (without treatment failure according to European LeukemiaNet [ELN] recommendations), and had a confirmed deep molecular response for at least 1 year. The primary endpoint was molecular relapse-free survival, defined by loss of major molecular response (MMR; >0·1% BCR-ABL1 on the International Scale) and assessed in all patients with at least one molecular result. Secondary endpoints were a prognostic analysis of factors affecting maintenance of MMR at 6 months in learning and validation samples and the cost impact of stopping TKI therapy. We considered loss of haematological response, progress to accelerated-phase chronic myeloid leukaemia, or blast crisis as serious adverse events. This study presents the results of the prespecified interim analysis, which was done after the 6-month molecular relapse-free survival status was known for 200 patients. The study is ongoing and is registered with ClinicalTrials.gov, number NCT01596114.Findings: Between May 30, 2012, and Dec 3, 2014, we assessed 868 patients with chronic myeloid leukaemia for eligibility, of whom 758 were enrolled. Median follow-up of the 755 patients evaluable for molecular response was 27 months (IQR 21-34). Molecular relapse-free survival for these patients was 61% (95% CI 57-64) at 6 months and 50% (46-54) at 24 months. Of these 755 patients, 371 (49%) lost MMR after TKI discontinuation, four (1%) died while in MMR for reasons unrelated to chronic myeloid leukaemia (myocardial infarction, lung cancer, renal cancer, and heart failure), and 13 (2%) restarted TKI therapy while in MMR. A further six (1%) patients died in chronic-phase chronic myeloid leukaemia after loss of MMR and re-initiation of TKI therapy for reasons unrelated to chronic myeloid leukaemia, and two (<1%) patients lost MMR despite restarting TKI therapy. In the prognostic analysis in 405 patients who received imatinib as first-line treatment (learning sample), longer treatment duration (odds ratio [OR] per year 1·14 [95% CI 1·05-1·23]; p=0·0010) and longer deep molecular response durations (1·13 [1·04-1·23]; p=0·0032) were associated with increasing probability of MMR maintenance at 6 months. The OR for deep molecular response duration was replicated in the validation sample consisting of 171 patients treated with any TKI as first-line treatment, although the association was not significant (1·13 [0·98-1·29]; p=0·08). TKI discontinuation was associated with substantial cost savings (an estimated €22 million). No serious adverse events were reported.Interpretation: Patients with chronic myeloid leukaemia who have achieved deep molecular responses have good molecular relapse-free survival. Such patients should be considered for TKI discontinuation, particularly those who have been in deep molecular response for a long time. Stopping treatment could spare patients from treatment-induced side-effects and reduce health expenditure.Funding: ELN Foundation and France National Cancer Institute. [ABSTRACT FROM AUTHOR]

Abstract: Global soil moisture products retrieved from various remote sensing sensors are becoming readily available with a nearly daily temporal resolution. Active and passive microwave sensors are generally considered as the best technologies for retrieving soil moisture from space. The Advanced Microwave Scanning Radiometer for the Earth observing system (AMSR-E) on-board the Aqua satellite and the Advanced SCATterometer (ASCAT) on-board the MetOp (Meteorological Operational) satellite are among the sensors most widely used for soil moisture retrieval in the last years. However, due to differences in the spatial resolution, observation depths and measurement uncertainties, validation of satellite data with in situ observations and/or modelled data is not straightforward. In this study, a comprehensive assessment of the reliability of soil moisture estimations from the ASCAT and AMSR-E sensors is carried out by using observed and modelled soil moisture data over 17 sites located in 4 countries across Europe (Italy, Spain, France and Luxembourg). As regards satellite data, products generated by implementing three different algorithms with AMSR-E data are considered: (i) the Land Parameter Retrieval Model, LPRM, (ii) the standard NASA (National Aeronautics and Space Administration) algorithm, and (iii) the Polarization Ratio Index, PRI. For ASCAT the Vienna University of Technology, TUWIEN, change detection algorithm is employed. An exponential filter is applied to approach root-zone soil moisture. Moreover, two different scaling strategies, based respectively on linear regression correction and Cumulative Density Function (CDF) matching, are employed to remove systematic differences between satellite and site-specific soil moisture data. Results are shown in terms of both relative soil moisture values (i.e., between 0 and 1) and anomalies from the climatological expectation. Among the three soil moisture products derived from AMSR-E sensor data, for most sites the highest correlation with observed and modelled data is found using the LPRM algorithm. Considering relative soil moisture values for an ~5cm soil layer, the TUWIEN ASCAT product outperforms AMSR-E over all sites in France and central Italy while similar results are obtained in all other regions. Specifically, the average correlation coefficient with observed (modelled) data equals to 0.71 (0.74) and 0.62 (0.72) for ASCAT and AMSR-E-LPRM, respectively. Correlation values increase up to 0.81 (0.81) and 0.69 (0.77) for the two satellite products when exponential filtering and CDF matching approaches are applied. On the other hand, considering the anomalies, correlation values decrease but, more significantly, in this case ASCAT outperforms all the other products for all sites except the Spanish ones. Overall, the reliability of all the satellite soil moisture products was found to decrease with increasing vegetation density and to be in good accordance with previous studies. The results provide an overview of the ASCAT and AMSR-E reliability and robustness over different regions in Europe, thereby highlighting advantages and shortcomings for the effective use of these data sets for operational applications such as flood forecasting and numerical weather prediction. [Copyright &y& Elsevier]

Mutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection. [ABSTRACT FROM AUTHOR]

Abstract: The full greenhouse gas balance of nine contrasted grassland sites covering a major climatic gradient over Europe was measured during two complete years. The sites include a wide range of management regimes (rotational grazing, continuous grazing and mowing), the three main types of managed grasslands across Europe (sown, intensive permanent and semi-natural grassland) and contrasted nitrogen fertilizer supplies. At all sites, the net ecosystem exchange (NEE) of CO2 was assessed using the eddy covariance technique. N2O emissions were monitored using various techniques (GC-cuvette systems, automated chambers and tunable diode laser) and CH4 emissions resulting from enteric fermentation of the grazing cattle were measured in situ at four sites using the SF6 tracer method. Averaged over the two measurement years, net ecosystem exchange (NEE) results show that the nine grassland plots displayed a net sink for atmospheric CO2 of −240±70gCm−2 year−1 (mean±confidence interval at p >0.95). Because of organic C exports (from cut and removed herbage) being usually greater than C imports (from manure spreading), the average C storage (net biome productivity, NBP) in the grassland plots was estimated at −104±73gCm−2 year−1, that is 43% of the atmospheric CO2 sink. On average of the 2 years, the grassland plots displayed annual N2O and CH4 (from enteric fermentation by grazing cattle) emissions, in CO2-C equivalents, of 14±4.7 and 32±6.8g CO2-Cequiv.m−2 year−1, respectively. Hence, when expressed in CO2-C equivalents, emissions of N2O and CH4 resulted in a 19% offset of the NEE sink activity. An attributed GHG balance has been calculated by subtracting from the NBP: (i) N2O and CH4 emissions occurring within the grassland plot and (ii) off-site emissions of CO2 and CH4 as a result of the digestion and enteric fermentation by cattle of the cut herbage. On average of the nine sites, the attributed GHG balance was not significantly different from zero (−85±77gCO2-Cequiv.m−2 year−1). The net exchanges by the grassland ecosystems of CO2 and of GHG were highly correlated with the difference in carbon used by grazing versus cutting, indicating that cut grasslands have a greater on-site sink activity than grazed grasslands. However, the net biome productivity was significantly correlated to the total C used by grazing and cutting, indicating that, on average, net carbon storage declines with herbage utilisation for herbivores. [Copyright &y& Elsevier]

This is the third in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on recognising and addressing CF health issues. The guidance was produced with wide stakeholder engagement, including people from the CF community, using an evidence-based framework. Authors contributed sections, and summary statements which were reviewed by a Delphi consultation. Monitoring and treating airway infection, inflammation and pulmonary exacerbations remains important, despite the widespread availability of CFTR modulators and their accompanying health improvements. Extrapulmonary CF-specific health issues persist, such as diabetes, liver disease, bone disease, stones and other renal issues, and intestinal obstruction. These health issues require multidisciplinary care with input from the relevant specialists. Cancer is more common in people with CF compared to the general population, and requires regular screening. The CF life journey requires mental and emotional adaptation to psychosocial and physical challenges, with support from the CF team and the CF psychologist. This is particularly important when life gets challenging, with disease progression requiring increased treatments, breathing support and potentially transplantation. Planning for end of life remains a necessary aspect of care and should be discussed openly, honestly, with sensitivity and compassion for the person with CF and their family. CF teams should proactively recognise and address CF-specific health issues, and support mental and emotional wellbeing while accompanying people with CF and their families on their life journey., Competing Interests: Declaration of competing interest The authors had no declarations of interest in relation to the current work. Declarations of interest for each author outside the current work are summarised in Supplementary Table 4., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Pre-travel counselling has demonstrated its efficacy in decreasing travel-related health complications. The current profile of people living with HIV (PLWH) in Europe [increasing age, visiting friends and relatives (VFR)] makes pre-travel counselling crucial. We aimed to survey the self-reported travel patterns and advice-seeking behaviour among PLWH followed up at the HIV Reference Centre (HRC) of Saint-Pierre Hospital, Brussels., Methods: A survey was conducted in all PLWH presenting at the HRC from February to June 2021. The survey covered demographic elements, travel and pre-travel consultation habits over the last 10 years, or since the diagnosis of HIV if it was made less than 10 years earlier., Results: The survey was completed by 1024 PLWH (35% women, median age 49 years, the majority being virologically controlled). A substantial number of PLWH were involved in VFR travel in low-resource countries and 65% sought pre-travel advice before travelling: if not, it was because they did not know it was necessary (91%)., Conclusion: Travel is common among PLWH. Raising awareness of the importance of pre-travel counselling should be a routine part of every healthcare encounter and especially during regular contact with HIV physicians., (© 2023 British HIV Association.)

To meet the 1.5 °C target, methane (CH4) from ruminants must be reduced by 11 to 30% by 2030 and 24 to 47% by 2050 compared to 2010 levels. A meta-analysis identified strategies to decrease product-based (PB; CH4 per unit meat or milk) and absolute (ABS) enteric CH4 emissions while maintaining or increasing animal productivity (AP; weight gain or milk yield). Next, the potential of different adoption rates of one PB or one ABS strategy to contribute to the 1.5 °C target was estimated. The database included findings from 430 peer-reviewed studies, which reported 98 mitigation strategies that can be classified into three categories: animal and feed management, diet formulation, and rumen manipulation. A random-effects meta-analysis weighted by inverse variance was carried out. Three PB strategies—namely, increasing feeding level, decreasing grass maturity, and decreasing dietary forage-to-concentrate ratio—decreased CH4 per unit meat or milk by on average 12% and increased AP by a median of 17%. Five ABS strategies—namely CH4 inhibitors, tanniferous forages, electron sinks, oils and fats, and oilseeds—decreased daily methane by on average 21%. Globally, only 100% adoption of the most effective PB and ABS strategies can meet the 1.5 °C target by 2030 but not 2050, because mitigation effects are offset by projected increases in CH4 due to increasing milk and meat demand. Notably, by 2030 and 2050, low- and middle-income countries may not meet their contribution to the 1.5 °C target for this same reason, whereas high-income countries could meet their contributions due to only a minor projected increase in enteric CH4 emissions.

Background: People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool., Methods: We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R)., Results: Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers., Conclusions: Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies., Competing Interests: Declaration of Competing Interest RC, AC, VBontemps, EL, EB, VB, MK, FC, MB, HdeK, PdeC, KH and IH have no conflicts of interest. ISG has received grants and personal fees from Vertex Pharmaceuticals, personal fees from Eloxx, and non-financial support from PTC Therapeutics; P-RB has received personal fees from Astra Zeneca, Boehringer-Ingelheim, Chiesi, GSK, Insmed, Novartis and Pfizer and grant from GSK; DH has received personal fees from Vertex; CM personal fees from Chiesi and Zambon., (Copyright © 2021. Published by Elsevier B.V.)

Background: The pharmacy profession has an important role in the frontline healthcare response to COVID-19 across all settings., Objective: This study sought to explore the views and experiences of clinical pharmacists in relation to the provision of clinical pharmacy services during COVID-19., Methods: Semi-structured qualitative interviews were conducted with pharmacists working in clinical roles in healthcare settings across Europe. Participants were recruited through professional organisations of clinical and hospitals pharmacists combined with a snowballing technique. The Pharmacy Emergency Preparedness and Response Framework and Disaster Preparedness Framework for pharmacy services were used to generate data which were analysed using the thematic framework method., Results: Twenty-two participants from 16 European countries described a range of measures to protect patients, public and healthcare staff against virus transmission including developing and disseminating educational materials. Most described their involvement in aspects of evidence provision such as facilitating clinical trials, gathering and appraising evidence and disseminating clinical information. Many hospital-based pharmacists were reassigned to new roles such as intensive care. Routine clinical services were extensively interrupted and remote forms of communication were used. Most were motivated by a strong sense of professionalism to continue delivering services. A number of facilitators and barriers to prevention, preparedness and response actions were identified which related to uptake of new roles, recognition of pharmacists roles in the healthcare team, information gathering, communication with patients and healthcare professionals, and provision of routine clinical services., Conclusions: Participants in this multinational qualitative study described a range of service adaptations and adoption of novel roles to prevent and mitigate the public health impact of the pandemic. The study findings may help to inform governments, public health agencies and healthcare systems in harnessing ongoing service provision and adapt to any future interruptions., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background & Aims: We studied incidence and mortality trends of colorectal cancer (CRC) in 39 countries according to age, sex, and anatomic location (colon vs rectum)., Methods: We retrieved incidence data from registries from 36 countries. The registries included the following: Cancer Incidence in 5 Continents volumes I to XI; the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute; and the Nordic Cancer Registries from Europe. We obtained mortality data from 39 countries of the World Health Organization database. We evaluated average annual percentage changes in CRC incidence and mortality in the past decade using joinpoint regression analysis., Results: From 2007 to 2016, 2006 to 2015, or 2005 to 2014, depending on the availability of the data, the incidence of colon cancer increased in 10 of 36 countries analyzed (all in Asia or Europe); India had the greatest increase, followed by Poland. All 10 of these countries have medium to high Human Development Index (HDI) scores. Six countries had a decrease in colon cancer incidence; these countries had the highest HDI scores; the United States had the greatest decrease, followed by Israel. Seven countries (including all countries from Northern America) had a decrease in incidence among persons older than 50 years. Eight countries had an increase in colon cancer incidence among persons younger than 50 years, including the United Kingdom and India. Countries with a decreased or stable incidence among persons 50 years or older but a significant increase in persons younger than 50 years, included Germany, Australia, the United States, Sweden, Canada, and the United Kingdom. Only Italy had a decrease in CRC incidence among persons younger than 50 years. Among women, 12 of 36 countries (all from Asia and Europe) had an increase in colon cancer incidence and 7 countries had a decrease; India had the greatest increase followed by Slovenia. Five of 36 countries had an increase in incidence of rectal cancer and 8 countries had a decrease; Ecuador and Thailand had the greatest increases in incidence. The incidence of rectal cancer among persons younger than 50 years increased significantly in Finland, Australia, Canada, the United States, and The Netherlands. Four countries had an increase in the incidence of rectal cancer in women; Ecuador had the greatest increase followed by Thailand. The incidence of rectal cancer in women decreased in 8 countries. Among women younger than 50 years, rectal cancer incidence increased, despite a decrease in women older than 50 years, in Costa Rica, Slovenia, Japan, Slovakia, Canada, and the United States there was an increase in incidence, although their elder population had a stable or decreased incidence. Twenty-four countries reported a reduction in CRC mortality, including North America, Oceania, and most European countries. Nevertheless, some countries from Asia, Latin America, and Southern Europe had significant increases in CRC mortality., Conclusions: In an analysis of incidence and mortality databases from 39 countries, we found that the incidence of colon and rectal cancers has continued to increase in countries with medium to high HDI and in younger populations. Preventive strategies are needed for countries with increasing CRC and rectal cancer incidence and mortality., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The main aim of this study was to generate an adequate sub-phenotypic clustering model of class III skeletal malocclusion in an adult population of southern European origin. The study design was conducted in two phases, a preliminary cross-sectional study and a subsequent discriminatory evaluation by main component and cluster analysis to identify differentiated skeletal sub-groups with differentiated phenotypic characteristics. Radiometric data from 699 adult patients of southern European origin were analyzed in 212 selected subjects affected by class III skeletal malocclusion. The varimax rotation was used with Kaiser normalization, to prevent variables with more explanatory capacity from affecting the rotation. A total of 21,624 radiographic measurements were obtained as part of the cluster model generation, using a total set of 55 skeletal variables for the subsequent analysis of the major component and cluster analyses. Ten main axes were generated representing 92.7% of the total variation. Three main components represented 58.5%, with particular sagittal and vertical variables acting as major descriptors. Post hoc phenotypic clustering retrieved six clusters: C1:9.9%, C2:18.9%, C3:33%, C4:3.77%, C5:16%, and C6:16%. In conclusion, phenotypic variation was found in the southern European skeletal class III population, demonstrating the existence of phenotypic variations between identified clusters in different ethnic groups.

Background & Aims: Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies., Methods: An integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC., Results: KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFβ signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors., Conclusion: An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches., Lay Summary: Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications., Competing Interests: Conflict of interest J.M.L. is receiving research support from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen, and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche, Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca, and Exelixis. A.V. reports personal fees from NGM Pharmaceuticals, Gilead, Nucleix, Fuji Wako, Guidepoint and Exact Sciences. L.R.R. is receiving research support from Ariad Pharmaceuticals, Bayer, BTG International, Exact Sciences, Gilead Sciences, GRAIL Inc., RedHill Biopharma Ltd., TARGET PharmaSolutions and Wako Diagnostics, and is advisory board member of Bayer, Exact Sciences, Gilead Sciences, GRAIL, Inc., QED Therapeutics, Inc. and TAVEC. B.M. reports personal fees from Bayer and Gilead. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The aim of this study was to compare the new EuroSCORE (ES) 2 prediction model in high-risk patients with the 2 other oldest additive ES (aES) and logistic ES (lES)., Methods: Consecutive adult patients undergoing all cardiac surgery except heart transplantation and left ventricular assist device were included. The 3 risk scores were collected before surgery. We defined 4 high-risk groups of patients, patients ≥80 years, combined cardiac surgery, surgery of the thoracic aorta, and emergency cardiac surgery, and 2 low-risk groups, valve surgery and coronary artery bypass surgery. The predicted value of each score has been assessed by the area under the receiver operating characteristics curve (AUC)., Results: The study had included 3301 patients. Thirty-day mortality was 3.9% (95% confidence interval (CI), 3.3 - 4.6%). The AUC of ES2 was 0.81 (0.77 - 0.84), 0.82 (0.78 - 0.85), 0.70 (0.64 - 0.76), 0.79 (0.74 - 0.83), 0.85 (0.83 - 0.87), and 0.88 (0.86 - 0.90) for octogenarians, thoracic aortic surgery, combined surgery, emergency surgery, coronary surgery, and valve surgery, respectively. These ES2 AUC values were higher than those obtained with the aES for octogenarians, and with the lES for octogenarians and valve surgery. The ES2 calibration was better than the aES and lES calibration for the whole population, and low-risk groups. The ES2 calibration was superior to aES and lES in high-risk groups, except for octogenarians and thoracic aortic surgery compared to lES., Conclusion: In high-risk cardiac surgery patients, ES2 only marginally improve the predicted 30-day mortality in comparison to other ES.

In the WHO European Region, COVID-19 surveillance was implemented 27 January 2020. We detail the first European cases. As at 21 February, nine European countries reported 47 cases. Among 38 cases studied, 21 were linked to two clusters in Germany and France, 14 were infected in China. Median case age was 42 years; 25 were male. Late detection of the clusters' index cases delayed isolation of further local cases. As at 5 March, there were 4,250 cases.

Objectives: To evaluate the use of P-values and the terms "significant", "non-significant" and "suggestive" in Abstracts in the European Annals of Otorhinolaryngology, Head & Neck Diseases., Materials and Methods: Consecutive articles accepted for publication during the period January 2016 - February 2019 were systematically reviewed. Main goal: descriptive analysis of the citation of P-values and use of the terms "significant", "non-significant" and "suggestive" in Abstracts. Secondary goal: analytic study of: (i) correlations between citation of a P-value and the main characteristics of authors and topics; and (ii) misuse of the terms "significant", "non-significant" and "suggestive" with respect to cited P-values, and correlations with author and topic characteristics., Results: In all, 91 articles were included. P-values and the terms "significant", "non-significant" and "suggestive" were cited in 35.1%, 41.7%, 10.9% and 0% of Abstracts, respectively. Citing a P-value did not significantly correlate with author or topic characteristics. There were discrepancies between the terms "non-significant", "significant" and "suggestive" and P-values given in the body of the article in 57.1% of Abstracts, with 30.7% overestimation and 25.2% underestimation of results, without significant correlation with author or topic characteristics., Conclusion: Authors, editors and reviewers must pay particular attention to the spin resulting from inappropriate use of the terms "significant", "non-significant" and "suggestive" in Abstracts of articles submitted to the European Annals of Otorhinolaryngology, Head & Neck Diseases, to improve the rigor, quality and value of the scientific message delivered to the reader., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Enteric methane (CH 4 ) production from cattle contributes to global greenhouse gas emissions. Measurement of enteric CH 4 is complex, expensive, and impractical at large scales; therefore, models are commonly used to predict CH 4 production. However, building robust prediction models requires extensive data from animals under different management systems worldwide. The objectives of this study were to (1) collate a global database of enteric CH 4 production from individual lactating dairy cattle; (2) determine the availability of key variables for predicting enteric CH 4 production (g/day per cow), yield [g/kg dry matter intake (DMI)], and intensity (g/kg energy corrected milk) and their respective relationships; (3) develop intercontinental and regional models and cross-validate their performance; and (4) assess the trade-off between availability of on-farm inputs and CH 4 prediction accuracy. The intercontinental database covered Europe (EU), the United States (US), and Australia (AU). A sequential approach was taken by incrementally adding key variables to develop models with increasing complexity. Methane emissions were predicted by fitting linear mixed models. Within model categories, an intercontinental model with the most available independent variables performed best with root mean square prediction error (RMSPE) as a percentage of mean observed value of 16.6%, 14.7%, and 19.8% for intercontinental, EU, and United States regions, respectively. Less complex models requiring only DMI had predictive ability comparable to complex models. Enteric CH 4 production, yield, and intensity prediction models developed on an intercontinental basis had similar performance across regions, however, intercepts and slopes were different with implications for prediction. Revised CH 4 emission conversion factors for specific regions are required to improve CH 4 production estimates in national inventories. In conclusion, information on DMI is required for good prediction, and other factors such as dietary neutral detergent fiber (NDF) concentration, improve the prediction. For enteric CH 4 yield and intensity prediction, information on milk yield and composition is required for better estimation., (© 2018 John Wiley & Sons Ltd.)

To understand the dynamics behind the worldwide spread of the mcr-1 gene, we determined the population structure of Escherichia coli and of mobile genetic elements (MGEs) carrying the mcr-1 gene. After a systematic review of the literature we included 65 E. coli whole genome sequences (WGS), adding 6 recently sequenced travel related isolates, and 312 MLST profiles. We included 219 MGEs described in 7 Enterobacteriaceae species isolated from human, animal and environmental samples. Despite a high overall diversity, 2 lineages were observed in the E. coli population that may function as reservoirs of the mcr-1 gene, the largest of which was linked to ST10, a sequence type known for its ubiquity in human faecal samples and in food samples. No genotypic clustering by geographical origin or isolation source was observed. Amongst a total of 13 plasmid incompatibility types, the IncI2, IncX4 and IncHI2 plasmids accounted for more than 90% of MGEs carrying the mcr-1 gene. We observed significant geographical clustering with regional spread of IncHI2 plasmids in Europe and IncI2 in Asia. These findings point towards promiscuous spread of the mcr-1 gene by efficient horizontal gene transfer dominated by a limited number of plasmid incompatibility types.

Pancreatic cancer induces a substantial global burden. We examined its global incidence/mortality rates and their correlation with socioeconomic development (Human Development Index [HDI] and Gross Domestic Product [GDP] in 2000 as proxy measures). Data on age-standardized incidence/mortality rates in 2012 were retrieved from the GLOBOCAN database. Temporal patterns in 1998-2007 were assessed for 39 countries according to gender. The Average Annual Percent Change (AAPC) of the incidence/mortality trends was evaluated using joinpoint regression analysis. The age-standardized incidence ranged between 0.8-8.9/100,000. When compared among countries, Brazil (AAPC = 10.4, 95%C.I. = 0.8,21) and France (AAPC = 4.7, 95%C.I. = 3.6,5.9) reported the highest incidence rise in men. The greatest increase in women was reported in Thailand (AAPC = 7, 95%C.I. = 2.1,12.1) and Ecuador (AAPC = 4.3, 95%C.I. = 1.3,7.3). For mortality, the Philippines (APCC = 4.3, 95%C.I. = 2,6.6) and Croatia (AAPC = 2, 95% C.I. = 0,3.9) reported the biggest increase among men. The Philippines (AAPC = 5.8, 95% C.I. 4.5,7.2) and Slovakia (AAPC = 3.1, 95% C.I. 0.9,5.3) showed the most prominent rise among women. Its incidence was positively correlated with HDI (men: r = 0.66; women: r = 0.70) and GDP (men: r = 0.29; women: r = 0.28, all p < 0.05), and similarly for mortality (men: r = 0.67; women: r = 0.72 [HDI]; men: r = 0.23; women: r = 0.28 [GDP]). In summary, the incidence and mortality of pancreatic cancer were rising in many countries, requiring regular surveillance.

We describe a novel papillomavirus - Rusa alfredi papillomavirus 1 (RalPV1) - which causes endemic fibropapillomatosis in the European conservation breeding population of the highly endangered Visayan spotted deer (Rusa alfredi). Degenerated papillomavirus-specific primers were used to amplify and sequence parts of the viral DNA. Subsequently, the complete genomic DNA was cloned and the sequence was determined. The RalPV1 genome has a length of 8029 bp, encodes the early proteins E6, E7, E1, E2 and E5, the two late proteins L1 and L2 and contains an upstream regulatory region. Highest sequence identities were observed with two deltapapillomaviruses, the Capreolus capreolus PV1 and Cervus elaphus PV1. Pairwise comparisons and phylogenetic analysis based on the ORF L1 suggested that RalPV1 is a putative new type of the papillomavirus species Deltapapillomavirus 5.

In light of a growing role of research collaborations between academia and the pharmaceutical industry, we have explored expectations and experience of academic investigators with preclinical collaborations. Researchers from Western Europe, North America, and Japan with preclinical publications in the obstructed airways or diabetes fields were invited to anonymously participate in a web-based survey. A total of 134 investigators (28 % of invitees) participated in the two sequentially performed surveys with similar responses in both therapeutic areas. A secondary but prespecified subgroup analysis was based on region of residence, gender, and career level of the investigator. Across all groups, responders considered freedom to publish, obtaining funding and obtaining compounds to be the most important objectives of nonclinical collaborations with the pharmaceutical industry, whereas cultivating professional relationships, getting external scientific input, direct relationship to disease treatment, and involvement with drug development were less important. Among eight attributes of the primary contact person in the company, trustworthiness ranked highest, followed by a collaborative spirit and transparent information sharing; supportiveness, scientific qualification, accessibility, and timeliness of responses ranked lower, and friendliness, lowest. Related to their most recent collaboration, investigators also expressed the highest level of satisfaction with the trustworthiness attribute. On the other hand, the process of reaching a contract was often considered too long and difficult, for which both university and company legal departments were reported as culprits. We conclude that academic researchers are generally satisfied with their preclinical collaboration with the pharmaceutical industry but look for improved contracting procedures.

Genetic adaptation to different environmental conditions is expected to lead to large differences between populations at selected loci, thus providing a signature of positive selection. Whereas balancing selection can maintain polymorphisms over long evolutionary periods and even geographic scale, thus leads to low levels of divergence between populations at selected loci. However, little is known about the relative importance of these two selective forces in shaping genomic diversity, partly due to difficulties in recognizing balancing selection in species showing low levels of differentiation. Here we address this problem by studying genomic diversity in the European common vole (Microtus arvalis) presenting high levels of differentiation between populations (average F ST = 0.31). We studied 3,839 Amplified Fragment Length Polymorphism (AFLP) markers genotyped in 444 individuals from 21 populations distributed across the European continent and hence over different environmental conditions. Our statistical approach to detect markers under selection is based on a Bayesian method specifically developed for AFLP markers, which treats AFLPs as a nearly codominant marker system, and therefore has increased power to detect selection. The high number of screened populations allowed us to detect the signature of balancing selection across a large geographic area. We detected 33 markers potentially under balancing selection, hence strong evidence of stabilizing selection in 21 populations across Europe. However, our analyses identified four-times more markers (138) being under positive selection, and geographical patterns suggest that some of these markers are probably associated with alpine regions, which seem to have environmental conditions that favour adaptation. We conclude that despite favourable conditions in this study for the detection of balancing selection, this evolutionary force seems to play a relatively minor role in shaping the genomic diversity of the common vole, which is more influenced by positive selection and neutral processes like drift and demographic history.

Introduction: The aim of the study was to assess whether adults admitted to hospitals with both Intensive Care Units (ICU) and Intermediate Care Units (IMCU) have lower in-hospital mortality than those admitted to ICUs without an IMCU., Methods: An observational multinational cohort study performed on patients admitted to participating ICUs during a four-week period. IMCU was defined as any physically and administratively independent unit open 24 hours a day, seven days a week providing a level of care lower than an ICU but higher than a ward. Characteristics of hospitals, ICUs and patients admitted to study ICUs were recorded. The main outcome was all-cause in-hospital mortality until hospital discharge (censored at 90 days)., Results: One hundred and sixty-seven ICUs from 17 European countries enrolled 5,834 patients. Overall, 1,113 (19.1%) patients died in the ICU and 1,397 died in hospital, with a total of 1,397 (23.9%) deaths. The illness severity was higher for patients in ICUs with an IMCU (median Simplified Acute Physiology Score (SAPS) II: 37) than for patients in ICUs without an IMCU (median SAPS II: 29, P <0.001). After adjustment for patient characteristics at admission such as illness severity, and ICU and hospital characteristics, the odds ratio of mortality was 0.63 (95% CI 0.45 to 0.88, P = 0.007) in favour of the presence of IMCU. The protective effect of the IMCU was absent in patients who were admitted for basic observation, for example, after surgery (odds ratio 1.15, 95% CI 0.65 to 2.03, P = 0.630) but was strong in patients admitted to an ICU for other reasons (odds ratio 0.54, 95% CI 0.37 to 0.80, P = 0.002)., Conclusions: The presence of an IMCU in the hospital is associated with significantly reduced adjusted hospital mortality for adults admitted to the ICU. This effect is relevant for the patients requiring full intensive treatment., Trial Registration: Clinicaltrials.gov NCT01422070. Registered 19 August 2011.

Objective: We investigated the epidemiology of ventilator-associated pneumonia in elderly ICU patients. More precisely, we assessed prevalence, risk factors, signs and symptoms, causative bacterial pathogens, and associated outcomes., Design: Secondary analysis of a multicenter prospective cohort (EU-VAP project)., Setting: Twenty-seven European ICUs., Patients: Patients who were mechanically ventilated for greater than or equal to 48 hours. We compared middle-aged (45-64 yr; n = 670), old (65-74 yr; n = 549), and very old patients (≥ 75 yr; n= 516)., Measurements and Main Results: Ventilator-associated pneumonia occurred in 103 middle-aged (14.6%), 104 old (17.0%), and 73 very old patients (12.8%). The prevalence (n ventilator-associated pneumonia/1,000 ventilation days) was 13.7 in middle-aged patients, 16.6 in old patients, and 13.0 in very old patients. Logistic regression analysis could not demonstrate older age as a risk factor for ventilator-associated pneumonia. Ventilator-associated pneumonia in elderly patients was more frequently caused by Enterobacteriaceae (24% in middle-aged, 32% in old, and 43% in very old patients; p = 0.042). Regarding clinical signs and symptoms at ventilator-associated pneumonia onset, new temperature rise was less frequent among very old patients (59% vs 76% and 74% for middle-aged and old patients, respectively; p = 0.035). Mortality among patients with ventilator-associated pneumonia was higher among elderly patients: 35% in middle-aged patients versus 51% in old and very old patients (p = 0.036). Logistic regression analysis confirmed the importance of older age in the risk of death (adjusted odds ratio for old age, 2.1; 95% CI, 1.2-3.9 and adjusted odds ratio for very old age, 2.3; 95% CI, 1.2-4.4). Other risk factors for mortality in ventilator-associated pneumonia were diabetes mellitus, septic shock, and a high-risk pathogen as causative agent., Conclusions: In this multicenter cohort study, ventilator-associated pneumonia did not occur more frequently among elderly, but the associated mortality in these patients was higher. New temperature rise was less common in elderly patients with ventilator-associated pneumonia, whereas more episodes among elderly patients were caused by Enterobacteriaceae.