Suchergebnisse

Appendix A. Supplementary data: Supplementary material 1: https://ars.els-cdn.com/content/image/1-s2.0-S0006320719317124-mmc1.pdf (284KB) - Supplementary material 2: https://ars.els-cdn.com/content/image/1-s2.0-S0006320719317124-mmc2.pdf (276KB). ; EUs H2020 Marie Skłodowska-Curie Actions (No 676108); Villum Fonden (VKR023371); National Council for Scientific and Technological Development (CNPq) (203407/2017-2); The Australian Research Council Future Fellowship (FT180100354); The Grantham Foundation for the Protection of the Environment; The Kenneth Miller Trust; Natural Environment Research Council (NERC DTP [NE/L002507/1]); Cambridge International Scholarship from the Cambridge Trust; Newton International Fellowship of the Royal Society; Australian Government, Endeavor Postgraduate Scholarship; Branco Weiss Fellowship Administered by the ETH Zürich; Drapers' Company Fellowship, Pembroke College; Natural Environment Research Council (NERC DTP [NE/L002507/1 and NE/S001395/1]); Royal Commission for the Exhibition of 1851 Research Fellowship; Cambridge Trust Cambridge-Australia Poynton Scholarship; Cambridge Department of Zoology J. S. Gardiner Scholarship.

Conservation science is a crisis-oriented discipline focused on reducing human impacts on nature. To explore how the field has changed over the past two decades, we analyzed 3245 applications for oral presentations submitted to the Student Conference on Conservation Science (SCCS) in Cambridge, UK. SCCS has been running every year since 2000, aims for global representation by providing bursaries to early-career conservationists from lower-income countries, and has never had a thematic focus, beyond conservation in the broadest sense. We found that the majority of projects submitted to SCCS were based on primary biological data collected from local scale field studies in the tropics, contrary to established literature which highlights gaps in tropical research. Our results showed a small increase over time in submissions framed around how nature benefits people as well as a small increase in submissions integrating social science. Our findings suggest that students and early-career conservationists could provide pathways to increase availability of data from the tropics and address well-known biases in the published literature towards wealthier countries. We hope this research will motivate efforts to support student projects, ensuring data and results are published and data made publicly available. ; The project was made possible through funding from: JG: EUs Horizon 2020 Marie Skłodowska-Curie program (No 676108) and VILLUM FONDEN (VKR023371), HA-P; National Council for Scientific and Technological Development (CNPq) (203407/2017-2), TA: The Australian Research Council Future Fellowship (FT180100354), The Grantham Foundation for the Protection of the Environment and The Kenneth Miller Trust, APC: the Natural Environment Research Council (NERC DTP [NE/L002507/1]), LC: Cambridge International Scholarship from the Cambridge Trust, FH: the Newton International Fellowship of the Royal Society, DM: the Australian Government, Endeavor Postgraduate Scholarhip, HM: Branco Weiss Fellowship Administered by the ETH Zürich and Drapers' Company Fellowship, Pembroke College BIS: the Natural Environment Research Council (NERC DTP[NE/L002507/1 and NE/S001395/1]) and the Royal Commission for the Exhibition of 1851 Research Fellowship, HW: Cambridge Trust Cambridge-Australia Poynton Scholarship and Cambridge Department of Zoology J. S. Gardiner Scholarship.

This is the author accepted manuscroipt. The final version is available from Elsevier via the DOI in this record ; Conservation science is a crisis-oriented discipline focused on reducing human impacts on nature. To explore how the field has changed over the past two decades, we analyzed 3245 applications for oral presentations submitted to the Student Conference on Conservation Science (SCCS) in Cambridge, UK. SCCS has been running every year since 2000, aims for global representation by providing bursaries to early-career conservationists from lower-income countries, and has never had a thematic focus, beyond conservation in the broadest sense. We found that the majority of projects submitted to SCCS were based on primary biological data collected from local scale field studies in the tropics, contrary to established literature which highlights gaps in tropical research. Our results showed a small increase over time in submissions framed around how nature benefits people as well as a small increase in submissions integrating social science. Our findings suggest that students and early-career conservationists could provide pathways to increase availability of data from the tropics and address well-known biases in the published literature towards wealthier countries. We hope this research will motivate efforts to support student projects, ensuring data and results are published and data made publicly available. ; European Union Horizon 2020 ; Villum Fonden ; National Council for Scientific and Technological Development (CNPq) ; Australian Research Council Future Fellowship ; Grantham Foundation for the Protection of the Environment ; Kenneth Miller Trust ; Natural Environment Research Council (NERC) ; Cambridge Trust ; Royal Society ; Australian Government ; Branco Weiss Fellowship ; Royal Commission for the Exhibition of 1851

Biosimilar filgrastims are primarily indicated for chemotherapy‐induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%–40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital‐only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the "rebate trap" with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus ...

Academic, government, and private organizations from around the globe have established High Frequency radar (hereinafter, HFR) networks at regional or national levels. Partnerships have been established to coordinate and collaborate on a single global HFR network (http://global-hfradar.org/). These partnerships were established in 2012 as part of the Group on Earth Observations (GEO) to promote HFR technology and increase data sharing among operators and users. The main product of HFR networks are continuous maps of ocean surface currents within 200 km of the coast at high spatial (1–6 km) and temporal resolution (hourly or higher). Cutting-edge remote sensing technologies are becoming a standard component for ocean observing systems, contributing to the paradigm shift toward ocean monitoring. In 2017 the Global HFR Network was recognized by the Joint Technical WMO-IOC Commission for Oceanography and Marine Meteorology (JCOMM) as an observing network of the Global Ocean Observing System (GOOS). In this paper we will discuss the development of the network as well as establishing goals for the future. The U.S. High Frequency Radar Network (HFRNet) has been in operation for over 13 years, with radar data being ingested from 31 organizations including measurements from Canada and Mexico. HFRNet currently holds a collection from over 150 radar installations totaling millions of records of surface ocean velocity measurements. During the past 10 years in Europe, HFR networks have been showing steady growth with over 60 stations currently deployed and many in the planning stage. In Asia and Oceania countries, more than 110 radar stations are in operation. HFR technology can be found in a wide range of applications: for marine safety, oil spill response, tsunami warning, pollution assessment, coastal zone management, tracking environmental change, numerical model simulation of 3-dimensional circulation, and research to generate new understanding of coastal ocean dynamics, depending mainly on each country's coastal sea characteristics. These radar networks are examples of national inter-agency and inter-institutional partnerships for improving oceanographic research and operations. As global partnerships grow, these collaborations and improved data sharing enhance our ability to respond to regional, national, and global environmental and management issues.

Academic, government, and private organizations from around the globe have established High Frequency radar (hereinafter, HFR) networks at regional or national levels. Partnerships have been established to coordinate and collaborate on a single global HFR network (http://global-hfradar.org/). These partnerships were established in 2012 as part of the Group on Earth Observations (GEO) to promote HFR technology and increase data sharing among operators and users. The main product of HFR networks are continuous maps of ocean surface currents within 200 km of the coast at high spatial (1–6 km) and temporal resolution (hourly or higher). Cutting-edge remote sensing technologies are becoming a standard component for ocean observing systems, contributing to the paradigm shift toward ocean monitoring. In 2017 the Global HFR Network was recognized by the Joint Technical WMO-IOC Commission for Oceanography and Marine Meteorology (JCOMM) as an observing network of the Global Ocean Observing System (GOOS). In this paper we will discuss the development of the network as well as establishing goals for the future. The U.S. High Frequency Radar Network (HFRNet) has been in operation for over 13 years, with radar data being ingested from 31 organizations including measurements from Canada and Mexico. HFRNet currently holds a collection from over 150 radar installations totaling millions of records of surface ocean velocity measurements. During the past 10 years in Europe, HFR networks have been showing steady growth with over 60 stations currently deployed and many in the planning stage. In Asia and Oceania countries, more than 110 radar stations are in operation. HFR technology can be found in a wide range of applications: for marine safety, oil spill response, tsunami warning, pollution assessment, coastal zone management, tracking environmental change, numerical model simulation of 3-dimensional circulation, and research to generate new understanding of coastal ocean dynamics, depending mainly on each country's coastal sea characteristics. These radar networks are examples of national inter-agency and inter-institutional partnerships for improving oceanographic research and operations. As global partnerships grow, these collaborations and improved data sharing enhance our ability to respond to regional, national, and global environmental and management issues.

Background: improving cancer immunotherapy long-term clinical benefit is a major priority. It has become apparent that multiple axes of immune suppression restrain the capacity of T cells to provide anti-tumour activity including signalling through PD1/PD-L1 and LAG3/MHC-II. Methods: CB213 has been developed as a fully human PD1/LAG3 co-targeting multi-specific Humabody composed of linked VH domains that avidly bind and block PD1 and LAG3 on dual-positive T cells. We present the preclinical primary pharmacology of CB213: biochemistry, cell-based function vs. immune-suppressive targets, induction of T cell proliferation ex vivo using blood obtained from NSCLC patients, and syngeneic mouse model anti-tumour activity. CB213 pharmacokinetics was assessed in cynomolgus macaques. Results: CB213 shows picomolar avidity when simultaneously engaging PD1 and LAG3. Assessing LAG3/MHC-II or PD1/PD-L1 suppression individually, CB213 preferentially counters the LAG3 axis. CB213 showed superior activity vs. αPD1 antibody to induce ex vivo NSCLC patient T cell proliferation and to suppress tumour growth in a syngeneic mouse tumour model, for which both experimental systems possess PD1 and LAG3 suppressive components. Non-human primate PK of CB213 suggests weekly clinical administration. Conclusions: CB213 is poised to enter clinical development and, through intercepting both PD1 and LAG3 resistance mechanisms, may benefit patients with tumours escaping front-line immunological control. ; The Oncoimmunology group is supported by grants from: Asociación Española Contra el Cáncer (AECC, PROYE16001ESCO); Instituto de Salud Carlos III, Spain (FIS project grant PI17/02119); 'Precipita' Crowdfunding grant (FECYT); Crowdfunding grant from Sociedad Española de Inmunología (SEI); DESCARTHES project grant (Industry department, Government of Navarre); and Gobierno de Navarra Biomedicine Project grant (BMED 050-2019). DE is funded by a Miguel Servet Fellowship (ISC III, CP12/03114, Spain); HA is supported by the Clinico Junior 2019 scholarship from AECC; MZ is supported by a scholarship from Universidad Pública de Navarra; and MG is supported by a scholarship from the Government of Navarre.

PurposePhosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data.Patients and MethodsAssociations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes.ResultsData from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P amp;lt; .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P amp;lt; .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P amp;lt; .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); amp;gt; 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS (P = .043), but not for the DDFS and OS end points.ConclusionIn this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors. (C) 2018 by American Society of Clinical Oncology ; Funding Agencies|Cancer Council Victoria; National Health and Medical Research Council of Australia; National Breast Cancer Foundation, Australia; Breast Cancer Research Foundation, New York; Fonds de la Recherche Scientifique; Ontario Institute for Cancer Research; Government of Ontario; Trentino Biomolecular Oncologic Network (Trebionet) project; Swedish Research Council; Swedish Cancer Society

We are partnered by the World Psychiatric Association, and would like to thank them for financial help with initial research and funding for accommodation. TW acknowledges the support of the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King's College London and her NIHR Senior Investigator Award. ; Background This Commission addresses several priority areas for psychiatry over the next decade, and into the 21st century. These represent challenges and opportunities for the profession to sustain and develop itself to secure the best possible future for the millions of people worldwide who will face life with mental illness. Part 1: The patient and treatment Who will psychiatrists help? The patient population of the future will reflect general demographic shifts towards older, more urban, and migrant populations. While technical advances such as the development of biomarkers will potentially alter diagnosis and treatment, and digital technology will facilitate assessment of remote populations, the human elements of practice such as cultural sensitivity and the ability to form a strong therapeutic alliance with the patient will remain central. Part 2: Psychiatry and health-care systems Delivering mental health services to those who need them will require reform of the traditional structure of services. Few existing models have evidence of clinical effectiveness and acceptability to service users. Services of the future should consider stepped care, increased use of multidisciplinary teamwork, more of a public health approach, and the integration of mental and physical health care. These services will need to fit into the cultural and economic framework of a diverse range of settings in high-income, low-income, and middle-income countries. Part 3: Psychiatry and society Increased emphasis on social interventions and engagement with societal expectations might be an important area for psychiatry's development. This could encompass advocacy for the rights of individuals living with mental illnesses, political involvement concerning the social risk factors for mental illness, and, on a smaller scale, work with families and local social networks and communities. Psychiatrists should therefore possess communication skills and knowledge of the social sciences as well as the basic biological sciences. Part 4: The future of mental health law Mental health law worldwide tends to be based on concerns about risk rather than the protection of the rights of individuals experiencing mental illness. The United Nations Convention on the Rights of Persons with Disabilities, which states that compulsion based in whole or in part on mental disability is discriminatory, is a landmark document that should inform the future formulation and reform of mental health laws. An evidence-based approach needs to be taken: mental health legislation should mandate mental health training for all health professionals; ensure access to good-quality care; and cover wider societal issues, particularly access to housing, resources, and employment. All governments should include a mental health impact assessment when drafting relevant legislation. Part 5: Digital psychiatry—enhancing the future of mental health Digital technology might offer psychiatry the potential for radical change in terms of service delivery and the development of new treatments. However, it also carries the risk of commercialised, unproven treatments entering the medical marketplace with detrimental effect. Novel research methods, transparency standards, clinical evidence, and care delivery models must be created in collaboration with a wide range of stakeholders. Psychiatrists need to remain up to date and educated in the evolving digital world. Part 6: Training the psychiatrist of the future Rapid scientific advance and evolving models of health-care delivery have broad implications for future psychiatry training. The psychiatrist of the future must not only be armed with the latest medical knowledge and clinical skills but also be prepared to adapt to a changing landscape. Training programmes in an age in which knowledge of facts is less important than how new knowledge is accessed and deployed must refocus from the simple delivery of information towards acquisition of skills in lifelong learning and quality improvement. Conclusion Psychiatry faces major challenges. The therapeutic relationship remains paramount, and psychiatrists will need to acquire the necessary communication skills and cultural awareness to work optimally as patient demographics change. Psychiatrists must work with key stakeholders, including policy makers and patients, to help to plan and deliver the best services possible. The contract between psychiatry and society needs to be reviewed and renegotiated on a regular basis. Mental health law should be reformed on the basis of evidence and the rights of the individual. Psychiatry should embrace the possibilities offered by digital technology, and take an active role in ensuring research and care delivery in this area is ethically sound and evidence based. Psychiatry training must reflect these multiple pressures and demands by focusing on lifelong learning rather than simply knowledge delivery. Introduction ; We are partnered by the World Psychiatric Association, and would like to thank them for financial help with initial research and funding for accommodation. TW acknowledges the support of the NIHR Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King's College London and her NIHR Senior Investigator Award.

Background Sepsis and severe focal infections represent a substantial disease burden in children admitted to hospital. We aimed to understand the burden of disease and outcomes in children with life-threatening bacterial infections in Europe. Methods The European Union Childhood Life-threatening Infectious Disease Study (EUCLIDS) was a prospective, multicentre, cohort study done in six countries in Europe. Patients aged 1 month to 18 years with sepsis (or suspected sepsis) or severe focal infections, admitted to 98 participating hospitals in the UK, Austria, Germany, Lithuania, Spain, and the Netherlands were prospectively recruited between July 1, 2012, and Dec 31, 2015. To assess disease burden and outcomes, we collected demographic and clinical data using a secured web-based platform and obtained microbiological data using locally available clinical diagnostic procedures. Findings 2844 patients were recruited and included in the analysis. 1512 (53·2%) of 2841 patients were male and median age was 39·1 months (IQR 12·4–93·9). 1229 (43·2%) patients had sepsis and 1615 (56·8%) had severe focal infections. Patients diagnosed with sepsis had a median age of 27·6 months (IQR 9·0–80·2), whereas those diagnosed with severe focal infections had a median age of 46·5 months (15·8–100·4; p<0·0001). Of 2844 patients in the entire cohort, the main clinical syndromes were pneumonia (511 [18·0%] patients), CNS infection (469 [16·5%]), and skin and soft tissue infection (247 [8·7%]). The causal microorganism was identified in 1359 (47·8%) children, with the most prevalent ones being Neisseria meningitidis (in 259 [9·1%] patients), followed by Staphylococcus aureus (in 222 [7·8%]), Streptococcus pneumoniae (in 219 [7·7%]), and group A streptococcus (in 162 [5·7%]). 1070 (37·6%) patients required admission to a paediatric intensive care unit. Of 2469 patients with outcome data, 57 (2·2%) deaths occurred: seven were in patients with severe focal infections and 50 in those with sepsis. Interpretation Mortality in children ...