| 1. |
- Eriksson, Jonas, et al.
(författare)
-
Small Molecule Screening for Inhibitors of the YopH Phosphatase of Yersinia pseudotuberculosis
- 2012
-
Ingår i: Advances in Yersinia Research. - New York : Springer. - 9781461435600 - 9781461435617 ; , s. 357-363
-
Bokkapitel (refereegranskat)abstract
- Bacterial virulence systems are attractive targets for development of new antibacterial agents. Yersinia spp. utilize the type III secretion (T3S) system to secrete and translocate Yersinia outer proteins (Yop effectors) into the cytosol of the target cell and thereby overcome host defenses to successfully establish an infection. Thus, the Yop effectors constitute attractive targets for drug development. In the present study we apply small molecule screening to identify inhibitors of one of the secreted proteins YopH, a tyrosine phosphatase required for virulence. Characterization of seven inhibitors indicated that both competitive and noncompetitive inhibitors were identified with IC50 values of 6–20 μM.
|
|
| 2. |
- Erlinge, D., et al.
(författare)
-
Bivalirudin versus Heparin Monotherapy in Myocardial Infarction
- 2017
-
Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 377:12, s. 1132-1142
-
Tidskriftsartikel (refereegranskat)abstract
- Background The comparative efficacy of various anticoagulation strategies has not been clearly established in patients with acute myocardial infarction who are undergoing percutaneous coronary intervention (PCI) according to current practice, which includes the use of radial-artery access for PCI and administration of potent P2Y12 inhibitors without the planned use of glycoprotein IIb/IIIa inhibitors. Methods In this multicenter, randomized, registry-based, open-label clinical trial, we enrolled patients with either ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI) who were undergoing PCI and receiving treatment with a potent P2Y12 inhibitor (ticagrelor, prasugrel, or cangrelor) without the planned use of glycoprotein IIb/IIIa inhibitors. The patients were randomly assigned to receive bivalirudin or heparin during PCI, which was performed predominantly with the use of radial-artery access. The primary end point was a composite of death from any cause, myocardial infarction, or major bleeding during 180 days of follow-up. Results A total of 6006 patients (3005 with STEMI and 3001 with NSTEMI) were enrolled in the trial. At 180 days, a primary end-point event had occurred in 12.3% of the patients (369 of 3004) in the bivalirudin group and in 12.8% (383 of 3002) in the heparin group (hazard ratio, 0.96; 95% confidence interval [CI], 0.83 to 1.10; P=0.54). The results were consistent between patients with STEMI and those with NSTEMI and across other major subgroups. Myocardial infarction occurred in 2.0% of the patients in the bivalirudin group and in 2.4% in the heparin group (hazard ratio, 0.84; 95% CI, 0.60 to 1.19; P=0.33), major bleeding in 8.6% and 8.6%, respectively (hazard ratio, 1.00; 95% CI, 0.84 to 1.19; P=0.98), definite stent thrombosis in 0.4% and 0.7%, respectively (hazard ratio, 0.54; 95% CI, 0.27 to 1.10; P=0.09), and death in 2.9% and 2.8%, respectively (hazard ratio, 1.05; 95% CI, 0.78 to 1.41; P=0.76). Conclusions Among patients undergoing PCI for myocardial infarction, the rate of the composite of death from any cause, myocardial infarction, or major bleeding was not lower among those who received bivalirudin than among those who received heparin monotherapy. (Funded by the Swedish Heart-Lung Foundation and others; VALIDATE-SWEDEHEART ClinicalTrialsRegister.eu number, 2012-005260-10 ; ClinicalTrials.gov number, NCT02311231 .).
|
|
| 3. |
- Negrea, Aurel, et al.
(författare)
-
Salicylidene Acylhydrazides That Affect Type III Protein Secretion in Salmonella enterica Serovar Typhimurium
- 2007
-
Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804. ; 51:8, s. 2867-76
-
Tidskriftsartikel (refereegranskat)abstract
- A collection of nine salicylidene acylhydrazide compounds were tested for their ability to inhibit the activity of virulence-associated type III secretion systems (T3SSs) in Salmonella enterica serovar Typhimurium. The compounds strongly affected Salmonella pathogenicity island 1 (SPI1) T3SS-mediated invasion of epithelial cells and in vitro secretion of SPI1 invasion-associated effector proteins. The use of a SPI1 effector ß-lactamase fusion protein implicated intracellular entrapment of the protein construct upon application of a salicylidene acylhydrazide, whereas the use of chromosomal transcriptional gene fusions revealed a compound-mediated transcriptional silencing of SPI1. Salicylidene acylhydrazides also affected intracellular bacterial replication in murine macrophage-like cells and blocked the transport of an epitope-tagged SPI2 effector protein. Two of the compounds significantly inhibited bacterial motility and expression of extracellular flagellin. We conclude that salicylidene acylhydrazides affect bacterial T3SS activity in S. enterica and hence could be used as lead substances when designing specific inhibitors of bacterial T3SSs in order to pharmaceutically intervene with bacterial virulence.
|
|
| 4. |
- von Tottleben, Malte, et al.
(författare)
-
An Integrated Care Platform System (C3-Cloud) for Care Planning, Decision Support, and Empowerment of Patients With Multimorbidity: Protocol for a Technology Trial
- 2022
-
Ingår i: JMIR Research Protocols. - : JMIR Publications. - 1929-0748. ; 11:7
-
Tidskriftsartikel (refereegranskat)abstract
- Background: There is an increasing need to organize the care around the patient and not the disease, while considering the complex realities of multiple physical and psychosocial conditions, and polypharmacy. Integrated patient-centered care delivery platforms have been developed for both patients and clinicians. These platforms could provide a promising way to achieve a collaborative environment that improves the provision of integrated care for patients via enhanced information and communication technology solutions for semiautomated clinical decision support.Objective: The Collaborative Care and Cure Cloud project (C3-Cloud) has developed 2 collaborative computer platforms for patients and members of the multidisciplinary team (MDT) and deployed these in 3 different European settings. The objective of this study is to pilot test the platforms and evaluate their impact on patients with 2 or more chronic conditions (diabetes mellitus type 2, heart failure, kidney failure, depression), their informal caregivers, health care professionals, and, to some extent, health care systems.Methods: This paper describes the protocol for conducting an evaluation of user experience, acceptability, and usefulness of the platforms. For this, 2 “testing and evaluation” phases have been defined, involving multiple qualitative methods (focus groups and surveys) and advanced impact modeling (predictive modeling and cost-benefit analysis). Patients and health care professionals were identified and recruited from 3 partnering regions in Spain, Sweden, and the United Kingdom via electronic health record screening.Results: The technology trial in this 4-year funded project (2016-2020) concluded in April 2020. The pilot technology trial for evaluation phases 3 and 4 was launched in November 2019 and carried out until April 2020. Data collection for these phases is completed with promising results on platform acceptance and socioeconomic impact. We believe that the phased, iterative approach taken is useful as it involves relevant stakeholders at crucial stages in the platform development and allows for a sound user acceptance assessment of the final product.Conclusions: Patients with multiple chronic conditions often experience shortcomings in the care they receive. It is hoped that personalized care plan platforms for patients and collaboration platforms for members of MDTs can help tackle the specific challenges of clinical guideline reconciliation for patients with multimorbidity and improve the management of polypharmacy. The initial evaluative phases have indicated promising results of platform usability. Results of phases 3 and 4 were methodologically useful, yet limited due to the COVID-19 pandemic.
|
|
| 5. |
- Ahlborg, Mikael, 1985-, et al.
(författare)
-
SoCap YMH - youth mental health, social capital and help-seeking : a study protocol
- 2024
-
Ingår i: Frontiers in Public Health. - Lausanne : Frontiers Media S.A.. - 2296-2565. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The increase in adolescents reporting mental health problems presents a major public health challenge. The complex association between mental health and social capital motivates further investigation of social capital as a crucial aspect in shaping adolescents' help-seeking knowledge, attitudes, and behaviours. Aim: This protocol presents a project that aims to investigate social capital in relation to help-seeking and mental health in close collaboration with adolescents and key stakeholders in the school setting, in the southern part of Sweden. Methods: A mixed-method design with three interconnected work packages (WP) will be undertaken with an emphasis on co-production where adolescents are involved throughout the process. WP1 is a development and validation of two questionnaire instruments for assessing social capital and help-seeking in adolescence. WP2 is a longitudinal quantitative study involving 1,500 adolescents from two regions representing rural and suburban/urban settings. Adolescents aged 15 will be asked to complete questionnaires concerning social capital, mental health, and help-seeking in a baseline and one-year follow-up, allowing for investigation of the role of social capital for help-seeking. WP3 is designed to elucidate experiences and knowledge of adolescents and key stakeholders via collaborative World Café workshops. These will be held along the project to evolve the generated knowledge and maximize it's applicability during and after the project is finalized. Conclusion: The results are expected to further the understanding of the relationship between adolescents' social capital, mental health, and help-seeking, to contribute to a deeper understanding of the mechanisms behind the paradoxical help-seeking patterns among adolescents today and to narrow the gap between research and practice to produce sustainable and efficient strategies, which may facilitate help-seeking and improve the mental health of adolescents within existing organizational structures. Copyright © 2024 Ahlborg, Morgan, Svedberg, Nygren, Eriksson and Westberg.
|
|
| 6. |
- Andersen, Niels S., et al.
(författare)
-
Pre-Emptive Treatment With Rituximab of Molecular Relapse After Autologous Stem Cell Transplantation in Mantle Cell Lymphoma
- 2009
-
Ingår i: Journal of Clinical Oncology. - 0732-183X .- 1527-7755. ; 27:26, s. 4365-4370
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). Patients and Materials MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m(2) weekly for 4 weeks. Results Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. Conclusion Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.
|
|
| 7. |
- Ashelford, Kevin, et al.
(författare)
-
Full genome re-sequencing reveals a novel circadian clock mutationin Arabidopsis
- 2011
-
Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 12, s. R28-
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Map based cloning in Arabidopsis thaliana can be a difficult and time-consuming process,specifically if the phenotype is subtle and scoring labour intensive. An alternative to map basedcloning would be to directly sequence the whole genome of a mutant to uncover the mutationresponsible for the phenotype. Results: Here, we have re-sequenced the 120 Mb genome of a novel Arabidopsis clock mutant earlybird (ebi-1), using massively parallel sequencing by ligation. This process was further complicated by the fact that ebi-1 is in Wassilewskija (Ws-2), not the reference accession ofArabidopsis. The approach reveals evidence of DNA strand bias in the ethyl methanesulfonate(EMS) mutation process. We have demonstrated the utility of sequencing a backcrossed line andusing gene expression data to limit the number of SNP considered. Using new SNP informationwe have excluded a previously identified clock gene, PRR7. Finally, we have identified a SNPin the gene AtNFXL-2 as the likely cause of the ebi-1 phenotype and validated this bycharacterising a further allele. Conclusion: In Arabidopsis, as in other organisms, the (EMS) mutation load can be high. Here wedescribe how sequencing a backcrossed line, using functional genomics and analysing new SNPinformation can be used to reduce the number EMS mutations for consideration. Moreover, theapproach we describe here does not require out-crossing and scoring F2 mapping populations, anapproach which can be compromised by background effects. The strategy has broad utility andwill be an extremely useful tool to identify causative SNP in other organisms.
|
|
| 8. |
- Awad, Amar, et al.
(författare)
-
Preserved somatosensory conduction in complete spinal cord injury : Discomplete SCI
- 2020
-
Ingår i: Clinical Neurophysiology. - : Elsevier. - 1388-2457 .- 1872-8952. ; 131:5, s. 1059-1067
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Spinal cord injury (SCI) disrupts the communication between brain and body parts innervated from below-injury spinal segments, but rarely results in complete anatomical transection of the spinal cord. The aim of this study was to investigate residual somatosensory conduction in clinically complete SCI, to corroborate the concept of sensory discomplete SCI.Methods: We used fMRI with a somatosensory protocol in which blinded and randomized tactile and nociceptive stimulation was applied on both legs (below-injury level) and one arm (above-injury level) in eleven participants with chronic complete SCI. The experimental design accounts for possible confounding mechanical (e.g. vibration) and cortico-cortical top-down mechanisms (e.g. attention/expectation).Results: Somatosensory stimulation on below-level insensate body regions activated the somatotopically corresponding part of the contralateral primary somatosensory cortex in six out of eleven participants.Conclusions: Our results represent afferent-driven cortical activation through preserved somatosensory connections to the brain in a subgroup of participants with clinically complete SCI, i.e. sensory discomplete SCI.Significance: Identifying patients with residual somatosensory connections might open the door for new rehabilitative and restorative strategies as well as inform research on SCI-related conditions such as neuropathic pain and spasticity.
|
|
| 9. |
- Bergström, Göran, 1964, et al.
(författare)
-
Body weight at age 20 and in midlife is more important than weight gain for coronary atherosclerosis: Results from SCAPIS.
- 2023
-
Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 373, s. 46-54
-
Tidskriftsartikel (refereegranskat)abstract
- Elevated body weight in adolescence is associated with early cardiovascular disease, but whether this association is traceable to weight in early adulthood, weight in midlife or to weight gain is not known. The aim of this study is to assess the risk of midlife coronary atherosclerosis being associated with body weight at age 20, body weight in midlife and body weight change.We used data from 25,181 participants with no previous myocardial infarction or cardiac procedure in the Swedish CArdioPulmonary bioImage Study (SCAPIS, mean age 57 years, 51% women). Data on coronary atherosclerosis, self-reported body weight at age 20 and measured midlife weight were recorded together with potential confounders and mediators. Coronary atherosclerosis was assessed using coronary computed tomography angiography (CCTA) and expressed as segment involvement score (SIS).The probability of having coronary atherosclerosis was markedly higher with increasing weight at age 20 and with mid-life weight (p<0.001 for both sexes). However, weight increase from age 20 until mid-life was only modestly associated with coronary atherosclerosis. The association between weight gain and coronary atherosclerosis was mainly seen in men. However, no significant sex difference could be detected when adjusting for the 10-year delay in disease development in women.Similar in men and women, weight at age 20 and weight in midlife are strongly related to coronary atherosclerosis while weight increase from age 20 until midlife is only modestly related to coronary atherosclerosis.
|
|
| 10. |
- Bley, Jessica, et al.
(författare)
-
Design friction in autonomous drive : exploring transitions between autonomous and manual drive in non-urgent situations
- 2023
-
Ingår i: Personal and Ubiquitous Computing. - : Springer. - 1617-4909 .- 1617-4917. ; 27:6, s. 2291-2305
-
Tidskriftsartikel (refereegranskat)abstract
- In the ongoing turn to automation, the growing trend towards the design of conditionally and highly automated vehicles (C/HAV) is evident. In a CAV, the driver no longer needs to partake in the driving. However, the vehicle might send a takeover request (TOR) when the CAV's system reaches its operational boundaries, i.e. a call for a transition from autonomous to manual drive. Previous research on TORs has focused on the context of urgent situations, e.g. hazards and unpredictable events. Furthermore, it has been noted that drivers’ situation awareness (SA) deteriorates after being in autonomous drive. However, less is known about TORs in non-urgent situations. Motivated by this need, the study explores how design friction can serve as a guiding concept for transferring control between autonomous and manual drive in non-urgent situations to increase situation awareness. Design friction is defined as elements of interactions that steer attention and guides the driver to take informed decisions. The work resulted in prototypes that leveraged design friction as part of a takeover sequence. The proposed design was empirically evaluated in a fixed-base medium-fidelity driving simulator. The results indicated that the level of friction might have been too extensive, as some annoyance was expressed. However, participants claimed to feel calm and aware of their surroundings at the moment of regaining control of the vehicle. This suggests that design friction is a promising tool for guiding concept design to enhance transitions from autonomous to manual drive.
|
|
