| 1. |
- Gehlen, J., et al.
(author)
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First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B
- 2022
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In: Human Genetics and Genomics Advances. - : Elsevier BV. - 2666-2477. ; 3:2
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Journal article (peer-reviewed)abstract
- Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 × 10−8; odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10–5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 10−16; OR = 1.75; 95% CI, 1.64–1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% ± 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes. © 2022 The Authors
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| 2. |
- Soda, T., et al.
(author)
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International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic)
- 2020
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In: European Archives of Psychiatry and Clinical Neuroscience. - : Springer Science and Business Media LLC. - 0940-1334 .- 1433-8491. ; 270:7, s. 921-932
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Journal article (peer-reviewed)abstract
- Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.
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| 3. |
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| 4. |
- Sahlén, Pelin, et al.
(author)
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Chromatin interactions in differentiating keratinocytes reveal novel atopic dermatitis– and psoriasis-associated genes
- 2020
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In: Journal of Allergy and Clinical Immunology. - : Mosby Inc.. - 0091-6749 .- 1097-6825.
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Journal article (peer-reviewed)abstract
- Background: Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear. Objective: We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate. Methods: We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies. Results: We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis. Conclusions: Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.
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| 5. |
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| 6. |
- Eggers, Kai M., 1962-, et al.
(author)
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Clinical and prognostic implications of C-reactive protein levels in myocardial infarction with nonobstructive coronary arteries
- 2021
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In: Clinical Cardiology. - : John Wiley & Sons. - 0160-9289 .- 1932-8737. ; 44:7, s. 1019-1027
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Journal article (peer-reviewed)abstract
- Background Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous condition. Recent studies suggest that MINOCA patients may have a proinflammatory disposition. The role of inflammation in MINOCA may thus be distinct to myocardial infarction with significant coronary artery disease (MI-CAD). Hypothesis We hypothesized that inflammation reflected by C-reactive protein (CRP) levels might carry unique clinical information in MINOCA. Methods This retrospective registry-based cohort study (SWEDEHEART) included 9916 patients with MINOCA and 97 970 MI-CAD patients, used for comparisons. Multivariable-adjusted regressions were applied to investigate the associations of CRP levels with clinical variables, all-cause mortality and major cardiovascular events (MACE) during a median follow-up of up to 5.3 years. Results Median admission CRP levels in patients with MINOCA and MI-CAD were 5.0 (interquartile range 2.0-9.0) mg/dl and 5.0 (interquartile range 2.1-10.0 mg/dl), respectively. CRP levels in MINOCA exhibited independent associations with various cardiovascular risk factors, comorbidities and estimates of myocardial damage. The association of CRP with peripheral artery disease tended to be stronger compared to MI-CAD. The associations with female sex, renal dysfunction and myocardial damage were stronger in MI-CAD. CRP independently predicted all-cause mortality in MINOCA (hazard ratio 1.22 [95% confidence interval 1.17-1.26]), similar to MI-CAD (p interaction = 0.904). CRP also predicted MACE (hazard ratio 1.08 [95% confidence interval 1.04-1.12]) but this association was weaker compared to MI-CAD (p interaction<.001). Conclusions We found no evidence indicating the presence of a specific inflammatory pattern in acute MINOCA compared to MI-CAD. However, CRP levels were independently, albeit moderately associated with adverse outcome.
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| 7. |
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| 8. |
- Ivanov Öfverholm, I., et al.
(author)
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Overexpression of chromatin remodeling and tyrosine kinase genes in iAMP21-positive acute lymphoblastic leukemia
- 2020
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In: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 61:3, s. 604-613
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Journal article (peer-reviewed)abstract
- Intrachromosomal amplification of chromosome 21 (iAMP21) is a cytogenetic subtype associated with relapse and poor prognosis in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). The biology behind the high relapse risk is unknown and the aim of this study was to further characterize the genomic and transcriptional landscape of iAMP21. Using DNA arrays and sequencing, we could identify rearrangements and aberrations characteristic for iAMP21. RNA sequencing revealed that only half of the genes in the minimal region of amplification (20/45) were differentially expressed in iAMP21. Among them were the top overexpressed genes (p < 0.001) in iAMP21 vs. BCP ALL without iAMP21 and three candidate genes could be identified, the tyrosine kinase gene DYRK1A and chromatin remodeling genes CHAF1B and SON. While overexpression of DYRK1A and CHAF1B is associated with poor prognosis in malignant diseases including myeloid leukemia, this is the first study to show significant correlation with iAMP21-positive ALL.
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| 9. |
- Lindblad, L., et al.
(author)
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Risk factors for mortality of medical causes within 30 days of electroconvulsive therapy
- 2023
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In: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 320, s. 527-533
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Journal article (peer-reviewed)abstract
- BACKGROUND: Electroconvulsive therapy (ECT) is used to treat severe psychiatric disorders and is associated with reduced risk of suicide and all-cause mortality in patients with severe depression. We investigated the causes of death occurring shortly after ECT and identified potential risk factors for medical causes of death.METHODS: Patients treated with ECT between 2012 and 2018 were included in this Swedish register-based study. Multivariate binary logistic regression was used to calculate odds ratios for covariates to determine potential predictors of 30-day mortality.RESULTS: Of the 20,225 included patients, 93 (0.46 %) died of suicide and 123 (0.61 %) died of medical causes after ECT. Cardiovascular disease was the most common medical cause of death (n = 49, 40 %). An older age, a Charlson Comorbidity Index of 1 or more, atrial fibrillation, kidney disease, reflux disease, dementia, and cancer were associated with increased risk of death by medical causes.LIMITATIONS: Real-life observational studies based on registry data may demonstrate associations, but cannot determine causality. If medical records had been available, we would be better able to determine if deaths were due to the ECT, anesthesia, pre-existing medical conditions, or the mental disorder.CONCLUSIONS: ECT appears to be a low-risk medical procedure. Older individuals with severe somatic diseases have the highest risk of death and extra measures should be considered to optimize their medical health during the pre-ECT workup, and during and after ECT.
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| 10. |
- Nordenskjöld, A., et al.
(author)
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Copy number variants suggest different molecular pathways for the pathogenesis of bladder exstrophy
- 2023
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In: American Journal of Medical Genetics, Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 191:2, s. 378-390
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Journal article (peer-reviewed)abstract
- Bladder exstrophy is a rare congenital malformation leaving the urinary bladder open in the midline of the abdomen at birth. There is a clear genetic background with chromosome aberrations, but so far, no consistent findings apart from 22q11-duplications detected in about 2%–3% of all patients. Some genes are implicated like the LZTR1, ISL1, CELSR3, and the WNT3 genes, but most are not explained molecularly. We have performed chromosomal microarray analysis on a cohort of 140 persons born with bladder exstrophy to look for submicroscopic chromosomal deletions and duplications. Pathogenic or possibly pathogenic microdeletions or duplications were found in 16 patients (11.4%) and further 9 with unknown significance. Two findings were in regions linked to known syndromes, two findings involved the same gene (MCC), and all other findings were unique. A closer analysis suggests a few gene networks that are involved in the pathogenesis of bladder exstrophy; the WNT-signaling pathway, the chromosome 22q11 region, the RIT2 and POU families, and involvement of the Golgi apparatus. Bladder exstrophy is a rare malformation and is reported to be associated with several chromosome aberrations. Our data suggest involvement of some specific molecular pathways.
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| 11. |
- Nordenskjöld, Axel, 1977-, et al.
(author)
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Major adverse cardiovascular events following electroconvulsive therapy in depression : A register-based nationwide Swedish cohort study with 1-year follow-up
- 2022
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In: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 296, s. 298-304
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Journal article (peer-reviewed)abstract
- BACKGROUND: The cardiovascular response during electroconvulsive therapy (ECT) could induce major adverse cardiovascular events (MACE) in the short-term, while reduced depression could decrease the risk of MACE in the long-term. The balance between these potential effects has not been thoroughly investigated.METHODS: This nationwide, registry-based cohort study included all patients admitted to Swedish hospitals due to moderate or severe unipolar depression between 2011 and 2018. Patients were divided into an ECT group and a non-ECT group, and followed for 1 year. Patients were matched by risk factors for cardiovascular disease by propensity score matching. Cox regression was used to examine the association between ECT and MACE.RESULTS: Out of a total of 28 584 inpatients, 5476 patients who had received ECT were matched to 5476 non-ECT patients. ECT was associated with reduced risk of MACE within 90 days and 1 year. Within 1 year after admission, a total of 127 patients (2.3%) in the non-ECT group and 82 patients (1.4%) in the ECT group had at least one MACE (hazard ratio [HR], 0.65; 95% confidence interval, 0.49-0.85).LIMITATIONS: Real-life observational studies carry risk for residual confounding.CONCLUSIONS: ECT in patients hospitalized for depression was not associated with any significant short-term risks of cardiovascular events. Instead, ECT was associated with a reduced risk of MACE within 1 year after admission compared with patients not treated with ECT. This association may be explained by reduced depressive symptoms after ECT, improved risk factor management in the ECT-group or by residual confounding by indication.
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| 12. |
- Pasupathy, Sivabaskari, et al.
(author)
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Survival in Patients With Suspected Myocardial Infarction With Nonobstructive Coronary Arteries : A Comprehensive Systematic Review and Meta-Analysis From the MINOCA Global Collaboration
- 2021
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In: Circulation. Cardiovascular Quality and Outcomes. - : Lippincott Williams & Wilkins. - 1941-7713 .- 1941-7705. ; 14:11
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Research review (peer-reviewed)abstract
- BACKGROUND: Suspected myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) occurs in ≈5% to 10% of patients with MI referred for coronary angiography. The prognosis of these patients may differ to those with MI and obstructive coronary artery disease (MI-CAD) and those without a MI (patients without known history of MI [No-MI]). The primary objective of this study is to evaluate the 12-month all-cause mortality of patients with MINOCA.METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, the terms "MI," "nonobstructive," "angiography," and "prognosis" were searched in PubMed and Embase databases from inception to December 2018, including original, English language MINOCA studies with >100 consecutive patients. Publications with a heterogeneous cohort, unreported coronary stenosis, or exclusively focusing on MINOCA-mimicking conditions, were excluded. Unpublished data were obtained from the MINOCA Global Collaboration. Data were pooled and analyzed using Paule-Mandel, Hartung, Knapp, Sidik & Jonkman, or restricted maximum-likelihood random-effects meta-analysis methodology. Heterogeneity was assessed using Cochran's Q and I2 statistics. The primary outcome was 12-month all-cause mortality in patients with MINOCA, with secondary comparisons to MI-CAD and No-MI.RESULTS: The 23 eligible studies yielded 55 369 suspected MINOCA, 485 382 MI-CAD, and 33 074 No-MI. Pooled meta-analysis of 14 MINOCA studies accounting for 30 733 patients revealed an unadjusted 12-month all-cause mortality rate of 3.4% (95% CI, 2.6%-4.2%) and reinfarction (n=27 605; 10 studies) in 2.6% (95% CI, 1.7%-3.5%). MINOCA had a lower 12-month all-cause mortality than those with MI-CAD (3.3% [95% CI, 2.5%-4.1%] versus 5.6% [95% CI, 4.1%-7.0%]; odds ratio, 0.60 [95% CI, 0.52-0.70], P<0.001). In contrast, there was a statistically nonsignificant trend towards increased 12-month all-cause mortality in patients with MINOCA (2.6% [95% CI, 0%-5.9%]) compared with No-MI (0.7% [95% CI, 0.1%-1.3%]; odds ratio, 3.71 [95% CI, 0.58-23.61], P=0.09).CONCLUSIONS: In the largest contemporary MINOCA meta-analysis to date, patients with suspected MINOCA had a favorable prognosis compared with MI-CAD, but statistically nonsignificant trend toward worse outcomes compared to those with No-MI. Registration: URL: https://www.crd.york.ac.uk/PROSPERO/; Unique identifier: CRD42020145356.
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| 13. |
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| 14. |
- Ahmad, I., et al.
(author)
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Validity of diagnoses, treatment dates, and rating scales in the Swedish national quality register for electroconvulsive therapy
- 2022
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In: Nordic Journal of Psychiatry. - : Informa UK Limited. - 0803-9488 .- 1502-4725. ; 76:2, s. 96-103
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Journal article (peer-reviewed)abstract
- Background The Swedish national quality register for electroconvulsive therapy (Q-ECT) contains data on patients receiving treatment with electroconvulsive therapy (ECT) in Sweden. Aim This study determined the validity of diagnoses, treatment dates, and rating scales in the Q-ECT by investigating the degree of accordance between data from the Q-ECT and patient records. Materials and methods From January 2016 to December 2017, 200 treatment series were randomly selected from the Q-ECT. The corresponding patient records were requested from the treating hospitals. Data on the indicative diagnosis, dates for the first and the last ECT session, and rating scales were compared between the Q-ECT and patient records using (i) a strict and (ii) a liberal method of assessment. Using the liberal method, each variable was assessed as accordant if it belonged to the same diagnosis group, or if the dates differed by less than 1 week, or ratings differed by only 1 point on the Clinical Global Impression Scale (CGI- S), or no more than 3 points on the Montgomery angstrom sberg Depression Rating Scale between the Q-ECT and the patient record. Results A total of 179 patient records were received. The strict method of assessment showed an accordance of 89% or higher for all studied variables. The liberal method showed an accordance of 95% or higher. Conclusions We conclude that data on the studied variables in the Q-ECT have high validity. However, limited use of some rating scales makes the results uncertain. Measures can be taken to further improve the data quality.
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| 15. |
- Clements, C. C., et al.
(author)
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Genome-wide association study of patients with a severe major depressive episode treated with electroconvulsive therapy
- 2021
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In: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 26:10
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Journal article (peer-reviewed)abstract
- Although large genome-wide association studies (GWAS) of major depressive disorder (MDD) have identified many significant loci, the SNP-based heritability remains notably low, which might be due to etiological heterogeneity in existing samples. Here, we test the utility of targeting the severe end of the MDD spectrum through genome-wide SNP genotyping of 2725 cases who received electroconvulsive therapy (ECT) for a major depressive episode (MDE) and 4035 controls. A subset of cases (n = 1796) met a narrow case definition (MDE occurring in the context of MDD). Standard GWAS quality control procedures and imputation were conducted. SNP heritability and genetic correlations with other traits were estimated using linkage disequilibrium score regression. Results were compared with MDD cases of mild-moderate severity receiving internet-based cognitive behavioral therapy (iCBT) and summary results from the Psychiatric Genomics Consortium (PGC). The SNP-based heritability was estimated at 29-34% (SE: 6%) for the narrow case definition, considerably higher than the 6.5-8.0% estimate in the most recent PGC MDD study. Our severe MDE cases had smaller genetic correlations with neurodevelopmental disorders and neuroticism than PGC MDD cases but higher genetic risk scores for bipolar disorder than iCBT MDD cases. One genome-wide significant locus was identified (rs114583506, P = 5e-8) in an intron of HLA-B in the major histocompatibility locus on chr6. These results indicate that individuals receiving ECT for an MDE have higher burden of common variant risk loci than individuals with mild-moderate MDD. Furthermore, severe MDE shows stronger relations with other severe adult-onset psychiatric disorders but weaker relations with personality and stress-related traits than mild-moderate MDD. These findings suggest a different genetic architecture at the severest end of the spectrum, and support further study of the severest MDD cases as an extreme phenotype approach to understand the etiology of MDD.
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| 16. |
- Djekic, Demir, 1989-
(author)
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Novel and Traditional Risk Factors for Coronary Artery Disease : Role of Coronary Artery Calcium, Lipidomics, Psychosocial Factors and Diet
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Background: The aim of the research reported in this thesis was to determine the association of novel and traditional risk factors with coronary artery calcium (CAC), a marker of subclinical coronary artery disease (CAD) in healthy individuals. In addition, we investigated the effects of a vegetarian, compared to a meat diet, on novel and traditional risk factors in patients with diagnosed CAD.Methods: Studies I-II evaluated the inter-laboratory reproducibility of liquid chromatography-mass spectrometry (LC-MS) lipid analysis and the association of serum lipidome with CAC in a cohort of 70 patients. Studies III and IV analysed data of 1067 participants in the pilot study of the Swedish CArdioPulmonary bioImage Study to determine associations of psychosocial (residential area, education, housing, and social support) and traditional risk factors with CAC. Cardiac computed tomography was used to obtain a coronary artery calcium score (CACS) (Studies I–IV). Study V employed a crossover design in which 31 patients with CAD were randomly allocated to a four-week vegetarian diet alternating with four weeks of an isocaloric meat diet. Enzyme-linked immunosorbent assay was used to measure oxidised LDL-cholesterol. Plasma metabolome, including choline, trimethylamine N-oxide, L-carnitine, and acetyl-carnitine, as well as plasma lipidome were determined with LC-MS. Gut microbiota and faecal short- and branched-chain fatty acids were analysed with 16S rRNA gene sequencing and gas chromatography-MS, respectively.Results: In Study I, two laboratories independently identified six lipids in common that differentiated serum of patients with CACS >250 from that of those with CACS=0. Study II, revealed higher levels of phosphatidylcholine(PC)(16:0/20:4) and lower levels of PC(18:2/18:2), PC(36:3) and phosphatidylethanolamine (PE)(20:0/18:2) in patients with CACS >250 than found in those with CACS=0. Study III showed a CACS >0 prevalence of 46.3% and 36.6% in low and high socioeconomic residential areas, respectively, but the traditional risk factor–adjusted odds ratio for CACS >0 was not significantly higher in subjects living in low socioeconomic areas. In Study III, the traditional risk factor–adjusted odds ratio for CACS >100 relative to CACS=0 was significantly higher in women with low education level and living in a rented apartment. Studies III and IV showed traditional risk factor–adjusted odds ratios for CACS >0 to be significantly higher in women with a family history of premature cardiovascular disease and low social support. No relationship of psychosocial factors with CAC was observed in men. The vegetarian diet implemented in Study V significantly lowered mean oxidized LDL-cholesterol (-2.73 U/L), total cholesterol (-0.13 mmol/L), LDL-cholesterol (-0.10 mmol/L), and body mass index (-0.21 kg/m2), as well as the relative abundance of PCs, PEs, and several microbial genera compared with the meat diet. The effect of the vegetarian diet on oxidized LDL-C was associated with higher relative abundance of Ruminococcaceae genera and of Barnesiella and reduced abundance of Flavonifractor. The vegetarian diet lowered the relative abundance of ceramide(d18:1/16:0) and triacylglycerols with saturated fatty acyl chains and raised the relative abundance of triacylglycerols with high carbon and polyunsaturated fatty acyl chains compared with the meat diet.Conclusions: Novel and traditional cardiovascular risk factors are associated with subclinical CAD. Psychosocial factors are associated with subclinical CAD in women, but not in men. Short-term intervention with a vegetarian diet in individuals with CAD can positively impact novel and traditional factors that have been associated with risk of future cardiovascular events.
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| 17. |
- Green, Anna, 1973-, et al.
(author)
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Copy number variants in familial hypercholesterolemia genes using targeted NGS, validated through optical genome mapping
- 2024
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In: European Journal of Human Genetics. - : Nature Portfolio. - 1018-4813 .- 1476-5438. ; 32:Suppl. 1, s. 159-159
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Journal article (other academic/artistic)abstract
- Background/Objectives: Familial hypercholesterolemia (FH) is a common genetic disorder which is primarily caused by pathogenic variants in the LDLR, APOB, and PCSK9 genes. Approximately 10% of pathogenic variants in LDLR may be CNVs. Here, we combine NGS, MLPA, and Optical Genome Mapping (OGM) to investigate CNVs in LDLR.Methods: A NGS panel was designed for whole gene sequencing (8 genes) of 100 FH patients using Twist technology and Illumina platform. CNVs were detected using CNVexpo, and an in-house pipeline for base-resolved normalized coverage. Identified CNVs were validated using MLPA and OGM. Bionano Services Lab performed the OGM procedure. Purified gDNA was labeled using Direct Label and Stain DNA Labeling Kit. Saphyr chip was run aiming for 100X coverage. De novo assembly and Variant Annotation pipelines were executed on Bionano Solve v3.7. Bionano Access v1.7 was used for CNV reporting and visualization.Results: In five out of 100 samples NGS and MLPA data showed heterozygous deletions in LDLR. Three deletions, affecting different exons, was analyzed and confirmed using OGM. In two samples, OGM better defined the breakpoints as well as the size of the event, which expanded far beyond the gene of interest. In one sample, an additional CNV of SLCO1B1, a pharmaco-gene, important for transport of statins used for FH treatment was identified.Conclusion: CNVs in FH genes in FH patients could be detected using targeted NGS, which was further confirmed by MLPA and characterized using OGM.
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| 18. |
- Larsson, E., et al.
(author)
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Evaluation of the ImmuView RSV Test for Rapid Detection of Respiratory Syncytial Virus in Adult Patients with Influenza-Like Symptoms
- 2021
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In: Microbiology Spectrum. - : American Society for Microbiology. - 2165-0497. ; 9:3
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Journal article (peer-reviewed)abstract
- Rapid antigen tests may enhance the diagnostic yield of respiratory syncytial virus (RSV) infections, but studies have shown low sensitivity in adults. We evaluated the novel ImmuView RSV test in adult patients with influenza-like symptoms who were prospectively enrolled at three emergency departments in two Swedish hospitals during two influenza seasons, 2017 to 2018 and 2018 to 2019. The ImmuView RSV test was performed on nasopharyngeal swabs and results were compared to those of the BinaxNOW RSV test. In the first season, tests were performed on frozen samples, while unfrozen samples were used in the second season. For comparison, tests were also performed on selected samples from children. Of 333 included adult patients, the sensitivity of ImmuView and BinaxNOW was 27% for both tests and specificities were 98% and 100%, respectively. The interassay agreement was good (κ = 0.61). There was no significant difference in test performance between frozen and unfrozen samples. In samples from children, the sensitivities of ImmuView and BinaxNOW were 67% and 70%, respectively. In conclusion, the ImmuView RSV test showed low sensitivity and high specificity for identifying RSV in adult patients with influenza-like symptoms, comparable with the BinaxNOW RSV test. Rapid RSV testing is of limited value for diagnosing RSV infection in adults. IMPORTANCE: By timely RSV diagnosis among patients with influenza-like symptoms, especially when influenza diagnostics turn negative, it is possible to prevent unnecessary antibiotic usage as well as reduce diagnostic testing, nosocomial transmission, and hospital stay. Previous rapid RSV tests have demonstrated poor sensitivity in adults, and we could demonstrate that the novel ImmuView RSV test similarly showed limited value for diagnosing RSV infection in adult patients. However, in contrast to many other studies, we investigated patient characteristics in cases with false-positive tests and we compared the performance between unfrozen and frozen samples. Thus, our results are important, as they generate new knowledge about rapid antigen tests.
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| 19. |
- Nordenskjöld, Anna M., 1977-, et al.
(author)
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Prevalence and prognostic implications of myocardial injury in patients with influenza
- 2022
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In: European Heart Journal Open. - : Oxford University Press. - 2752-4191. ; 2:5
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Journal article (peer-reviewed)abstract
- Aims: Influenza may cause myocardial injury and trigger acute cardiovascular events. The aim of this study was to investigate the prevalence and prognostic implications of elevated high-sensitivity cardiac troponin I (hs-cTnI) in patients with influenza.Methods and results: In this prospective cohort study, we consecutively enrolled patients with influenza-like illness from two emergency departments in Sweden during three seasons of influenza, 2017-20. Ongoing Influenza infection was diagnosed by polymerase chain reaction and blood samples were collected for later analysis of hs-cTnI. All patients were followed-up for a composite endpoint of major adverse cardiovascular events (MACE) including death, myocardial infarction, unstable angina, heart failure, atrial fibrillation, and stroke within 1 year. Of the 466 patients with influenza-like symptoms, 181 (39%) were positive for influenza. Fifty (28%) patients were hospitalized. High-sensitivity cTnI was elevated in 11 (6%) patients and 8 (4%) experienced MACE. In univariate analyses, MACE was associated with age [hazard ratio (HR): 1.14, 95% confidence interval (CI): 1.05-1.23], hypertension (HR 5.56, 95%CI: 1.12-27.53), estimated glomerular filtration rate (HR: 0.94, 95%CI: 0.91-0.97), and elevated hs-cTnI (HR: 18.29, 95%CI: 4.57-73.24), N-terminal prohormone of brain natriuretic peptide (HR: 14.21, 95%CI: 1.75-115.5), hs-CRP (HR: 1.01, 95%CI: 1.00-1.02), and white blood cell count (HR: 1.12, 95%CI: 1.01-1.25). In multivariate analysis, elevated hs-cTnI was independently associated with MACE (HR: 4.96, 95%CI: 1.10-22.41).Conclusion: The prevalence of elevated hs-cTnI is low in unselected patients with influenza. Elevated hs-cTnI was associated with poor prognosis. A limitation is that the estimated associations are uncertain due to few events.
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| 20. |
- Nordenskjöld Syrous, Alma, 1979, et al.
(author)
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Reasons for physician-related variability in end-of-life decision-making in intensive care
- 2021
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In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 65:8, s. 1102-1108
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Journal article (peer-reviewed)abstract
- Background There is increasing evidence that the individual physician is the main factor influencing variability in end-of-life decision-making in intensive care units. End-of-life decisions are complex and should be adapted to each patient. Physician-related variability is problematic as it may result in unequal assessments that affect patient outcomes. The primary aim of this study was to investigate factors contributing to physician-related variability in end-of-life decision-making. Method This is a qualitative substudy of a previously conducted study. In-depth thematic analysis of semistructured interviews with 19 critical care specialists from five different Swedish intensive care units was performed. Interviews took place between 1 February 2017 and 31 May 2017. Results Factors influencing physician-related variability consisted of different assessment of patient preferences, as well as intensivists' personality and values. Personality was expressed mainly through pace and determination in the decision-making process. Personal prejudices appeared in decisions, but few respondents had personally witnessed this. Avoidance of criticism and conflicts as well as individual strategies for emotional coping were other factors that influenced physician-related variability. Many respondents feared criticism for making their assessments, and the challenging nature of end-of-life decision-making lead to avoidance as well as emotional stress. Conclusion Variability in end-of-life decision-making is an important topic that needs further investigation. It is imperative that such variability be acknowledged and addressed in a more formal and transparent manner. The ethical issues faced by intensivists have recently been compounded by the devastating impact of the COVID-19 pandemic, demonstrating in profound terms the importance of the topic.
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| 21. |
- Nordenskjöld Syrous, Anna, et al.
(author)
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Swedish intensivists' experiences and attitudes regarding end-of-life decisions
- 2020
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In: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 64:5, s. 656-62
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Journal article (peer-reviewed)abstract
- Background To make end-of-life (EOL) decisions is a complex and challenging task for intensive care physicians and a substantial variability in this process has been previously reported. However, a deeper understanding of intensivists' experiences and attitudes regarding the decision-making process is still, to a large extent, lacking. The primary aim of this study was to address Swedish intensivists' experiences, beliefs and attitudes regarding decision-making pertaining to EOL decisions. Second, we aimed to identify underlying factors that may contribute to variability in the decision-making process. Method This is a descriptive, qualitative study. Semi-structured interviews with nineteen intensivists from five different Swedish hospitals, with different ICU levels, were performed from 1 February 2017 to 31 May 2017. Results Intensivists strive to make end-of-life decisions that are well-grounded, based on sufficient information. Consensus with the patient, family and other physicians is important. Concurrently, decisions that are made with scarce information or uncertain medical prognosis, decisions made during on-call hours and without support from senior consultants cause concern for many intensivists. Underlying factors that contribute to the variability in decision-making are lack of continuity among senior intensivists, lack of needed support during on-call hours and disagreements with physicians from other specialties. There is also an individual variability primarily depending on the intensivist's personality. Conclusion Swedish intensivists' wish to make end-of-life decisions based on sufficient information, medically certain prognosis and consensus with the patient, family, staff and other physicians. Swedish intensivists' experience a variability in end-of-life decisions, which is generally accepted and not questioned.
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| 22. |
- Pasupathy, Sivabaskari, et al.
(author)
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Randomized Evaluation of Beta Blocker and ACE-Inhibitor/Angiotensin Receptor Blocker Treatment for Post Infarct Angina in Patients With Myocardial Infarction With Non-obstructive Coronary Arteries : A MINOCA-BAT Sub Study Rationale and Design
- 2021
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In: Frontiers in Cardiovascular Medicine. - : Frontiers Media S.A.. - 2297-055X. ; 8
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Journal article (peer-reviewed)abstract
- Introduction: Myocardial infarction with non-obstructive coronary arteries (MINOCA) occurs in ~10% of all patients with acute myocardial infarction (AMI), with an over-representation amongst women. Remarkably, it is estimated that as many as 1 in 4 patients with MINOCA experience ongoing angina at 12 months despite having no flow-restricting stenoses in their epicardial arteries. This manuscript presents the rationale behind Randomized Evaluation of Beta Blocker and Angiotensin-converting enzyme inhibitors/Angiotensin Receptor Blocker Treatment (ACEI/ARB) for Post Infarct Angina in MINOCA patients-The MINOCA BAT post infarct angina sub study.Methods: This trial is a registry-based, randomized, parallel, open-label, multicenter trial with 2 × 2 factorial design. The primary aim is to determine whether oral beta blockade compared with no oral beta blockade, and ACEI/ARB compared with no ACEI/ARB, reduce post infarct angina in patients discharged after MINOCA without clinical signs of heart failure and with left ventricular ejection fraction ≥40%. A total of 664 patients will be randomized into four groups; (i) ACEI/ARB with beta blocker, (ii) beta blocker only, (iii) ACEI/ARB only, or (iv) neither ACEI/ARB nor beta blocker and followed for 12 months. Results: The trial is currently recruiting in Australia and Sweden. Fifty six patients have been recruited thus far. Both sexes were equally distributed (52% women and 48% men) and the mean age was 56.3 ± 9.9 years.Conclusions: It remains unclear whether conventional secondary preventive therapies are beneficial to MINOCA patients in regard to post infarct angina. Existing registry-based literature suggest cardioprotective agents are less likely to be used in MINOCA patients. Thus, results from this trial will provide insights for future treatment strategies and guidelines specific to MINOCA patients.
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| 23. |
- Pålsson, Erik, 1975, et al.
(author)
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Cohort profile: the Swedish National Quality Register for bipolar disorder(BipolaR)
- 2022
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In: Bmj Open. - : BMJ. - 2044-6055. ; 12:12
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Journal article (peer-reviewed)abstract
- PurposeThe Swedish National Quality Register for bipolar affective disorder, BipolaR, was established in 2004 to provide nationwide indicators for quality assessment and development in the clinical care of individuals with bipolar spectrum disorder. An ancillary aim was to provide data for bipolar disorder research.ParticipantsInclusion criteria for registration in BipolaR is a diagnosis of bipolar spectrum disorder (ICD codes: F25.0, F30.1-F30.2, F30.8-F31.9, F34.0) and treatment at an outpatient clinic in Sweden. BipolaR collects data from baseline and annual follow-up visits throughout Sweden. Data is collected using questionnaires administered by healthcare staff. The questions cover sociodemographic, diagnostic, treatment, outcomes and patient reported outcome variables. The register currently includes 39 583 individual patients with a total of 75 423 baseline and follow-up records.Findings to dateData from BipolaR has been used in several peer-reviewed publications. Studies have provided knowledge on effectiveness, side effects and use of pharmacological and psychological treatment in bipolar disorder. In addition, findings on the diagnosis of bipolar disorder, risk factors for attempted and completed suicide and health economics have been reported. The Swedish Bipolar Collection project has contributed to a large number of published studies and provides important information on the genetic architecture of bipolar disorder, the impact of genetic variation on disease characteristics and treatment outcome.Future plansData collection is ongoing with no fixed end date. Currently, approximately 5000 new registrations are added each year. Cohort data are available via a formalised request procedure from Centre of Registers Vastra Gotaland (e-mail: registercentrum@vgregion.se). Data requests for research purposes require an entity responsible for the research and an ethical approval.
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| 24. |
- Sabatier, Pierre, et al.
(author)
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An integrative proteomics method identifies a regulator of translation during stem cell maintenance and differentiation
- 2021
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 12
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Journal article (peer-reviewed)abstract
- To characterize molecular changes during cell type transitions, the authors develop a method to simultaneously measure protein expression and thermal stability changes. They apply this approach to study differences between human pluripotent stem cells, their progenies, parental and allogeneic cells. Detailed characterization of cell type transitions is essential for cell biology in general and particularly for the development of stem cell-based therapies in regenerative medicine. To systematically study such transitions, we introduce a method that simultaneously measures protein expression and thermal stability changes in cells and provide the web-based visualization tool ProteoTracker. We apply our method to study differences between human pluripotent stem cells and several cell types including their parental cell line and differentiated progeny. We detect alterations of protein properties in numerous cellular pathways and components including ribosome biogenesis and demonstrate that modulation of ribosome maturation through SBDS protein can be helpful for manipulating cell stemness in vitro. Using our integrative proteomics approach and the web-based tool, we uncover a molecular basis for the uncoupling of robust transcription from parsimonious translation in stem cells and propose a method for maintaining pluripotency in vitro.
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