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2.
Front Immunol ; 10: 2168, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572379

RESUMO

The heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-κB transcription factor is a highly regulated, dynamic event in IBD pathogenesis. Using a lentivirus approach, NF-κB-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-κB-regulated luciferase response. The ulcerative colitis (UC) samples appeared only in the hypo-responsive Cluster 1, and in Cluster 2. Conversely, Crohn's disease (CD) patients appeared in all Clusters with their percentage being higher in the hyper-responsive Cluster 3. A positive correlation was seen between NF-κB-induced luciferase activity and the concentrations of cytokines released into medium from stimulated macrophages, but not with serum or biopsy cytokine levels. Confocal imaging of lentivirally-expressed p65 activation revealed that a higher proportion of macrophages from CD patients responded to endotoxin lipid A compared to controls. In contrast, cells from UC patients exhibited a shorter duration of NF-κB p65 subunit nuclear localization compared to healthy controls, and CD donors. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between CD patients who smoked and hyper-activation of p65. These in vitro dynamic assays of NF-κB activation in blood-derived macrophages have the potential to segregate IBD patients into groups with different phenotypes and may therefore help determine response to therapy.

3.
Eur J Cancer ; 120: 75-85, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31499383

RESUMO

INTRODUCTION: The use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated. METHODS: Blood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed. RESULTS: Drug exposure varied significantly between patients, with a >12-fold variation in AUC0-12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC0-12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction. CONCLUSION: The potential significance of dexamethasone AUC0-12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective.

4.
Nat Med ; 25(9): 1408-1414, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31477906

RESUMO

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.


Assuntos
Antígenos CD19/administração & dosagem , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/imunologia , Adolescente , Antígenos CD19/genética , Antígenos CD19/imunologia , Criança , Pré-Escolar , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Recidiva , Linfócitos T/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-31394275

RESUMO

Outcomes for adolescents and young adults (AYAs) with leukemia differ from other age groups and are still under-represented in clinical research. The aim of this study was to analyze outcomes of umbilical cord blood transplant (UCBT) in AYAs with acute leukemia reported to Eurocord/European Society for Blood and Marrow Transplantation. Patients (N = 504) had acute lymphoblastic (59%) or myeloid leukemia (41%), were aged 15 to 25 years, and received UCBT after myeloablative conditioning regimens between 2004 and 2016. The primary endpoint was 3-year overall survival (OS). Median follow-up was 3.9 years. Transplant was single in 58% and double UCBT in 42%. Three-year OS was 45% and leukemia free survival (LFS) was 41%. Cumulative incidence functions (CIFs) of nonrelapse mortality (NRM) and relapse were 31% and 28%, respectively. CIF of acute graft-versus-host disease (GVHD) grades II to IV at day 100 was 28%. Three-year CIF of chronic GVHD was 25%. In adjusted analysis, better disease status at UCBT (hazard ratio [HR], 2.74; P < .001) and more recent UCBT (HR, 1.43; P = .01) were associated with increased OS, and a similar effect of these factors was observed on LFS. Contrastingly, the use of antithymocyte globulin had a negative effect in LFS. The risk of acute GVHD grades II to IV increased with the use of double UCBT (HR, 1.65; P  = .02) and decreased with more recent transplant period (HR, .65; P = .02) and antithymocyte globulin use (HR, .55; P  = .01). Outcomes of AYA UCBT improved in more recent years, becoming comparable with pediatric results. Demonstrating the feasibility of UCBT in AYAs facilitates stem cell source selection and provides the basis for future prospective studies.

6.
BMJ Open ; 9(8): e028119, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31383701

RESUMO

OBJECTIVES: To conduct a UK-wide survey of young people who have experienced cancer, carers and professionals, to identify and prioritise research questions to inform decisions of research funders and support the case for research with this unique cancer population. DESIGN: James Lind Alliance Priority Setting Partnership. SETTING: UK health service and community. METHODS: A steering group oversaw the initiative and partner organisations were recruited. Unanswered questions were collected in an online survey. Evidence searching verified uncertainties. An interim survey was used to rank questions prior to a final prioritisation workshop. PARTICIPANTS: Young people aged 13-24 years with a current or previous cancer diagnosis, their families, friends, partners and professionals who work with this population. RESULTS: Two hundred and ninety-two respondents submitted 855 potential questions. Following a refining process and removal of 'out of scope' questions, 208 unique questions remained. Systematic evidence checking identified seven answered questions and 16 were the subject of ongoing studies. The interim survey was completed by 174 participants. The top 30 questions were prioritised at a workshop attended by 25 young people, parents and multidisciplinary professionals. The top three priorities are: (1) What psychological support package improves psychological well-being, social functioning and mental health during and after treatment? (2) What interventions, including self-care, can reduce or reverse adverse short-term and long-term effects of cancer treatment? (3) What are the best strategies to improve access to clinical trials? The remaining questions reflect the complete cancer pathway: new therapies, life after cancer, support, education/employment, relapse and end-of-life care. CONCLUSIONS: We have identified shared research priorities for young people with cancer using a rigorous, person-centred approach involving stakeholders typically not involved in setting the research agenda. The breadth of priorities suggest future research should focus on holistic and psychosocial care delivery as well as traditional drug/biology research.

7.
J Pediatr Oncol Nurs ; 36(6): 424-435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31068048

RESUMO

Young people with cancer are at increased risk of psychological difficulty; yet there is little research on their experiences of low mood or depressive symptoms to help inform treatment interventions. This qualitative study explored experiences and opinions of low mood or depression in young people with cancer, how their mood related to developmental challenges, strategies used to cope, and how services could improve support. Nineteen young people diagnosed and treated for cancer completed semistructured interviews. Transcripts were thematically analyzed using the framework approach, and analysis produced eight themes, organized into three domains: "A Harder Time of Life," "Interpersonal Impact of Cancer," and "Learning to Understand and Describe Low Mood," Participants interviewed experienced low mood during cancer and predominantly felt "low mood" was a helpful term to describe their emotions. There were similarities and variations in their reported mood compared with clinical depression. The developmental challenges of being a young person with cancer negatively affected their mood. Participants used a variety of different coping strategies to manage these challenges. Young people were clear that they would like others to help them understand negative emotions experienced through cancer are normal to feel and support for low mood to be accessible and available.

8.
Cancer Nurs ; 2019 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-30921031

RESUMO

BACKGROUND: Teenagers and young adults (TYAs) with cancer are known to suffer poor sleep quality and sleep disturbances; understanding the level of burden is essential to improving patient outcomes via supportive care interventions. OBJECTIVES: To compare sleep quality and the prevalence of sleep disturbances among TYA cancer patients, TYA survivors, and general population TYAs with no history of cancer. METHODS: Teenager and young adult patients receiving active cancer treatment (n = 70), TYA cancer survivors (n = 151), and general population TYAs (n = 324) aged between 13 and 24 years completed the Pittsburgh Sleep Quality Index. Analyses of covariance were used to investigate potential group differences. Age at survey diagnosis, gender, ethnicity, and health status were included as covariates. RESULTS: 84.29% of TYA patients, 62.91% of TYA cancer survivors, and 65.12% of general population TYAs reported Pittsburgh Sleep Quality Index scores greater than 5, suggesting clinically significant sleep disorders. Teenager and young adult patients reported significantly poorer global sleep quality compared with TYA survivors (mean difference, 0.99; 95% confidence interval, 0.03-1.96; P = .044) and general population TYAs (mean difference, 1.34; 95% confidence interval, 0.26-2.41; P = .009). Teenager and young adult patients and survivors reported significantly poorer sleep latency (P = .003 for TYA patients, P = .035 for TYA survivors off treatment) and habitual sleep efficiency (P < .001 for TYA patients, P = .014 for TYA survivors) than general population controls. CONCLUSIONS: The significant differences observed suggest young people with cancer, particularly those on treatment, may benefit from specialized sleep interventions. IMPLICATIONS FOR PRACTICE: Efforts to ensure health professionals have the knowledge and skills to provide advice about sleep to young people with cancer are needed.

10.
BMJ Open ; 9(1): e024397, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30696681

RESUMO

OBJECTIVES: To understand the experiences of young adults with cancer for whom cure is not likely, in particular what may be specific for people aged 16-40 years and how this might affect care. DESIGN: We used data from multiple sources (semi-structured interviews with people with cancer, nominated family members and healthcare professionals, and workshops) informed by a preliminary programme theory: realist analysis of data within these themes enabled revision of our theory. A realist logic of analysis explored contexts and mechanisms affecting outcomes of care. SETTING: Three cancer centres and associated palliative care services across England. PARTICIPANTS: We aimed for a purposive sample of 45 people with cancer from two groups: those aged 16-24 years for whom there may be specialist cancer centres and those 16-40 years cared for through general adult services; each could nominate for interview one family member and one healthcare professional. We interviewed three people aged 16-24 years and 30 people 25-40 years diagnosed with cancer (carcinomas; blood cancers; sarcoma; central nervous system tumours) with a clinician-estimated prognosis of <12 months along with nominated family carers and healthcare professionals. 19 bereaved family members and 47 healthcare professionals participated in workshops. RESULTS: Data were available from 69 interviews (33 people with cancer, 14 family carers, 22 healthcare professionals) and six workshops. Qualitative analysis revealed seven key themes: loss of control; maintenance of normal life; continuity of care; support for professionals; support for families; importance of language chosen by professionals; and financial concerns. CONCLUSIONS: Current care towards end of life for young adults with cancer and their families does not meet needs and expectations. We identified challenges specific to those aged 16-40 years. The burden that care delivery imposes on healthcare professionals must be recognised. These findings can inform recommendations for measures to be incorporated into services.

11.
Pediatr Blood Cancer ; 66(1): e27424, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30209864

RESUMO

Skin cancers are a common form of second malignant neoplasm among teenage and young adult cancer survivors (TYACS). The Children's Oncology Group specifies that TYACS should adhere to safe sun practices and be screened for skin cancer annually. Cross-sectional self-report data collected by our group indicate over a third of TYACS (n = 229; mean age: 19.8 years) intentionally sunbathe, with many reporting sunburn. TYACS sunbathing, sunburn, and sunbed use are similar to the general population (P > 0.05). These data suggest TYACS require intervention to limit sun exposure and improve their sun safety habits.


Assuntos
Sobreviventes de Câncer/estatística & dados numéricos , Exposição Ambiental/efeitos adversos , Comportamentos Relacionados com a Saúde , Conhecimentos, Atitudes e Prática em Saúde , Neoplasias/prevenção & controle , Queimadura Solar/etiologia , Luz Solar/efeitos adversos , Adolescente , Adulto , Sobreviventes de Câncer/psicologia , Criança , Pré-Escolar , Estudos Transversais , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Neoplasias/epidemiologia , Prognóstico , Protetores Solares/administração & dosagem , Taxa de Sobrevida , Reino Unido/epidemiologia , Adulto Jovem
13.
Artigo em Inglês | MEDLINE | ID: mdl-30418093

RESUMO

PURPOSE: Young people with cancer are at increased risk of depression, yet evidence-based psychological interventions that are tailored to the specific needs of young people with cancer are scarce, and depression in this group may be particularly challenging to recognize and treat. The aims of this study were to (1) explore the views of health professionals in recognizing and treating low mood in young people with cancer and (2) identify the key components of an effective online treatment package for depression in this population. METHODS: Eighteen NHS health professionals with a range of professional backgrounds working directly with young people with cancer were interviewed using a semi-structured interview schedule. Responses were analyzed using thematic analysis. RESULTS: Five themes emerged: (1) one size doesn't fit all-the nature of depression is complex and varied, and symptoms fluctuate greatly in relation to physical health; (2) distress is completely understandable-it is important not to pathologize a normal reaction; (3) a stepping stone intervention-online interventions may promote engagement with face-to-face therapy; (4) connecting with others-the intervention should promote sharing experiences with others to reduce isolation; and (5) ownership and empowerment-lack of independence may be a cause of distress, and young people should have control of the intervention. CONCLUSION: The nature of depression in young people with cancer is complex and multifaceted. Online guided self-help may be useful when added as a component or first step of a treatment package including face-to-face talking therapies.

14.
FASEB J ; : fj201800076RR, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30359099

RESUMO

Metabolomics studies have the potential to discover biomarkers. Fecal volatile organic compounds (VOCs) have been found to differ in patients with inflammatory bowel disease and irritable bowel syndrome. Murine models of colitis offer an alternative to human studies in which diet can be controlled. We aimed to investigate fecal VOCs from mice in which acute and chronic colitis was induced. Groups of adult C57BL/6 mice underwent treatment with oral dextran sulfate sodium to induce colitis. Control mice received no treatment or had acute osmotic diarrhea induced with magnesium sulfate. Colitis was assessed clinically and by histology. Samples of feces and/or colon contents were collected and volatile compounds determined by solid phase microextraction-GC-MS. Statistics were performed using metabolomics tools. Acute colitis was associated with an increase in aldehydes and chronic colitis with one specific ketone. Osmotic diarrhea was associated with a significant reduction in VOCs, especially alcohols. We provide evidence that the identification of disease-associated VOC concentration ranges, combined with specific marker compounds, would potentially increase the likelihood of finding an inflammatory bowel disease-specific fecal VOC marker profile.-Reade, S., Williams, J. M., Aggio, R., Duckworth, C. A., Mahalhal, A., Hough, R., Pritchard, D. M., Probert, C. S., Potential role of fecal volatile organic compounds as biomarkers of chemically induced intestinal inflammation in mice.

15.
J Adolesc Young Adult Oncol ; 7(5): 604-611, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30036113

RESUMO

PURPOSE: The diagnosis of cancer is often prolonged in teenagers and young adults (TYA). There may be lessons in improving this from international comparisons. However, international studies are complex and so we conducted a pilot study to examine the key barriers to large-scale research in this field. METHODS: We provided translated questionnaires covering key aspects of presentation and clinical management within 60 days of a confirmed cancer diagnosis, to patients 13-29 years of age inclusive, to their primary care physicians and to the cancer specialists managing their cancer. We conducted descriptive analyses of the data and also the process of study implementation. RESULTS: For our pilot, collecting triangulated data was feasible, but varying regulatory requirements and professional willingness to contribute data were key barriers. The time of data collection and the method for collecting symptom reports were important for timely and accurate data synthesis. Patients reported more symptoms than professionals recorded. We observed substantial variation in pathways to cancer diagnosis to explore definitively in future studies. CONCLUSION: Focused research upon the mechanisms underpinning complex cancer pathways, and focusing that research upon specific cancer types within TYA may be the next key areas of study.

16.
Br J Haematol ; 181(4): 515-522, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29687881

RESUMO

Outcomes for teenage and young adult (TYA) patients with acute lymphoblastic leukaemia (ALL) who relapse on contemporary risk-adapted paediatric protocols are largely unknown and there is no consensus on optimal salvage strategies. We assessed the treatment and outcome of TYA patients (aged 16-24 years) recruited to the UKALL2003 trial, who relapsed following attainment of complete morphological remission. Forty-two of 223 patients (18·8%) relapsed, the majority (n = 26, 62%) on treatment. Thirty-eight (90%) patients received salvage treatment, with 22 (58%) achieving second remission (CR2) and 21 patients receiving an allogeneic haematopoietic cell transplant (alloHSCT). Post-relapse outcomes were poor with a 5-year overall survival (OS) of 23% (95% confidence interval; 11-37%). Outcomes for patients relapsing on active treatment were inferior to those relapsing after completing treatment (5-year OS 9% vs. 52%, log-rank P = 0·001). No patient with B cell ALL relapsing on treatment was alive at the end of the study period. TYA patients with ALL who relapse on the UK paediatric protocol, UKALL2003, are largely unsalvageable with conventional approaches aimed at achieving CR2 followed by alloHSCT. Future efforts should be aimed at identifying those patients who are destined to relapse and exploring novel treatment approaches for this high-risk group and for those who do relapse.

17.
Blood Adv ; 2(7): 777-786, 2018 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-29618462

RESUMO

Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft-versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely.

18.
J Adolesc Young Adult Oncol ; 7(4): 465-471, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29634427

RESUMO

PURPOSE: Teenage and young adult (TYA) cancer survivors experience a range of health-related problems during and beyond the active treatment period. This study examined associations between fatigue, sleep quality, and health-related quality of life (HRQOL) among TYA survivors. METHODS: Self-reported data on sleep quality (Pittsburgh Sleep Quality Index), fatigue (Functional Assessment of Chronic Illness Therapy Fatigue), and HRQOL (EuroQoL-5) were gathered from United Kingdom TYA survivors between 13 and 24 years of age. TYA survivors were stratified into those on (n = 67) and off (n = 135) treatment. Linear regression analyses were used with HRQOL as the dependent variable to investigate potential associations. Fatigue and sleep were entered separately and together in the same model. Age at survey and diagnosis, gender, and ethnicity were included as covariates. RESULTS: 85.07% of TYAs on and 62.69% of TYAs off treatment had sleep quality scores suggestive of clinically significant sleep disorders. 56.72% of TYAs on and 26.67% of TYAs off treatment reported clinically significant levels of fatigue. Strong independent associations between sleep (B = 0.05, 95% confidence intervals [CI] = 0.03-0.07, p < 0.001), fatigue (B = 0.02, 95% CI = 0.01-0.03, p < 0.001), and HRQOL were observed among TYA survivors on treatment. TYAs off treatment showed moderate to strong associations between sleep (B = 0.04, 95% CI = 0.02-0.05, p < 0.001) and fatigue (B = 0.02, 95% CI = 0.01-0.02, p < 0.001), and HRQOL, when examined separately. Sleep was not independently associated with HRQOL among TYAs off treatment (B = 0.01, 95% CI = -0.01 to 0.02, p = 0.296). CONCLUSION: The significant associations reported suggest that sleep quality and fatigue are potential modifiable factors associated with HRQOL. Further research is warranted to understand the direction of associations.

19.
Bone Marrow Transplant ; 53(9): 1165-1169, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29545594

RESUMO

Paediatric therapy-related acute myeloid leukaemia (t-AML) is rare and the outcome is poor. While allogeneic haematopoietic stem cell transplantation (HSCT) is generally the accepted modality of treatment, data regarding salvage chemotherapy, remission induction, conditioning regimens, transplant-related mortality and outcome is scarce. Between 2000 and2016, 36 children with t-AML were treated in seven UK paediatric HSCT centres. The most common salvage protocol for remission induction was FLAG with or without idarubicin and 28 patients were in complete morphological remission prior to BMT. Only 12 patients survived (33%). Transplant-related mortality (TRM) was the leading cause of death.

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