| 1. |
- Mak, Jonathan K. L., et al.
(författare)
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Development of an Electronic Frailty Index for Hospitalized Older Adults in Sweden
- 2022
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : Oxford University Press. - 1079-5006 .- 1758-535X. ; 77:11, s. 2311-2319
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Tidskriftsartikel (refereegranskat)abstract
- Background Frailty assessment in the Swedish health system relies on the Clinical Frailty Scale (CFS), but it requires training, in-person evaluation, and is often missing in medical records. We aimed to develop an electronic frailty index (eFI) from routinely collected electronic health records (EHRs) and assess its association with adverse outcomes in hospitalized older adults. Methods EHRs were extracted for 18 225 patients with unplanned admissions between 1 March 2020 and 17 June 2021 from 9 geriatric clinics in Stockholm, Sweden. A 48-item eFI was constructed using diagnostic codes, functioning and other health indicators, and laboratory data. The CFS, Hospital Frailty Risk Score, and Charlson Comorbidity Index were used for comparative assessment of the eFI. We modeled in-hospital mortality and 30-day readmission using logistic regression; 30-day and 6-month mortality using Cox regression; and length of stay using linear regression. Results Thirteen thousand one hundred and eighty-eight patients were included in analyses (mean age 83.1 years). A 0.03 increment in the eFI was associated with higher risks of in-hospital (odds ratio: 1.65; 95% confidence interval: 1.54-1.78), 30-day (hazard ratio [HR]: 1.43; 1.38-1.48), and 6-month mortality (HR: 1.34; 1.31-1.37) adjusted for age and sex. Of the frailty and comorbidity measures, the eFI had the highest area under receiver operating characteristic curve for in-hospital mortality of 0.813. Higher eFI was associated with longer length of stay, but had a rather poor discrimination for 30-day readmission. Conclusions An EHR-based eFI has robust associations with adverse outcomes, suggesting that it can be used in risk stratification in hospitalized older adults.
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| 2. |
- Mak, Jonathan K. L., et al.
(författare)
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Two Years with COVID-19 : The Electronic Frailty Index Identifies High-Risk Patients in the Stockholm GeroCovid Study
- 2023
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Ingår i: Gerontology. - : S. Karger. - 0304-324X .- 1423-0003. ; 69:4, s. 396-405
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Frailty, a measure of biological aging, has been linked to worse COVID-19 outcomes. However, as the mortality differs across the COVID-19 waves, it is less clear whether a medical record-based electronic frailty index (eFI) that we have previously developed for older adults could be used for risk stratification in hospitalized COVID-19 patients. Objectives: The aim of the study was to examine the association of frailty with mortality, readmission, and length of stay in older COVID-19 patients and to compare the predictive accuracy of the eFI to other frailty and comorbidity measures. Methods: This was a retrospective cohort study using electronic health records (EHRs) from nine geriatric clinics in Stockholm, Sweden, comprising 3,980 COVID-19 patients (mean age 81.6 years) admitted between March 2020 and March 2022. Frailty was assessed using a 48-item eFI developed for Swedish geriatric patients, the Clinical Frailty Scale, and the Hospital Frailty Risk Score. Comorbidity was measured using the Charlson Comorbidity Index. We analyzed in-hospital mortality and 30-day readmission using logistic regression, 30-day and 6-month mortality using Cox regression, and the length of stay using linear regression. Predictive accuracy of the logistic regression and Cox models was evaluated by area under the receiver operating characteristic curve (AUC) and Harrell's C-statistic, respectively. Results: Across the study period, the in-hospital mortality rate decreased from 13.9% in the first wave to 3.6% in the latest (Omicron) wave. Controlling for age and sex, a 10% increment in the eFI was significantly associated with higher risks of in-hospital mortality (odds ratio = 2.95; 95% confidence interval = 2.42-3.62), 30-day mortality (hazard ratio [HR] = 2.39; 2.08-2.74), 6-month mortality (HR = 2.29; 2.04-2.56), and a longer length of stay (beta-coefficient = 2.00; 1.65-2.34) but not with 30-day readmission. The association between the eFI and in-hospital mortality remained robust across the waves, even after the vaccination rollout. Among all measures, the eFI had the best discrimination for in-hospital (AUC = 0.780), 30-day (Harrell's C = 0.733), and 6-month mortality (Harrell's C = 0.719). Conclusion: An eFI based on routinely collected EHRs can be applied in identifying high-risk older COVID-19 patients during the continuing pandemic.
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| 3. |
- Xu, Hong, et al.
(författare)
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Decreased Mortality Over Time During the First Wave in Patients With COVID-19 in Geriatric Care : Data From the Stockholm GeroCovid Study.
- 2021
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier. - 1525-8610 .- 1538-9375. ; 22:8, s. 1565-1573
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To describe temporal changes in treatment, care, and short-term mortality outcomes of geriatric patients during the first wave of the COVID-19 pandemic.DESIGN: Observational study.SETTING AND PARTICIPANTS: Altogether 1785 patients diagnosed with COVID-19 and 6744 hospitalized for non-COVID-19 causes at 7 geriatric clinics in Stockholm from March 6 to July 31, 2020, were included.METHODS: Across admission month, patient vital signs and pharmacological treatment in relationship to risk for in-hospital death were analyzed using the Poisson regression model. Incidence rates (IRs) and incidence rate ratios (IRRs) of death are presented.RESULTS: In patients with COVID-19, the IR of mortality were 27%, 17%, 10%, 8%, and 2% from March to July, respectively, after standardization for demographics and vital signs. Compared with patients admitted in March, the risk of in-hospital death decreased by 29% [IRR 0.71, 95% confidence interval (CI) 0.51-0.99] in April, 61% (0.39, 0.26-0.58) in May, 68% (0.32, 0.19-0.55) in June, and 86% (0.14, 0.03-0.58) in July. The proportion of patients admitted for geriatric care with oxygen saturation <90% decreased from 13% to 1%, which partly explains the improvement of COVID-19 patient survival. In non-COVID-19 patients during the pandemic, mortality rates remained relatively stable (IR 1.3%-2.3%). Compared with non-COVID-19 geriatric patients, the IRR of death declined from 11 times higher (IRR 11.7, 95% CI 6.11-22.3) to 1.6 times (2.61, 0.50-13.7) between March and July in patients with COVID-19.CONCLUSIONS AND IMPLICATIONS: Mortality risk in geriatric patients from the Stockholm region declined over time throughout the first pandemic wave of COVID-19. The improved survival rate over time was only partly related to improvement in saturation status at the admission of the patients hospitalized later throughout the pandemic. Lower incidence during the later months could have led to less severe hospitalized cases driving down mortality.
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| 4. |
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| 5. |
- Aranzana-Climent, Vincent, et al.
(författare)
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Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia
- 2022
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Ingår i: Clinical Microbiology and Infection. - : Elsevier B.V.. - 1198-743X .- 1469-0691. ; 28:10, s. 1367-1374
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: New drugs and methods to efficiently fight carbapenem-resistant gram-negative pathogens are sorely needed. In this study, we characterized the preclinical pharmacokinetics (PK) and pharmacodynamics of the clinical stage drug candidate apramycin in time kill and mouse lung infection models. Based on in vitro and in vivo data, we developed a mathematical model to predict human efficacy. Methods: Three pneumonia-inducing gram-negative species Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied. Bactericidal kinetics were evaluated with time-kill curves; in vivo PK were studied in healthy and infected mice, with sampling in plasma and epithelial lining fluid after subcutaneous administration; in vivo efficacy was measured in a neutropenic mouse pneumonia model. A pharmacokinetic-pharmacodynamic model, integrating all the data, was developed and simulations were performed. Results: Good lung penetration of apramycin in epithelial lining fluid (ELF) was shown (area under the curve (AUC)ELF/AUCplasma = 88%). Plasma clearance was 48% lower in lung infected mice compared to healthy mice. For two out of five strains studied, a delay in growth (∼5 h) was observed in vivo but not in vitro. The mathematical model enabled integration of lung PK to drive mouse PK and pharmacodynamics. Simulations predicted that 30 mg/kg of apramycin once daily would result in bacteriostasis in patients. Discussion: Apramycin is a candidate for treatment of carbapenem-resistant gram-negative pneumonia as demonstrated in an integrated modeling framework for three bacterial species. We show that mathematical modelling is a useful tool for simultaneous inclusion of multiple data sources, notably plasma and lung in vivo PK and simulation of expected scenarios in a clinical setting, notably lung infections. © 2022 The Author(s)
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| 6. |
- Arrazuria, Rakel, et al.
(författare)
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Expert workshop summary : Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections
- 2022
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Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The rise in antimicrobial resistance (AMR), and increase in treatment-refractory AMR infections, generates an urgent need to accelerate the discovery and development of novel anti-infectives. Preclinical animal models play a crucial role in assessing the efficacy of novel drugs, informing human dosing regimens and progressing drug candidates into the clinic. The Innovative Medicines Initiative-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium is establishing a validated and globally harmonized preclinical model to increase reproducibility and more reliably translate results from animals to humans. Toward this goal, in April 2021, COMBINE organized the expert workshop "Advancing toward a standardized murine model to evaluate treatments for AMR lung infections". This workshop explored the conduct and interpretation of mouse infection models, with presentations on PK/PD and efficacy studies of small molecule antibiotics, combination treatments (beta -lactam/beta -lactamase inhibitor), bacteriophage therapy, monoclonal antibodies and iron sequestering molecules, with a focus on the major Gram-negative AMR respiratory pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Here we summarize the factors of variability that we identified in murine lung infection models used for antimicrobial efficacy testing, as well as the workshop presentations, panel discussions and the survey results for the harmonization of key experimental parameters. The resulting recommendations for standard design parameters are presented in this document and will provide the basis for the development of a harmonized and bench-marked efficacy studies in preclinical murine pneumonia model.
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| 7. |
- Arrazuria, Rakel, et al.
(författare)
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Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents
- 2022
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Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 13
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Forskningsöversikt (refereegranskat)abstract
- Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.
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| 8. |
- Arvidsson, Fredrik, et al.
(författare)
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Visions of Future News - Consensus or Conflict?
- 2002
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Ingår i: Proceedings of the 25th Information Systems Research Seminar in Scandinavia (IRIS). - : IRIS. ; , s. 25-
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Konferensbidrag (refereegranskat)abstract
- The move from print to multimedia will cause changes not only to the form of the news service but also the involved processes in the news organizations. The cooperative scenario building technique is used on a number of groups; end-users, management and media professionals to envisioning the news services of the future. We take the perspective of consensus and conflict to illustrate the identified visions. Firstly, we illuminate conflicts and consensus between the groups, regarding their visions and future use scenarios. Secondly, we show the implications of using the cooperative scenariobuilding technique in relation the consensus and conflict perspectives in cooperative design. We conclude that both consensus and conflicts could be found in the scenarios described in the paper and that the cooperative technique was suitable in this context.
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| 9. |
- Aspholm-Hurtig, Marina, et al.
(författare)
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Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin.
- 2004
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 305:5683, s. 519-22
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Tidskriftsartikel (refereegranskat)abstract
- Adherence by Helicobacter pylori increases the risk of gastric disease. Here, we report that more than 95% of strains that bind fucosylated blood group antigen bind A, B, and O antigens (generalists), whereas 60% of adherent South American Amerindian strains bind blood group O antigens best (specialists). This specialization coincides with the unique predominance of blood group O in these Amerindians. Strains differed about 1500-fold in binding affinities, and diversifying selection was evident in babA sequences. We propose that cycles of selection for increased and decreased bacterial adherence contribute to babA diversity and that these cycles have led to gradual replacement of generalist binding by specialist binding in blood group O-dominant human populations.
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| 10. |
- Aspholm, Marina, et al.
(författare)
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SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans.
- 2006
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Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374 .- 1553-7366. ; 2:10
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Tidskriftsartikel (refereegranskat)abstract
- Adherence of Helicobacter pylori to inflamed gastric mucosa is dependent on the sialic acid-binding adhesin (SabA) and cognate sialylated/fucosylated glycans on the host cell surface. By in situ hybridization, H. pylori bacteria were observed in close association with erythrocytes in capillaries and post-capillary venules of the lamina propria of gastric mucosa in both infected humans and Rhesus monkeys. In vivo adherence of H. pylori to erythrocytes may require molecular mechanisms similar to the sialic acid-dependent in vitro agglutination of erythrocytes (i.e., sialic acid-dependent hemagglutination). In this context, the SabA adhesin was identified as the sialic acid-dependent hemagglutinin based on sialidase-sensitive hemagglutination, binding assays with sialylated glycoconjugates, and analysis of a series of isogenic sabA deletion mutants. The topographic presentation of binding sites for SabA on the erythrocyte membrane was mapped to gangliosides with extended core chains. However, receptor mapping revealed that the NeuAcalpha2-3Gal-disaccharide constitutes the minimal sialylated binding epitope required for SabA binding. Furthermore, clinical isolates demonstrated polymorphism in sialyl binding and complementation analysis of sabA mutants demonstrated that polymorphism in sialyl binding is an inherent property of the SabA protein itself. Gastric inflammation is associated with periodic changes in the composition of mucosal sialylation patterns. We suggest that dynamic adaptation in sialyl-binding properties during persistent infection specializes H. pylori both for individual variation in mucosal glycosylation and tropism for local areas of inflamed and/or dysplastic tissue.
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| 11. |
- Broqvist, Mari, 1958-, et al.
(författare)
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Beslutsstöd för prioriteringar på individnivå : Exempel från hjälpmedelsverksamhet
- 2019
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Alltsedan 1997 då den etiska plattformen för resursfördelning introducerades i den svenska hälso- och sjukvården har metodutveckling pågått i syfte att stödja vårdens aktörer i de svåra avvägningar som prioriteringar ofta innebär. Fokus har varit på de stora frågorna, om resursfördelning på regionnivå och policybeslut i olika verksamheter, men det stora antalet prioriteringar görs på daglig basis i mötet mellan personal och patienter.Den här rapporten vänder sig till er som vill arbeta med att göra prioriteringar på individnivå på mer likvärdiga grunder i linje med de riktlinjer om prioriteringar som riksdagen beslutat om. Här presenteras ett verktyg, Beslutsstöd för prioriteringar på individnivå, som syftar till att styra insamlandet och analys gällande vårdbehov så att behovs-solidaritetsprincipen och kostnadseffektivitetsprincipen i riksdagens riktlinjer för prioriteringar beaktas vid bedömningen. Beslutsstödet är resultatet av ett mångårigt utvecklingsarbete, byggt på erfarenheter framför allt inom hjälpmedelsverksamheter i flera olika regioner. Utöver att användas vid hjälpmedelsförskrivning är beslutsstödet även tänkt att kunna prövas för andra typer av hälso- och sjukvårdsåtgärder.Beslutsstödet som används för att avgöra hur prioriterat en persons hälsoproblem och en tänkt åtgärd bör vara består av ett bedömningsformulär och en manual. Svårighetsgrad, patientnytta och patientnytta i relation till kostnad bedöms där i ett antal bedömningspunkter som styr bedömningen mot en prioriteringsgrad.Ett syfte med beslutsstödet är att skapa prioriteringar på mer lika grunder. Infört på ett välorganiserat sätt, kan det bidra till att skapa förståelse och acceptans för gemensamma grunder och en större öppenhet i prioriteringar. I den här rapporten ges ett exempel på en genomtänkt implementeringsprocess från hjälpmedelsverksamheten i Region Jönköpings län. En viktig slutsats av det arbetet är att stöd från ledning och politiker, metodstöd till användarna av beslutsstödet samt uthållighet är huvudingredienser för att lyckas i ett sådant arbete.
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| 12. |
- Elmqvist, Carina, 1964-, et al.
(författare)
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”Vi vill ha en statlig nationell översikt över mobil vård”
- 2019
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Ingår i: Dagens medicin. - : Bonnier Business Media AB. - 1104-7488 .- 1402-1943. ; :2019-09-26
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Den mobila vården behöver definieras nationellt och bli en egen organisationsform och vårdnivå, skriver företrädare från Centrum för interprofessionell samverkan inom akut vård.
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| 13. |
- Frimodt-Møller, Niels, et al.
(författare)
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Apramycin efficacy against carbapenem- and aminoglycoside-resistant Escherichia coli and Klebsiella pneumoniae in murine bloodstream infection models
- 2024
-
Ingår i: International Journal of Antimicrobial Agents. - : Elsevier. - 0924-8579 .- 1872-7913. ; 64:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe aminoglycoside apramycin has been proposed as a drug candidate for the treatment of critical Gram-negative systemic infections. However, the potential of apramycin in the treatment of drug-resistant bloodstream infections (BSIs) has not yet been assessed.MethodsThe resistance gene annotations of 40 888 blood-culture isolates were analysed. In vitro profiling of apramycin comprised cell-free translation assays, broth microdilution, and frequency of resistance determination. The efficacy of apramycin was studied in a mouse peritonitis model for a total of nine Escherichia coli and Klebsiella pneumoniae isolates.ResultsGenotypic aminoglycoside resistance was identified in 87.8% of all 6973 carbapenem-resistant Enterobacterales blood-culture isolates, colistin resistance was shown in 46.4% and apramycin in 2.1%. Apramycin activity against methylated ribosomes was > 100-fold higher than that for other aminoglycosides. Frequencies of resistance were < 10-9 at 8 × minimum inhibitory concentration (MIC). Tentative epidemiological cut-offs (TECOFFs) were determined as 8 µg/mL for E. coli and 4 µg/mL for K. pneumoniae. A single dose of 5 to 13 mg/kg resulted in a 1-log colony-forming unit (CFU) reduction in the blood and peritoneum. Two doses of 80 mg/kg resulted in an exposure that resembles the AUC observed for a single 30 mg/kg dose in humans and led to complete eradication of carbapenem- and aminoglycoside-resistant bacteraemia.ConclusionEncouraging coverage and potent in vivo efficacy against a selection of highly drug-resistant Enterobacterales isolates in the mouse peritonitis model warrants the conduct of clinical studies to validate apramycin as a drug candidate for the prophylaxis and treatment of BSI.
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| 14. |
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| 15. |
- Gunnarsson, Carina, et al.
(författare)
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Ullpellets från outnyttjad ull på Gotland – ett utvecklingsprojekt med fokus på pelleteringsprocessen
- 2022
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Wool pellets from unutilized wool on Gotland – a development project with focus on the pelleting processA large proportion of the wool produced in Sweden is discarded as it cannot be used by the textile industry. Before the wool can be used it must be collected and washed. However, a large quantity of low-quality wool is mixed in with the high-quality wool and thus enter the processing industry when the wool is collected. As it is not usable by the industry, this low-quality wool simply takes up space and lowers the processing speed as it must be separated from the high-quality wool and be discarded, lowering the economic output of the wool processing industry. However, unutilized wool has the potential to be used as a slow-acting fertilizer, soil amendment, or mulch for cultivation purposes. Pelleting is an attractive method of processing biomass into a product that is efficient and easy to handle, transport and use. Pellet presses are commercially available from small farm-scale to large-scale facilities. The aim of the project was to develop and adapt the pelleting technology to work with Swedish wool that cannot be used to produce yarns or other textiles. The goal was to develop methods and technology for pre-treating or disintegrate the wool, adapt the input and pelleting part of the pelleting process to work with low-quality wool and try to optimize the quality of the pellets. Furthermore, the goal was to analyze the plant nutrient value and strength of the pellets produced and create a packaging prototype. During the project, additional goals were added: to automate the process from pre-treatment to packaging as much as possible, and to use literature to determine if the pelletizing process is likely to be sufficient enough to hygenize the wool from weed seeds. An automated production line from wool to finished pellets has been built at Ullkontoret (Sweden’s only full-scale wool washing facility). Coarse and fine shredding, feeding and regulation of feed capacity function well, while the pelleting pressing does not work sufficiently well. Wool pelleting of only low-quality wool proved technologically challenging and neither the modified pellet presses nor the imported wool pellet press worked, despite modifications. In other European countries, this problem is solved by mixing in higher quality wool. Further technological development of wool pelleting is needed to obtain a system that can handle all types of low-quality Swedish wool. Literature studies and nutritional analyses confirm that wool pellets work well as a slow-acting fertilizer (often in mixture due to a very low phosphorus content), but the potential of wool as a soil amendment, mulch and snail repellent requires more studies. Pelleting is probably not enough to hygenize the wool from weed seeds. It is a challenge to produce a packaging that both meets the quality requirements of the product (e.g., maintain the right humidity, preventing odors) and at the same time meets the demands of the type of environmentally conscious consumer who is the main target group for a nature-based product.
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| 16. |
- Holmdahl, Rikard, et al.
(författare)
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Genetic control of arthritis in rats
- 2000
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Ingår i: Journal of Experimental Animal Science. - 0939-8600. ; 41, s. 7-13
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Tidskriftsartikel (refereegranskat)
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| 17. |
- Ihlström, Carina, 1960-, et al.
(författare)
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Audience of Local Online Newspapers in Sweden, Slovakia and Spain - a comparative study
- 2003
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Ingår i: Proccedings of HCI International 2003. - London : Lawrence Erlbaum Associates. ; , s. 749-753, s. 749-753
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Konferensbidrag (refereegranskat)abstract
- Since a new online audience for local newspapers has emerged during the last years, in response to the growth of the Internet, we need to know who they are, what their reading habits are, and what their view on emerging technologies are, to be able to design good online newspapers. We have conducted a study using online questionnaires at three local online newspapers in three different countries: Sweden, Slovakia and Spain. The objective of this paper is to describe the differences and similarities between the three countries regarding audience profiles, scenarios of use, opinions of current and future issues and to discuss design implications.
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| 18. |
- Ihlström, Carina, et al.
(författare)
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Local Swedish Newspapers Approaching e-Business?
- 2002
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Ingår i: Technology interactions. - Berlin : VWF. - 3897003570 ; , s. 81-91
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Konferensbidrag (refereegranskat)abstract
- Most Swedish newspapers have experienced receding advertising revenues during the last years and are now searching for new ways to profit from their online editions. We have conducted three future workshops with both management and end users to envision possible new services that could be profitable for the local newspapers. Furthermore we have conducted an online survey with users selected from a previous study. The objective of this paper is to describe these services and to give a user response to them. We have identified three kinds of services: advertisement services, intermediary services and news services. The results show that the end users preferred the intermediary services and that there is an interest for advertisements in a new setting.
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| 19. |
- Ihlström, Carina, et al.
(författare)
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Online Newspapers in Search for Profitable Services
- 2002
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Ingår i: Challenges and Achievements in E-business and E-work. - Washington : IOS Press. - 9781586032845 - 1586032844 ; , s. 1455-1462, s. 1455-1462
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Konferensbidrag (refereegranskat)abstract
- Today online newspapers are putting a lot of resources into their news sites without profiting from them. They have to find ways to gain from them in order to keep them going. Lately there has been a move from print to multimedia, i.e. news is only a part among other services at the news sites and is presented as audio and video as well. We have conducted interviews at nine local newspapers in Sweden about their current situation and future plans. We have also used a cooperative scenario building technique aiming at finding new online services that could be profitable with both newspaper management and end users. The objective of this paper is to describe the current situation for these newspapers and to discuss possible new future services. Examples of services from the workshops are e.g. advertisement on demand and intermediary services.
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| 20. |
- Ihlström, Carina, et al.
(författare)
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The Audience of Swedish Local Online Newspapers : - a Longitudinal Study
- 2002
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Ingår i: Technology interactions. - Berlin : VWF. ; , s. 92-102, s. 92-102
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Konferensbidrag (refereegranskat)abstract
- We have conducted a partly longitudinal study using online questionnaires at four Swedish local online newspapers in two different studies. The objective of this paper is to describe the users’ demographics and reading habits as well as the users’ expectations of current and future issues regarding the online edition. We also discuss online questionnaires having tried three different approaches to receive as many answers as possible. We have found that the subscribing readers of online editions have increased from one forth to more than a half of the audience, and concluded that the subscribers and nonsubscribers have different reading habits. The findings also show that almost two thirds of the respondents are men and more than 80% prefer the paper edition of the newspaper. The results indicate an interest for a multimedia paper edition for the future.
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| 21. |
- Ihlström, Carina, et al.
(författare)
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The Online News Genre through the User Perspective
- 2003
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Ingår i: Proceedings of the 36th Annual Hawaii International Conference on System Sciences. - Los Alamitos, Calif. : IEEE Computer Society. - 0769518745 ; , s. 1-10
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Konferensbidrag (refereegranskat)abstract
- Online newspapers, having existed on the Internet for acouple of years, are now having similar form and content,starting to shape what could be called a genre. We have analyzed the news sites of nine Swedish local newspapers using a repertoire of genre elements consisting ofnavigation elements, landmarks, news streams, headlines,search/archives and advertisements. We have alsointerviewed 153 end users at these newspapers. Theobjective of this paper is to describe the user’s perspective of the online news genre described in terms of therepertoire of genre elements. The results indicate what elements seems to be the better design choice through theuser perspective. Due to remaining similarities with the printed edition, the online newspaper genre is still avariant genre.
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| 22. |
- Ihlström Eriksson, Carina, et al.
(författare)
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A Genre Perspective on Online Newspaper Front Page Design
- 2004
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Ingår i: Journal of Web Engineering. - : Rinton Press, Princeton, New Jersey. - 1540-9589. ; 3:1, s. 50-74
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Tidskriftsartikel (refereegranskat)abstract
- Taking a genre perspective on design, this article proposes eight design recommendations for online newspapers. These recommendations are based on features that mediate a specific purpose and use between publisher and audience, which we describe as genre rules in terms of purpose, form, and positioning. They are also based on genre change regarding design, and the heritage from print regarding form and shared content elements. We have a) studied genre change through a web page analysis of nine Swedish online newspapers in 2001 and 2003, using the genre concepts content, form, functionality and positioning, and b) derived genre rules through publishers and audience understanding of the genre. We have interviewed managers, designers and editors-in-chief at the nine newspapers as well as 153 members of their audience. We show that in the design process for digital documents, it is useful to have genre awareness, i.e. to be aware of the genre characteristics, the producer's design purpose and the audience recognition and response.
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| 23. |
- Jansson, Emmelie Å, et al.
(författare)
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A mammalian functional nitrate reductase that regulates nitrite and nitric oxide homeostasis
- 2008
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 4:7, s. 411-417
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Tidskriftsartikel (refereegranskat)abstract
- Inorganic nitrite (NO(2)(-)) is emerging as a regulator of physiological functions and tissue responses to ischemia, whereas the more stable nitrate anion (NO(3)(-)) is generally considered to be biologically inert. Bacteria express nitrate reductases that produce nitrite, but mammals lack these specific enzymes. Here we report on nitrate reductase activity in rodent and human tissues that results in formation of nitrite and nitric oxide (NO) and is attenuated by the xanthine oxidoreductase inhibitor allopurinol. Nitrate administration to normoxic rats resulted in elevated levels of circulating nitrite that were again attenuated by allopurinol. Similar effects of nitrate were seen in endothelial NO synthase-deficient and germ-free mice, thereby excluding vascular NO synthase activation and bacteria as the source of nitrite. Nitrate pretreatment attenuated the increase in systemic blood pressure caused by NO synthase inhibition and enhanced blood flow during post-ischemic reperfusion. Our findings suggest a role for mammalian nitrate reduction in regulation of nitrite and NO homeostasis.
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| 24. |
- Lundberg, Angela, et al.
(författare)
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Arena Global Resources : Experiences from the first Study Semester
- 2003
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Ingår i: Proceedings 2003 Utvecklingskonferensen 26 - 28 november i Gävle. - : Rådet för högre utbildning. - 9185027200 ; , s. 20-40
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Luleå University of Technology is implementing a new type of open programs called Arenas. An Arena is more interdisciplinary than a traditional program and allows a wider entrance and a wider exit. Key words that characterise the arena concept are: Knowledge construction, research connection, collaboration with the surrounding society and individual choice. During the first semester in the Arena global resources the student learning during is focused on a) the development of essential academic skills required for successful studies such as improving personal responsibility and selfassessment skills b) basic knowledge about global resources (scientific, technical, economic, political and legal aspects) c) orientation about available courses, university research and professions within the field of global resources in order for the students to design an individual curriculum. Examples of activities are: a three-day study trip, team-work activities, process writing with student reflection on their learning process. Many teachers are involved in the work with the first study semester and one of the aims with this project is that these teachers should work with an action research approach to improve the student learning. Experiences from the first semester showed that we were successful in creating a good study atmosphere - students that had other first hand choices stayed at the arena, good study results (95% passed the exams). We were less successful with providing the information the students needed to design their individual curriculum.
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| 25. |
- Lundberg, Angela, et al.
(författare)
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Teaching community in sustainable development : aim, realization and evaluation. Final report from project "Teaching communities" (självförbättrande lärartem)
- 2006
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- A model for the educational development of university teachers (a type of teaching community) has been tested. University staff from different faculties worked and reflected together over the teaching and learning practice in a couple of courses. The community was supervised by an educational developer with a doctoral degree in psychology, and they worked in close collaboration with both undergraduate students and PhD students. The teaching staff that participated improved their teaching skills, extended their repertoire of learning tools, and experienced increased self-reliance. Their motivation and enthusiasm for teaching increased, and today they act as "missionaries" for good teaching and learning practices at the University. It was not obvious, however, that this educational development promoted their academic careers. New project ideas emerged from the teaching community.
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| 26. |
- Lundberg, Johan, et al.
(författare)
-
Access to the brain parenchyma using endovascular techniques and a micro-working channel
- 2017
-
Ingår i: Journal of Neurosurgery. - 0022-3085 .- 1933-0693. ; 126:2, s. 511-517
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Several older studies report a low risk for parenchymal access to the CNS by surgical techniques. In more recent studies, including those with post-puncture CT scans, there are indications that the risk of bleeding might approach 8%. New therapies, such as those that use viral vectors, modified mRNA, or cell transplantation, will probably warrant more parenchymal access to the CNS. Other minimally invasive routes might then be tempting to explore. This study was designed in 2 parts to address the possibility of using the endovascular route. The first aim was to test the ability to create a parenchymal micro-working channel to the CNS in macaque monkeys through the vessel wall. Second, the biocompatibility of a device-associated, detached, distal securing plug that was made of nitinol was investigated in swine for 1 year. METHODS Trans-vessel wall intervention in the middle cerebral artery and associated cerebral parenchyma was performed in 4 rhesus macaque monkeys using a full clinical angiography suite. A contrast agent and methylene blue were injected to test the working channel and then detached at the distal end to act as a securing plug through the vessel wall. One-year follow-ups were also performed using angiography and histological analysis in 10 swine with 24 implants that were distributed in the external carotid artery tree. RESULTS The cerebral interventions were performed without acute bleeding. Both the contrast agent and methylene blue were infused into the brain parenchyma and subarachnoidal space via the endovascular micro-working channel (7 injections in 4 animals). In the 1-year follow-up period, the implant that was left in the external carotid vessel wall in the swine was covered by the endothelium, which was followed by dislodgement just outside the blood vessel with thin capsule formation. No stenosis in the artery was detected on 1-year angiography. The animals showed normal behavior and blood sample results during the follow-up period. This is the first histological demonstration of nitinol biocompatibility when the implant is positioned through an arterial wall and indicates that the trans-vessel wall technique is not comparable with stent placement and its ability to induce intimal hyperplasia and restenosis. CONCLUSIONS This study demonstrates that the trans-vessel wall technique is applicable to brain intervention in macaque monkeys, providing a micro-working channel for delivery or sampling. The long-term follow-up study of the detached device in swine showed no clinical or biochemical complications and a normal angiography appearance.
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| 27. |
- Lundberg, J., et al.
(författare)
-
Access to the brain parenchyma using endovascular techniques and a micro-working channel
- 2017
-
Ingår i: Journal of Neurosurgery. - : Journal of Neurosurgery Publishing Group (JNSPG). - 0022-3085 .- 1933-0693. ; 126:2, s. 511-517
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Several older studies report a low risk for parenchymal access to the CNS by surgical techniques. In more recent studies, including those with post-puncture CT scans, there are indications that the risk of bleeding might approach 8%. New therapies, such as those that use viral vectors, modified mRNA, or cell transplantation, will probably warrant more parenchymal access to the CNS. Other minimally invasive routes might then be tempting to explore. This study was designed in 2 parts to address the possibility of using the endovascular route. The first aim was to test the ability to create a parenchymal micro-working channel to the CNS in macaque monkeys through the vessel wall. Second, the biocompatibility of a device-associated, detached, distal securing plug that was made of nitinol was investigated in swine for 1 year. METHODS Trans-vessel wall intervention in the middle cerebral artery and associated cerebral parenchyma was performed in 4 rhesus macaque monkeys using a full clinical angiography suite. A contrast agent and methylene blue were injected to test the working channel and then detached at the distal end to act as a securing plug through the vessel wall. One-year follow-ups were also performed using angiography and histological analysis in 10 swine with 24 implants that were distributed in the external carotid artery tree. RESULTS The cerebral interventions were performed without acute bleeding. Both the contrast agent and methylene blue were infused into the brain parenchyma and subarachnoidal space via the endovascular micro-working channel (7 injections in 4 animals). In the 1-year follow-up period, the implant that was left in the external carotid vessel wall in the swine was covered by the endothelium, which was followed by dislodgement just outside the blood vessel with thin capsule formation. No stenosis in the artery was detected on 1-year angiography. The animals showed normal behavior and blood sample results during the follow-up period. This is the first histological demonstration of nitinol biocompatibility when the implant is positioned through an arterial wall and indicates that the trans-vessel wall technique is not comparable with stent placement and its ability to induce intimal hyperplasia and restenosis. CONCLUSIONS This study demonstrates that the trans-vessel wall technique is applicable to brain intervention in macaque monkeys, providing a micro-working channel for delivery or sampling. The long-term follow-up study of the detached device in swine showed no clinical or biochemical complications and a normal angiography appearance.
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| 28. |
- Lundberg, Tove, et al.
(författare)
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How young people talk about their variations in sex characteristics : making the topic of intersex talkable via sex education
- 2021
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Ingår i: Sex Education. - : Informa UK Limited. - 1468-1811 .- 1472-0825. ; 21:5, s. 552-567
-
Tidskriftsartikel (refereegranskat)abstract
- Classrooms are important spaces for young people with variations in sex characteristics and their classmates. Sex education can promote agency and well-being by helping young people make sense of their embodiment and form rewarding social relationships and by changing societal understandings about variations in sex characteristics. Realising this potential however may hinge on how sex education makes intersex (un)talkable. We draw on interviews with 22 young people on how and why they try to make their variation in sex characteristics talkable with others. By focusing on how they talk to others and why they do not talk to others, this research highlights how participants ‘fear rejection’ but need to talk to others about their variation in the process of ‘dealing with it’. Participants also struggle with ‘secrecy versus privacy’ and how to ‘communicate strategically.’ Findings acknowledge the emotional work required of people with variations in sex characteristics when making intersex talkable. The analysis points to the role of both talking and silence. We conclude by envisaging a norm-critical sex education that engages with the responsibilities of both talking and listening, shifting the burden away from individual young people with variations in sex characteristics and working towards more mutual social relationships.
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| 29. |
- Lövgren, Mattias, et al.
(författare)
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The PRC-barrel domain of the ribosome maturation protein RimM mediates binding to ribosomal protein S19 in the 30S ribosomal subunits
- 2004
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Ingår i: RNA. - : Cold Spring Harbor Laboratory Press (CSHL). - 1355-8382 .- 1469-9001. ; 10:11, s. 1798-1812
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Tidskriftsartikel (refereegranskat)abstract
- The RimM protein in Escherichia coli is associated with free 30S ribosomal subunits but not with 70S ribosomes. A DeltarimM mutant is defective in 30S maturation and accumulates 17S rRNA. To study the interaction of RimM with the 30S and its involvement in 30S maturation, RimM amino acid substitution mutants were constructed. A mutant RimM (RimM-YY-->AA), containing alanine substitutions for two adjacent tyrosines within the PRC beta-barrel domain, showed a reduced binding to 30S and an accumulation of 17S rRNA compared to wild-type RimM. The (RimM-YY-->AA) and DeltarimM mutants had significantly lower amounts of polysomes and also reduced levels of 30S relative to 50S compared to a wild-type strain. A mutation in rpsS, which encodes r-protein S19, suppressed the polysome- and 16S rRNA processing deficiencies of the RimM-YY-->AA but not that of the DeltarimM mutant. A mutation in rpsM, which encodes r-protein S13, suppressed the polysome deficiency of both rimM mutants. Suppressor mutations, found in either helices 31 or 33b of 16S rRNA, improved growth of both the RimM-YY-->AA and DeltarimM mutants. However, they suppressed the 16S rRNA processing deficiency of the RimM-YY-->AA mutant more efficiently than that of the DeltarimM mutant. Helices 31 and 33b are known to interact with S13 and S19, respectively, and S13 is known to interact with S19. A GST-RimM but not a GST-RimM(YY-->AA) protein bound strongly to S19 in 30S. Thus, RimM likely facilitates maturation of the region of the head of 30S that contains S13 and S19 as well as helices 31 and 33b.
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| 30. |
- Narbe, Ulrik, et al.
(författare)
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AIB1 is a new putative prognostic biomarker in the luminal A and B-like (HER2-negative) classification of invasive lobular carcinoma
- 2017
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Ingår i: ; , s. 1-07
-
Konferensbidrag (refereegranskat)abstract
- Body: Background: Estrogen receptor (ER) positive HER2-negative breast cancer comprises 75–80% of all breast cancer. Thisfraction is even higher (>90%) in invasive lobular carcinoma (ILC). According to the St Gallen surrogate definitions of the intrinsicsubtypes, Ki67 and progesterone receptor (PgR) are used to classify these tumors as luminal A- and luminal B-like(HER2-negative). These guidelines are based on information derived from patient materials with mixed histological types, wherethe vast majority of the patients have invasive ductal carcinoma. The `luminal-like classification´ together with histological grade,tumor size and lymph node status is widely used in the clinic for prognostication. The aim of the present study was to investigateif the same markers are applicable for ILC, and furthermore, if additional biomarkers involved in the endocrine signaling system,e.g. Amplified in breast cancer 1 (AIB1) and the putative G protein-coupled estrogen receptor (GPER), might providecomplementary prognostic information.Patients: Two hundred and thirty-three (N = 233) well-characterized patients with primary ILC, diagnosed between 1980 and1991 were included. Forty-two percent of the patients received adjuvant endocrine treatment and 2 % received adjuvantchemotherapy. All biomarkers were analyzed immunohistochemically on tissue microarray, whereas histological grade wasevaluated on whole sections according to Elston and Ellis (NHG). The primary endpoint was breast cancer mortality (BCM).Results: In univariable analyses with 10-year follow-up, Ki67 (high vs. low), NHG (3 vs. 1+2) and AIB1 (high vs. low) weresignificantly associated to BCM (Hazard Ratio: 4.7, 95% CI: 2.1–10.4, p 95% CI: 1.4–7.2, p = 0.005 respectively), whereas PgR (respectively). Essentially the same effect was seen after multivariable adjustment for lymph node status (+ vs. -), tumor size (>20mm vs. according to St Gallen surrogate definitions did not show significant prognostic differences between the two groups (p = 0.12).Patients with AIB1) had a 10-year BCM of 4.2% (95% CI: 1.4–12%). This group constituted 34% of the patients included in the present study.Conclusions: In contrast to other previous studies, where breast cancers of mixed histological types were included, PgR was notsignificantly associated to prognosis in the ER-positive HER2-negative subgroup in the present study, consisting only of ILC. Theprognostic role of PgR and the clinical usefulness of the luminal A and B-like (HER2-negative) classification (using only Ki67 andPgR) in ILC is still to be further investigated. The prognostic importance of Ki67 and NHG in this subgroup was, however,confirmed also in ILC, and AIB1 might be a new putative prognostic factor. By combining Ki67, NHG, and AIB1, together withlymph node status and tumor size, a group of patients with an excellent prognosis could be identified.
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| 31. |
- Narbe, Ulrik, et al.
(författare)
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The estrogen receptor coactivator AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative invasive lobular carcinoma of the breast
- 2019
-
Ingår i: Breast Cancer Research and Treatment. - : Springer Science and Business Media LLC. - 0167-6806 .- 1573-7217. ; 175:2, s. 305-316
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: According to the 2017 St Gallen surrogate definitions of the intrinsic subtypes, Ki67, progesterone receptor (PR) and Nottingham histological grade (NHG) are used for prognostic classification of estrogen receptor (ER) positive/HER2-negative breast cancer into luminal A- or luminal B-like. The aim of the present study was to investigate if additional biomarkers, related to endocrine signaling pathways, e.g., amplified in breast cancer 1 (AIB1), androgen receptor (AR), and G protein-coupled estrogen receptor (GPER), can provide complementary prognostic information in a subset of ER-positive/HER-negative invasive lobular carcinoma (ILC). Methods: Biomarkers from 224 patients were analyzed immunohistochemically on tissue microarray. The primary endpoint was breast cancer mortality (BCM), analyzed with 10- and 25-year follow-up (FU). In addition, the prognostic value of gene expression data for these biomarkers was analyzed in three publicly available ILC datasets. Results: AIB1 (high vs. low) was associated to BCM in multivariable analysis (adjusted for age, tumor size, nodal status, NHG, Ki67, luminal-like classification, and adjuvant systemic therapy) with 10-year FU (HR 6.8, 95% CI 2.3–20, P = 0.001) and 25-year FU (HR 3.0, 95% CI 1.1–7.8, P = 0.03). The evidence of a prognostic effect of AIB1 could be confirmed by linking gene expression data to outcome in independent publicly available ILC datasets. AR and GPER were neither associated to BCM with 10-year nor with 25-year FU (P > 0.33). Furthermore, Ki67 and NHG were prognostic for BCM at both 10-year and 25-year FU, whereas PR was not. Conclusions: AIB1 is a new putative prognostic biomarker in ER-positive/HER2-negative ILC.
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| 32. |
- Nordquist, Niklas, et al.
(författare)
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A genetic linkage map of the rat
- 1999
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Ingår i: Rat genome. - 1081-4205. ; 15, s. 15-20
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Tidskriftsartikel (refereegranskat)
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| 33. |
- Olliver, Marie, et al.
(författare)
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ENABLE : an engine for European antibacterial drug discovery and development
- 2021
-
Ingår i: Nature reviews. Drug discovery. - : Springer Nature. - 1474-1776 .- 1474-1784. ; 20:6, s. 407-408
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- ENABLE is an antibacterial drug discovery and development consortium formed as a publicprivate partnership in 2014 as part of the Innovative Medicines Initiative (IMI) New Drugs for Bad Bugs (ND4BB) programme. With the project soon ending, here we provide a brief overview and reflect on its achievements, strengths and weaknesses.
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| 34. |
- Olofsson, Peter, et al.
(författare)
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Genetic links between the acute-phase response and arthritis development in rats.
- 2002
-
Ingår i: Arthritis and Rheumatism. - 1529-0131 .- 0004-3591. ; 46:1, s. 259-268
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The acute-phase inflammatory response is closely correlated with the development of rheumatoid arthritis, but the pathophysiologic role of its specific components is largely unknown. We investigated the genetic control of the acute-phase protein response in pristane-induced arthritis (PIA), which is a chronic erosive arthritis model in rats. METHODS: Plasma levels of the acute-phase proteins interleukin-6 (IL-6), alpha1-acid glycoprotein (orosomucoid), fibrinogen, and alpha1-inhibitor3 were quantified in 3 strains of rats during the development and progression of disease: DA and LEW.1F, which are susceptible to arthritis, and E3, which is resistant. Genetic linkage analysis was performed on an F2 intercross between E3 and DA to determine the genetic control of the acute-phase response in arthritis. Elevated levels of alpha1-acid glycoprotein were associated with acute inflammation, whereas levels of IL-6 were increased during the entire course of the disease. RESULTS: Using these acute-phase markers as quantitative traits in linkage analysis revealed a colocalization of loci controlling the acute-phase response and regions previously shown to control the development of arthritis in chromosomes 10, 12, and 14. In addition, 2 loci that were not associated with arthritis were found to regulate serum levels of the acute-phase protein Apr1 (acute-phase response 1) at the telomeric end of chromosome 12 and Apr2 on chromosome 5. CONCLUSION: The PIA model in rats is a useful tool for understanding some of the pathways leading to chronic erosive arthritis. The analysis of acute-phase proteins in PIA and its application as quantitative traits for studying the genetics of arthritis will promote the understanding of the genetic regulation of the acute-phase response.
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| 35. |
- Pantel, Lucile, et al.
(författare)
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Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site
- 2018
-
Ingår i: Molecular Cell. - : CELL PRESS. - 1097-2765 .- 1097-4164. ; 70:1, s. 83-94
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Tidskriftsartikel (refereegranskat)abstract
- Growing resistance of pathogenic bacteria and shortage of antibiotic discovery platforms challenge the use of antibiotics in the clinic. This threat calls for exploration of unconventional sources of antibiotics and identification of inhibitors able to eradicate resistant bacteria. Here we describe a different class of antibiotics, odilorhabdins (ODLs), produced by the enzymes of the non-ribosomal peptide synthetase gene cluster of the nematode-symbiotic bacterium Xenorhabdus nematophila. ODLs show activity against Gram-positive and Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae, and can eradicate infections in animal models. We demonstrate that the bactericidal ODLs interfere with protein synthesis. Genetic and structural analyses reveal that ODLs bind to the small ribosomal subunit at a site not exploited by current antibiotics. ODLs induce miscoding and promote hungry codon readthrough, amino acid misincorporation, and premature stop codon bypass. We propose that ODLs' miscoding activity reflects their ability to increase the affinity of non-cognate aminoacyl-tRNAs to the ribosome.
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| 36. |
- Proletov, Ian, et al.
(författare)
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Primary and secondary glomerulonephritides 1.
- 2014
-
Ingår i: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. - : Oxford University Press (OUP). - 1460-2385. ; 29 Suppl 3:May, s. 186-200
-
Tidskriftsartikel (refereegranskat)
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| 37. |
- Sou, Tomás, et al.
(författare)
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Model-Informed Drug Development for Antimicrobials : Translational PK and PK/PD Modeling to Predict an Efficacious Human Dose for Apramycin
- 2021
-
Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 109:4, s. 1063-1073
-
Tidskriftsartikel (refereegranskat)abstract
- Apramycin represents a subclass of aminoglycoside antibiotics that has been shown to evade almost all mechanisms of clinically relevant aminoglycoside resistance. Model-informed drug development may facilitate its transition from preclinical to clinical phase. This study explored the potential of pharmacokinetic/pharmacodynamic (PK/PD) modeling to maximize the use of in vitro time-kill and in vivo preclinical data for prediction of a human efficacious dose (HED) for apramycin. PK model parameters of apramycin from four different species (mouse, rat, guinea pig, and dog) were allometrically scaled to humans. A semimechanistic PK/PD model was developed from the rich in vitro data on four Escherichia coli strains and subsequently the sparse in vivo efficacy data on the same strains were integrated. An efficacious human dose was predicted from the PK/PD model and compared with the classical PK/PD index methodology and the aminoglycoside dose similarity. One-compartment models described the PK data and human values for clearance and volume of distribution were predicted to 7.07 L/hour and 26.8 L, respectively. The required fAUC/MIC (area under the unbound drug concentration-time curve over MIC ratio) targets for stasis and 1-log kill in the thigh model were 34.5 and 76.2, respectively. The developed PK/PD model predicted the efficacy data well with strain-specific differences in susceptibility, maximum bacterial load, and resistance development. All three dose prediction approaches supported an apramycin daily dose of 30 mg/kg for a typical adult patient. The results indicate that the mechanistic PK/PD modeling approach can be suitable for HED prediction and serves to efficiently integrate all available efficacy data with potential to improve predictive capacity.
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| 38. |
- Tängdén, Thomas, et al.
(författare)
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How preclinical infection models help define antibiotic doses in the clinic
- 2020
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Ingår i: International Journal of Antimicrobial Agents. - : Elsevier BV. - 0924-8579 .- 1872-7913. ; 56:2, s. 106008-
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Tidskriftsartikel (refereegranskat)abstract
- Appropriate dosing of antibiotics is key in the treatment of bacterial infections to ensure clinical efficacy while avoiding toxic drug concentrations and minimizing emergence of resistance. As collection of sufficient clinical evidence is difficult for specific patient populations, infection types and pathogens, market authorization, dosing strategies and recommendations often rely on data obtained from in vitro and animal experiments. The aim of this review is to provide an overview of commonly used preclinical infection models, including their strengths and limitations. In vitro, static and dynamic time-kill experiments are the most frequently used methods for assessing pharmacokinetic/pharmacodynamic (PK/PD) associations. Limitations of in vitro models include the inability to account for the effects of the immune system, and uncertainties in clinically relevant bacterial concentrations, growth conditions and the implications of emerging resistant bacterial populations during experiments. Animal experiments, most commonly murine lung and thigh infections models, are considered a necessary link between in vitro data and the clinical situation. However, there are differences in pathophysiology, immunology, and PK between species. Mathematical modeling in which preclinical data are integrated with human population PK can facilitate translation of preclinical data to the patient's clinical situation. Moreover, PK/PD modeling and simulations can help in the design of clinical trials aiming to establish optimal dosing regimens to improve patient outcomes. (C) 2020 The Authors. Published by Elsevier B.V.
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| 39. |
- Vaid, Roshan, et al.
(författare)
-
METTL3 drives telomere targeting of TERRA lncRNA through m6A-dependent R-loop formation: a therapeutic target for ALT-positive neuroblastoma
- 2024
-
Ingår i: NUCLEIC ACIDS RESEARCH. - 0305-1048 .- 1362-4962.
-
Tidskriftsartikel (refereegranskat)abstract
- Telomerase-negative tumors maintain telomere length by alternative lengthening of telomeres (ALT), but the underlying mechanism behind ALT remains poorly understood. A proportion of aggressive neuroblastoma (NB), particularly relapsed tumors, are positive for ALT (ALT+), suggesting that a better dissection of the ALT mechanism could lead to novel therapeutic opportunities. TERRA, a long non-coding RNA (lncRNA) derived from telomere ends, localizes to telomeres in a R-loop-dependent manner and plays a crucial role in telomere maintenance. Here we present evidence that RNA modification at the N-6 position of internal adenosine (m(6)A) in TERRA by the methyltransferase METTL3 is essential for telomere maintenance in ALT+ cells, and the loss of TERRA m(6)A/METTL3 results in telomere damage. We observed that m(6)A modification is abundant in R-loop enriched TERRA, and the m(6)A-mediated recruitment of hnRNPA2B1 to TERRA is critical for R-loop formation. Our findings suggest that m(6)A drives telomere targeting of TERRA via R-loops, and this m(6)A-mediated R-loop formation could be a widespread mechanism employed by other chromatin-interacting lncRNAs. Furthermore, treatment of ALT+ NB cells with a METTL3 inhibitor resulted in compromised telomere targeting of TERRA and accumulation of DNA damage at telomeres, indicating that METTL3 inhibition may represent a therapeutic approach for ALT+ NB. [Graphical Abstract]
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| 40. |
- Vingsbo Lundberg, Carina
(författare)
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Chronic Arthritis in Rats; Pathogenesis and genetic factors
- 1997
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The immune pathology and MHC association of chronic arthritis was studied in three rat models for reumatoid arthritis (RA). Susceptible rat strains develop a T cell dependent chronic disease after immunization with rat collagen type II (CII). The LEW rat does not develop arthritis after immunization with rat CII, but a heterologous immune response to pepsin can break the tolerance to CII and render it susceptible to collagen induced arthritis (CIA). DA rats are protected against CIA if pre-treated with denatured CII or native CII in a non arthritogenic fashion. This was associated with a poor B cell response but a normal T cell response compared to that of CIA, suggesting that B cells specific for conformational epitopes on the CII molecule are essential for the development of chronic CIA. The non-immunogenic adjuvants, avridine and pristane induced chronic T cell dependent arthritis in rats. CIA, AvIA and PIA had a similar MHC association, with RT1a and RT1f being the most susceptible haplotypes. In AvIA and PIA, the MHC mainly influenced the chronicity of arthritis. The genetic control of the PIA model, apart from the MHC association (pia1), was further analyzed in a cross between E3 and DA. A total genome scan of the F2 progeny revealed an additional loci; pia2 on chromosome 12 and two suggestive loci pia3 on chromosome 6 and pia4 on chromosome 11. Pia2 and pia4 were also associated with an a1-acid glycoprotein production and an IgG2b and rheumatoid factor response, whereas pia3 was associated with a fibronectin and IL-6 response.
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| 41. |
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| 42. |
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