| 1. |
|
|
| 2. |
- Van den Brink, P. J., et al.
(författare)
-
Toward sustainable environmental quality: Priority research questions for Europe
- 2018
-
Ingår i: Environmental Toxicology and Chemistry. - : Wiley. - 0730-7268 .- 1552-8618. ; 37:9, s. 2281-2295
-
Tidskriftsartikel (refereegranskat)abstract
- The United Nations' Sustainable Development Goals have been established to end poverty, protect the planet, and ensure prosperity for all. Delivery of the Sustainable Development Goals will require a healthy and productive environment. An understanding of the impacts of chemicals which can negatively impact environmental health is therefore essential to the delivery of the Sustainable Development Goals. However, current research on and regulation of chemicals in the environment tend to take a simplistic view and do not account for the complexity of the real world, which inhibits the way we manage chemicals. There is therefore an urgent need for a step change in the way we study and communicate the impacts and control of chemicals in the natural environment. To do this requires the major research questions to be identified so that resources are focused on questions that really matter. We present the findings of a horizon-scanning exercise to identify research priorities of the European environmental science community around chemicals in the environment. Using the key questions approach, we identified 22 questions of priority. These questions covered overarching questions about which chemicals we should be most concerned about and where, impacts of global megatrends, protection goals, and sustainability of chemicals; the development and parameterization of assessment and management frameworks; and mechanisms to maximize the impact of the research. The research questions identified provide a first-step in the path forward for the research, regulatory, and business communities to better assess and manage chemicals in the natural environment. Environ Toxicol Chem 2018;37:2281-2295. (c) 2018 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Järver, Peter, et al.
(författare)
-
Single-Stranded Nucleic Acids Regulate TLR3/4/7 Activation through Interference with Clathrin-Mediated Endocytosis
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Recognition of nucleic acids by endosomal Toll-like receptors (TLR) is essential to combat pathogens, but requires strict control to limit inflammatory responses. The mechanisms governing this tight regulation are unclear. We found that single-stranded oligonucleotides (ssON) inhibit endocytic pathways used by cargo destined for TLR3/4/7 signaling endosomes. Both ssDNA and ssRNA conferred the endocytic inhibition, it was concentration dependent, and required a certain ssON length. The ssON-mediated inhibition modulated signaling downstream ofTLRs that localized within the affected endosomal pathway. We further show that injection of ssON dampens dsRNA-mediated inflammatory responses in the skin of non-human primates. These studies reveal a regulatory role for extracellular ssON in the endocytic uptake of TLR ligands and provide a mechanistic explanation of their immunomodulation. The identified ssON-mediated interference of endocytosis (SOMIE) is a regulatory process that temporarily dampens TLR3/4/7 signaling, thereby averting excessive immune responses.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
|
|
| 12. |
|
|
| 13. |
- Ran, C, et al.
(författare)
-
Genetic Variations and mRNA Expression of NRF2 in Parkinson's Disease
- 2017
-
Ingår i: Parkinson's disease. - : Hindawi Limited. - 2090-8083 .- 2042-0080. ; 2017, s. 4020198-
-
Tidskriftsartikel (refereegranskat)abstract
- Nuclear factor erythroid 2-like 2 (NRF2) encodes a transcription factor regulating mechanisms of cellular protection and is activated by oxidative stress. NRF2 has therefore been hypothesized to confer protection against Parkinson’s disease and so far an NRF2 haplotype has been reported to decrease the risk of developing disease and delay disease onset. Also NRF2 adopts a nuclear localization in Parkinson’s disease, which is indicative of increased NRF2 activity. We have investigated the association between NRF2 and Parkinson’s disease in a Swedish case-control material and whether NRF2 expression levels correlate with NRF2 genetic variants, disease, or disease onset. Using pyrosequencing, we genotyped one intronic and three promoter variants in 504 patients and 509 control subjects from Stockholm. Further, we quantified NRF2 mRNA expression in EBV transfected human lymphocytes from patients and controls using quantitative real-time reverse transcription PCR. We found that one of the promoter variants, rs35652124, was associated with age of disease onset (Χ2 = 14.19, p value = 0.0067). NRF2 mRNA expression levels however did not correlate with the rs35652124 genotype, Parkinson’s disease, or age of onset in our material. More detailed studies on NRF2 are needed in order to elucidate how this gene affects pathophysiology of Parkinson’s disease.
|
|
| 14. |
- Ran, C., et al.
(författare)
-
Strong association between glucocerebrosidase mutations and Parkinson's disease in Sweden
- 2016
-
Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 45
-
Tidskriftsartikel (refereegranskat)abstract
- Several genetic studies have demonstrated an association between mutations in glucocerebrosidase (GBA), originally implicated in Gaucher's disease, and an increased risk of Parkinson's disease (PD). We have investigated the possible involvement of genetic GBA variations in PD in the Swedish population. Three GBA variants, E326K, N370S, and L444P were screened in the largest Swedish Parkinson cohort reported to date; 1625 cases and 2025 control individuals. We found a significant association with high effect size of the rare variant L444P with PD (odds ratio 8.17; 95% confidence interval: 2.51-26.23; p-value = 0.0020) and a significant association of the common variant E326K (odds ratio 1.60; 95% confidence interval: 1.16-2.22; p-value = 0.026). The rare variant N370S showed a trend for association. Most L444P carriers (68%) were found to reside in northern Sweden, which is consistent with a higher prevalence of Gaucher's disease in this part of the country. Our findings support the role of GBA mutations as risk factors for PD and point to lysosomal dysfunction as a mechanism contributing to PD etiology. (C) 2016 The Author(s). Published by Elsevier Inc.
|
|
| 15. |
|
|
| 16. |
- Adegoke, Olutayo, et al.
(författare)
-
Laser beam powder bed fusion and post processing of alloy 247LC
- 2019
-
Ingår i: MS and T 2019 - Materials Science and Technology. - : Materials Science and Technology. - 9780873397704 ; , s. 27-34
-
Konferensbidrag (refereegranskat)abstract
- Alloy 247LC is sensitive to cracking during laser beam powder bed fusion (PBF-LB) manufacturing. Post processing is thus required to close cracks and achieve desired properties. In this study, samples of Alloy 247LC were manufactured by PBF-LB and subsequently post processed by hot isostatic pressing (HIP), HIP + solution and ageing heat treatments. The microstructure was characterized. Results showed cracks in the as-built condition. Cracks were not detected after HIP. Bright microconstituents were observed in the region between the cells, mainly, because of the partitioning of Hf and Ta into the intercellular region, where they presumably form carbides. What is assumed to be oxides were prominent in the microstructure. Thermodynamic calculations showed rapid formation of ?’ precipitates in the alloy, due to the high total concentration of Al and Ta and this was linked to the high hardness values in the as-built condition. © 2019 MS&T19®
|
|
| 17. |
|
|
| 18. |
- Bereczki, E., et al.
(författare)
-
Synaptic proteins in CSF relate to Parkinson's disease stage markers
- 2017
-
Ingår i: Npj Parkinsons Disease. - : Springer Science and Business Media LLC. - 2373-8057. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- Recent findings of morphological and functional changes in Parkinson's disease brains have shown altered synapse formation, but their role in cognitive decline is still an area under exploration. Here we measured the concentration of three key synaptic proteins, Rab3A, SNAP25 and neurogranin by enzyme-linked immunosorbent assay, in cerebrospinal fluid from a total of 139 participants (87 controls and 52 Parkinson's disease patients out of which 30 were drug-naive) and explored their associations with motor and cognitive symptoms. Associations with motor disease stage (assessed by Hoehn and Yahr scale) and cognitive performance (assessed by the Montreal Cognitive Assessment scores) were explored. An overall increase in the concentration of SNAP25 was found in Parkinson's disease patients (p = 0.032). Increased neurogranin levels were found in the drug naive patients subgroup (p = 0.023). Significant associations were observed between increased concentration of neurogranin and cognitive impairment in total Parkinson's disease group (p = 0.017), as well as in the drug naive (p = 0.021) and with motor disease stage (p = 0.041). There were no significant disease-driven changes observed in the concentration of Rab3a. Concentrations SNAP25 and neurogranin were increased in cerebrospinal fluid of Parkinson's disease patients in a disease specific manner and related to cognitive and motor symptom severity. Future longitudinal studies should explore whether cerebrospinal fluid synaptic proteins can predict cognitive decline in Parkinson's disease.
|
|
| 19. |
- Brodin, Bertha A., et al.
(författare)
-
Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas
- 2019
-
Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 120:4, s. 435-443
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
- Combe, B, et al.
(författare)
-
2016 update of the EULAR recommendations for the management of early arthritis
- 2017
-
Ingår i: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 76:6, s. 948-959
-
Tidskriftsartikel (refereegranskat)abstract
- Since the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of the 2007 European League Against Rheumatism (EULAR) recommendations for management of early arthritis.MethodsIn accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 healthcare professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of ‘management’ and selected the research questions. A systematic literature research (SLR) was performed by two fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation, the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process.ResultsThe updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research.ConclusionsThese recommendations provide rheumatologists, general practitioners, healthcare professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis.
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
- Engert, Andreas, et al.
(författare)
-
The European Hematology Association Roadmap for European Hematology Research : a consensus document
- 2016
-
Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:2, s. 115-208
-
Tidskriftsartikel (refereegranskat)abstract
- The European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at (sic)23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
- Greenwood, John, et al.
(författare)
-
Current research into brain barriers and the delivery of therapeutics for neurological diseases : a report on CNS barrier congress London, UK, 2017
- 2017
-
Ingår i: Fluids and Barriers of the CNS. - : Springer Science and Business Media LLC. - 2045-8118. ; 14
-
Forskningsöversikt (refereegranskat)abstract
- This is a report on the CNS barrier congress held in London, UK, March 22-23rd 2017 and sponsored by Kisaco Research Ltd. The two 1-day sessions were chaired by John Greenwood and Margareta Hammarlund-Udenaes, respectively, and each session ended with a discussion led by the chair. Speakers consisted of invited academic researchers studying the brain barriers in relation to neurological diseases and industry researchers studying new methods to deliver therapeutics to treat neurological diseases. We include here brief reports from the speakers.
|
|
| 33. |
- Hashemi, Nashmil, et al.
(författare)
-
Improved right ventricular index of myocardial performance in the assessment of right ventricular function after coronary artery bypass grafting
- 2018
-
Ingår i: Interactive Cardiovascular and Thoracic Surgery. - : Oxford University Press. - 1569-9293 .- 1569-9285. ; 26:5, s. 798-804
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Decreased right ventricular (RV) longitudinal function following coronary artery bypass grafting (CABG), as assessed by tricuspid annular systolic excursion (TAPSE) and RV peak systolic velocity (RVS') is a known condition. We aimed to explore the feasibility of the right ventricular index of myocardial performance (RIMP) in the assessment of RV function after CABG at rest and during peak dobutamine stress echocardiography (DSE). METHODS: Forty-two patients indicated for CABG were included in this study. Coronary angiography, DSE and exercise bicycle test were performed within 6 weeks before and 3 months after CABG. The RIMP, RVS' and TAPSE at the lateral tricuspid annulus were also assessed. The results were presented as mean +/- standard deviation. RESULTS: The RIMP improved after CABG both at rest (0.45 +/- 0.11 before vs 0.38 +/- 0.08 after CABG, P= 0.013) and during DSE (0.75 +/- 0.23 vs 0.49 +/- 0.14, P < 0.001). TAPSE declined significantly when comparing the values from before CABG to after CABG both at rest (23.9 +/- 4.46 vs 14.6 +/- 3.67, P < 0.001) and during DSE (20.9 +/- 4.16 vs 11.9 +/- 3.60, P < 0.001). RVS' also decreased after CABG both at rest (11.9 +/- 2.40 vs 8.5 +/- 1.93, P < 0.001) and during DSE (15.6 +/- 4.30 vs 10.5 +/- 3.21, P <0.001). On the other hand, exercise capacity improved after CABG compared with baseline (128.4 +/- 40.12 W vs 142.1 +/- 46.73 W, P = 0.014). CONCLUSIONS: RIMP improved after CABG both at rest and during DSE. The reduction in TAPSE and RVS' after CABG indicate reduced regional mechanical RV function along the long axis rather than reduced global RV function.
|
|
| 34. |
- Hashemi, Nashmil, et al.
(författare)
-
Right ventricular mechanics and contractility after aortic valve replacement surgery : a randomised study comparing minimally invasive versus conventional approach
- 2018
-
Ingår i: Open heart. - : BMJ Publishing Group Ltd. - 2053-3624. ; 5:2
-
Tidskriftsartikel (refereegranskat)abstract
- Objective Minimally invasive aortic valve replacementsurgery (MIAVR) is an alternative surgical technique to conventional aortic valve replacement surgery (AVR) in selected patients. The randomised study Cardiac Function after Minimally Invasive Aortic Valve Implantation (CMILE) showed that right ventricular (RV) longitudinal function was reduced after both MIAVR and AVR, but the reduction was more pronounced following AVR. However, postoperative global RV function was equally impaired in both groups. The purpose of this study was to explore alterations in RV mechanics and contractility following MIAVR as compared with AVR. Methods A predefined post hoc analysis of CMILE consisting of 40 patients with severe aortic valve stenosis who were eligible for isolated surgical aortic valve replacement were randomised to MIAVR or AVR. RV function was assessed by echocardiography prior to surgery and 40 days post-surgery. Results Comparing preoperative to postoperative values, RV longitudinal strain rate was preserved following MIAVR (-1.5 +/- 0.5 vs -1.5 +/- 0.4 1/s, p=0.84) but declined following AVR (-1.7 +/- 0.3 vs -1.4 +/- 0.3 its, p<0.01). RV longitudinal strain reduced following AVR (-27.4 +/- 2.9% vs -18.8%+/- 4.7%, p<0.001) and MIAVR (-26.5 +/- 5.3% vs -20.7%+/- 4.5%, p<0.01). Peak systolic velocity of the lateral tricuspid annulus reduced by 36.6% in the AVR group (9.3 +/- 2.1 vs 5.9 +/- 1.5 cm/s, p<0.01) and 18.8% in the MIAVR group (10.1 +/- 2.9 vs 8.2 +/- 1.4 cm/s, p<0.01) when comparing preoperative values with postoperative values. Conclusions RV contractility was preserved following MIAVR but was deteriorated following AVR. RV longitudinal function reduced substantially following AVR. A decline in RV longitudinal function was also observed following MIAVR, however, to a much lesser extent.
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
- Isaksson, Emil, et al.
(författare)
-
High level of self-control ability in a small passerine bird
- 2018
-
Ingår i: Behavioral Ecology and Sociobiology. - : Springer Science and Business Media LLC. - 0340-5443 .- 1432-0762. ; 72:7
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract: Cognitively advanced animals are usually assumed to possess better self-control, or ability to decline immediate rewards in favour of delayed ones, than less cognitively advanced animals. It has been claimed that the best predictor of high such ability is absolute brain volume meaning that large-brained animals should perform better than small-brained ones. We tested self-control ability in the great tit, a small passerine. In the common test of this ability, the animal is presented with a transparent cylinder that contains a piece of food. If the animal tries to take the reward through the transparent wall of the cylinder, this is considered an impulsive act and it fails the test. If it moves to an opening and takes the reward this way, it passes the test. The average performance of our great tits was 80%, higher than most animals that have been tested and almost in level with the performance in corvids and apes. This is remarkable considering that the brain volume of a great tit is 3% of that of a raven and 0.1% of that of a chimpanzee. Significance statement: The transparent cylinder test is the most common way to test the ability of self-control in animals. If an animal understands that it only can take food in the cylinder from the cylinder’s opening and controls its impulsivity, it passes the test. A high level of self-control has been demonstrated only in cognitively advanced animals such as apes and corvids. Here, we demonstrate that the great tit, a small song bird that is very good at learning, performs almost in level with chimpanzees and ravens in this test.
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
- Lakshmikanth, T, et al.
(författare)
-
An assay for immunological health
- 2017
-
Ingår i: SCANDINAVIAN JOURNAL OF IMMUNOLOGY. - 0300-9475. ; 86:4, s. 300-301
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)
|
|
| 41. |
|
|
| 42. |
- Ljungstrom, L., et al.
(författare)
-
Clinical evaluation of commercial nucleic acid amplification tests in patients with suspected sepsis
- 2015
-
Ingår i: Bmc Infectious Diseases. - : Springer Science and Business Media LLC. - 1471-2334. ; 15
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Sepsis is a serious medical condition requiring timely administered, appropriate antibiotic therapy. Blood culture is regarded as the gold standard for aetiological diagnosis of sepsis, but it suffers from low sensitivity and long turnaround time. Thus, nucleic acid amplification tests (NAATs) have emerged to shorten the time to identification of causative microbes. The aim of the present study was to evaluate the clinical utility in everyday practice in the emergency department of two commercial NAATs in patients suspected with sepsis. Methods: During a six-week period, blood samples were collected consecutively from all adult patients admitted to the general emergency department for suspicion of a community-onset sepsis and treated with intravenous antibiotics. Along with conventional blood cultures, multiplex PCR (Magicplex (TM)) was performed on whole blood specimens whereas portions from blood culture bottles were used for analysis by microarray-based assay (Prove-it (TM)). The aetiological significance of identified organisms was determined by two infectious disease physicians based on clinical presentation and expected pathogenicity. Results: Among 382 episodes of suspected sepsis, clinically relevant microbes were detected by blood culture in 42 episodes (11%), by multiplex PCR in 37 episodes (9.7%), and by microarray in 32 episodes (8.4%). Although moderate agreement with blood culture (kappa 0.50), the multiplex PCR added diagnostic value by timely detection of 15 clinically relevant findings in blood culture-negative specimens. Results of the microarray corresponded very well to those of blood culture (kappa 0.90), but were available just marginally prior to blood culture results. Conclusions: The use of NAATs on whole blood specimens in adjunct to current culture-based methods provides a clinical add-on value by allowing for detection of organisms missed by blood culture. However, the aetiological significance of findings detected by NAATs should be interpreted with caution as the high analytical sensitivity may add findings that do not necessarily corroborate with the clinical diagnosis.
|
|
| 43. |
|
|
| 44. |
- Mellin, Pelle, et al.
(författare)
-
Moisture content analysis of metal powders, using oven desorption followed by Karl Fischer titration
- 2018
-
Ingår i: Euro PM 2018 Congress and Exhibition. - : European Powder Metallurgy Association (EPMA). - 9781899072507
-
Konferensbidrag (refereegranskat)abstract
- In this paper, we use Oven Desorption followed by Karl Fischer Titration (KF), to measure moisture content in a newly opened PBF-LB Hasteloy X powder (we found 28.8 ppm), an PBF-EB powder (13.7 ppm) and a HIP powder (6.7 ppm). This method heats a powder sample inside a hermetically closed vial, in an oven. At the same time an inert gas flow enters, flushes out the evaporated water and exits the vial, via a double hollow needle. The gas-water mixture that exits is directed to the Karl Fischer Titration, where the evaporated moisture is quantified. Included is also a comparison with thermogravimetric analysis (TGA) and a climate chamber moisturization experiment of a PBF-LB HX powder followed by KF analysis. After the moisturization and KF analysis, the same powder was characterized in terms of oxygen content.
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
|
|
