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1.
  • Klionsky, Daniel J., et al. (author)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • Research review (peer-reviewed)abstract
    • In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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  • Bentham, James, et al. (author)
  • A century of trends in adult human height
  • 2016
  • In: eLIFE. - 2050-084X. ; 5
  • Journal article (peer-reviewed)abstract
    • Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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4.
  • Ihne-Schubert, Sandra Michaela, et al. (author)
  • Cardio-Hepatic Interaction in Cardiac Amyloidosis
  • 2024
  • In: Journal of Clinical Medicine. - 2077-0383. ; 13:5
  • Journal article (peer-reviewed)abstract
    • Background: Congestion is associated with poor prognosis in cardiac amyloidosis (CA). The cardio-hepatic interaction and the prognostic impact of secondary liver affection by cardiac congestion in CA are poorly understood and require further characterisation. Methods: Participants of the amyloidosis cohort study AmyKoS at the Interdisciplinary Amyloidosis Centre of Northern Bavaria with proven transthyretin (ATTR-CA) and light chain CA (AL-CA) underwent serial work-up including laboratory tests, echocardiography, and in-depth hepatic assessment by vibration-controlled transient elastography (VCTE) and 13C-methacetin breath test. Results: In total, 74 patients with AL-CA (n = 17), ATTR-CA (n = 26) and the controls (n = 31) were analysed. ATTR-CA patients showed decreased microsomal liver function expressed by maximal percentage of dose rate (PDRpeak) related to hepatic congestion. Reduced PDRpeak in AL-CA could result from altered pharmacokinetics due to changed hepatic blood flow. Liver stiffness as a combined surrogate of chronic liver damage and congestion was identified as a predictor of all-cause mortality. Statistical modelling of the cardio-hepatic interaction revealed septum thickness, NT-proBNP and PDRpeak as predictors of liver stiffness in both CA subtypes; dilatation of liver veins and the fibrosis score FIB-4 were only significant for ATTR-CA. Conclusions: Non-invasive methods allow us to characterise CA-associated hepatic pathophysiology. Liver stiffness might be promising for risk stratification in CA.
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  • Ihne-Schubert, Sandra Michaela, et al. (author)
  • Single German centre experience with patient journey and care-relevant needs in amyloidosis : The German AMY-NEEDS research and care program
  • 2024
  • In: PLoS ONE. - 1932-6203. ; 19:5 May
  • Journal article (peer-reviewed)abstract
    • Background Amyloidosis is a rare multi-system disorder associated with frequently delayed diagnosis, enormous disease burden and psychosocial distress. Methods Systematic assessment of needs was performed by a subtype-spanning questionnairebased survey within the AMY-NEEDS research and care program. Results 118 patients with proven amyloidosis (62.7% ATTR, 22.0% AL, 15.3% other forms) were included in August 2020 until February 2021 (mean age 71.2 ±11.3 years; 30% women). The median diagnostic delay between onset of symptoms and diagnosis was 9.0 (range: 2.5; 33.0) months. Local health care providers (HCPs) play a central role on the way to diagnosis. Diagnosis itself typically requires a clinical but not necessarily a university setting. In the treatment phase, the focus moves to the amyloidosis centre as primary contact and coordinator, with general practitioners (GPs) acting predominantly as a contact point in crisis and link to additional services. About half of patients reported impaired quality of life and one third suffering from anxiety and depressed mood, respectively. The majority of patients talk about their concerns with close caregivers and local HCPs. Advance care planning is a relevant, yet insufficiently met need. Conclusion The journey of patients with amyloidotic disease, their contact partners and needs at different stages were characterized in detail within the German health care system. An amyloidosis- specific care concept has to master the multitude of interfaces connecting the numerous treatment providers involved with the amyloidosis centre and GPs as key players. Telemedical approaches could be a promising and well-accepted option allowing optimal coordination and communication.
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6.
  • Pattaro, Cristian, et al. (author)
  • Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
  • 2016
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
  • Journal article (peer-reviewed)abstract
    • Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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7.
  • Bentham, James, et al. (author)
  • A century of trends in adult human height
  • 2016
  • In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
  • Journal article (peer-reviewed)abstract
    • Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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  • Brunner, Fabian J., et al. (author)
  • Application of non-HDL cholesterol for population-based cardiovascular risk stratification : results from the Multinational Cardiovascular Risk Consortium
  • 2019
  • In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 394:10215, s. 2173-2183
  • Journal article (peer-reviewed)abstract
    • Background: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment.Methods: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol.Findings: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7–59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0–20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0–1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6–2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0–1·3 to 2·3, 2·0–2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced.Interpretation: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician–patient communication about primary prevention strategies.
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  • Di Castelnuovo, Augusto, et al. (author)
  • Alcohol intake and total mortality in 142 960 individuals from the MORGAM Project: a population-based study
  • 2022
  • In: Addiction. - : John Wiley & Sons. - 0965-2140 .- 1360-0443. ; 117:2, s. 312-325
  • Journal article (peer-reviewed)abstract
    • Aim: To test the association of alcohol consumption with total and cause-specific mortality risk. Design: Prospective observational multi-centre population-based study.Setting: Sixteen cohorts (15 from Europe) in the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project.Participants: A total of 142 960 individuals (mean age 50 ± 13 years, 53.9% men).Measurements: Average alcohol intake by food frequency questionnaire, total and cause-specific mortality.Findings: In comparison with life-time abstainers, consumption of alcohol less than 10 g/day was associated with an average 11% [95% confidence interval (CI) = 7–14%] reduction in the risk of total mortality, while intake > 20 g/day was associated with a 13% (95% CI = 7–20%) increase in the risk of total mortality. Comparable findings were observed for cardiovascular (CV) deaths. With regard to cancer, drinking up to 10 g/day was not associated with either mortality risk reduction or increase, while alcohol intake > 20 g/day was associated with a 22% (95% CI = 10–35%) increased risk of mortality. The association of alcohol with fatal outcomes was similar in men and women, differed somewhat between countries and was more apparent in individuals preferring wine, suggesting that benefits may not be due to ethanol but other ingredients. Mediation analysis showed that high-density lipoprotein cholesterol explained 2.9 and 18.7% of the association between low alcohol intake and total as well as CV mortality, respectively.Conclusions: In comparison with life-time abstainers, consuming less than one drink per day (nadir at 5 g/day) was associated with a reduced risk of total, cardiovascular and other causes mortality, except cancer. Intake of more than two drinks per day was associated with an increased risk of total, cardiovascular and especially cancer mortality.
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  • Di Castelnuovo, Augusto, et al. (author)
  • Drinking alcohol in moderation is associated with lower rate of all-cause mortality in individuals with higher rather than lower educational level : findings from the MORGAM project
  • 2023
  • In: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 38:8, s. 869-881
  • Journal article (peer-reviewed)abstract
    • The association between socioeconomic status (SES) and alcohol-related diseases has been widely explored. Less is known, however, on whether the association of moderate drinking with all-cause mortality is modified by educational level (EL). Using harmonized data from 16 cohorts in the MORGAM Project (N = 142,066) the association of pattern of alcohol intake with hazard of all-cause mortality across EL (lower = primary-school; middle = secondary-school; higher = university/college degree) was assessed using multivariable Cox-regression and spline curves. A total of 16,695 deaths occurred in 11.8 years (median). In comparison with life-long abstainers, participants drinking 0.1–10 g/d of ethanol had 13% (HR = 0.87; 95%CI: 0.74–1.02), 11% (HR = 0.89; 0.84–0.95) and 5% (HR = 0.95; 0.89–1.02) lower rate of death in higher, middle and lower EL, respectively. Conversely, drinkers > 20 g/d had 1% (HR = 1.01; 0.82–1.25), 10% (HR = 1.10; 1.02–1.19) and 17% (HR = 1.17; 1.09–1.26) higher rate of death. The association of alcohol consumption with all-cause mortality was nonlinear, with a different J-shape by EL levels. It was consistent across both sexes and in various approaches of measuring alcohol consumption, including combining quantity and frequency and it was more evident when the beverage of preference was wine. We observed that drinking in moderation (≤ 10 g/d) is associated with lower mortality rate more evidently in individuals with higher EL than in people with lower EL, while heavy drinking is associated with higher mortality rate more evidently in individuals with lower EL than in people with higher EL, suggesting that advice on reducing alcohol intake should especially target individuals of low EL.
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  • Feigin, Valery L., et al. (author)
  • Global, regional, and national burden of stroke and its risk factors, 1990-2019 : a systematic analysis for the Global Burden of Disease Study 2019
  • 2021
  • In: Lancet Neurology. - : Elsevier. - 1474-4422 .- 1474-4465. ; 20:10, s. 795-820
  • Journal article (peer-reviewed)abstract
    • Background Regularly updated data on stroke and its pathological types, including data on their incidence, prevalence, mortality, disability, risk factors, and epidemiological trends, are important for evidence-based stroke care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) aims to provide a standardised and comprehensive measurement of these metrics at global, regional, and national levels. Methods We applied GBD 2019 analytical tools to calculate stroke incidence, prevalence, mortality, disability-adjusted life-years (DALYs), and the population attributable fraction (PAF) of DALYs (with corresponding 95% uncertainty intervals [UIs]) associated with 19 risk factors, for 204 countries and territories from 1990 to 2019. These estimates were provided for ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and all strokes combined, and stratified by sex, age group, and World Bank country income level. Findings In 2019, there were 12.2 million (95% UI 11.0-13.6) incident cases of stroke, 101 million (93.2-111) prevalent cases of stroke, 143 million (133-153) DALYs due to stroke, and 6.55 million (6.00-7.02) deaths from stroke. Globally, stroke remained the second-leading cause of death (11.6% [10.8-12.2] of total deaths) and the third-leading cause of death and disability combined (5.7% [5.1-6.2] of total DALYs) in 2019. From 1990 to 2019, the absolute number of incident strokes increased by 70.0% (67.0-73.0), prevalent strokes increased by 85.0% (83.0-88.0), deaths from stroke increased by 43.0% (31.0-55.0), and DALYs due to stroke increased by 32.0% (22.0-42.0). During the same period, age-standardised rates of stroke incidence decreased by 17.0% (15.0-18.0), mortality decreased by 36.0% (31.0-42.0), prevalence decreased by 6.0% (5.0-7.0), and DALYs decreased by 36.0% (31.0-42.0). However, among people younger than 70 years, prevalence rates increased by 22.0% (21.0-24.0) and incidence rates increased by 15.0% (12.0-18.0). In 2019, the age-standardised stroke-related mortality rate was 3.6 (3.5-3.8) times higher in the World Bank low-income group than in the World Bank high-income group, and the age-standardised stroke-related DALY rate was 3.7 (3.5-3.9) times higher in the low-income group than the high-income group. Ischaemic stroke constituted 62.4% of all incident strokes in 2019 (7.63 million [6.57-8.96]), while intracerebral haemorrhage constituted 27.9% (3.41 million [2.97-3.91]) and subarachnoid haemorrhage constituted 9.7% (1.18 million [1.01-1.39]). In 2019, the five leading risk factors for stroke were high systolic blood pressure (contributing to 79.6 million [67.7-90.8] DALYs or 55.5% [48.2-62.0] of total stroke DALYs), high body-mass index (34.9 million [22.3-48.6] DALYs or 24.3% [15.7-33.2]), high fasting plasma glucose (28.9 million [19.8-41.5] DALYs or 20.2% [13.8-29.1]), ambient particulate matter pollution (28.7 million [23.4-33.4] DALYs or 20.1% [16.6-23.0]), and smoking (25.3 million [22.6-28.2] DALYs or 17.6% [16.4-19.0]). Interpretation The annual number of strokes and deaths due to stroke increased substantially from 1990 to 2019, despite substantial reductions in age-standardised rates, particularly among people older than 70 years. The highest age-standardised stroke-related mortality and DALY rates were in the World Bank low-income group. The fastest-growing risk factor for stroke between 1990 and 2019 was high body-mass index. Without urgent implementation of effective primary prevention strategies, the stroke burden will probably continue to grow across the world, particularly in low-income countries.
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  • Godoy, Patricio, et al. (author)
  • Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
  • 2013
  • In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
  • Research review (peer-reviewed)abstract
    • This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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  • Haller, Paul M., et al. (author)
  • Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus
  • 2023
  • In: European Journal of Preventive Cardiology. - 2047-4873 .- 2047-4881. ; 30:12, s. 1218-1226
  • Journal article (peer-reviewed)abstract
    • AIMS: The role of biomarkers in predicting cardiovascular outcomes in high-risk individuals is not well established. We aimed to investigate benefits of adding biomarkers to cardiovascular risk assessment in individuals with and without diabetes. 'METHODS AND RESULTS: We used individual-level data of 95 292 individuals of the European population harmonized in the Biomarker for Cardiovascular Risk Assessment across Europe consortium and investigated the prognostic ability of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Cox-regression models were used to determine adjusted hazard ratios of diabetes and log-transformed biomarkers for fatal and non-fatal cardiovascular events. Models were compared using the likelihood ratio test. Stratification by specific biomarker cut-offs was performed for crude time-to-event analysis using Kaplan-Meier plots. Overall, 6090 (6.4%) individuals had diabetes at baseline, median follow-up was 9.9 years. Adjusting for classical risk factors and biomarkers, diabetes [HR 2.11 (95% CI 1.92, 2.32)], and all biomarkers (HR per interquartile range hs-cTnI 1.08 [95% CI 1.04, 1.12]; NT-proBNP 1.44 [95% CI 1.37, 1.53]; hs-CRP 1.27 [95% CI 1.21, 1.33]) were independently associated with cardiovascular events. Specific cut-offs for each biomarker identified a high-risk group of individuals with diabetes losing a median of 15.5 years of life compared to diabetics without elevated biomarkers. Addition of biomarkers to the Cox-model significantly improved the prediction of outcomes (likelihood ratio test for nested models P < 0.001), accompanied by an increase in the c-index (increase to 0.81).CONCLUSION: Biomarkers improve cardiovascular risk prediction in individuals with and without diabetes and facilitate the identification of individuals with diabetes at highest risk for cardiovascular events.
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  • Ihne-Schubert, Sandra Michaela, et al. (author)
  • Needs of amyloidosis patients and their care providers : design & first results of the AMY-NEEDS research and care program
  • 2024
  • In: Orphanet Journal of Rare Diseases. - 1750-1172. ; 19:1
  • Journal article (peer-reviewed)abstract
    • Background: Amyloidosis represents a rare yet heterogeneous multi-system disorder associated with a grave prognosis and an enormous psycho-emotional strain on patients, relatives, and caregivers. We here present the overall study design and first results of AMY-NEEDS, a research program aiming to systematically assess the needs of patients suffering from amyloidosis, their relatives and health care professionals (HCPs), and develop an amyloidosis-specific care approach. Methods: AMY-NEEDS uses a mixed-methods approach including focus groups (step 1), a questionnaire-based broad evaluation within the local amyloidosis patient collective (step 2), and the development of a needs-adapted care concept (step 3). Results: Seven patients, six relatives and five HCPs participated in the focus groups (step 1). At the time of diagnosis, patients expressed the need of a smooth diagnostic process, possibly enhanced through improved awareness and better education of local HCPs. There was a strong wish to receive well-founded information and comprehensive support including companionship during medical visits, experience the feeling of being understood, find trust in that “everything possible” is being done, and have effortless access to centre staff. In the course of the disease, patients favoured that the specialized centre should manage treatment coordination, monitoring and psychosocial support. The interface between centre and local HCPs was regarded of particular importance, requiring further investigation into its optimal design. Conclusions: Patients with amyloidosis express particular needs that should appropriately be considered in specifically tailored care concepts.
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  • Magnussen, Christina, et al. (author)
  • Global effect of modifiable risk factors on cardiovascular disease and mortality
  • 2023
  • In: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 389:14, s. 1273-1285
  • Journal article (peer-reviewed)abstract
    • Background: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking.Methods: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality.Results: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6).Conclusions: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.)
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  • Mauritsen, Thorsten, et al. (author)
  • Developments in the MPI-M Earth System Model version 1.2 (MPI-ESM1.2) and Its Response to Increasing CO2
  • 2019
  • In: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 11:4, s. 998-1038
  • Journal article (peer-reviewed)abstract
    • A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI-ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low-level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two-layer model. 
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  • Sinning, Christoph, et al. (author)
  • Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population : results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium
  • 2021
  • In: Cardiovascular Diabetology. - : BioMed Central. - 1475-2840. ; 20:1
  • Journal article (peer-reviewed)abstract
    • Background: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population.Methods: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684).Results: Kaplan–Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02–1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03–1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02–1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01–1.25, p = 0.04) and HR 1.10; 95% CI 1.01–1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk.Conclusions: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.
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21.
  • Stanaway, Jeffrey D., et al. (author)
  • Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
  • 2018
  • In: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
  • Journal article (peer-reviewed)abstract
    • Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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22.
  • Zhou, Bin, et al. (author)
  • Worldwide trends in diabetes since 1980: A pooled analysis of 751 population-based studies with 4.4 million participants
  • 2016
  • In: The Lancet. - : Elsevier B.V.. - 0140-6736 .- 1474-547X. ; 387:10027, s. 1513-1530
  • Journal article (peer-reviewed)abstract
    • Background: One of the global targets for non-communicable diseases is to halt, by 2025, the rise in the age standardised adult prevalence of diabetes at its 2010 levels. We aimed to estimate worldwide trends in diabetes, how likely it is for countries to achieve the global target, and how changes in prevalence, together with population growth and ageing, are aff ecting the number of adults with diabetes.Methods: We pooled data from population-based studies that had collected data on diabetes through measurement of its biomarkers. We used a Bayesian hierarchical model to estimate trends in diabetes prevalence-defined as fasting plasma glucose of 7.0 mmol/L or higher, or history of diagnosis with diabetes, or use of insulin or oral hypoglycaemic drugs-in 200 countries and territories in 21 regions, by sex and from 1980 to 2014. We also calculated the posterior probability of meeting the global diabetes target if post-2000 trends continue.Findings: We used data from 751 studies including 4372000 adults from 146 of the 200 countries we make estimates for. Global age-standardised diabetes prevalence increased from 4.3% (95% credible interval 2.4-17.0) in 1980 to 9.0% (7.2-11.1) in 2014 in men, and from 5.0% (2.9-7.9) to 7.9% (6.4-9.7) in women. The number of adults with diabetes in the world increased from 108 million in 1980 to 422 million in 2014 (28.5% due to the rise in prevalence, 39.7% due to population growth and ageing, and 31.8% due to interaction of these two factors). Age-standardised adult diabetes prevalence in 2014 was lowest in northwestern Europe, and highest in Polynesia and Micronesia, at nearly 25%, followed by Melanesia and the Middle East and north Africa. Between 1980 and 2014 there was little change in age-standardised diabetes prevalence in adult women in continental western Europe, although crude prevalence rose because of ageing of the population. By contrast, age-standardised adult prevalence rose by 15 percentage points in men and women in Polynesia and Micronesia. In 2014, American Samoa had the highest national prevalence of diabetes (>30% in both sexes), with age-standardised adult prevalence also higher than 25% in some other islands in Polynesia and Micronesia. If post-2000 trends continue, the probability of meeting the global target of halting the rise in the prevalence of diabetes by 2025 at the 2010 level worldwide is lower than 1% for men and is 1% for women. Only nine countries for men and 29 countries for women, mostly in western Europe, have a 50% or higher probability of meeting the global target.Interpretation: Since 1980, age-standardised diabetes prevalence in adults has increased, or at best remained unchanged, in every country. Together with population growth and ageing, this rise has led to a near quadrupling of the number of adults with diabetes worldwide. The burden of diabetes, both in terms of prevalence and number of adults aff ected, has increased faster in low-income and middle-income countries than in high-income countries.
  •  
23.
  • Abbafati, Cristiana, et al. (author)
  • 2020
  • Journal article (peer-reviewed)
  •  
24.
  • Abdalla, H., et al. (author)
  • Gamma-ray blazar spectra with HESS II mono analysis : The case of PKS2155-304 and PG1553+113
  • 2017
  • In: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 600
  • Journal article (peer-reviewed)abstract
    • Context. The addition of a 28 m Cherenkov telescope (CT5) to the H.E.S.S. array extended the experiment's sensitivity to lower energies. The lowest energy threshold is obtained using monoscopic analysis of data taken with CT5, providing access to gamma-ray energies below 100 GeV for small zenith angle observations. Such an extension of the instrument's energy range is particularly beneficial for studies of active galactic nuclei with soft spectra, as expected for those at a redshift >= 0.5. The high-frequency peaked BL Lac objects PKS 2155-304 (z = 0.116) and PG 1553 + 113 (0.43 < z < 0.58) are among the brightest objects in the gamma-ray sky, both showing clear signatures of gamma-ray absorption at E > 100 GeV interpreted as being due to interactions with the extragalactic background light (EBL). Aims. The aims of this work are twofold: to demonstrate the monoscopic analysis of CT5 data with a low energy threshold, and to obtain accurate measurements of the spectral energy distributions (SED) of PKS 2155-304 and PG 1553 + 113 near their SED peaks at energies approximate to 100 GeV. Methods. Multiple observational campaigns of PKS 2155 304 and PG 1553 + 113 were conducted during 2013 and 2014 using the full H.E.S.S. II instrument (CT1-5). A monoscopic analysis of the data taken with the new CT5 telescope was developed along with an investigation into the systematic uncertainties on the spectral parameters which are derived from this analysis. Results. Using the data from CT5, the energy spectra of PKS 2155 304 and PG 1553 + 113 were reconstructed down to conservative threshold energies of 80 GeV for PKS 2155 304, which transits near zenith, and 110 GeV for the more northern PG 1553 + 113. The measured spectra, well fitted in both cases by a log-parabola spectral model ( with a 5.0 similar to statistical preference for non-zero curvature for PKS 2155 304 and 4.5 sigma for PG 1553+113), were found consistent with spectra derived from contemporaneous Fermi-LAT data, indicating a sharp break in the observed spectra of both sources at E approximate to 100 GeV. When corrected for EBL absorption, the intrinsic H.E.S.S. II mono and Fermi-LAT spectrum of PKS 2155 304 was found to show significant curvature. For PG 1553+113, however, no significant detection of curvature in the intrinsic spectrum could be found within statistical and systematic uncertainties.
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25.
  • Amadou, Amina, et al. (author)
  • Prevalent diabetes and risk of total, colorectal, prostate and breast cancers in an ageing population : meta-analysis of individual participant data from cohorts of the CHANCES consortium
  • 2021
  • In: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 124:11, s. 1882-1890
  • Journal article (peer-reviewed)abstract
    • Background: We investigated whether associations between prevalent diabetes and cancer risk are pertinent to older adults and whether associations differ across subgroups of age, body weight status or levels of physical activity.Methods: We harmonised data from seven prospective cohort studies of older individuals in Europe and the United States participating in the CHANCES consortium. Cox proportional hazard regression was used to estimate the associations of prevalent diabetes with cancer risk (all cancers combined, and for colorectum, prostate and breast). We calculated summary risk estimates across cohorts using pooled analysis and random-effects meta-analysis.Results: A total of 667,916 individuals were included with an overall median (P25–P75) age at recruitment of 62.3 (57–67) years. During a median follow-up time of 10.5 years, 114,404 total cancer cases were ascertained. Diabetes was not associated with the risk of all cancers combined (hazard ratio (HR) = 0.94; 95% confidence interval (CI): 0.86–1.04; I2 = 63.3%). Diabetes was positively associated with colorectal cancer risk in men (HR = 1.17; 95% CI: 1.08–1.26; I2 = 0%) and a similar HR in women (1.13; 95% CI: 0.82–1.56; I2 = 46%), but with a confidence interval including the null. Diabetes was inversely associated with prostate cancer risk (HR = 0.81; 95% CI: 0.77–0.85; I2 = 0%), but not with postmenopausal breast cancer (HR = 0.96; 95% CI: 0.89–1.03; I2 = 0%). In exploratory subgroup analyses, diabetes was inversely associated with prostate cancer risk only in men with overweight or obesity.Conclusions: Prevalent diabetes was positively associated with colorectal cancer risk and inversely associated with prostate cancer risk in older Europeans and Americans.
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26.
  • Anzt, Hartwig, et al. (author)
  • An environment for sustainable research software in Germany and beyond: current state, open challenges, and call for action
  • 2020
  • In: F1000 Research. - : F1000 Research Ltd. - 2046-1402. ; 9
  • Journal article (peer-reviewed)abstract
    • Research software has become a central asset in academic research. It optimizes existing and enables new research methods, implements and embeds research knowledge, and constitutes an essential research product in itself. Research software must be sustainable in order to understand, replicate, reproduce, and build upon existing research or conduct new research effectively. In other words, software must be available, discoverable, usable, and adaptable to new needs, both now and in the future. Research software therefore requires an environment that supports sustainability. Hence, a change is needed in the way research software development and maintenance are currently motivated, incentivized, funded, structurally and infrastructurally supported, and legally treated. Failing to do so will threaten the quality and validity of research. In this paper, we identify challenges for research software sustainability in Germany and beyond, in terms of motivation, selection, research software engineering personnel, funding, infrastructure, and legal aspects. Besides researchers, we specifically address political and academic decision-makers to increase awareness of the importance and needs of sustainable research software practices. In particular, we recommend strategies and measures to create an environment for sustainable research software, with the ultimate goal to ensure that software-driven research is valid, reproducible and sustainable, and that software is recognized as a first class citizen in research. This paper is the outcome of two workshops run in Germany in 2019, at deRSE19 - the first International Conference of Research Software Engineers in Germany - and a dedicated DFG-supported follow-up workshop in Berlin.
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27.
  • Ben-Menachem, Elinor, 1945, et al. (author)
  • Topiramate monotherapy in the treatment of newly or recently diagnosed epilepsy.
  • 2008
  • In: Clinical therapeutics. - 0149-2918. ; 30:7, s. 1180-95
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The efficacy of topiramate (TPM) as an adjunctive treatment for epilepsy has been established in placebo-controlled clinical trials. Clinical trials of antiepileptic monotherapy usually evaluate low and high doses of study drug or compare study drug with another active agent. OBJECTIVE: This article reviews available evidence for the use of TPM as monotherapy in patients with newly or recently diagnosed epilepsy. METHODS: A search of MEDLINE, EMBASE, BIOSIS, SCISEARCH, and the Cochrane Database of Systematic Reviews (all years) for reports of controlled trials of TPM monotherapy in patients with recently diagnosed (within the previous 3 years) epilepsy was conducted in January 2008 using the terms topiramate, epilepsy, newly diagnosed, recently diagnosed, and monotherapy. Identified trials were included in the review if they were published in peer-reviewed journals and enrolled > or = 20 patients. RESULTS: Three randomized, double-blind, controlled trials met the criteria for inclusion in the review. In a comparison of TPM 50 and 500 mg/d, the higher dose was associated with significantly greater freedom from seizures at 6 months compared with the lower dose (54% vs 39%, respectively; P = 0.02). The time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.015). In a comparison of TPM 50 and 400 mg/d, the time to first seizure was significantly longer with the higher dose compared with the lower dose (P<0.001, Kaplan-Meier analysis), and the probability of 12-month seizure freedom was significantly higher (76% vs 59%, respectively; P = 0.001). Again, the time to first seizure was significantly associated with mean plasma TPM concentrations (P = 0.029). In a comparative study of TPM 100 and 200 mg/d, carbamazepine 600 mg/d, and valproate 1250 mg/d, there was no significant difference in rates of 6-month seizure freedom with TPM 100 and 200 mg/d (49% and 44%, respectively), carbamazepine (44%), and valproate (44%). Adverse events in the 3 studies were similar between TPM dose groups, although the incidence generally increased with increasing doses, occurred early in treatment, and decreased with prolonged therapy. In a pooled analysis of the 3 trials, the most commonly occurring adverse events during dose titration were paresthesia (25%), fatigue (16%), dizziness (13%), somnolence (13%), and nausea (10%); the most frequent adverse events during maintenance therapy were headache (20%), decreased appetite (11%), and weight loss (11%). CONCLUSION: In the 3 studies reviewed, TPM monotherapy was effective and generally well tolerated in patients with newly diagnosed epilepsy.
  •  
28.
  • Beniczky, Sandor, et al. (author)
  • Standardized Computer-based Organized Reporting of EEG: SCORE
  • 2013
  • In: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 54:6, s. 1112-1124
  • Journal article (peer-reviewed)abstract
    • The electroencephalography (EEG) signal has a high complexity, and the process of extracting clinically relevant features is achieved by visual analysis of the recordings. The interobserver agreement in EEG interpretation is only moderate. This is partly due to the method of reporting the findings in free-text format. The purpose of our endeavor was to create a computer-based system for EEG assessment and reporting, where the physicians would construct the reports by choosing from predefined elements for each relevant EEG feature, as well as the clinical phenomena (for video-EEG recordings). A working group of EEG experts took part in consensus workshops in Dianalund, Denmark, in 2010 and 2011. The faculty was approved by the Commission on European Affairs of the International League Against Epilepsy (ILAE). The working group produced a consensus proposal that went through a pan-European review process, organized by the European Chapter of the International Federation of Clinical Neurophysiology. The Standardised Computer-based Organised Reporting of EEG (SCORE) software was constructed based on the terms and features of the consensus statement and it was tested in the clinical practice. The main elements of SCORE are the following: personal data of the patient, referral data, recording conditions, modulators, background activity, drowsiness and sleep, interictal findings, episodes (clinical or subclinical events), physiologic patterns, patterns of uncertain significance, artifacts, polygraphic channels, and diagnostic significance. The following specific aspects of the neonatal EEGs are scored: alertness, temporal organization, and spatial organization. For each EEG finding, relevant features are scored using predefined terms. Definitions are provided for all EEG terms and features. SCORE can potentially improve the quality of EEG assessment and reporting; it will help incorporate the results of computer-assisted analysis into the report, it will make possible the build-up of a multinational database, and it will help in training young neurophysiologists.
  •  
29.
  • Beniczky, Sándor, et al. (author)
  • Standardized computer-based organized reporting of EEG : SCORE - Second version
  • 2017
  • In: Clinical Neurophysiology. - : Elsevier BV. - 1388-2457. ; 128:11, s. 2334-2346
  • Journal article (peer-reviewed)abstract
    • Standardized terminology for computer-based assessment and reporting of EEG has been previously developed in Europe. The International Federation of Clinical Neurophysiology established a taskforce in 2013 to develop this further, and to reach international consensus. This work resulted in the second, revised version of SCORE (Standardized Computer-based Organized Reporting of EEG), which is presented in this paper. The revised terminology was implemented in a software package (SCORE EEG), which was tested in clinical practice on 12,160 EEG recordings. Standardized terms implemented in SCORE are used to report the features of clinical relevance, extracted while assessing the EEGs. Selection of the terms is context sensitive: initial choices determine the subsequently presented sets of additional choices. This process automatically generates a report and feeds these features into a database. In the end, the diagnostic significance is scored, using a standardized list of terms. SCORE has specific modules for scoring seizures (including seizure semiology and ictal EEG patterns), neonatal recordings (including features specific for this age group), and for Critical Care EEG Terminology. SCORE is a useful clinical tool, with potential impact on clinical care, quality assurance, data-sharing, research and education.
  •  
30.
  • Betti, Marco, et al. (author)
  • Manipulating photorespiration to increase plant productivity : recent advances and perspectives for crop improvement
  • 2016
  • In: Journal of Experimental Botany. - : Oxford University Press (OUP). - 0022-0957 .- 1460-2431. ; 67:10, s. 2977-2988
  • Research review (peer-reviewed)abstract
    • Recycling of the 2-phosphoglycolate generated by the oxygenase reaction of Rubisco requires a complex and energy-consuming set of reactions collectively known as the photorespiratory cycle. Several approaches aimed at reducing the rates of photorespiratory energy or carbon loss have been proposed, based either on screening for natural variation or by means of genetic engineering. Recent work indicates that plant yield can be substantially improved by the alteration of photorespiratory fluxes or by engineering artificial bypasses to photorespiration. However, there is also evidence indicating that, under certain environmental and/or nutritional conditions, reduced photorespiratory capacity may be detrimental to plant performance. Here we summarize recent advances obtained in photorespiratory engineering and discuss prospects for these advances to be transferred to major crops to help address the globally increasing demand for food and biomass production.
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31.
  • Blaudeck, Thomas, et al. (author)
  • Biocomputation Using Molecular Agents Moving in Microfluidic Channel Networks : An Alternative Platform for Information Technology
  • 2022
  • In: Cyber-Physical Systems : Intelligent Models and Algorithms - Intelligent Models and Algorithms. - Cham : Springer International Publishing. - 2198-4190 .- 2198-4182. - 9783030951153 - 9783030951160 ; 417, s. 15-27
  • Book chapter (peer-reviewed)abstract
    • Deficiencies in software or computer chips cause computers or smartphones to crash and allow hackers to steal passwords. Automated test procedures could avoid these problems. However, the computing power and cooling requirements of conventional computers increase exponentially with the size of the problem, so that the technological limits for solving these problems will soon be reached. The EU project Bio4Comp aims to develop concepts for a bio-computer to help overcome these two main problems. Compared to conventional computers, computers based on biological molecular motors only consume a fraction of the energy per arithmetic operation and scale very well for problems that can be parallelized (“multitasking”). In this article, the topic network-based biocomputation (NBC) i.e. computing with biological molecules as agents that are driven by molecular motors in microfluidic networks, is presented as an alternative approach to computing, data processing, and information technology.
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32.
  • Burmester, Gerd, et al. (author)
  • The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel
  • 2011
  • In: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 70:5, s. 818-822
  • Journal article (peer-reviewed)abstract
    • Introduction Given the safety issues of nonsteroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease. Methods Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications. Results All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered. Discussion The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile.
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33.
  • Chen, Jing, et al. (author)
  • Low-bias phosphopeptide enrichment from scarce samples using plastic antibodies
  • 2015
  • In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 5
  • Journal article (peer-reviewed)abstract
    • Phosphospecific enrichment techniques and mass spectrometry (MS) are essential tools for comprehending the cellular phosphoproteome. Here, we report a fast and simple approach for low sequence-bias phosphoserine (pS) peptide capture and enrichment that is compatible with low biological or clinical sample input. The approach exploits molecularly imprinted polymers (MIPs, "plastic antibodies") featuring tight neutral binding sites for pS or pY that are capable of cross-reacting with phosphopeptides of protein proteolytic digests. The versatility of the resulting method was demonstrated with small samples of whole-cell lysate from human embryonic kidney (HEK) 293T cells, human neuroblastoma SH-SY5Y cells, mouse brain or human cerebrospinal fluid (CSF). Following pre-fractionation of trypsinized proteins by strong cation exchange (SCX) chromatography, pS-MIP enrichment led to the identification of 924 phosphopeptides in the HEK 293T whole-cell lysate, exceeding the number identified by TiO2-based enrichment (230). Moreover, the phosphopeptides were extracted with low sequence bias and showed no evidence for the characteristic preference of TiO2 for acidic amino acids (aspartic and glutamic acid). Applying the method to human CSF led to the discovery of 47 phosphopeptides belonging to 24 proteins and revealed three previously unknown phosphorylation sites.
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34.
  • Cunnea, Paula M, et al. (author)
  • ERdj5, an endoplasmic reticulum (ER)-resident protein containing DnaJ and thioredoxin domains, is expressed in secretory cells or following ER stress.
  • 2003
  • In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 278:2, s. 1059-66
  • Journal article (peer-reviewed)abstract
    • A complex array of chaperones and enzymes reside in the endoplasmic reticulum (ER) to assist the folding and assembly of and the disulfide bond formation in nascent secretory proteins. Here we characterize a novel human putative ER co-chaperone (ERdj5) containing domains resembling DnaJ, protein-disulfide isomerase, and thioredoxin domains. Homologs of ERdj5 have been found in Caenorhabditis elegans and Mus musculus. In vitro experiments demonstrated that ERdj5 interacts via its DnaJ domain with BiP in an ATP-dependent manner. ERdj5 is a ubiquitous protein localized in the ER and is particularly abundant in secretory cells. Its transcription is induced during ER stress, suggesting potential roles for ERdj5 in protein folding and translocation across the ER membrane.
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35.
  • Di Angelantonio, Emanuele, et al. (author)
  • Association of Cardiometabolic Multimorbidity With Mortality : The Emerging Risk Factors Collaboration
  • 2015
  • In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 314:1, s. 52-60
  • Journal article (peer-reviewed)abstract
    • IMPORTANCE The prevalence of cardiometabolic multimorbidity is increasing.OBJECTIVE To estimate reductions in life expectancy associated with cardiometabolic multimorbidity.DESIGN, SETTING, AND PARTICIPANTS Age-and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI).MAIN OUTCOMES AND MEASURES All-cause mortality and estimated reductions in life expectancy.RESULTS In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy.CONCLUSIONS AND RELEVANCE Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.
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36.
  • Durr, Hermann A., et al. (author)
  • A Closer Look Into Magnetism : Opportunities With Synchrotron Radiation
  • 2009
  • In: IEEE transactions on magnetics. - 0018-9464 .- 1941-0069. ; 45:1, s. 15-57
  • Research review (peer-reviewed)abstract
    • The unique properties of synchrotron radiation, such as broad energy spectrum, variable light polarization, and flexible time structure, have made it an enormously powerful tool in the study of magnetic phenomena and materials. The refinement of experimental techniques has led to many new research opportunities, keeping up with the challenges put up by modern magnetism research. In this contribution, we review some of the recent developments in the application of synchrotron radiation and particularly soft X-rays to current problems in magnetism, and we discuss future perspectives.
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37.
  • Edlbauer, Hermann, et al. (author)
  • Semiconductor-based electron flying qubits: review on recent progress accelerated by numerical modelling
  • 2022
  • In: EPJ Quantum Technology. - : Springer Science and Business Media LLC. - 2196-0763 .- 2662-4400. ; 9:1
  • Research review (peer-reviewed)abstract
    • The progress of charge manipulation in semiconductor-based nanoscale devices opened up a novel route to realise a flying qubit with a single electron. In the present review, we introduce the concept of these electron flying qubits, discuss their most promising realisations and show how numerical simulations are applicable to accelerate experimental development cycles. Addressing the technological challenges of flying qubits that are currently faced by academia and quantum enterprises, we underline the relevance of interdisciplinary cooperation to move emerging quantum industry forward. The review consists of two main sections: Pathways towards the electron flying qubit: We address three routes of single-electron transport in GaAs-based devices focusing on surface acoustic waves, hot-electron emission from quantum dot pumps and Levitons. For each approach, we discuss latest experimental results and point out how numerical simulations facilitate engineering the electron flying qubit. Numerical modelling of quantum devices: We review the full stack of numerical simulations needed for fabrication of the flying qubits. Choosing appropriate models, examples of basic quantum mechanical simulations are explained in detail. We discuss applications of open-source (KWANT) and the commercial (nextnano) platforms for modelling the flying qubits. The discussion points out the large relevance of software tools to design quantum devices tailored for efficient operation.
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38.
  • Ferreira, Monica E, et al. (author)
  • Mechanism of transcription factor recruitment by acidic activators
  • 2005
  • In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 280:23, s. 21779-21784
  • Journal article (peer-reviewed)abstract
    • Many transcriptional activators are intrinsically unstructured yet display unique, defined conformations when bound to target proteins. Target-induced folding provides a mechanism by which activators could form specific interactions with an array of structurally unrelated target proteins. Evidence for such a binding mechanism has been reported previously in the context of the interaction between the cancer-related c-Myc protein and the TATA-binding protein, which can be modeled as a two-step process in which a rapidly forming, low affinity complex slowly converts to a more stable form, consistent with a coupled binding and folding reaction. To test the generality of the target-induced folding model, we investigated the binding of two widely studied acidic activators, Gal4 and VP16, to a set of target proteins, including TATA-binding protein and the Swi1 and Snf5 subunits of the Swi/Snf chromatin remodeling complex. Using surface plasmon resonance, we show that these activator-target combinations also display bi-phasic kinetics suggesting two distinct steps. A fast initial binding phase that is inhibited by high ionic strength is followed by a slow phase that is favored by increased temperature. In all cases, overall affinity increases with temperature and, in most cases, with increased ionic strength. These results are consistent with a general mechanism for recruitment of transcriptional components to promoters by naturally occurring acidic activators, by which the initial contact is mediated predominantly through electrostatic interactions, whereas subsequent target-induced folding of the activator results in a stable complex.
  •  
39.
  • Flinn, Elizabeth M, et al. (author)
  • Recruitment of Gen5-containing complexes during c-Myc-dependent gene activation - Structure and function aspects
  • 2002
  • In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 277:26, s. 23399-23406
  • Journal article (peer-reviewed)abstract
    • The N-terminal domain of c-Myc plays a key role in cellular transformation and is involved in both activation and repression of target genes as well as in modulated proteolysis of c-Myc via the proteasome. Given this functional complexity, it has been difficult to clarify the structures within the N terminus that contribute to these different processes as well as the mechanisms by which they function. We have used a simplified yeast model system to identify the primary determinants within the N terminus for W chromatin remodeling of a promoter, (ii) gene activation from a chromatin template in vivo, and (iii) interaction with highly purified Gcn5 complexes as well as other chromatin-remodeling complexes in vitro. The results identify two regions that contain autonomous chromatin opening and gene activation activity, but both regions are required for efficient interaction with chromatin-remodeling complexes in vitro. The conserved Myc boxes do not play a direct role in gene activation, and Myc box II is not generally required for in vitro interactions with remodeling complexes. The yeast SAGA complex, which is orthologous to the human GCN5-TRRAP complex that interacts with Myc in human cells, plays a role in Myc-mediated chromatin opening at the promoter but may also be involved in later steps of gene activation.
  •  
40.
  • Forouzanfar, Mohammad H, et al. (author)
  • Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013 : a systematic analysis for the Global Burden of Disease Study 2013.
  • 2015
  • In: The Lancet. - 0140-6736 .- 1474-547X. ; 386:10010, s. 2287-2323
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution.METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol.FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa.INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks.FUNDING: Bill & Melinda Gates Foundation.
  •  
41.
  • Gaziano, Liam, et al. (author)
  • Mild-to-moderate kidney dysfunction and cardiovascular disease : Observational and mendelian randomization analyses
  • 2022
  • In: Circulation. - : Wolters Kluwer. - 0009-7322 .- 1524-4539. ; 146:20, s. 1507-1517
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke.METHODS: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank.RESULTS: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD.CONCLUSIONS: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.
  •  
42.
  • Gorski, Mathias, et al. (author)
  • Genetic loci and prioritization of genes for kidney function decline derived from a meta-analysis of 62 longitudinal genome-wide association studies
  • 2022
  • In: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 102:3, s. 624-639
  • Journal article (peer-reviewed)abstract
    • Estimated glomerular filtration rate (eGFR) reflects kidney function. Progressive eGFR-decline can lead to kidney failure, necessitating dialysis or transplantation. Hundreds of loci from genome-wide association studies (GWAS) for eGFR help explain population cross section variability. Since the contribution of these or other loci to eGFR-decline remains largely unknown, we derived GWAS for annual eGFR-decline and meta-analyzed 62 longitudinal studies with eGFR assessed twice over time in all 343,339 individuals and in high-risk groups. We also explored different covariate adjustment. Twelve genomewide significant independent variants for eGFR-decline unadjusted or adjusted for eGFR- baseline (11 novel, one known for this phenotype), including nine variants robustly associated across models were identified. All loci for eGFR-decline were known for cross-sectional eGFR and thus distinguished a subgroup of eGFR loci. Seven of the nine variants showed variant- by-age interaction on eGFR cross section (further about 350,000 individuals), which linked genetic associations for eGFR-decline with agedependency of genetic cross- section associations. Clinically important were two to four-fold greater genetic effects on eGFR-decline in high-risk subgroups. Five variants associated also with chronic kidney disease progression mapped to genes with functional in- silico evidence (UMOD, SPATA7, GALNTL5, TPPP). An unfavorable versus favorable nine-variant genetic profile showed increased risk odds ratios of 1.35 for kidney failure (95% confidence intervals 1.03- 1.77) and 1.27 for acute kidney injury (95% confidence intervals 1.08-1.50) in over 2000 cases each, with matched controls). Thus, we provide a large data resource, genetic loci, and prioritized genes for kidney function decline, which help inform drug development pipelines revealing important insights into the age-dependency of kidney function genetics.
  •  
43.
  • Gorski, Mathias, et al. (author)
  • Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
  • 2021
  • In: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
  • Journal article (peer-reviewed)abstract
    • Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
  •  
44.
  • Günther, René, et al. (author)
  • Alteration of Mitochondrial Integrity as Upstream Event in the Pathophysiology of SOD1-ALS
  • 2022
  • In: Cells. - : MDPI. - 2073-4409. ; 11:7
  • Journal article (peer-reviewed)abstract
    • Little is known about the early pathogenic events by which mutant superoxide dismutase 1 (SOD1) causes amyotrophic lateral sclerosis (ALS). This lack of mechanistic understanding is a major barrier to the development and evaluation of efficient therapies. Although protein aggregation is known to be involved, it is not understood how mutant SOD1 causes degeneration of motoneurons (MNs). Previous research has relied heavily on the overexpression of mutant SOD1, but the clinical relevance of SOD1 overexpression models remains questionable. We used a human induced pluripotent stem cell (iPSC) model of spinal MNs and three different endogenous ALS-associated SOD1 mutations (D90Ahom, R115Ghet or A4Vhet) to investigate early cellular disturbances in MNs. Although enhanced misfolding and aggregation of SOD1 was induced by proteasome inhibition, it was not affected by activation of the stress granule pathway. Interestingly, we identified loss of mitochondrial, but not lysosomal, integrity as the earliest common pathological phenotype, which preceded elevated levels of insoluble, aggregated SOD1. A super-elongated mitochondrial morphology with impaired inner mitochondrial membrane potential was a unifying feature in mutant SOD1 iPSC-derived MNs. Impaired mitochondrial integrity was most prominent in mutant D90Ahom MNs, whereas both soluble disordered and detergent-resistant misfolded SOD1 was more prominent in R115Ghet and A4Vhet mutant lines. Taking advantage of patient-specific models of SOD1-ALS in vitro, our data suggest that mitochondrial dysfunction is one of the first crucial steps in the pathogenic cascade that leads to SOD1-ALS and also highlights the need for individualized medical approaches for SOD1-ALS.
  •  
45.
  • Gösweiner, Christian, et al. (author)
  • Tuning Nuclear Quadrupole Resonance : A Novel Approach for the Design of Frequency-Selective MRI Contrast Agents
  • 2018
  • In: Physical Review X. - : American Physical Society. - 2160-3308. ; 8:2
  • Journal article (peer-reviewed)abstract
    • The interaction between water protons and suitable quadrupolar nuclei (QN) can lead to quadrupole relaxation enhancement (QRE) of proton spins, provided the resonance condition between both spin transitions is fulfilled. This effect could be utilized as a frequency selective mechanism in novel, responsive T-1 shortening contrast agents (CAs) for magnetic resonance imaging (MRI). In particular, the proposed contrast mechanism depends on the applied external flux density-a property that can be exploited by special field-cycling MRI scanners. For the design of efficient CA molecules, exhibiting narrow and pronounced peaks in the proton T-1 relaxation dispersion, the nuclear quadrupole resonance (NQR) properties, as well as the spin dynamics of the system QN-H-1, have to be well understood and characterized for the compounds in question. In particular, the energy-level structure of the QN is a central determinant for the static flux densities at which the contrast enhancement appears. The energy levels depend both on the QN and the electronic environment, i.e., the chemical bonding structure in the CA molecule. In this work, the NQR properties of a family of promising organometallic compounds containing Bi-209 as QN have been characterized. Important factors like temperature, chemical structure, and chemical environment have been considered by NQR spectroscopy and ab initio quantum chemistry calculations. The investigated Bi-aryl compounds turned out to fulfill several crucial requirements: NQR transition frequency range applicable to clinical 1.5- and 3 T MRI systems, low temperature dependency, low toxicity, and tunability in frequency by chemical modification.
  •  
46.
  • Hasse, Dirk, et al. (author)
  • Alternative splicing produces an H-protein with better substrate properties for the P-protein of glycine decarboxylase.
  • 2009
  • In: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 276:23
  • Journal article (peer-reviewed)abstract
    • Several thousand plant genes are known to produce multiple transcripts, but the precise function of most of the alternatively encoded proteins is not known. Alternative splicing has been reported for the H-protein subunit of glycine decarboxylase in the genus Flaveria. H-protein has no catalytic activity itself but is a substrate of the three enzymatically active subunits, P-, T- and L-protein. In C(4) species of Flaveria, two H-proteins originate from single genes in an organ-dependent manner. Here, we report on differences between the two alternative H-protein variants with respect to their interaction with the glycine-decarboxylating subunit, P-protein. Steady-state kinetic analyses of the alternative Flaveria H-proteins and artificially produced 'alternative' Arabidopsis H-proteins, using either pea mitochondrial matrix extracts or recombinant cyanobacterial P-protein, consistently demonstrate that the alternative insertion of two alanine residues at the N-terminus of the H-protein elevates the activity of P-protein by 20%in vitro, and could promote glycine decarboxylase activity in vivo.
  •  
47.
  • Hasse, Dirk, et al. (author)
  • Properties of recombinant glycine decarboxylase P- and H-protein subunits from the cyanobacterium Synechocystis sp. strain PCC 6803.
  • 2007
  • In: FEBS Letters. - : Wiley. - 0014-5793 .- 1873-3468. ; 581:7
  • Journal article (peer-reviewed)abstract
    • The multi-enzyme complex glycine decarboxylase is important for one-carbon metabolism, essential for the photorespiratory glycolate cycle of plants, and comprises four different polypeptides, P-, H-, T-, and L-protein. We report on the production and properties of recombinant P-protein from the cyanobacterium Synechocystis and also describe features of recombinant H-protein from the same organism. The P-protein shows enzymatic activity with lipoylated H-protein and very low activity with H-apoprotein or lipoate as artificial cofactors. Its affinity towards glycine is unaffected by the presence and nature of the methyleneamine acceptor molecule. The cyanobacterial H-protein apparently forms stable dimers.
  •  
48.
  • Hermann, Stefan, et al. (author)
  • Calcium regulation of basic helix-loop-helix transcription factors
  • 1998
  • In: Cell Calcium. - : Elsevier. - 0143-4160 .- 1532-1991. ; 23:2-3, s. 135-142
  • Journal article (peer-reviewed)abstract
    • The basic helix-loop-helix (bHLH) family of transcription factors is essential for numerous developmental and growth control processes. The regulation of bHLH proteins occurs at many levels, including tissue specific expression, differential oligomerization and DNA binding specificities, interaction with negatively acting HLH proteins and post-translational modifications. This review focuses on what is emerging as another level of bHLH protein regulation, calcium regulation through interaction with Ca2+ loaded calmodulin and S-100 proteins. The mechanism and implications of these Ca2+ regulated interactions are discussed.
  •  
49.
  • Hermann, Stefan, et al. (author)
  • How transcriptional activators bind target proteins
  • 2001
  • In: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 276:43, s. 40127-40132
  • Journal article (peer-reviewed)abstract
    • The product of the proto-oncogene c-myc influences many cellular processes through the regulation of specific target genes. Through its transactivation domain (TAD), c-Myc protein interacts with several transcription factors, including TATA-binding protein (TBP). We present data that suggest that in contrast to some other transcriptional activators, an extended length of the c-Myc TAD is required for its binding to TBP. Our data also show that this interaction is a multistep process, in which a rapidly forming low affinity complex slowly converts to a more stable form. The initial complex formation results from ionic or polar interactions, whereas the slow conversion to a more stable form is hydrophobic in nature. Based on our results, we suggest two alternative models for activation domain/target protein interactions, which together provide a single universal paradigm for understanding activator-target factor interactions.
  •  
50.
  • Jansen, Willemijn J, et al. (author)
  • Prevalence Estimates of Amyloid Abnormality Across the Alzheimer Disease Clinical Spectrum.
  • 2022
  • In: JAMA neurology. - : American Medical Association (AMA). - 2168-6157 .- 2168-6149. ; 79:3, s. 228-243
  • Journal article (peer-reviewed)abstract
    • One characteristic histopathological event in Alzheimer disease (AD) is cerebral amyloid aggregation, which can be detected by biomarkers in cerebrospinal fluid (CSF) and on positron emission tomography (PET) scans. Prevalence estimates of amyloid pathology are important for health care planning and clinical trial design.To estimate the prevalence of amyloid abnormality in persons with normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia and to examine the potential implications of cutoff methods, biomarker modality (CSF or PET), age, sex, APOE genotype, educational level, geographical region, and dementia severity for these estimates.This cross-sectional, individual-participant pooled study included participants from 85 Amyloid Biomarker Study cohorts. Data collection was performed from January 1, 2013, to December 31, 2020. Participants had normal cognition, subjective cognitive decline, mild cognitive impairment, or clinical AD dementia. Normal cognition and subjective cognitive decline were defined by normal scores on cognitive tests, with the presence of cognitive complaints defining subjective cognitive decline. Mild cognitive impairment and clinical AD dementia were diagnosed according to published criteria.Alzheimer disease biomarkers detected on PET or in CSF.Amyloid measurements were dichotomized as normal or abnormal using cohort-provided cutoffs for CSF or PET or by visual reading for PET. Adjusted data-driven cutoffs for abnormal amyloid were calculated using gaussian mixture modeling. Prevalence of amyloid abnormality was estimated according to age, sex, cognitive status, biomarker modality, APOE carrier status, educational level, geographical location, and dementia severity using generalized estimating equations.Among the 19097 participants (mean [SD] age, 69.1 [9.8] years; 10148 women [53.1%]) included, 10139 (53.1%) underwent an amyloid PET scan and 8958 (46.9%) had an amyloid CSF measurement. Using cohort-provided cutoffs, amyloid abnormality prevalences were similar to 2015 estimates for individuals without dementia and were similar across PET- and CSF-based estimates (24%; 95% CI, 21%-28%) in participants with normal cognition, 27% (95% CI, 21%-33%) in participants with subjective cognitive decline, and 51% (95% CI, 46%-56%) in participants with mild cognitive impairment, whereas for clinical AD dementia the estimates were higher for PET than CSF (87% vs 79%; mean difference, 8%; 95% CI, 0%-16%; P=.04). Gaussian mixture modeling-based cutoffs for amyloid measures on PET scans were similar to cohort-provided cutoffs and were not adjusted. Adjusted CSF cutoffs resulted in a 10% higher amyloid abnormality prevalence than PET-based estimates in persons with normal cognition (mean difference, 9%; 95% CI, 3%-15%; P=.004), subjective cognitive decline (9%; 95% CI, 3%-15%; P=.005), and mild cognitive impairment (10%; 95% CI, 3%-17%; P=.004), whereas the estimates were comparable in persons with clinical AD dementia (mean difference, 4%; 95% CI, -2% to 9%; P=.18).This study found that CSF-based estimates using adjusted data-driven cutoffs were up to 10% higher than PET-based estimates in people without dementia, whereas the results were similar among people with dementia. This finding suggests that preclinical and prodromal AD may be more prevalent than previously estimated, which has important implications for clinical trial recruitment strategies and health care planning policies.
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