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  • Nyholm, Tufve, et al. (författare)
  • A national approach for automated collection of standardized and population-based radiation therapy data in Sweden
  • 2016
  • Ingår i: Radiotherapy and Oncology. - Elsevier. - 0167-8140. ; 119:2, s. 344-350
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose To develop an infrastructure for structured and automated collection of interoperable radiation therapy (RT) data into a national clinical quality registry. Materials and methods The present study was initiated in 2012 with the participation of seven of the 15 hospital departments delivering RT in Sweden. A national RT nomenclature and a database for structured unified storage of RT data at each site (Medical Information Quality Archive, MIQA) have been developed. Aggregated data from the MIQA databases are sent to a national RT registry located on the same IT platform (INCA) as the national clinical cancer registries. Results The suggested naming convention has to date been integrated into the clinical workflow at 12 of 15 sites, and MIQA is installed at six of these. Involvement of the remaining 3/15 RT departments is ongoing, and they are expected to be part of the infrastructure by 2016. RT data collection from ARIA®, Mosaiq®, Eclipse™, and Oncentra® is supported. Manual curation of RT-structure information is needed for approximately 10% of target volumes, but rarely for normal tissue structures, demonstrating a good compliance to the RT nomenclature. Aggregated dose/volume descriptors are calculated based on the information in MIQA and sent to INCA using a dedicated service (MIQA2INCA). Correct linkage of data for each patient to the clinical cancer registries on the INCA platform is assured by the unique Swedish personal identity number. Conclusions An infrastructure for structured and automated prospective collection of syntactically interoperable RT data into a national clinical quality registry for RT data is under implementation. Future developments include adapting MIQA to other treatment modalities (e.g. proton therapy and brachytherapy) and finding strategies to harmonize structure delineations. How the RT registry should comply with domain-specific ontologies such as the Radiation Oncology Ontology (ROO) is under discussion.
  • Bach, Anders, et al. (författare)
  • A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage
  • 2012
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - National Academy of Sciences. - 0027-8424. ; 109:9, s. 3317-3322
  • Tidskriftsartikel (refereegranskat)abstract
    • Inhibition of the ternary protein complex of the synaptic scaffolding protein postsynaptic density protein-95 (PSD-95), neuronal nitric oxide synthase (nNOS), and the N-methyl-D-aspartate (NMDA) receptor is a potential strategy for treating ischemic brain damage, but high-affinity inhibitors are lacking. Here we report the design and synthesis of a novel dimeric inhibitor, Tat-NPEG4(IETDV)(2) (Tat-N-dimer), which binds the tandem PDZ1-2 domain of PSD-95 with an unprecedented high affinity of 4.6 nM, and displays extensive protease-resistance as evaluated in vitro by stability-measurements in human blood plasma. X-ray crystallography, NMR, and small-angle X-ray scattering (SAXS) deduced a true bivalent interaction between dimeric inhibitor and PDZ1-2, and also provided a dynamic model of the conformational changes of PDZ1-2 induced by the dimeric inhibitor. A single intravenous injection of Tat-N-dimer (3 nmol/g) to mice subjected to focal cerebral ischemia reduces infarct volume with 40% and restores motor functions. Thus, Tat-N-dimer is a highly efficacious neuroprotective agent with therapeutic potential in stroke.
  • Bach, Anders, et al. (författare)
  • Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction
  • 2009
  • Ingår i: Angewandte Chemie International Edition. - Wiley-VCH. - 1433-7851 .- 1521-3773. ; 48:51, s. 9685-9689
  • Tidskriftsartikel (refereegranskat)abstract
    • On the double: Dimerization of monomeric peptide ligands towards the PDZ domains of the protein PSD-95 (postsynaptic density 95) leads to potent inhibitors of protein-protein interactions with stability in blood plasma. Optimization of the length of the polyethylene glycol linker results in unprecedented affinity for inhibitors of the PDZ1-2 domain.
  • Behrens, Anders, et al. (författare)
  • The Computerized General Neuropsychological INPH Test (CoGNIT) revealed improvement in Idiopathic Normal Pressure Hydrocephalus (INPH) after shunt surgery
  • ????
  • Annan publikation (övrigt vetenskapligt)abstract
    • BackgroundWe have developed the COmputerized General Neuropsychological INPH Test (CoGNIT) dedicated for patients with idiopathic normal pressure hydrocephalus (INPH). Previously, validity and reliability of included tests have been established. The aim was to evaluate the battery’s sensitivity to detect cognitive changes after shunt surgery in INPH patients.MethodsPreoperatively, thirty-one INPH patients were given CoGNIT, which includes tests assessing memory, executive functions, attention, manual dexterity and psychomotor speed. CoGNIT also includes the Geriatric Depression Scale (GDS). Re-examination was done four months after shunt surgery. Scores and test completion were examined and compared to healthy elderly (n=44).ResultsPreoperative INPH test results were significantly lower in all tests compared to healthy. Improvements after shunt surgery were seen in all cognitive domains: memory (Ten-word list test, p<0,01), executive functions (Stroop incongruent, (p<0.05), attention (Two choice reaction test, p<0.01), psychomotor speed (Stroop congruent, p<0.05) and manual dexterity (Four- finger tapping, p<0.01). No ceiling effects were observed. Depressive symptoms were more common in INPH versus healthy and did not change postoperatively. Preoperatively 81 % of INPH patients completed at least eight of the nine included test.ConclusionsCoGNIT is sensitive to cognitive impairment and to investigate changes after shunt surgery in INPH. Completion rates are good. CoGNIT has a potential to be useful in the cognitive assessment of INPH. 
  • Chi, Celestine N., et al. (författare)
  • Deciphering the kinetic binding mechanism of dimeric ligands, using a potent plasma-stable dimeric inhibitor of postsynaptic density protein-95 as an example
  • 2010
  • Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 285:36, s. 28252-28260
  • Tidskriftsartikel (refereegranskat)abstract
    • Dimeric ligands can be potent inhibitors of protein-protein or enzyme-substrate interactions. They have increased affinity and specificity towards their targets due to their ability to bind simultaneously to two binding sites and are therefore very attractive in drug design. However, few studies have addressed the kinetic mechanism of interaction of such bivalent ligands. We have investigated the binding interaction of a recently identified potent plasma-stable dimeric pentapeptide of PDZ1-2 of PSD-95 using protein engineering in combination with fluorescence polarisation, isothermal titration calorimetry and stopped-flow fluorimetry. Our experiments demonstrate that binding occurs via a two-step process, where an initial binding to either one of the two PDZ domains is followed by an intramolecular step, which produces the bidentate complex. We have determined all rate constants involved in the binding reaction and we also find evidence for a conformational transition of the complex. Our data demonstrate the importance of a slow dissociation for a successful dimeric ligand, but also highlight the possibility of optimizing the intramolecular association rate. The results may therefore aid the design of dimeric inhibitors in general.
  • Kristensen, Karl, et al. (författare)
  • Continuous glucose monitoring in pregnant women with type 1 diabetes : : an observational cohort study of 186 pregnancies
  • 2019
  • Ingår i: Diabetologia. - Springer. - 0012-186X. ; 62:7, s. 1143-1153
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims/hypothesis: The aim of this study was to analyse patterns of continuous glucose monitoring (CGM) data for associations with large for gestational age (LGA) infants and an adverse neonatal composite outcome (NCO) in pregnancies in women with type 1 diabetes. Methods: This was an observational cohort study of 186 pregnant women with type 1 diabetes in Sweden. The interstitial glucose readings from 92 real-time (rt) CGM and 94 intermittently viewed (i) CGM devices were used to calculate mean glucose, SD, CV%, time spent in target range (3.5–7.8 mmol/l), mean amplitude of glucose excursions and also high and low blood glucose indices (HBGI and LBGI, respectively). Electronic records provided information on maternal demographics and neonatal outcomes. Associations between CGM indices and neonatal outcomes were analysed by stepwise logistic regression analysis adjusted for confounders. Results: The number of infants born LGA was similar in rtCGM and iCGM users (52% vs 53%). In the combined group, elevated mean glucose levels in the second and the third trimester were significantly associated with LGA (OR 1.53, 95% CI 1.12, 2.08, and OR 1.57, 95% CI 1.12, 2.19, respectively). Furthermore, a high percentage of time in target in the second and the third trimester was associated with lower risk of LGA (OR 0.96, 95% CI 0.94, 0.99 and OR 0.97, 95% CI 0.95, 1.00, respectively). The same associations were found for mean glucose and for time in target and the risk of NCO in all trimesters. SD was significantly associated with LGA in the second trimester and with NCO in the third trimester. Glucose patterns did not differ between rtCGM and iCGM users except that rtCGM users had lower LBGI and spent less time below target. Conclusions/interpretation: Higher mean glucose levels, higher SD and less time in target range were associated with increased risk of LGA and NCO. Despite the use of CGM throughout pregnancy, the day-to-day glucose control was not optimal and the incidence of LGA remained high.
  • Nissen, Klaus B., et al. (författare)
  • Targeting Protein-Protein Interactions with Trimeric Ligands High Affinity Inhibitors of the MAGUK Protein Family
  • 2015
  • Ingår i: PLoS ONE. - 1932-6203 .- 1932-6203. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • PDZ domains in general, and those of PSD-95 in particular, are emerging as promising drug targets for diseases such as ischemic stroke. We have previously shown that dimeric ligands that simultaneously target PDZ1 and PDZ2 of PSD-95 are highly potent inhibitors of PSD-95. However, PSD-95 and the related MAGUK proteins contain three consecutive PDZ domains, hence we envisioned that targeting all three PDZ domains simultaneously would lead to more potent and potentially more specific interactions with the MAGUK proteins. Here we describe the design, synthesis and characterization of a series of trimeric ligands targeting all three PDZ domains of PSD-95 and the related MAGUK proteins, PSD93, SAP-97 and SAP-102. Using our dimeric ligands targeting the PDZ1-2 tandem as starting point, we designed novel trimeric ligands by introducing a PDZ3-binding peptide moiety via a cysteine-derivatized NPEG linker. The trimeric ligands generally displayed increased affinities compared to the dimeric ligands in fluorescence polarization binding experiments and optimized trimeric ligands showed low nanomolar inhibition towards the four MAGUK proteins, thus being the most potent inhibitors described. Kinetic experiments using stopped-flow spectrometry showed that the increase in affinity is caused by a decrease in the dissociation rate of the trimeric ligand as compared to the dimeric ligands, likely reflecting the lower probability of simultaneous dissociation of all three PDZ ligands. Thus, we have provided novel inhibitors of the MAGUK proteins with exceptionally high affinity, which can be used to further elucidate the therapeutic potential of these proteins.
  • Ahadi, Aylin, et al. (författare)
  • Simulation of Nanoindentation Response of Empty and Filled Viral Capsids
  • 2009
  • Ingår i: DCE Technical Memorandum. - Aalborg University, Department of Civil Engineering. - 1901-7278. ; 11
  • Konferensbidrag (refereegranskat)abstract
    • The nanoindentation response of empty and filled viral capsids is modelled using three dimensional finite element analysis. Simulation with two different geometries, spherical and icosahedral, are performed using the finite element code Abaqus. The capsids are modeled as non-linear Hookean elastic and both small and large deformation analysis is performed. Force-indentation curves for three different viral capsids are directly compared to experimental data and the Young’s modulus is determined by calibrating the force-indentation curve to data from atomic force microscopy (AFM) experiments. Predictions are made for two additional viral capsids. The results from the simulation showed a good agreement with AFM data, see [1].
  • Ahnfeldt-Mollerup, Peder, et al. (författare)
  • Medical engagement and organizational characteristics in general practice
  • 2016
  • Ingår i: Family Practice. - Oxford University Press. - 1460-2229. ; 33:1, s. 69-74
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Medical engagement is a mutual concept of the active and positive contribution of doctors to maintaining and enhancing the performance of their health care organization, which itself recognizes this commitment in supporting and encouraging high quality care. A Medical Engagement Scale (MES) was developed by Applied Research Ltd (2008) on the basis of emerging evidence that medical engagement is critical for implementing radical improvements.OBJECTIVES: To study the importance of medical engagement in general practice and to analyse patterns of association with individual and organizational characteristics.DESIGN AND SETTING: A cross-sectional study using a sampled survey questionnaire and the official register from the Danish General Practitioners' Organization comprising all registered Danish GPs.METHOD: The Danish version of the MES Questionnaire was distributed and the survey results were analysed in conjunction with the GP register data.RESULTS: Statistically adjusted analyses revealed that the GPs' medical engagement varied substantially. GPs working in collaboration with colleagues were more engaged than GPs from single-handed practices, older GPs were less engaged than younger GPs and female GPs had higher medical engagement than their male colleagues. Furthermore, GPs participating in vocational training of junior doctors were more engaged than GPs not participating in vocational training.CONCLUSION: Medical engagement in general practice varies a great deal and this is determined by a complex interaction between both individual and organizational characteristics. Working in collaboration, having staff and being engaged in vocational training of junior doctors are all associated with enhanced levels of medical engagement among GPs.
  • Ahnfeldt-Mollerup, Peder, et al. (författare)
  • Resource allocation and the burden of co-morbidities among patients diagnosed with chronic obstructive pulmonary disease : an observational cohort study from Danish general practice
  • 2016
  • Ingår i: BMC Health Services Research. - BioMed Central. - 1472-6963. ; 16:1
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Chronic obstructive pulmonary disease is a leading cause of mortality, and associated with increased healthcare utilization and healthcare expenditure. In several countries, morbidity-based systems have changed the way resources are allocated in general practice. In primary care, fee-for-services tariffs are often based on political negotiation rather than costing systems. The potential for comprehensive measures of patient morbidity to explain variation in negotiated expenditures for patients with chronic obstructive pulmonary disease has not previously been examined. The aim of this study is to analyze fee-for-service expenditure of patients diagnosed with chronic obstructive pulmonary disease visiting Danish general practice clinics and further to assess what proportion of fee-for-service expenditure variation was explained by patient morbidity and general practice clinic characteristics, respectively.METHODS: We used patient morbidity characteristics such as diagnostic markers and multi-morbidity adjustment based on adjusted clinical groups (ACGs) and fee-for-service expenditure for a sample of primary care patients for the year 2010. Our sample included 3,973 patients in 59 general practices. We used a multi-level approach.RESULTS: The average annual fee-for-service expenditure of caring for patients diagnosed with chronic obstructive pulmonary disease in general practice was about EUR 400 per patient. Variation in the expenditures was driven by multimorbidity characteristics up to 28 % where as characteristics such as age and gender only explained 5 %. Expenditures increased progressively with the degree of multimorbidity. In addition, expenditures were higher for patients who had diagnostic markers based on ICPC-2 (body systems and/or components such as infections and symptoms). Nevertheless, 9.8-15.4 % of the variation in expenditure was related to the clinic in which the patient was cared for.CONCLUSION: Patient morbidity and general practice clinic characteristics are significant patient-related fee-for-service expenditure drivers in chronic obstructive pulmonary disease care.
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