| 1. |
- Lestinsky, M., et al.
(author)
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Physics book: CRYRING@ESR
- 2016
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In: European Physical Journal: Special Topics. - : Springer Science and Business Media LLC. - 1951-6401 .- 1951-6355. ; 225:5, s. 797-882
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Research review (peer-reviewed)abstract
- The exploration of the unique properties of stored and cooled beams of highly-charged ions as provided by heavy-ion storage rings has opened novel and fascinating research opportunities in the realm of atomic and nuclear physics research. Since the late 1980s, pioneering work has been performed at the CRYRING at Stockholm (Abrahamsson et al. 1993) and at the Test Storage Ring (TSR) at Heidelberg (Baumann et al. 1988). For the heaviest ions in the highest charge-states, a real quantum jump was achieved in the early 1990s by the commissioning of the Experimental Storage Ring (ESR) at GSI Helmholtzzentrum für Schwerionenforschung (GSI) in Darmstadt (Franzke 1987) where challenging experiments on the electron dynamics in the strong field regime as well as nuclear physics studies on exotic nuclei and at the borderline to atomic physics were performed. Meanwhile also at Lanzhou a heavy-ion storage ring has been taken in operation, exploiting the unique research opportunities in particular for medium-heavy ions and exotic nuclei (Xia et al. 2002).
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| 2. |
- Ardura-Fabregat, A., et al.
(author)
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Targeting Neuroinflammation to Treat Alzheimer’s Disease
- 2017
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In: CNS Drugs. - : Springer Science and Business Media LLC. - 1172-7047 .- 1179-1934. ; 31:12, s. 1-26
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Research review (peer-reviewed)abstract
- Over the past few decades, research on Alzheimer’s disease (AD) has focused on pathomechanisms linked to two of the major pathological hallmarks of extracellular deposition of beta-amyloid peptides and intra-neuronal formation of neurofibrils. Recently, a third disease component, the neuroinflammatory reaction mediated by cerebral innate immune cells, has entered the spotlight, prompted by findings from genetic, pre-clinical, and clinical studies. Various proteins that arise during neurodegeneration, including beta-amyloid, tau, heat shock proteins, and chromogranin, among others, act as danger-associated molecular patterns, that—upon engagement of pattern recognition receptors—induce inflammatory signaling pathways and ultimately lead to the production and release of immune mediators. These may have beneficial effects but ultimately compromise neuronal function and cause cell death. The current review, assembled by participants of the Chiclana Summer School on Neuroinflammation 2016, provides an overview of our current understanding of AD-related immune processes. We describe the principal cellular and molecular players in inflammation as they pertain to AD, examine modifying factors, and discuss potential future therapeutic targets.
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| 3. |
- Roselli, Carolina, et al.
(author)
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Multi-ethnic genome-wide association study for atrial fibrillation
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:9, s. 1225-1233
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Journal article (peer-reviewed)abstract
- Atrial fibrillation (AF) affects more than 33 million individuals worldwide(1) and has a complex heritability(2). We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.
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| 4. |
- Turcu, I. C. E., et al.
(author)
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HIGH FIELD PHYSICS AND QED EXPERIMENTS AT ELI-NP
- 2016
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In: Romanian Reports on Physics. - 1221-1451 .- 1841-8759. ; 68, s. S145-S231
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Journal article (peer-reviewed)abstract
- ELI-NP facility will enable for the first time the use of two 10 PW laser beams for quantum electrodynamics (QED) experiments. The first beam will accelerate electrons to relativistic energies. The second beam will subject relativistic electrons to the strong electromagnetic field generating QED processes: intense gamma ray radiation and electron-positron pair formation. The laser beams will be focused to intensities above 10(21) Wcm(-2) and reaching 10(22)-10(23) Wcm(-2) for the first time. We propose to use this capability to investigate new physical phenomena at the interfaces of plasma, nuclear and particle physics at ELI-NP. This High Power Laser System Technical Design Report (HPLS-TDR2) presents the experimental area E6 at ELI-NP for investigating high field physics and quantum electrodynamics and the production of electron-positron-pairs and of energetic gamma-rays. The scientific community submitted 12 commissioning runs for E6 interaction chamber with two 10 PW laser beams and one proposal for the CETAL interaction chamber with 1 PW laser. The proposals are representative of the international high field physics community being written by 48 authors from 14 European and US organizations. The proposals are classified according to the science area investigated into: Radiation Reaction Physics: Classical and Quantum; Compton and Thomson Scattering Physics: Linear and Non Linear Regimes; QED in Vacuum; Atoms in Extreme Fields. Two pump-probe colliding 10 PW laser beams are proposed for the E6 interaction chamber. The focused pump laser beam accelerates the electrons to relativistic energies. The accelerated electron bunches interact with the very high electro-magnetic field of the focused probe laser beam. We propose two main types of experiments with: (a) gas targets in which the pump laser-beam is focused by a long focal length mirror and drives a wakefield in which the electron bunch is accelerated to multi-GeV energies and then exposed to the EM field of the probe laser which is tightly focused; (b) solid targets in which both the pump and probe laser beams are focused on the solid target, one accelerating the electrons in the solid and the other, delayed, providing the high electric field to which the relativistic electrons are subjected. We propose four main focusing configurations for the pump and probe laser beams, two for each type of target: counter-propagating 10 PW focused laser beams and the two 10 PW laser beams focused in the same direction. For solid targets we propose an additional configuration with plasma-mirror on the pump laser beam: the plasma mirror placed between the focusing mirror and target. It is proposed that the 10 PW laser beams will have polarization control and focus control by means of adaptive optics. Initially only one 10 PW may have polarization control and adaptive optics. In order to accommodate the two laser beams and diagnostics the proposed interaction chamber is quasi-octagonal with a diameter of 4.5 m. A large electron-spectrometer is proposed for multi-GeV electrons. Other diagnostics are requested for: gamma-rays, electrons and positrons, protons and ions, plasma characterization, transmitted and reflected laser beam. Targets will be provided by the ELI-NP Target Laboratory or purchased. The E6 experiments and diagnostics will benefit from the ELI-NP Electronics Laboratory, the Workshop and the Optics Laboratory. In order to ensure radiation-protection, a large beam-dump is planned for both multi-GeV electrons and multi-100 MeV protons.
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| 5. |
- Paulus, A, et al.
(author)
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Coinhibition of the deubiquitinating enzymes, USP14 and UCHL5, with VLX1570 is lethal to ibrutinib- or bortezomib-resistant Waldenstrom macroglobulinemia tumor cells
- 2016
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In: Blood cancer journal. - : Springer Science and Business Media LLC. - 2044-5385. ; 6:11, s. e492-
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Journal article (peer-reviewed)abstract
- The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics. Here we provide a comprehensive preclinical report on the anti-WM activity of VLX1570, a novel small-molecule inhibitor of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 14 (USP14) and ubiquitin carboxyl-terminal hydrolase isozyme L5 (UCHL5). Both DUBs reside in the 19 S proteasome cap and their inhibition by VLX1570 results in rapid and tumor-specific apoptosis in bortezomib- or ibrutinib-resistant WM cells. Notably, treatment of WM cells with VLX1570 downregulated BCR-associated elements BTK, MYD88, NFATC, NF-κB and CXCR4, the latter whose dysregulated function is linked to ibrutinib resistance. VLX1570 administered to WM-xenografted mice resulted in decreased tumor burden and prolonged survival (P=0.0008) compared with vehicle-treated mice. Overall, our report demonstrates significant value in targeting USP14/UCHL5 with VLX1570 in drug-resistant WM and carries a high potential for clinical translation.
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| 6. |
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| 7. |
- Castellani, Joëlle, et al.
(author)
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Impact of Improving Community-Based Access to Malaria Diagnosis and Treatment on Household Costs.
- 2016
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In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 63:suppl 5
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Journal article (peer-reviewed)abstract
- Community health workers (CHWs) were trained in Burkina Faso, Nigeria, and Uganda to diagnose febrile children using malaria rapid diagnostic tests, and treat positive malaria cases with artemisinin-based combination therapy (ACT) and those who could not take oral medicines with rectal artesunate. We quantified the impact of this intervention on private household costs for childhood febrile illness.Households with recent febrile illness in a young child in previous 2 weeks were selected randomly before and during the intervention and data obtained on household costs for the illness episode. Household costs included consultation fees, registration costs, user fees, diagnosis, bed, drugs, food, and transport costs. Private household costs per episode before and during the intervention were compared. The intervention's impact on household costs per episode was calculated and projected to districtwide impacts on household costs.Use of CHWs increased from 35% of illness episodes before the intervention to 50% during the intervention (P < .0001), and total household costs per episode decreased significantly in each country: from US Dollars (USD) $4.36 to USD $1.54 in Burkina Faso, from USD $3.90 to USD $2.04 in Nigeria, and from USD $4.46 to USD $1.42 in Uganda (all P < .0001). There was no difference in the time used by the child's caregiver to care for a sick child (59% before intervention vs 51% during intervention spent ≤2 days). Using the most recent population figures for each study district, we estimate that the intervention could save households a total of USD $29 965, USD $254 268, and USD $303 467, respectively, in the study districts in Burkina Faso, Nigeria, and Uganda.Improving access to malaria diagnostics and treatments in malaria-endemic areas substantially reduces private household costs. The key challenge is to develop and strengthen community human resources to deliver the intervention, and ensure adequate supplies of commodities and supervision. We demonstrate feasibility and benefit to populations living in difficult circumstances.ISRCTN13858170.
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| 8. |
- Castellani, Joëlle, et al.
(author)
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Quantifying and Valuing Community Health Worker Time in Improving Access to Malaria Diagnosis and Treatment.
- 2016
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In: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. - : Oxford University Press (OUP). - 1537-6591. ; 63:suppl 5
-
Journal article (peer-reviewed)abstract
- Community health workers (CHWs) are members of a community who are chosen by their communities as first-line, volunteer health workers. The time they spend providing healthcare and the value of this time are often not evaluated. Our aim was to quantify the time CHWs spent on providing healthcare before and during the implementation of an integrated program of diagnosis and treatment of febrile illness in 3 African countries.In Burkina Faso, Nigeria, and Uganda, CHWs were trained to assess and manage febrile patients in keeping with Integrated Management of Childhood Illness recommendations to use rapid diagnostic tests, artemisinin-based combination therapy, and rectal artesunate for malaria treatment. All CHWs provided healthcare only to young children usually <5 years of age, and hence daily time allocation of their time to child healthcare was documented for 1 day (in the high malaria season) before the intervention and at several time points following the implementation of the intervention. Time spent in providing child healthcare was valued in earnings of persons with similar experience.During the high malaria season of the intervention, CHWs spent nearly 50 minutes more in daily healthcare provision (average daily time, 30.2 minutes before the intervention vs 79.5 minutes during the intervention; test for difference in means P < .01). On average, the daily time spent providing healthcare during the intervention was 55.8 minutes (Burkina Faso), 77.4 minutes (Nigeria), and 72.2 minutes (Uganda). Using the country minimum monthly salary, CHWs' time allocated to child healthcare for 1 year was valued at US Dollars (USD) $52 in Burkina Faso, USD $295 in Nigeria, and USD $141 in Uganda.CHWs spend up to an hour and a half daily on child healthcare in their communities. These data are informative in designing reward systems to motivate CHWs to continue providing good-quality services.ISRCTN13858170.
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| 9. |
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| 10. |
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| 11. |
- Kirchhof, Paulus, et al.
(author)
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A roadmap to improve the quality of atrial fibrillation management : proceedings from the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference
- 2016
-
In: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 18:1, s. 37-50
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Journal article (peer-reviewed)abstract
- At least 30 million people worldwide carry a diagnosis of atrial fibrillation (AF), and many more suffer from undiagnosed, subclinical, or 'silent' AF. Atrial fibrillation-related cardiovascular mortality and morbidity, including cardiovascular deaths, heart failure, stroke, and hospitalizations, remain unacceptably high, even when evidence-based therapies such as anticoagulation and rate control are used. Furthermore, it is still necessary to define how best to prevent AF, largely due to a lack of clinical measures that would allow identification of treatable causes of AF in any given patient. Hence, there are important unmet clinical and research needs in the evaluation and management of AF patients. The ensuing needs and opportunities for improving the quality of AF care were discussed during the fifth Atrial Fibrillation Network/European Heart Rhythm Association consensus conference in Nice, France, on 22 and 23 January 2015. Here, we report the outcome of this conference, with a focus on (i) learning from our 'neighbours' to improve AF care, (ii) patient-centred approaches to AF management, (iii) structured care of AF patients, (iv) improving the quality of AF treatment, and (v) personalization of AF management. This report ends with a list of priorities for research in AF patients.
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| 12. |
- Kotecha, Dipak, et al.
(author)
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Integrating new approaches to atrial fibrillation management : the 6th AFNET/EHRA Consensus Conference.
- 2018
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In: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 20:3, s. 395-407
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Journal article (peer-reviewed)abstract
- There are major challenges ahead for clinicians treating patients with atrial fibrillation (AF). The population with AF is expected to expand considerably and yet, apart from anticoagulation, therapies used in AF have not been shown to consistently impact on mortality or reduce adverse cardiovascular events. New approaches to AF management, including the use of novel technologies and structured, integrated care, have the potential to enhance clinical phenotyping or result in better treatment selection and stratified therapy. Here, we report the outcomes of the 6th Consensus Conference of the Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association (EHRA), held at the European Society of Cardiology Heart House in Sophia Antipolis, France, 17-19 January 2017. Sixty-two global specialists in AF and 13 industry partners met to develop innovative solutions based on new approaches to screening and diagnosis, enhancing integration of AF care, developing clinical pathways for treating complex patients, improving stroke prevention strategies, and better patient selection for heart rate and rhythm control. Ultimately, these approaches can lead to better outcomes for patients with AF.
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| 13. |
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| 14. |
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| 15. |
- Schnabel, Renate B., et al.
(author)
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Searching for Atrial Fibrillation Poststroke : A White Paper of the AF-SCREEN International Collaboration
- 2019
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In: Circulation. - 1524-4539. ; 140:22, s. 1834-1850
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Journal article (peer-reviewed)abstract
- Cardiac thromboembolism attributed to atrial fibrillation (AF) is responsible for up to one-third of ischemic strokes. Stroke may be the first manifestation of previously undetected AF. Given the efficacy of oral anticoagulants in preventing AF-related ischemic strokes, strategies of searching for AF after a stroke using ECG monitoring followed by oral anticoagulation (OAC) treatment have been proposed to prevent recurrent cardioembolic strokes. This white paper by experts from the AF-SCREEN International Collaboration summarizes existing evidence and knowledge gaps on searching for AF after a stroke by using ECG monitoring. New AF can be detected by routine plus intensive ECG monitoring in approximately one-quarter of patients with ischemic stroke. It may be causal, a bystander, or neurogenically induced by the stroke. AF after a stroke is a risk factor for thromboembolism and a strong marker for atrial myopathy. After acute ischemic stroke, patients should undergo 72 hours of electrocardiographic monitoring to detect AF. The diagnosis requires an ECG of sufficient quality for confirmation by a health professional with ECG rhythm expertise. AF detection rate is a function of monitoring duration and quality of analysis, AF episode definition, interval from stroke to monitoring commencement, and patient characteristics including old age, certain ECG alterations, and stroke type. Markers of atrial myopathy (eg, imaging, atrial ectopy, natriuretic peptides) may increase AF yield from monitoring and could be used to guide patient selection for more intensive/prolonged poststroke ECG monitoring. Atrial myopathy without detected AF is not currently sufficient to initiate OAC. The concept of embolic stroke of unknown source is not proven to identify patients who have had a stroke benefitting from empiric OAC treatment. However, some embolic stroke of unknown source subgroups (eg, advanced age, atrial enlargement) might benefit more from non-vitamin K-dependent OAC therapy than aspirin. Fulfilling embolic stroke of unknown source criteria is an indication neither for empiric non-vitamin K-dependent OAC treatment nor for withholding prolonged ECG monitoring for AF. Clinically diagnosed AF after a stroke or a transient ischemic attack is associated with significantly increased risk of recurrent stroke or systemic embolism, in particular, with additional stroke risk factors, and requires OAC rather than antiplatelet therapy. The minimum subclinical AF duration required on ECG monitoring poststroke/transient ischemic attack to recommend OAC therapy is debated.
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| 16. |
- Boza-Serrano, Antonio, et al.
(author)
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Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease
- 2019
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In: Acta Neuropathologica. - : Springer Science and Business Media LLC. - 0001-6322 .- 1432-0533. ; 138:2, s. 251-273
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer’s disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2–DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.
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| 17. |
- Camm, A John, et al.
(author)
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XANTUS : a real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation.
- 2016
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 37:14, s. 1145-53
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Journal article (peer-reviewed)abstract
- AIMS: Although non-vitamin K antagonist oral anticoagulants are recommended for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) based on clinical trial results, there is a need for safety and efficacy data from unselected patients in everyday clinical practice. XANTUS investigated the safety and efficacy of the Factor Xa inhibitor rivaroxaban in routine clinical use in the NVAF setting.METHODS AND RESULTS: Consecutive consenting patients with NVAF newly started on rivaroxaban were eligible and were followed up at ∼3-month intervals for 1 year, or for at least 30 days after permanent discontinuation. All adverse events (AEs) were recorded as AEs or serious AEs; major outcomes (including major bleeding, symptomatic thromboembolic events [stroke, systemic embolism, transient ischaemic attack, and myocardial infarction], and all-cause death) were centrally adjudicated. There were 6784 patients treated with rivaroxaban at 311 centres in Europe, Israel, and Canada. Mean patient age was 71.5 years (range 19-99), 41% were female, and 9.4% had documented severe or moderate renal impairment (creatinine clearance <50 mL/min). The mean CHADS2 and CHA2DS2-VASc scores were 2.0 and 3.4, respectively; 859 (12.7%) patients had a CHA2DS2-VASc score of 0 or 1. The mean treatment duration was 329 days. Treatment-emergent major bleeding occurred in 128 patients (2.1 events per 100 patient-years), 118 (1.9 events per 100 patient-years) died, and 43 (0.7 events per 100 patient-years) suffered a stroke.CONCLUSION: XANTUS is the first international, prospective, observational study to describe the use of rivaroxaban in a broad NVAF patient population. Rates of stroke and major bleeding were low in patients receiving rivaroxaban in routine clinical practice.TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT01606995.
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| 18. |
- Castellani, J., et al.
(author)
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Out-of-Pocket Costs and Other Determinants of Access to Healthcare for Children with Febrile Illnesses: A Case-Control Study in Rural Tanzania
- 2015
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In: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Journal article (peer-reviewed)abstract
- Objectives To study private costs and other determinants of access to healthcare for childhood fevers in rural Tanzania. A case-control study was conducted in Tanzania to establish factors that determine access to a health facility in acute febrile illnesses in children less than 5 years of age. Carers of eligible children were interviewed in the community; cases were represented by patients who went to a facility and controls by those who did not. A Household Wealth Index was estimated using principal components analysis. A multivariable logistic regression analysis was performed to understand the factors which influenced attendance of healthcare facility including severity of the illness and household wealth/socio-demographic indicators. To complement the data on costs from community interviews, a hospital-based study obtained details of private expenditures for hospitalised children under the age of 5. Severe febrile illness is strongly associated with health facility attendance (OR: 35.76, 95% CI: 3.68-347.43, p = 0.002 compared with less severe febrile illness). Overall, the private costs of an illness for patients who went to a hospital were six times larger than private costs of controls ($5.68 vs. $0.90, p<0.0001). Household wealth was not significantly correlated with total costs incurred. The separate hospital based cost study indicated that private costs were three times greater for admissions at the mission versus public hospital: $13.68 mission vs. $4.47 public hospital (difference $9.21 (95% CI: 7.89 - 10.52), p<0.0001). In both locations, approximately 50% of the cost was determined by the duration of admission, with each day in hospital increasing private costs by about 12% (95% CI: 5% - 21%). The more severely ill a child, the higher the probability of attending hospital. We did not find association between household wealth and attending a health facility; nor was there an association between household wealth and private cost.
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| 19. |
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| 20. |
- Freedman, Ben, et al.
(author)
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Screening for Atrial Fibrillation A Report of the AF-SCREEN International Collaboration
- 2017
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In: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0009-7322 .- 1524-4539. ; 135:19, s. 1851-
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Journal article (peer-reviewed)abstract
- Approximately 10% of ischemic strokes are associated with atrial fibrillation (AF) first diagnosed at the time of stroke. Detecting asymptomatic AF would provide an opportunity to prevent these strokes by instituting appropriate anticoagulation. The AF-SCREEN international collaboration was formed in September 2015 to promote discussion and research about AF screening as a strategy to reduce stroke and death and to provide advocacy for implementation of country-specific AF screening programs. During 2016, 60 expert members of AF-SCREEN, including physicians, nurses, allied health professionals, health economists, and patient advocates, were invited to prepare sections of a draft document. In August 2016, 51 members met in Rome to discuss the draft document and consider the key points arising from it using a Delphi process. These key points emphasize that screen-detected AF found at a single timepoint or by intermittent ECG recordings over 2 weeks is not a benign condition and, with additional stroke factors, carries sufficient risk of stroke to justify consideration of anticoagulation. With regard to the methods of mass screening, handheld ECG devices have the advantage of providing a verifiable ECG trace that guidelines require for AF diagnosis and would therefore be preferred as screening tools. Certain patient groups, such as those with recent embolic stroke of uncertain source (ESUS), require more intensive monitoring for AF. Settings for screening include various venues in both the community and the clinic, but they must be linked to a pathway for appropriate diagnosis and management for screening to be effective. It is recognized that health resources vary widely between countries and health systems, so the setting for AF screening should be both country-and health system-specific. Based on current knowledge, this white paper provides a strong case for AF screening now while recognizing that large randomized outcomes studies would be helpful to strengthen the evidence base.
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| 21. |
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| 22. |
- Heidbuchel, Hein, et al.
(author)
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Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation : Executive summary
- 2017
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In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 38:27, s. 2137-2149
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Journal article (peer-reviewed)abstract
- In 2013, the European Heart Rhythm Association (EHRA) published a Practical Guide on the use of non-VKA oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) (Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, European Heart Rhythm A. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013;34:2094-2106). The document received widespread interest, not only from cardiologists but also from neurologists, geriatricians, and general practitioners, as became evident from the distribution of >350 000 copies of its pocket version (the EHRA Key Message Booklet) world-wide. Since 2013, numerous new studies have appeared on different aspects of NOAC therapy in AF patients. Therefore, EHRA updated the Practical Guide, including new information but also providing balanced guiding in the many areas where prospective data are still lacking. The outline of the original guide that addressed 15 clinical scenarios has been preserved, but all chapters have been rewritten. Main changes in the Update comprise a discussion on the definition of 'non-valvular AF' and eligibility for NOAC therapy, inclusion of finalized information on the recently approved edoxaban, tailored dosing information dependent on concomitant drugs, and/or clinical characteristics, an expanded chapter on neurologic scenarios (ischaemic stroke or intracranial haemorrhage under NOAC), an updated anticoagulation card and more specifics on start-up and follow-up issues. There are also many new flow charts, like on appropriate switching between anticoagulants (VKA to NOAC or vice versa), default scenarios for acute management of coronary interventions, step-down schemes for long-term combined antiplatelet-anticoagulant management in coronary heart disease, management of bleeding, and cardioversion under NOAC therapy. The Updated Guide is available in full in EP Europace (Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, HackeW, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, Advisors. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507), while additional resources can be found at the related ESC/EHRA website (www.NOACforAF.eu).
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| 23. |
- Heidbuchel, Hein, et al.
(author)
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Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation
- 2015
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In: Europace. - : Oxford University Press (OUP). - 1099-5129 .- 1532-2092. ; 17:10, s. 1467-1507
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Journal article (peer-reviewed)abstract
- The current manuscript is an update of the original Practical Guide, published in June 2013[Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation. Europace 2013; 15: 625-51; Heidbuchel H, Verhamme P, Alings M, Antz M, HackeW, Oldgren J, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34: 2094-106]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with non-valvular atrial fibrillation (AF). Both physicians and patients have to learn how to use these drugs effectively and safely in clinical practice. Many unresolved questions on how to optimally use these drugs in specific clinical situations remain. The European Heart Rhythm Association set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group defined what needs to be considered as 'non-valvular AF' and listed 15 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 15 topics are (i) practical start-up and follow-up scheme for patients on NOACs; (ii) how to measure the anticoagulant effect of NOACs; (iii) drug-drug interactions and pharmacokinetics of NOACs; (iv) switching between anticoagulant regimens; (v) ensuring adherence of NOAC intake; (vi) how to deal with dosing errors; (vii) patients with chronic kidney disease; (viii) what to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a risk of bleeding?; (xi) management of bleeding complications; (x) patients undergoing a planned surgical intervention or ablation; (xi) patients undergoing an urgent surgical intervention; (xii) patients with AF and coronary artery disease; (xiii) cardioversion in a NOAC-treated patient; (xiv) patients presenting with acute stroke while onNOACs; and (xv) NOACs vs. VKAs in AF patients with a malignancy. Additional information and downloads of the text and anticoagulation cards in >16 languages can be found on an European Heart Rhythm Association web site (www.NOACforAF.eu).
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| 24. |
- Henje Blom, Eva, 1962-, et al.
(author)
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Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.
- 2015
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In: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 5
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Journal article (peer-reviewed)abstract
- Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.
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| 25. |
- Ho, Tiffany C, et al.
(author)
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Emotion-Dependent Functional Connectivity of the Default Mode Network in Adolescent Depression.
- 2015
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 78:9, s. 635-46
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Journal article (peer-reviewed)abstract
- BACKGROUND: Functional magnetic resonance imaging research suggests that major depressive disorder (MDD) in both adults and adolescents is marked by aberrant connectivity of the default mode network (DMN) during resting state. However, emotional dysregulation is also a key feature of MDD. No studies to date have examined emotion-related DMN pathology in adolescent depression. Comprehensively understanding the dynamics of DMN connectivity across brain states in individuals with depression with short disease histories could provide insight into the etiology of MDD.METHODS: We collected functional magnetic resonance imaging data during an emotion identification task and during resting state from 26 medication-free adolescents (13-17 years old) with MDD and 37 well-matched healthy control subjects. We examined between-group differences in blood oxygenation level-dependent task responses and emotion-dependent and resting-state functional connectivity of the two primary nodes of the DMN: medial prefrontal cortex and posterior cingulate cortex (PCC). Additionally, we examined between-group differences in DMN functional connectivity and its relationship to depression severity and onset.RESULTS: Relative to healthy control subjects, unmedicated adolescents with MDD demonstrated reduced medial prefrontal cortex and PCC emotion-related deactivation and greater medial prefrontal cortex and PCC emotion-dependent functional connectivity with precuneus, cingulate gyrus, and striatum/subcallosal cingulate gyrus. The PCC-subcallosal cingulate connectivity remained inflexibly elevated in the subjects with MDD versus healthy control subjects during resting state. Stronger PCC emotion-dependent functional connectivity was associated with greater depression severity and an earlier age of depression onset.CONCLUSIONS: Adolescent depression is associated with inflexibly elevated DMN connections. Given more recent evidence of DMN maturation throughout adolescence, our findings suggest that early-onset depression adversely affects normal development of functional brain networks.
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| 26. |
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| 27. |
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| 28. |
- Winkler, Christiane, et al.
(author)
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Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials—GPPAD-02 study design and first results
- 2019
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In: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 20:6, s. 720-727
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Journal article (peer-reviewed)abstract
- Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D.
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