| 1. |
- Björkman, Kristoffer, et al.
(författare)
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Clinical course of patients with single large-scale mtDNA deletions and childhood onset anemia
- 2022
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Ingår i: 14th European Paediatric Neurology Society Congress, Glasgow, UK (ISBN 978-3-00-072065-9).
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: To add to our knowledge of the clinical spectrum of patients with single large-scale mitochondrial DNA (mtDNA) deletion and childhood onset anemia. Methods: Retrospective collection of clinical data from medical records for patients, both living and deceased, with a single large-scale mtDNA deletion from seven mitochondrial disease centers in five countries. Statistical analysis with descriptive methods and Kaplan-Meier survival analysis. Results: Seventeen patients matching the genetic criterium and with anemia onset before six years of age. Exocrine pancreatic insufficiency was only seen in five patients in this group. Multiple organs were involved in all patients, with the most common non-hematologic ones being skeletal muscle, central nervous system, endocrine, eyes, gastrointestinal system, kidneys, hearing, liver and heart. Psychomotor retardation was seen in ten patients, hearing impairment in nine patients, failure to thrive in eight patients. Eight later developed Kearns-Sayre syndrome. Eleven patients were deceased, with a median age at death of 7.5 years. Conclusions: The classically described phenotype of patients with large-scale mtDNA deletions and early onset anemia is Pearson marrow-pancreas syndrome, characterized by sideroblastic anemia and exocrine pancreas dysfunction. Only a minority of our patients fulfill the original criteria of Pearson syndrome though. Involvement of other organs than the pancreas is more common. The clinical course vary, but multi-system impact is the rule and life-expectancy is low. Early onset anemia in patients with large-scale mtDNA deletions is most frequently not associated with exocrine pancreas dysfunction. Better knowledge of the phenotype is helpful for diagnosis and more accurate prognosis.
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| 2. |
- Brundin, Peik M.A., et al.
(författare)
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Blood hormones and torque teno virus in peripheral blood mononuclear cells
- 2020
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Ingår i: Heliyon. - : Elsevier. - 2405-8440. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- Men and women respond differently to infectious diseases. Women show less morbidity and mortality, partially due to the differences in sex hormone levels which can influence the immune response. Torque teno virus (TTV) is non-pathogenic and ubiquitously present in serum from a large proportion (up to 90%) of adult humans with virus levels correlating with the status of the host immune response. The source of TTV replication is unknown, but T-lymphocytes have been proposed. In this study we investigated the presence and levels of TTV in peripheral blood mononuclear cells (PBMCs) in premenopausal (pre-MP) women, post-menopausal (post-MP) women, and men, and determined their serum sex hormone levels. Of the examined subjects (n = 27), we found presence of TTV in PMBC from 17.6% pre-MP (n = 17), 25.0% post-MP (n = 4) and 50.0% men (n = 6). The levels of TTV/μg DNA were lower among TTV-positive men and post-MP women compared to pre-MP women. All the positive pre-MP women were either anovulatory, hypothyroid, or both. In addition, the TTV-positive pre-MP women had significantly lower progesterone levels compared to TTV-negative pre-MP women. Although our study was performed on a limited number of subjects, the data suggests that TTV in PBMC is associated with an anovulatory menstrual cycle with low progesterone levels, and possibly with male sex.
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| 3. |
- Einarsdottir, Sigrun, et al.
(författare)
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Deficiency of SARS-CoV-2 T-cell responses after vaccination in long-term allo-HSCT survivors translates into abated humoral immunity.
- 2022
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Ingår i: Blood advances. - : American Society of Hematology. - 2473-9537 .- 2473-9529. ; 6:9, s. 2723-2730
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Tidskriftsartikel (refereegranskat)abstract
- Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological diseases are at risk of severe disease and death from COVID-19. To determine the safety and immunogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines, samples from 50 infection-naive allo-HSCT recipients (median, 92 months from transplantation, range, 7-340 months) and 39 healthy controls were analyzed for serum immunoglobulin G (IgG) against the receptor binding domain (RBD) within spike 1 (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; anti-RBD-S1 IgG) and for SARS-CoV-2-specific T-cell immunity, reflected by induction of T-cell-derived interferon-γ in whole blood stimulated ex vivo with 15-mer SI-spanning peptides with 11 amino acid overlapS1-spanning peptides. The rate of seroconversion was not significantly lower in allo-transplanted patients than in controls with 24% (12/50) and 6% (3/50) of patients remaining seronegative after the first and second vaccination, respectively. However, 58% of transplanted patients lacked T-cell responses against S1 peptides after 1 vaccination compared with 19% of controls (odds ratio [OR] 0.17; P = .009, Fisher's exact test) with a similar trend after the second vaccination where 28% of patients were devoid of detectable specific T-cell immunity, compared with 6% of controls (OR 0.18; P = .02, Fisher's exact test). Importantly, lack of T-cell reactivity to S1 peptides after vaccination heralded substandard levels (<100 BAU/mL) of anti-RBD-S1 IgG 5 to 6 months after the second vaccine dose (OR 8.2; P = .007, Fisher's exact test). We conclude that although allo-HSCT recipients achieve serum anti-RBD-S1 IgG against SARS-CoV-2 after 2 vaccinations, a deficiency of SARS-CoV-2-specific T-cell immunity may subsequently translate into insufficient humoral responses.
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| 4. |
- Deribe, Leul, et al.
(författare)
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Stress and coping strategies among parents of children with cancer at Tikur Anbessa Specialized Hospital paediatric oncology unit, Ethiopia: a phenomenological study
- 2023
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Ingår i: BMJ. British Medical Journal. - : BMJ. - 0959-8146. ; 13:e065090, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Objective This study explores sources of stress, conditions that help reduce stress levels and coping strategies among parents of children with cancer receiving chemotherapy at Tikur Anbessa Specialized Hospital (TASH) in Ethiopia. Design A qualitative phenomenological approach was used. Setting Parents of children receiving chemotherapy at the TASH paediatric oncology unit. Participants Fifteen semistructured in-depth interviews were conducted with nine mothers and six fathers of children with cancer from November 2020 to January 2021. Results Sources of stress related to child’s health condition as the severity of the child’s illness, fear of treatment side effects and loss of body parts were identified. Parents mentioned experiencing stress arising from limited access to health facilities, long waiting times, prolonged hospital stays, lack of chemotherapy drugs, and limited or inadequate information about their child’s disease condition and treatment. Other sources of stress were insufficient social support, stigmatisation of cancer and financial problems. Conditions decreasing parents’ stress included positive changes in the child’s health, receiving cancer treatment and access to drugs. Receiving counselling from healthcare providers, getting social support and knowing someone who had a positive treatment outcome also helped reduce stress. Coping strategies used by parents were religious practices including prayer, crying, accepting the child’s condition, denial and communication with health providers. Conclusion The main causes of stress identified by parents of children with cancer in Ethiopia were the severity of their child’s illness, expectations of poor treatment outcomes, unavailability of cancer treatment services and lack of social/financial support. Measures that should be considered to reduce parents’ stress include providing psycho-oncological care for parents and improving the counselling available to parents concerning the nature of the child’s illness, its treatment, diagnostic procedures and treatment side effects. It may also be helpful to establish and strengthen family support groups and parent-to-parent communication, improve the availability of chemotherapy drugs and offer more education on coping strategies.
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| 5. |
- Steen Carlsson, Katarina, et al.
(författare)
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Pain, depression and anxiety in people with haemophilia from three Nordic countries: Cross-sectional survey data from the MIND study
- 2022
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Ingår i: Haemophilia. - : Wiley. - 1351-8216 .- 1365-2516. ; 28:4, s. 557-567
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Tidskriftsartikel (refereegranskat)abstract
- Introduction People with haemophilia (PwH) may experience symptoms of haemophilia-related pain, depression or anxiety, which can negatively impact health-related quality of life. Aim To obtain the perspective of PwH and treaters from Sweden, Finland and Denmark on the management of haemophilia-related pain, depression and anxiety using cross-sectional survey data from the MIND study (NCT03276130). Methods PwH or their caregivers completed a survey about experiences of pain, depression and anxiety related to haemophilia, and the standard EQ-5D-5L instrument. Five investigators at haemophilia treatment centres (HTC) were sent a complementary survey containing questions about the management of pain and depression/anxiety. Results There were 343 PwH (mild: 103; moderate: 53; severe: 180; seven lacking severity information) and 71 caregiver responses. Experience of pain in the last 6 months was reported by 50% of PwH respondents and 46% of caregiver respondents. Anxiety/depression was reported by 28% of PwH respondents. Reporting of pain and anxiety/depression was associated with disease severity. Whilst 62% of PwH who had experienced pain at any time point (n = 242) felt this was adequately addressed and treated at their HTC, only 24% of those who had experienced depression/anxiety (n = 127) felt this was adequately addressed. Disease severity was negatively associated with EQ-5D-5L utility value (p < .001). In the HTC survey, 4/5 and 2/5 agreed that pain and depression/anxiety, respectively, are adequately addressed. Conclusions Pain and depression/anxiety occur more frequently with increasing haemophilia severity, with negative impacts on health-related quality of life. PwH with depression/anxiety or unaddressed pain could benefit from improved management strategies.
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| 6. |
- Berglund, Eva Caroline, et al.
(författare)
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A Study Protocol for Validation and Implementation of Whole-Genome and -Transcriptome Sequencing as a Comprehensive Precision Diagnostic Test in Acute Leukemias
- 2022
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Ingår i: Frontiers in Medicine. - Lausanne, Switzerland : Frontiers Media SA. - 2296-858X. ; 9, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Whole-genome sequencing (WGS) and whole-transcriptome sequencing (WTS), with the ability to provide comprehensive genomic information, have become the focal point of research interest as novel techniques that can support precision diagnostics in routine clinical care of patients with various cancer types, including hematological malignancies. This national multi-center study, led by Genomic Medicine Sweden, aims to evaluate whether combined application of WGS and WTS (WGTS) is technically feasible and can be implemented as an efficient diagnostic tool in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In addition to clinical impact assessment, a health-economic evaluation of such strategy will be performed. Methods and Analysis: The study comprises four phases (i.e., retrospective, prospective, real-time validation, and follow-up) including approximately 700 adult and pediatric Swedish AML and ALL patients. Results of WGS for tumor (90×) and normal/germline (30×) samples as well as WTS for tumors only will be compared to current standard of care diagnostics. Primary study endpoints are diagnostic efficiency and improved diagnostic yield. Secondary endpoints are technical and clinical feasibility for routine implementation, clinical utility, and health-economic impact. Discussion: Data from this national multi-center study will be used to evaluate clinical performance of the integrated WGTS diagnostic workflow compared with standard of care. The study will also elucidate clinical and health-economic impacts of a combined WGTS strategy when implemented in routine clinical care. Clinical Trial Registration: [https://doi.org/10.1186/ISRCTN66987142], identifier [ISRCTN66987142].
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| 7. |
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| 8. |
- Lindgren, Marie, 1971, et al.
(författare)
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Survival and risk of vascular complications in myelofibrosis—A population-based study from the Swedish MPN group
- 2022
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 109:4, s. 336-342
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To gain knowledge of underlying risk factors for vascular complications and their impact on life expectancy in myelofibrosis. Methods: From a cohort of 392 myelofibrosis patients registered in the Swedish MPN registry 58 patients with vascular complications during follow-up were identified. Patients with vascular complications were compared with both 1:1 matched controls and the entire myelofibrosis cohort to explore potential risk factors for vascular complications and their impact on survival. Results: Incidence of vascular complications was 2.8 events per 100 patient-years and the majority of complications were thrombotic. Patients with complications were significantly older and had lower hemoglobin when compared to the entire cohort. In the case–control analysis, no significant risk factor differences were observed. The major cause of death was vascular complications and median survival was significantly impaired in patients with vascular complications (48 months) compared to controls (92 months). Inferior survival in patients with vascular complications was found to be dependent on IPSS risk category in a Cox regression model. Conclusion: Vascular complications have a considerable impact on survival in MF. At diagnosis, risk assessment by IPSS does not only predict survival but is also associated with the risk of vascular complications.
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| 9. |
- Olsson Lindvall, Martina, et al.
(författare)
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Comparison of DNA Methylation Profiles of Hemostatic Genes between Liver Tissue and Peripheral Blood within Individuals
- 2021
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 121:5, s. 573-583
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation has become increasingly recognized in the etiology of complex diseases, including thrombotic disorders. Blood is often collected in epidemiological studies for genotyping and has recently also been used to examine DNA methylation in epigenome-wide association studies. DNA methylation patterns are often tissue-specific, thus, peripheral blood may not accurately reflect the methylation pattern in the tissue of relevance. Here, we collected paired liver and blood samples concurrently from 27 individuals undergoing liver surgery. We performed targeted bisulfite sequencing for a set of 35 hemostatic genes primarily expressed in liver to analyze DNA methylation levels of >10,000 cytosine-phosphate-guanine (CpG) dinucleotides. We evaluated whether DNA methylation in blood could serve as a proxy for DNA methylation in liver at individual CpGs. Approximately 30% of CpGs were nonvariable and were predominantly hypo- (<25%) or hypermethylated (>70%) in both tissues. While blood can serve as a proxy for liver at these CpGs, the low variability renders these unlikely to explain phenotypic differences. We therefore focused on CpG sites with variable methylation levels in liver. The level of blood-liver tissue correlation varied widely across these variable CpGs; moderate correlations (0.5 <= r <0.75) were detected for 6% and strong correlations ( r 0.75) for a further 4%. Our findings indicate that it is essential to study the concordance of DNA methylation between blood and liver at individual CpGs. This paired blood-liver dataset is intended as a resource to aid interpretation of blood-based DNA methylation results.
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| 10. |
- Sadik, May, 1970, et al.
(författare)
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Artificial Intelligence Increases the Agreement among Physicians Classifying Focal Skeleton/Bone Marrow Uptake in Hodgkin's Lymphoma Patients Staged with F-18 FDG PET/CT-a Retrospective Study
- 2023
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Ingår i: Nuclear Medicine and Molecular Imaging. - : Springer Science and Business Media LLC. - 1869-3474 .- 1869-3482. ; 57:2, s. 110-116
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Classification of focal skeleton/bone marrow uptake (BMU) can be challenging. The aim is to investigate whether an artificial intelligence-based method (AI), which highlights suspicious focal BMU, increases interobserver agreement among a group of physicians from different hospitals classifying Hodgkin's lymphoma (HL) patients staged with [F-18]FDG PET/CT. Methods Forty-eight patients staged with [F-18]FDG PET/CT at Sahlgenska University Hospital between 2017 and 2018 were reviewed twice, 6 months apart, regarding focal BMU. During the second time review, the 10 physicians also had access to AI-based advice regarding focal BMU. Results Each physician's classifications were pairwise compared with the classifications made by all the other physicians, resulting in 45 unique pairs of comparisons both without and with AI advice. The agreement between the physicians increased significantly when AI advice was available, which was measured as an increase in mean Kappa values from 0.51 (range 0.25-0.80) without AI advice to 0.61 (range 0.19-0.94) with AI advice (p = 0.005). The majority of the physicians agreed with the AI-based method in 40 (83%) of the 48 cases. Conclusion An AI-based method significantly increases interobserver agreement among physicians working at different hospitals by highlighting suspicious focal BMU in HL patients staged with [F-18]FDG PET/CT.
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| 11. |
- Swartling, L., et al.
(författare)
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Hepatitis E virus is an infrequent but potentially serious infection in allogeneic hematopoietic stem cell transplant recipients
- 2020
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 55:7, s. 1255-63
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Tidskriftsartikel (refereegranskat)abstract
- Hepatitis E virus (HEV) can cause chronic infection and liver cirrhosis in immunocompromised individuals. The frequency and clinical importance of HEV was studied retrospectively in a cohort of 236 Swedish allogeneic hematopoietic stem cell transplantation (HSCT) recipients. In blood samples collected at 6 months after HSCT, HEV RNA was identified in 8/236 (3.4%) patients, and 11/236 (4.7%) patients had detectable anti-HEV IgG and/or IgM, eight of whom were HEV RNA negative. Two of the patients with positive HEV RNA died with ongoing signs of hepatitis: one of acute liver and multiple organ failure, the other of unrelated causes. The remaining six patients with HEV RNA had cleared the infection at 7-24 (median 8.5) months after HSCT. HEV infection was associated with elevated alanine aminotransferase at 6 months after HSCT (OR 15, 1.3-174, p = 0.03). Active graft-versus-host disease of the liver at 6 months after HSCT was present in 3/8 (38%) patients with HEV RNA, but was not significantly associated with HEV infection. In conclusion, HEV infection is an important differential diagnosis in patients with elevated liver enzymes after HSCT. Although spontaneous clearance was common, the clinical course may be severe.
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| 12. |
- Bryl-Górecka, Paulina, et al.
(författare)
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Bilberry Supplementation after Myocardial Infarction Decreases Microvesicles in Blood and Affects Endothelial Vesiculation
- 2020
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Ingår i: Molecular Nutrition & Food Research. - : Wiley-VCH Verlagsgesellschaft. - 1613-4125 .- 1613-4133. ; 64:20
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Tidskriftsartikel (refereegranskat)abstract
- Scope: Diet rich in bilberries is considered cardioprotective, but the mechanisms of action are poorly understood. Cardiovascular disease is characterized by increased proatherogenic status and high levels of circulating microvesicles (MVs). In an open-label study patients with myocardial infarction receive an 8 week dietary supplementation with bilberry extract (BE). The effect of BE on patient MV levels and its influence on endothelial vesiculation in vitro is investigated.Methods and results: MVs are captured with acoustic trapping and platelet-derived MVs (PMVs), as well as endothelial-derived MVs (EMVs) are quantified with flow cytometry. The in vitro effect of BE on endothelial extracellular vesicle (EV) release is examined using endothelial cells and calcein staining. The mechanisms of BE influence on vesiculation pathways are studied by Western blot and qRT-PCR. Supplementation with BE decreased both PMVs and EMVs. Furthermore, BE reduced endothelial EV release, Akt phosphorylation, and vesiculation-related gene transcription. It also protects the cells from P2X(7)-induced EV release and increase in vesiculation-related gene expression.Conclusion: BE supplementation improves the MV profile in patient blood and reduces endothelial vesiculation through several molecular mechanisms related to the P2X(7)receptor. The findings provide new insight into the cardioprotective effects of bilberries.
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| 13. |
- Stratmann, Svea, 1989-, et al.
(författare)
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Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets
- 2021
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 5:3, s. 900-912
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Tidskriftsartikel (refereegranskat)abstract
- Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi-whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.
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| 14. |
- Almstedt, Elin, 1988-, et al.
(författare)
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Integrative discovery of treatments for high-risk neuroblastoma
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.
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| 15. |
- Kjellander, Christian, et al.
(författare)
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Sickle Cell Disease in Sweden - Prevalence and Resource Use Estimated through Population-Based National Registers
- 2021
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 138:Suppl 1, s. 2040-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Sickle cell disease (SCD) is an autosomal recessive disorder characterized by abnormal hemoglobin. SCD causes hemolytic anemia, vaso-occlusion leading to vaso-occlusive crises (VOC) and contributing to organ damage and early death. SCD is most prevalent in sub-Saharan Africa and the Middle East, but also countries such as Brazil, India and US, have comparatively high frequencies of SCD. Global migration has contributed to a greater geographical spread. The prevalence of SCD in Sweden is unknown.OBJECTIVE: The primary objectives of this study were to estimate the 1-year prevalence of SCD and SCD-associated resource use in Sweden. Secondary objectives were to estimate birth incidence, treatment patterns and survival.PATIENTS: Patients with an ICD-10 diagnosis code for SCD (any D57 [excluding D57.3, sickle cell trait]) were identified from the Swedish Patient Registry (between January 1 st 2001 and June 30 th 2018). Patients were assessed for 1-year prevalence and resource use per calendar year for a follow-up period of 13 years (2006-2018).METHODS: Patients were considered prevalent from birth or immigration to death or emigration. Resource use from specialized care, including all events recorded in the registry with any D57 as the main diagnosis was assessed in the follow up period 2006-2018 as number of outpatient visits and inpatient stays. Costs for this hospital resource use were estimated through remuneration amounts based on diagnosis related groups. Data on sick leave days and days with disability pension due to SCD in patients in working age (18-65 years) were retrieved from the Swedish Social Security Agency and costed with the mean salary in Sweden, plus social security contributions. Costs are reported in 2019 Swedish Krona (SEK, ≈$ 0.1).RESULTS: One-year prevalence of all SCD diagnosis increased from 504 patients (5.53 per 100,000 population) in 2006 to 670 patients (6.55 per 100,000 population) in 2018. The 1-year prevalence of SCD patients ever recorded with an ICD-10 code for SCD with VOC (D57.0) increased from 139 patients (1.53 per 100,000 population) in 2006 to 260 patients (2.54 per 100,000 population) in 2018. The proportion of prevalent patients that were born in Sweden decreased over the years, from approximately 55% in the beginning of the study period to 45% in the end of the study period. The mean and median age of the SCD population decreased over the study period. Individuals with SCD and VOC were, on average younger than the other SCD (D57) subgroups.Birth incidence was captured by calendar year 2006-2018 and was highest in 2007 with 15 children born with SCD. For Swedish-born children with SCD during the patient identification time (n=123), the mean time to identification in the registers was 2.6 years (SD 2.7, range 0-16 years).Hospital outpatient visits and inpatient stays with SCD (all events with D57 recorded) as main diagnosis increased from 57 to 189, and 250 to 1,003, respectively, over the years 2006-2018. This corresponded to costs of inpatient care increasing from 1.4 million (M) SEK in 2006 to 7.3 M SEK in 2018 and costs of outpatient visits increasing from 0.9 M SEK in 2006 to 4.6 M SEK in 2018. The vast majority of costs were incurred in individuals ever recorded with a SCD with VOC diagnosis (D57.0). The most frequent hospital treatment was blood transfusion, with 8-11% of patients receiving transfusion in each year studied, especially common in SCD and VOC diagnosis. The prescribed treatment with the highest increase of uptake over the study period were hydroxyurea, vitamins and paracetamol in all SCD.Individuals in working age had on average 2.3 days of sick leave per patient-year due to SCD (D57), and approximately 4% of these patients received disability benefits because of their SCD.During the follow-up period, the median age at death was 74 years for all SCD and 69 years for SCD with crisis, this is 7-10 years and 12-15 years less compared to the Swedish general population respectively.CONCLUSION: This study demonstrates that the prevalence, hospital resource use and associated costs have increased substantially in Sweden. In an era of emerging treatments for SCD we have for the first time comprehensively described epidemiological-, disease-related and economical aspects of SCD in Sweden.
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| 16. |
- Maasfeh, Lujain, et al.
(författare)
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Impaired Luminal Control of Intestinal Macrophage Maturation in Patients With Ulcerative Colitis During Remission
- 2021
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Ingår i: Cellular and Molecular Gastroenterology and Hepatology. - : Elsevier BV. - 2352-345X. ; 12:4, s. 1415-1432
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Intestinal macrophages adopt a hyporesponsive phenotype through education by local signals. Lack of proper macrophage maturation in patients with ulcerative colitis (UC) in remission may initiate gut inflammation. The aim, therefore, was to determine the effects of fecal luminal factors derived from healthy donors and UC patients in remission on macrophage phenotype and function. METHODS: Fecal supernatants (FS) were extracted from fecal samples of healthy subjects and UC patients in remission. Monocytes were matured into macrophages in the presence of granulocyte-macrophage colony-stimulating factor without/with FS, stimulated with lipopolysaccharide, and macrophage phenotype and function were assessed. Fecal metabolomic profiles were analyzed by gas-chromatography/mass-spectrometry. RESULTS: Fecal luminal factors derived from healthy donors were effective in down-regulating Toll-like receptor signaling, cytokine signaling, and antigen presentation in macrophages. Fecal luminal factors derived from UC patients in remission were less potent in inducing lipopolysaccharide hyporesponsiveness and modulating expression of genes involved in macrophage cytokine and Toll-like receptor signaling pathways. Although phagocytic and bactericidal abilities of macrophages were not affected by FS treatment, healthy FS-treated macrophages showed a greater ability to suppress cluster of differentiation 4(+) T-cell activation and interferon gamma secretion compared with UC remission FS-treated counterparts. Furthermore, metabolomic analysis showed differential fecal metabolite composition for healthy donors and UC patients in remission. CONCLUSIONS: Our data indicate that UC patients in remission lack luminal signals able to condition macrophages toward a hyporesponsive and tolerogenic phenotype, which may contribute to their persistent vulnerability to relapse.
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| 17. |
- Holmqvist, Jacob, et al.
(författare)
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Patterns and determinants of blood transfusion in intensive care in Sweden between 2010 and 2018: A nationwide, retrospective cohort study
- 2022
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Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 62:6, s. 1188-1198
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Tidskriftsartikel (refereegranskat)abstract
- Background Intensive care unit (ICU) patients are transfused with blood products for a number of reasons, from massive ongoing hemorrhage, to mild anemia following blood sampling, combined with bone marrow depression due to critical illness. There's a paucity of data on transfusions in ICUs and most studies are based on audits or surveys. The aim of this study was to provide a complete picture of ICU-related transfusions in Sweden. Methods We conducted a register based retrospective cohort study with data on all adult patient admissions from 82 of 84 Swedish ICUs between 2010 and 2018, as recorded in the Swedish Intensive Care Register. Transfusions were obtained from the SCANDAT-3 database. Descriptive statistics were computed, characterizing transfused and nontransfused patients. The distribution of blood use comparing different ICUs was investigated by computing the observed proportion of ICU stays with a transfusion, as well as the expected proportion. Results In 330,938 ICU episodes analyzed, at least one transfusion was administered for 106,062 (32%). For both red-cell units and plasma, the fraction of patients who were transfused decreased during the study period from 31.3% in 2010 to 24.6% in 2018 for red-cells, and from 16.6% in 2010 to 9.4% in 2018 for plasma. After adjusting for a range of factors, substantial variation in transfusion frequency remained, especially for plasma units. Conclusion Despite continuous decreases in utilization, transfusions remain common among Swedish ICU patients. There is considerable unexplained variation in transfusion rates. More research is needed to establish stronger critiera for when to transfuse ICU patients.
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| 18. |
- Li, Xiangyu, et al.
(författare)
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Classification of clear cell renal cell carcinoma based on PKM alternative splicing
- 2020
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Ingår i: Heliyon. - : Elsevier BV. - 2405-8440. ; 6:2
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Tidskriftsartikel (refereegranskat)abstract
- Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of kidney cancer diagnoses and displays high molecular and histologic heterogeneity. Hence, it is necessary to reveal the underlying molecular mechanisms involved in progression of ccRCC to better stratify the patients and design effective treatment strategies. Here, we analyzed the survival outcome of ccRCC patients as a consequence of the differential expression of four transcript isoforms of the pyruvate kinase muscle type (PKM). We first extracted a classification biomarker consisting of eight gene pairs whose within-sample relative expression orderings (REOs) could be used to robustly classify the patients into two groups with distinct molecular characteristics and survival outcomes. Next, we validated our findings in a validation cohort and an independent Japanese ccRCC cohort. We finally performed drug repositioning analysis based on transcriptomic expression profiles of drug-perturbed cancer cell lines and proposed that paracetamol, nizatidine, dimethadione and conessine can be repurposed to treat the patients in one of the subtype of ccRCC whereas chenodeoxycholic acid, fenoterol and hexylcaine can be repurposed to treat the patients in the other subtype.
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| 19. |
- Jadersten, M., et al.
(författare)
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Targeting SAMHD1 with hydroxyurea in first-line cytarabine-based therapy of newly diagnosed acute myeloid leukaemia: Results from the HEAT-AML trial
- 2022
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 292:6, s. 925-940
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Tidskriftsartikel (refereegranskat)abstract
- Background Treatment of newly diagnosed acute myeloid leukaemia (AML) is based on combination chemotherapy with cytarabine (ara-C) and anthracyclines. Five-year overall survival is below 30%, which has partly been attributed to cytarabine resistance. Preclinical data suggest that the addition of hydroxyurea potentiates cytarabine efficacy by increasing ara-C triphosphate (ara-CTP) levels through targeted inhibition of SAMHD1. Objectives In this phase 1 trial, we evaluated the feasibility, safety and efficacy of the addition of hydroxyurea to standard chemotherapy with cytarabine/daunorubicin in newly diagnosed AML patients. Methods Nine patients were enrolled and received at least two courses of ara-C (1 g/m(2)/2 h b.i.d. d1-5, i.e., a total of 10 g/m(2) per course), hydroxyurea (1-2 g d1-5) and daunorubicin (60 mg/m(2) d1-3). The primary endpoint was safety; secondary endpoints were complete remission rate and measurable residual disease (MRD). Additionally, pharmacokinetic studies of ara-CTP and ex vivo drug sensitivity assays were performed. Results The most common grade 3-4 toxicity was febrile neutropenia (100%). No unexpected toxicities were observed. Pharmacokinetic analyses showed a significant increase in median ara-CTP levels (1.5-fold; p = 0.04) in patients receiving doses of 1 g hydroxyurea. Ex vivo, diagnostic leukaemic bone marrow blasts from study patients were significantly sensitised to ara-C by a median factor of 2.1 (p = 0.0047). All nine patients (100%) achieved complete remission, and all eight (100%) with validated MRD measurements (flow cytometry or real-time quantitative polymerase chain reaction [RT-qPCR]) had an MRD level <0.1% after two cycles of chemotherapy. Treatment was well-tolerated, and median time to neutrophil recovery >1.0 x 10(9)/L and to platelet recovery >50 x 10(9)/L after the start of cycle 1 was 19 days and 22 days, respectively. Six of nine patients underwent allogeneic haematopoietic stem-cell transplantation (allo-HSCT). With a median follow-up of 18.0 (range 14.9-20.5) months, one patient with adverse risk not fit for HSCT experienced a relapse after 11.9 months but is now in second complete remission. Conclusion Targeted inhibition of SAMHD1 by the addition of hydroxyurea to conventional AML therapy is safe and appears efficacious within the limitations of the small phase 1 patient cohort. These results need to be corroborated in a larger study.
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| 20. |
- Danielsson, H., et al.
(författare)
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Blood protein profiles related to preterm birth and retinopathy of prematurity
- 2022
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Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 91:4, s. 937-946
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Tidskriftsartikel (refereegranskat)abstract
- Background Nearly one in ten children is born preterm. The degree of immaturity is a determinant of the infant's health. Extremely preterm infants have higher morbidity and mortality than term infants. One disease affecting extremely preterm infants is retinopathy of prematurity (ROP), a multifactorial neurovascular disease that can lead to retinal detachment and blindness. The advances in omics technology have opened up possibilities to study protein expressions thoroughly with clinical accuracy, here used to increase the understanding of protein expression in relation to immaturity and ROP. Methods Longitudinal serum protein profiles the first months after birth in 14 extremely preterm infants were integrated with perinatal and ROP data. In total, 448 unique protein targets were analyzed using Proximity Extension Assays. Results We found 20 serum proteins associated with gestational age and/or ROP functioning within mainly angiogenesis, hematopoiesis, bone regulation, immune function, and lipid metabolism. Infants with severe ROP had persistent lower levels of several identified proteins during the first postnatal months. Conclusions The study contributes to the understanding of the relationship between longitudinal serum protein levels and immaturity and abnormal retinal neurovascular development. This is essential for understanding pathophysiological mechanisms and to optimize diagnosis, treatment and prevention for ROP. Impact Longitudinal protein profiles of 14 extremely preterm infants were analyzed using a novel multiplex protein analysis platform combined with perinatal data. Proteins associated with gestational age at birth and the neurovascular disease ROP were identified. Among infants with ROP, longitudinal levels of the identified proteins remained largely unchanged during the first postnatal months. The main functions of the proteins identified were angiogenesis, hematopoiesis, immune function, bone regulation, lipid metabolism, and central nervous system development. The study contributes to the understanding of longitudinal serum protein patterns related to gestational age and their association with abnormal retinal neuro-vascular development.
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| 21. |
- Karlsson, Lene, et al.
(författare)
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Characteristics and outcome of primary resistant disease in paediatric acute myeloid leukaemia
- 2023
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 201:4, s. 757-765
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Tidskriftsartikel (refereegranskat)abstract
- A significant proportion of events in paediatric acute myeloid leukaemia (AML) are caused by resistant disease (RD). We investigated clinical and biological characteristics in 66 patients with RD from 1013 children with AML registered and treated according to the NOPHO-AML 93, NOPHO-AML 2004, DB AML-01 and NOPHO-DBH AML 2012 protocols. Risk factors for RD were age10 years or older and a white-blood-cell count (WBC) of 100 x 10(9)/L or more at diagnosis. The five-year overall survival (OS) was 38% (95% confidence interval [CI]: 28%-52%). Of the 63 children that received salvage therapy with chemotherapy, 59% (N = 37) achieved complete remission (CR) with OS 57% (95% CI: 42%-75%) compared to 12% (95% CI: 4%-35%) for children that did not achieve CR. Giving more than two salvage chemotherapy courses did not increase CR rates. OS for all 43 patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) was 49% (95% CI: 36%-66%). Those achieving CR and proceeding to HSCT had an OS of 56% (95% CI: 41%-77%, N = 30). This study showed that almost 40% of children with primary resistant AML can be cured with salvage therapy followed by HSCT. Children that did not achieve CR after two salvage courses with chemotherapy did not benefit from additional chemotherapy.
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| 22. |
- Versluys, A. B., et al.
(författare)
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Hematopoietic cell transplant in pediatric acute myeloid leukemia after similar upfront therapy; a comparison of conditioning regimens
- 2021
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 56:6, s. 1426-1432
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Tidskriftsartikel (refereegranskat)abstract
- The impact of conditioning regimen prior to hematopoietic cell transplant (HCT) in pediatric AML-patients is not well studied. We retrospectively analyzed the impact of Busulfan-Cyclophosphamide (BuCy), Busulfan-Cyclophosphamide-Melphalan (BuCyMel) and Clofarabine-Fludarabine-Busulfan (CloFluBu) in pediatric AML-patients, with similar upfront leukemia treatment (NOPHO-DBHconsortium), receiving an HCT between 2010 and 2015. Outcomes of interest were LFS, relapse, TRM and GvHD. 103 patients were included; 30 received BuCy, 37 BuCyMel, and 36 CloFluBu. The 5-years LFS was 43.3% (SE +/- 9.0) in the BuCy group, 59.2 % (SE +/- 8.1) after BuCyMel, and 66.7 % (SE +/- 7.9) after CloFluBu. Multivariable Cox regression analysis showed a trend to lower LFS after BuCy compared to CloFluBu (p = 0.07). BuCy was associated with a higher relapse incidence compared to the other regimens (p = 0.06). Younger age was a predictor for relapse (p = 0.02). A strong correlation between Busulfan Therapeutic Drug Monitoring (TDM) and lower incidence of aGvHD (p < 0.001) was found. In conclusion, LFS after BuCyMel and CloFluBu was comparable, lower LFS was found after BuCy, due to higher relapse incidence. CloFluBu was associated with lower incidence of aGvHD, suggesting lower toxicity with this type of conditioning. This finding is also explained by the impact of Busulfan monitoring.
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| 23. |
- Olsson Lindvall, Martina, et al.
(författare)
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A Comprehensive Sequencing-Based Analysis of Allelic Methylation Patterns in Hemostatic Genes in Human Liver
- 2020
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Ingår i: Thrombosis and Haemostasis. - : Georg Thieme Verlag KG. - 0340-6245 .- 2567-689X. ; 120:2, s. 229-242
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Tidskriftsartikel (refereegranskat)abstract
- Characterizing the relationship between genetic, epigenetic (e.g., deoxyribonucleic acid [DNA] methylation), and transcript variation could provide insights into mechanisms regulating hemostasis and potentially identify new drug targets. Several hemostatic factors are synthesized in the liver, yet high-resolution DNA methylation data from human liver tissue is currently lacking for these genes. Single-nucleotide polymorphisms (SNPs) can influence DNA methylation in cis which can affect gene expression. This can be analyzed through allele-specific methylation (ASM) experiments. We performed targeted genomic DNA- and bisulfite-sequencing of 35 hemostatic genes in human liver samples for SNP and DNA methylation analysis, respectively, and integrated the data for ASM determination. ASM-associated SNPs (ASM-SNPs) were tested for association to gene expression in liver using in-house generated ribonucleic acid-sequencing data. We then assessed whether ASM-SNPs associated with gene expression, plasma proteins, or other traits relevant for hemostasis using publicly available data. We identified 112 candidate ASM-SNPs. Of these, 68% were associated with expression of their respective genes in human liver or in other human tissues and 54% were associated with the respective plasma protein levels, activity, or other relevant hemostatic genome-wide association study traits such as venous thromboembolism, coronary artery disease, stroke, and warfarin dose maintenance. Our study provides the first detailed map of the DNA methylation landscape and ASM analysis of hemostatic genes in human liver tissue, and suggests that methylation regulated by genetic variants in cis may provide a mechanistic link between noncoding SNPs and variation observed in circulating hemostatic proteins, prothrombotic diseases, and drug response.
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| 24. |
- Nozohoor, Shahab, et al.
(författare)
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ABO blood group does not impact incidence or outcomes of surgery for acute type A aortic dissection
- 2020
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Ingår i: Scandinavian Cardiovascular Journal. - : Taylor & Francis. - 1401-7431 .- 1651-2006. ; 54:2, s. 124-129
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the distribution and impact of ABO blood groups on postoperative outcomes in patients undergoing surgery for acute type A aortic dissection (ATAAD).Design: A total of 1144 surgical ATAAD patients from eight Nordic centres constituting the Nordic consortium for acute type A aortic dissection (NORCAAD) were analysed. Blood group O patients were compared to non-O subjects. The relative frequency of blood groups was assessed with t-distribution, modified for weighted proportions. Multivariable logistic regression was performed to identify independent predictors of 30-day mortality. Cox regression analyses were performed for assessing independent predictors of late mortality.Results: There was no significant difference in the proportions of blood group O between the study populations in the NORCAAD registry and the background population (40.6 (95% CI 37.7-43.4)% vs 39.0 (95% CI 39.0-39.0)%). ABO blood group was not associated with any significant change in risk of 30-day or late mortality, with the exception of blood group A being an independent predictor of late mortality. Prevalence of postoperative complications was similar between the ABO blood groups.Conclusions: In this large cohort of Nordic ATAAD patients, there were no associations between ABO blood group and surgical incidence or outcomes, including postoperative complications and survival.
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| 25. |
- Mäkinen, Artturi, et al.
(författare)
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Expression of BCL6 in paediatric B-cell acute lymphoblastic leukaemia and association with prognosis
- 2021
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Ingår i: Pathology. - : Elsevier BV. - 0031-3025 .- 1465-3931. ; 53:7, s. 875-882
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Tidskriftsartikel (refereegranskat)abstract
- B-cell lineage acute lymphoblastic leukaemia (B-ALL) is the most common paediatric malignancy. Transcription factor B-cell lymphoma 6 (BCL6) is essential to germinal centre formation and antibody affinity maturation and plays a major role in mature B-cell malignancies. More recently, it was shown to act as a critical downstream regulator in pre-BCR+ B-ALL. We investigated the expression of the BCL6 protein in a population-based cohort of paediatric B-ALL cases and detected moderate to strong positivity through immunohistochemistry in 7% of cases (8/117); however, only two of eight BCL6 cases (25%) co-expressed the ZAP70 protein. In light of these data, the subtype with active pre-BCR signalling constitutes a rare entity in paediatric B-ALL. In three independent larger cohorts with gene expression data, high BCL6 mRNA levels were associated with the TCF3-PBX1, Ph-like, NUTM1, MEF2D and PAX5-alt subgroups and the ‘metagene’ signature for pre-BCR-associated genes. However, higher-than-median BCL6 mRNA level alone was associated with favourable event free survival in the Nordic paediatric cohort, indicating that using BCL6 as a diagnostic marker requires careful design, and evaluation of protein level is needed alongside the genetic or transcriptomic data.
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