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1.	Lindstrand, Anna, et al. (författare) From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability 2019 Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 11:1 Tidskriftsartikel (refereegranskat)abstract BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
2.	Strandqvist, Anna, et al. (författare) Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia : epidemiological studies in a nonbiased national cohort in Sweden 2014 Ingår i: The Journal of Clinical Endocrinology & Metabolism. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-972X .- 1945-7197. Tidskriftsartikel (refereegranskat)abstract Context: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. Objective: To study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. Design: An epidemiological study with a matched cohort control design. Setting: All known CAH patients in Sweden. Participants: 588 patients, >95% with known severity of CAH; 100 controls per patient matched for sex, year and place of birth. Main outcome and measures: Proxies for quality of life were selected: level of education, employment, income, sick-leave, disability pension, marriage and children. Results: Women with salt-wasting (SW) CAH had completed primary education less often (OR 0.3), not explained by neonatal salt-crisis or hypoglycemia since the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8) SW women were more likely to have an income in the top 20 percentile (OR 2.0 ). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long lasting employment (OR 3.1). Men were more often (OR 1.6) while women were less often married (OR 0.7). Patients had children less often (OR 0.3). Conclusions: This study shows important outcome differences regarding education, employment, marriage and fertility depending on sex and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.
3.	Butwicka, Agnieszka, et al. (författare) Hypospadias and increased risk for neurodevelopmental disorders 2014 Ingår i: Journal of Child Psychology and Psychiatry. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-9630 .- 1469-7610. Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Hypospadias (aberrant opening of the urethra on the underside of the penis) occurs in 1 per 300 newborn boys. It has been previously unknown whether this common malformation is associated with increased psychiatric morbidity later in life. Studies of individuals with hypospadias also provide an opportunity to examine whether difference in androgen signaling is related to neurodevelopmental disorders. To elucidate the mechanisms behind a possible association, we also studied psychiatric outcomes among brothers of the hypospadias patients. METHODS: Registry study within a national cohort of all 9,262 males with hypospadias and their 4,936 healthy brothers born in Sweden between 1973 and 2009. Patients with hypospadias and their brothers were matched with controls by year of birth and county. The following outcomes were evaluated (1) any psychiatric (2) psychotic, (3) mood, (4) anxiety, (5) eating, and (6) personality disorders, (7) substance misuse, (8) attention-deficit hyperactivity disorder (ADHD), (9) autism spectrum disorders (ASD), (10) intellectual disability, and (11) other behavioral/emotional disorders with onset in childhood. RESULTS: Patients with hypospadias were more likely to be diagnosed with intellectual disability (OR 3.2; 95% CI 2.8-3.8), ASD (1.4; 1.2-1.7), ADHD (1.5; 1.3-1.9), and behavioral/emotional disorders (1.4; 1.2-1.6) compared with the controls. Brothers of patients with hypospadias had an increased risk of ASD (1.6; 1.3-2.1) and other behavioral/emotional disorders with onset in childhood (1.2; 0.9-1.5) in comparison to siblings of healthy individuals. A slightly higher, although not statistically significant, risk was found for intellectual disability (1.3; 1.0-1.9). No relation between other psychiatric diagnosis and hypospadias was found. CONCLUSIONS: This is the first study to identify an increased risk for neurodevelopmental disorders in patients with hypospadias, as well as an increased risk for ASD in their brothers, suggesting a common familial (genetic and/or environmental) liability.
4.	Dar, Huma, et al. (författare) Assessment of 25-Year Survival of Women With Estrogen Receptor-Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy A Secondary Analysis of Data From the Stockholm Tamoxifen Randomized Clinical Trial 2021 Ingår i: JAMA Network Open. - : American Medical Association. - 2574-3805. ; 4:6 Tidskriftsartikel (refereegranskat)abstract IMPORTANCE Clinically used breast cancer markers, such as tumor size, tumor grade, progesterone receptor (PR) status, and Ki-67 status, are known to be associated with short-term survival, but the association of these markers with long-term (25-year) survival is unclear. OBJECTIVE To assess the association of clinically used breast cancer markers with long-term survival and treatment benefit among postmenopausal women with lymph node-negative, estrogen receptor [ER]-positive and ERBB2-negative breast cancer who received tamoxifen therapy. DESIGN, SETTING, AND PARTICIPANTS This study was a secondary analysis of data from a subset of 565 women with ER-positive/ERBB2-negative breast cancer who participated in the Stockholm tamoxifen (STO-3) randomized clinical trial. The STO-3 clinical trial was conducted from 1976 to 1990 and comprised 1780 postmenopausal women with lymph node-negative breast cancer who were randomized to receive adjuvant tamoxifen therapy or no endocrine therapy. Complete 25-year follow-up data through December 31, 2016, were obtained from Swedish national registers. Immunohistochemical markers were reannotated in 2014. Data were analyzed from April to December 2020. INTERVENTIONS Patients in the original STO-3 clinical trial were randomized to receive 2 years of tamoxifen therapy vs no endocrine therapy. In 1983, patients who received tamoxifen therapy without cancer recurrence during the 2-year treatment and who consented to continued participation in the STO-3 study were further randomized to receive 3 additional years of tamoxifen therapy or no endocrine therapy. MAIN OUTCOMES AND MEASURES Distant recurrence-free interval (DRFI) by clinically used breast cancer markers was assessed using Kaplan-Meier and multivariable Cox proportional hazards analyses adjusted for age, period of primary diagnosis, tumor size (T1a and T1b [T1a/b], T1c, and T2), tumor grade (1-3), PR status (positive vs negative), Ki-67 status (low vs medium to high), and STO-3 clinical trial arm (tamoxifen treatment vs no adjuvant treatment). A recursive partitioning analysis was performed to evaluate which markers were able to best estimate long-term DRFI. RESULTS The study population comprised 565 postmenopausal women (mean [SD] age, 62.0 [5.3] years) with lymph node-negative, ER-positive/ERBB2-negative breast cancer. A statistically significant difference in long-term DRFI was observed by tumor size (88% for T1a/b vs 76% for T1c vs 63% for T2 tumors; log-rank P <.001) and tumor grade (81% for grade 1 vs 77% for grade 2 vs 65% for grade 3 tumors; log-rank P =.02) but not by PR status or Ki-67 status. Patients with smaller tumors (hazard ratio [HR], 0.31 [95% CI, 0.17-0.55] for T1a/b tumors and 0.58 [95% CI, 0.38-0.88] for T1c tumors) and grade 1 tumors (HR, 0.48; 95% CI, 0.24-0.95) experienced a significant reduction in the long-term risk of distant recurrence compared with patients with larger (T2) tumors and grade 3 tumors, respectively. A significant tamoxifen treatment benefitwas observed among patients with larger tumors (HR, 0.53 [95% CI, 0.32-0.89] for T1c tumors and 0.34 [95% CI, 0.16-0.73] for T2 tumors), lower tumor grades (HR, 0.24 [95% CI, 0.07-0.82] for grade 1 tumors and 0.50 [95% CI, 0.31-0.80] for grade 2 tumors), and PR-positive status (HR, 0.38; 95% CI, 0.24-0.62). The recursive partitioning analysis revealed that tumor sizewas the most important characteristic associated with long-term survival, followed by clinical trial arm among patients with larger tumors. CONCLUSIONS AND RELEVANCE This secondary analysis of data from the STO-3 clinical trial indicated that, among the selected subgroup of patients, tumor size followed by tumor grade were the markers most significantly associated with long-term survival. Furthermore, a significant long-term tamoxifen treatment benefit was observed among patients with larger tumors, lower tumor grades, and PR-positive tumors.
5.	Eckerdal, David, et al. (författare) Finger Joint Contractures 5 Years After Treatment for Dupuytren Disease : A Comparative Cohort Study of Collagenase Injection Versus Surgical Fasciectomy 2022 Ingår i: Journal of Hand Surgery. - : Elsevier BV. - 0363-5023. ; 47:9, s. 834-842 Tidskriftsartikel (refereegranskat)abstract Purpose: To compare collagenase injection with surgical fasciectomy in Dupuytren disease (DD) for the prevalence of contracture in treated fingers 5 years after treatment. Methods: This was a single-center, comparative cohort study comprising 2 cohorts of patients treated for DD in 1 or more of 3 ulnar fingers with collagenase injection (159 patients) or surgical fasciectomy (59 patients). At 5 years after treatment, 13 collagenase-treated and 8 fasciectomy-treated patients had undergone subsequent treatment on the treated fingers and were considered to have current contracture. Of the remaining patients, 112 collagenase-treated patients (128 hands, 180 fingers) and 46 fasciectomy-treated patients (49 hands, 63 fingers) attended follow-up evaluation performed by 2 independent examiners (participation rate 84% and 93%, respectively). We defined current contracture in a treated finger as an active extension deficit of ≥20° in the metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joint or a total (MCP + PIP) active extension deficit (TAED) of ≥30°. We used linear mixed models to analyze differences between the cohorts over time. Results: In the collagenase cohort, current contracture was present in 45 (25%) MCP and 60 (33%) PIP joints, and in the fasciectomy cohort, current contracture was present in 12 MCP (19%) and 30 PIP (48%) joints; a TAED of ≥30° was present in 79 (44%) of the collagenase-treated and 30 (48%) of the fasciectomy-treated fingers. In MCP and PIP joints with ≥20° pretreatment contracture, complete correction was observed in 82 (56%) MCP and 30 (30%) PIP joints in the collagenase cohort and 23 (70%) MCP and 5 (16%) PIP joints in the fasciectomy cohort. There was no statistically significant difference between the 2 cohorts in the TAED change over time. Conclusions: In patients with DD, collagenase injection and surgical fasciectomy improved finger joint contracture over the pretreatment status but had a high prevalence of joint contracture in the treated fingers 5 years after treatment. Type of study/level of evidence: Therapeutic IV.
6.	Green, Anna, 1973-, et al. (författare) Copy number variants in familial hypercholesterolemia genes using targeted NGS, validated through optical genome mapping 2024 Ingår i: European Journal of Human Genetics. - : Nature Portfolio. - 1018-4813 .- 1476-5438. ; 32:Suppl. 1, s. 159-159 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)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.
7.	Johansson, Annelie, et al. (författare) Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial 2022 Ingår i: Journal of Clinical Oncology. - : Lippincott, Williams & Wilkins. - 0732-183X .- 1527-7755. ; 40:35, s. 4071-4082 Tidskriftsartikel (refereegranskat)abstract PURPOSETo assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer.METHODSSecondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.RESULTSIn estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.CONCLUSIONThis study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor-positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical.
8.	Lindblad, L., et al. (författare) Risk factors for mortality of medical causes within 30 days of electroconvulsive therapy 2023 Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 320, s. 527-533 Tidskriftsartikel (refereegranskat)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.
9.	Nordenskjöld, Anna, 1969, et al. (författare) Breast cancer survival and incidence of second primary cancers after 30 years in a randomized study of two versus five years of adjuvant tamoxifen therapy 2023 Ingår i: Breast. - : CHURCHILL LIVINGSTONE. - 0960-9776 .- 1532-3080. ; 71, s. 63-68 Tidskriftsartikel (refereegranskat)abstract Background: Tamoxifen is an established treatment for breast cancer, but its long-term effects on survival and on secondary cancers are not fully evaluated. Material and methods: We studied 30 years outcome of 4124 postmenopausal patients who were randomized to receive (totally) two or five years of adjuvant tamoxifen.Results: After 5 years of follow-up, when tamoxifen treatment was finished in both groups, until 15 years of follow-up, overall mortality (HR 0.80, 95% CI 0.72-0.90, p < 0.001), breast cancer mortality for all patients (HR 0.80, 95% CI 0.68-0.94, p = 0.006) and breast cancer mortality for patients with estrogen receptor positive disease (HR 0.67, 95% CI 0.55-0.83, p < 0.001) were significantly reduced in the five-year group as compared to the two-year group. After 15 years, the difference remained but did not further increase. In the five-year group, the incidence of contralateral breast cancer was gradually reduced during the entire period of observation. The incidence of lung cancer was also reduced in the five-year group. In contrast there was an increased endometrial cancer incidence in the five-year group and for those receiving 40 mg of tamoxifen this incidence was further increased.Conclusion: Three more years of tamoxifen therapy reduced the risk of breast cancer mortality. The difference was established during the first 15 years after randomization. Moreover, the incidence of contralateral breast cancer gradually decreased for 30 years. The incidence of lung cancer was reduced in the five-year group. In contrast the incidence of endometrial cancer was increased.
10.	Nordenskjöld, Axel, 1977-, et al. (författare) Major adverse cardiovascular events following electroconvulsive therapy in depression : A register-based nationwide Swedish cohort study with 1-year follow-up 2022 Ingår i: Journal of Affective Disorders. - : Elsevier. - 0165-0327 .- 1573-2517. ; 296, s. 298-304 Tidskriftsartikel (refereegranskat)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.
11.	Nordenskjöld, Anna, 1969, et al. (författare) No clear effect of postoperative radiotherapy on survival of breast cancer patients with one to three positive nodes: a population-based study 2015 Ingår i: Annals of Oncology. - : Oxford University Press (OUP): Policy B - Oxford Open Option F. - 0923-7534 .- 1569-8041. ; 26:6, s. 1149-1154 Tidskriftsartikel (refereegranskat)abstract Background: In published radiotherapy trials, the failure rate in the control arm among patients with one to three positive nodes is high compared with that seen with modern adjuvant treatments. Therefore, the generalizability of the results has been questioned. The aim of the present study was to compare relative survival in breast cancer patients between two Swedish regions with screening mammography programs and adjuvant treatment guidelines similar with the exception of the indication of radiotherapy for patients with one to three positive nodes. Patients and methods: Between 1989 and 2006, breast cancer patients were managed very similarly in the west and southeast regions, except for indication for postoperative radiotherapy. In patients with one to three positive nodes, post-mastectomy radiotherapy was generally given in the southeast region (89% of all cases) and generally not given in the west region (15% of all cases). For patients with one to three positive nodes who underwent breast-conserving surgery, patients in the west region had breast radiotherapy only, while patients in the southeast region had both breast and lymph nodes irradiated. Results: The 10-year relative survival for patients with one to three positive lymph nodes was 78% in the west region and 77% in the southeast region (P = 0.12). Separate analyses depending on type of surgery, as well as number of examined nodes, also revealed similar relative survival. Conclusion: Locoregional postoperative radiotherapy has well-known side-effects, but in this population-based study, there was little or no influence of this type of radiotherapy on survival when one to three lymph nodes were involved.
12.	Nordenskjöld, Jesper, et al. (författare) Collagenase injections for Dupuytren disease : 3-year treatment outcomes and predictors of recurrence in 89 hands 2019 Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 90:6, s. 517-522 Tidskriftsartikel (refereegranskat)abstract Background and purpose — Few prospective studies have reported the long-term effect durability of collagenase injections for Dupuytren disease. We assessed the 3-year treatment outcome of collagenase injections and predictors of recurrence. Patients and methods — We conducted a single-center prospective cohort study. Indication for collagenase injection was palpable Dupuytren’s cord and active extension deficit (AED) ≥ 20° in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joint. From November 2012 through June 2013, we treated 86 consecutive patients (92 hands, 126 fingers). A hand therapist measured joint contracture before, 5 weeks, and 3 years after injection. The patients rated their treatment satisfaction. Primary outcome was proportion of treated joints with ≥ 20° AED worsening between the 5-week and 3-year measurements. We analyzed predictors of recurrence. Results — 3-year outcomes were available for 83 of the 86 patients (89 hands, 120 treated fingers). Between the 5-week and 3-year measurements, AED worsened by ≥ 20° in 17 MCP (14%) and 28 PIP (23%) joints. At 3 years, complete correction (passive extension deficit 0–5°) was present in 73% of MCP and 35% of PIP joints. Treatment of small finger PIP joint contracture, greater pretreatment contracture severity, and previous fasciectomy on the treated finger were statistically significant predictors of recurrence. Treatment satisfaction was rated as very satisfied or satisfied in 59 of 87 hands. No long-term treatment-related adverse events were observed. Interpretation — 3 years after collagenase injections for Dupuytren disease, improvement was maintained and treatment satisfaction reported in two-thirds of the treated hands, with no adverse events. Complete contracture correction was achieved in 3 of 4 MCP joints, but in only a third of the PIP joints.
13.	Nordenvall, Anna Skarin, et al. (författare) Hypospadias as a novel feature in spinal bulbar muscle atrophy 2016 Ingår i: Journal of Neurology. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0340-5354 .- 1432-1459. Tidskriftsartikel (refereegranskat)abstract Spinal and bulbar muscle atrophy (SBMA) is an X-linked neuromuscular disorder caused by CAG repeat expansions in the androgen receptor (AR) gene. The SBMA phenotype consists of slowly progressive neuromuscular symptoms and undermasculinization features as the result of malfunction of the AR. The latter mainly includes gynecomastia and infertility. Hypospadias is also a feature of undermasculinization with an underdeveloped urethra and penis; it has not been described as part of the SBMA phenotype but has been suggested to be associated with a prolonged CAG repeat in the AR gene. This study includes the first epidemiologic description of the co-occurrence of hypospadias and SBMA in subjects and their male relatives in Swedish population-based health registers, as well as an additional clinical case. One boy with severe hypospadias was screened for mutations in the AR gene and was found to have 42 CAG repeats in it, which is in the full range of mutations causing SBMA later in life. We also detected a maximum of four cases displaying the combination of SBMA and hypospadias in our national register databases. This is the third case report with hypospadias in association with CAG repeat expansions in the AR gene in the full range known to cause SBMA later in life. Our findings suggest that hypospadias may be an under diagnosed feature of the SBMA phenotype and we propose that neurologists working with SBMA further investigate and report the true prevalence of hypospadias among patients with SBMA.
14.	Anh, Nhi, et al. (författare) High-resolution detection of chromosomal rearrangements in leukemias through mate pair whole genome sequencing 2018 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:3 Tidskriftsartikel (refereegranskat)abstract The detection of recurrent somatic chromosomal rearrangements is standard of care for most leukemia types. Even though karyotype analysis-a low-resolution genome-wide chromosome analysis-is still the gold standard, it often needs to be complemented with other methods to increase resolution. To evaluate the feasibility and applicability of mate pair whole genome sequencing (MP-WGS) to detect structural chromosomal rearrangements in the diagnostic setting, we sequenced ten bone marrow samples from leukemia patients with recurrent rearrangements. Samples were selected based on cytogenetic and FISH results at leukemia diagnosis to include common rearrangements of prognostic relevance. Using MP-WGS and in-house bioinformatic analysis all sought rearrangements were successfully detected. In addition, unexpected complexity or additional, previously undetected rearrangements was unraveled in three samples. Finally, the MP-WGS analysis pinpointed the location of chromosome junctions at high resolution and we were able to identify the exact exons involved in the resulting fusion genes in all samples and the specific junction at the nucleotide level in half of the samples. The results show that our approach combines the screening character from karyotype analysis with the specificity and resolution of cytogenetic and molecular methods. As a result of the straightforward analysis and high-resolution detection of clinically relevant rearrangements, we conclude that MP-WGS is a feasible method for routine leukemia diagnostics of structural chromosomal rearrangements.
15.	Athlin, Simon, 1971-, et al. (författare) Evaluation of the novel IMMUVIEW RSV antigen test for detection of respiratory syncytial virus in adults and children 2019 Konferensbidrag (övrigt vetenskapligt/konstnärligt)
16.	Atroshi, Isam, et al. (författare) Collagenase treatment of Dupuytrens contracture using a modified injection method 2015 Ingår i: Acta Orthopaedica. - : Informa Healthcare: Creative Commons Attribution Non-Commercial / Informa Healthcare. - 1745-3674 .- 1745-3682. ; 86:3, s. 310-315 Tidskriftsartikel (refereegranskat)abstract Background and purpose - Treatment of Dupuytrens contracture (DC) with collagenase Clostridium histolyticum (CCH) consists of injection followed by finger manipulation. We used a modified method, injecting a higher dose than recommended on the label into several parts of the cord, which allows treatment of multiple joint contractures in 1 session and may increase efficacy. We studied the occurrence of skin tears and short-term outcome with this procedure. Patients and methods - We studied 164 consecutive hands with DC, palpable cord, and extension deficit of greater than= 20 degrees in the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joint (mean patient age 70 years, 82% men). A hand surgeon injected all the content of 1 CCH vial (approximately 0.80 mg) into multiple spots in the cord and performed finger extension under local anesthesia after 1 or 2 days. A nurse recorded skin tears on a diagram and conducted a standard telephone follow-up within 4 weeks. A hand therapist measured joint contracture before injection and at a median of 23 (IQR: 7-34) days after finger extension. Results - A skin tear occurred in 66 hands (40%). The largest diameter of the tear was less than= 5 mm in 30 hands and greater than 10 mm in 14 hands. Hands with skin tear had greater mean pretreatment MCP extension deficit than those without tear: 59 degrees (SD 26) as opposed to 32 degrees (SD 23). Skin tear occurred in 21 of 24 hands with MCP contracture of greater than= 75 degrees. All tears healed with open-wound treatment. No infections occurred. Mean improvement in total (MCP + PIP) extension deficit was 55 degrees (SD 28). Interpretation - Skin tears occurred in 40% of hands treated with collagenase injections, but only a fifth of them were larger than 1 cm. Tears were more likely in hands with severe MCP joint contracture. All tears healed without complications. Short-term contracture reduction was good.
17.	Block, Linda, et al. (författare) Age, SAPS 3 and female sex are associated with decisions to withdraw or withhold intensive care 2019 Ingår i: Acta Anaesthesiologica Scandinavica. - : Wiley. - 0001-5172 .- 1399-6576. ; 63:9, s. 1210-1215 Tidskriftsartikel (refereegranskat)abstract Background: Intensive care treat critically ill patients. When intensive care is not considered beneficial for the patient, decisions to withdraw or withhold treatments are made. We aimed to identify independent patient variables that increase the odds for receiving a decision to withdraw or withhold intensive care. Methods: Registry study using data from the Swedish Intensive Care Registry (SIR) 2014-2016. Age, condition at admission, including co-morbidities (Simplified Acute Physiology Score version 3, SAPS 3), diagnosis, sex, and decisions on treatment limitations were extracted. Patient data were divided into a full care (FC) group, and a withhold or withdraw (WW) treatment group. Results: Of all 97095 cases, 47.1% were 61-80 years old, 41.9% were women and 58.1% men. 14996 (15.4%) were allocated to the WW group and 82149 (84.6%) to the FC group. The WW group, compared with the FC group, was older (P < 0.001), had higher SAPS 3 (P < 0.001) and were predominantly female (P < 0.001). Compared to patients 16-20 years old, patients >81 years old had 11 times higher odds of being allocated to the WW group. Higher SAPS 3 (continuous) increased the odds of being allocated to the WW group by odds ratio [OR] 1.085, (CI 1.084-1.087). Female sex increased the odds of being allocated to the WW group by 18% (1.18; CI 1.13- 1.23). Conclusion: Older age, higher SAPS 3 at admission and female sex were found to be independent variables that increased the odds to receive a decision to withdraw or withhold intensive care. © 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
18.	Bremer, Anna, et al. (författare) Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. 2011 Ingår i: American Journal of Medical Genetics, Part B, Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 156B156:2, s. 115-124 Tidskriftsartikel (refereegranskat)abstract Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P=0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs
19.	Djekic, Demir, 1989- (författare) Novel and Traditional Risk Factors for Coronary Artery Disease : Role of Coronary Artery Calcium, Lipidomics, Psychosocial Factors and Diet 2020 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)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.
20.	Eggers, Kai, et al. (författare) Combining different biochemical markers of myocardial ischemia does not improve risk stratification in chest pain patients compared to troponin I alone. 2005 Ingår i: Coronary Artery Disease. - 0954-6928. ; 16:5, s. 315-319 Tidskriftsartikel (refereegranskat)
21.	Eggers, Kai, et al. (författare) Diagnostic value of serial measurement of cardiac markers in patients with chest pain. : Limited value of adding myoglobin to troponin I for exclusion of myocardial infarction. 2004 Ingår i: American Heart Journal. - 0002-8703. ; 148:4, s. 574-581 Tidskriftsartikel (refereegranskat)
22.	Eggers, Kai, et al. (författare) Diagnostic value of serial measurement of cardiac markers in patients with chest pain : limited value of adding myoglobin to troponin I for exclusion of myocardial infarction 2004 Ingår i: American Heart Journal. - : Elsevier BV. - 0002-8703 .- 1097-6744. ; 148:4, s. 574-581 Tidskriftsartikel (refereegranskat)abstract BACKGROUND:Despite improved laboratory assays for cardiac markers and a revised standard for definition of myocardial infarction (AMI), early detection of coronary ischemia in unselected patients with chest pain remains a difficult challenge.METHODS:Rapid measurements of troponin I (TnI), creatine kinase MB (CK-MB), and myoglobin were performed in 197 consecutive patients with chest pain and a nondiagnostic electrocardiogram for AMI. The early diagnostic performances of these markers and different multimarker strategies were evaluated and compared. Diagnosis of AMI was based on European Society of Cardiology/American College of Cardiology criteria.RESULTS:At a given specificity of 95%, TnI yielded the highest sensitivity of all markers at all time points. A TnI cutoff corresponding to the 10% coefficient of variation (0.1 microg/L) demonstrated a cumulative sensitivity of 93% with a corresponding specificity of 81% at 2 hours. The sensitivity was considerably higher compared to CK-MB and myoglobin, even considering patients with a short delay until admission. Using the 99th percentile of TnI results as a cutoff (0.07 microg/L) produced a cumulative sensitivity of 98% at 2 hours, but its usefulness was limited due to low specificities. Multimarker strategies including TnI and/or myoglobin did not provide a superior overall diagnostic performance compared to TnI using the 0.1 microg/L cutoff.CONCLUSION:A TnI cutoff corresponding to the 10% coefficient of variation was most appropriate for early diagnosis of AMI. A lower TnI cutoff may be useful for very early exclusion of AMI. CK-MB and in particular myoglobin did not offer additional diagnostic value.
23.	Eggers, Kai Marten, et al. (författare) Analytic Performance of a Point-of-Care Instrument for Measurement of Cardiac Markers : An Evaluation Under Clinical Conditions 2003 Ingår i: Point of Care. - : Lippincott Williams & Wilkins. - 1533-029X .- 1533-0303. ; 2:4, s. 235-242 Tidskriftsartikel (refereegranskat)abstract Point-of-care testing of cardiac markers has been widely introduced into clinical practice. In this study, the authors examined the analytic qualities and the feasibility of a point-of-care device—the Stratus CS STAT Fluorometric Analyzer—under clinical conditions. Measurements of myoglobin, creatine kinase–MB (CK-MB), and troponin I (TnI) were performed in 197 consecutive patients admitted to the coronary care unit because of chest pain suggestive of a myocardial infarction. Additionally, all cardiac markers were determined on the AxSYM analyzer used as a comparative device. The Stratus CS demonstrated an average analytic imprecision (or coefficient of variation [CV]) of 4.0 to 5.1% for the TnI assay, 2.9 to 5.5% for CK-MB, and 3.7 to 4.7% for myoglobin. This was superior to CVs of AxSYM measurements, in particular concerning the lower range of TnI concentrations. The method comparison showed 17 to 22% lower Stratus CS myoglobin results and 24 to 29% lower Stratus CS CK-MB results. For TnI, Stratus CS results were factor 5 or factor 10 lower compared with AxSYM measurements and showed a great dispersion of values as a result of the higher CV of the AxSYM TnI assay. The diagnostic sensitivities and specificities of all 3 markers correlated well on both test systems. In conclusion, the Stratus CS showed an overall good performance, with analytic qualities and clinical performance as least as good as those of the AxSYM analyzer.A large number of patients are admitted to coronary care units (CCUs) with chest pain suggestive of an acute coronary syndrome (ie, unstable angina or acute myocardial infarction [AMI]). The diagnosis of AMI is immediately established only in case of ST elevation in the electrocardiogram (EKG). The large majority of chest pain patients, however, will have a nondiagnostic EKG for AMI. In those patients, confirmation of AMI is mainly dependent on serial testing of biochemical markers of myocardial damage, which currently is a time-consuming procedure.Fast evaluation of patients with chest pain leads to several advantages. First, tests or procedures for establishing a definite or alternative diagnosis can be initiated earlier or avoided in appropriate circumstances. Second, rapid identification of patients suitable for treatment aimed at reducing morbidity and mortality (eg, percutaneous coronary intervention or Gp IIb/IIIa receptor antagonist treatment) may be possible. Furthermore, considerable economic gains might be achieved by early identification of patients who are at sufficiently low risk to be discharged or transferred from the CCU to a less resource-demanding unit. 1–3To achieve fast assessment of chest pain patients, a short-assay turnaround time (TAT) is necessary. Normally, TAT includes the delay in the delivery of the sample to the laboratory, the preanalytic steps necessary to prepare the sample, the analysis time itself, and the effort it takes to deliver results to the ordering physician. To reach a TAT of less than 30 minutes, point-of-care (POC) instruments for analysis of cardiac markers have been developed, combining advantages such as near-patient assessment, a short sample-to-diagnosis time, and reasonable costs.The aim of the current study was to examine and validate the feasibility of such a POC instrument—the Stratus CS STAT Fluorometric Analyzer (Dade Behring, Deerfield, IL)—in a routine setting of patients presenting with chest pain suggestive of an AMI but without confirming EKG changes. The analytic qualities and clinical performance of the assays of the commonly used cardiac markers troponin I (TnI), creatine kinase–MB (CK-MB), and myoglobin were studied and compared with results obtained from the central laboratory. Additionally, clinical characteristics such as user friendliness and TAT were evaluated.
24.	Eggers, Kai M., 1962-, et al. (författare) Clinical and prognostic implications of C-reactive protein levels in myocardial infarction with nonobstructive coronary arteries 2021 Ingår i: Clinical Cardiology. - : John Wiley & Sons. - 0160-9289 .- 1932-8737. ; 44:7, s. 1019-1027 Tidskriftsartikel (refereegranskat)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.
25.	Eggers, Kai M., 1962-, et al. (författare) Combining different biochemical markers of myocardial ischemia does not improve risk stratification in chest pain patients compared to troponin I alone 2005 Ingår i: Coronary Artery Disease. - : Ovid Technologies (Wolters Kluwer Health). - 0954-6928 .- 1473-5830. ; 16:5, s. 315-9 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Early evaluation of patients with chest pain is important not only for the detection of acute myocardial infarction (AMI) but also for identification of patients at high risk for future cardiac events. A multimarker strategy applying results of early measurements of different biochemical markers of cardiac necrosis in combination may improve risk prediction in chest pain patients. METHODS: Rapid measurements of troponin I (TnI), creatine kinase MB and myoglobin were performed in 191 consecutive patients with chest pain and a non-diagnostic electrocardiogram for AMI. The prognostic value of these markers and different multimarker strategies was evaluated and compared. RESULTS: Ten (5.2%) patients died during follow-up, which for eight (4.2%) patients was due to cardiac causes. Myocardial reinfarctions occurred in 17 (6.8%) patients. TnI was most predictive for cardiac mortality (TnI>or=0.1 microg/l, 10.7% event rate compared with TnI<0.1 microg/l, 0%, P<0.001) and myocardial reinfarction (14.9% compared with 1.7%, P<0.001). The other markers and multimarker strategies had a lower capacity for predicting adverse events apart from myoglobin and the combination of TnI or myoglobin regarding the endpoint of total mortality. CONCLUSION: The combinations of different markers were prognostically non-superior compared to TnI, which thus, should be preferred as a biochemical marker for risk stratification in patients with chest pain.
26.	Eggers, Kai M., 1962-, et al. (författare) GRACE 2.0 Score for Risk Prediction in Myocardial Infarction With Nonobstructive Coronary Arteries 2021 Ingår i: Journal of the American Heart Association. - : John Wiley & Sons. - 2047-9980. ; 10:17 Tidskriftsartikel (refereegranskat)
27.	Eggers, Kai M., 1962-, et al. (författare) Myocardial Infarction with Non-Obstructive Coronary Arteries : The Importance of Achieving Secondary Prevention Targets 2018 Ingår i: American Journal of Medicine. - : Elsevier. - 0002-9343 .- 1555-7162. ; 131:5, s. 524-531 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Around 5-10% of all myocardial infarction patients have non-obstructive coronary arteries. Studies investigating the importance of follow-up and achievement of conventional secondary prevention targets in these patients are lacking.METHODS: In this analysis from the SWEDEHEART registry, we investigated 5830 myocardial infarction patients with non-obstructive coronary arteries (group 1) and 54,637 myocardial infarction patients with significant coronary artery disease (≥50% stenosis; group 2). Multivariable- and propensity score-adjusted statistics were used to assess the reduction in the one-year risk of major adverse events associated with prespecified secondary preventive measures: participation in follow-up at 6-10 weeks after the hospitalization; achievement of secondary prevention targets (blood pressure and low-density lipoprotein cholesterol levels in the target ranges, non-smoking, participation in exercise training).RESULTS: Patients in group 1 were less often followed up compared to patients in group 2 and less often achieved any of the secondary prevention targets. Participation in the 6-10 week follow-up was associated with a 3-20% risk reduction in group 1, similar as for group 2 according to interaction analysis. The improvement in outcome in group 1 was mainly mediated by achieving target range low-density lipoprotein cholesterol levels (24-32% risk reduction) and, to a smaller extent, by participation in exercise training (10-23% risk reduction).CONCLUSIONS: Selected secondary preventive measures are associated with prognostic benefit in myocardial infarction patients with non-obstructive coronary arteries, in particular achieving target range low-density lipoprotein cholesterol levels. Our results indicate that these patients should receive similar follow-up as myocardial infarction patients with significant coronary stenoses.
28.	Eggers, Kai M., 1962-, et al. (författare) Risk prediction in patients with chest pain : early assessment by the combination of troponin I results and electrocardiographic findings 2005 Ingår i: Coronary Artery Disease. - : Ovid Technologies (Wolters Kluwer Health). - 0954-6928 .- 1473-5830. ; 16:3, s. 181-9 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: To evaluate the prognostic value of point of care troponin I (TnI) results in combination with findings from the admission electrocardiogram (ECG) in patients with chest pain. METHODS: Rapid measurements of TnI were performed in 191 consecutive patients with chest pain and a non-diagnostic ECG for myocardial infarction. RESULTS: Within 6 h from admission, maximum TnI elevations of > or = 0.07 microg/l and > or = 0.1 microg/l were noted in 59 and 39% of all patients, respectively. TnI elevations in the range of 0.07-0.09 microg/l were found in many patients with diagnoses other than acute coronary syndrome. By 6-month follow-up, cardiac death had occurred in 7.1 and 11% of patients with maximum TnI > or = 0.07 microg/l and > or = 0.1 microg/l, respectively and myocardial reinfarction was documented in 12 and 15%, respectively. ST-segment depression on the admission ECG was present in 16% of all patients and was the electrocardiographic abnormality with the highest risk (cardiac death 7.7%, myocardial reinfarction 15%). The combination of TnI > or = 0.1 microg/l and ST-segment depression or an abnormal admission ECG in general allowed the identification of patients at low, intermediate and high cardiac risk, 3 h after admission. CONCLUSION: A threshold of TnI > or = 0.1 microg/l corresponding to the 10% coefficient of variation is prognostically most suitable for prediction of cardiac events in patients with chest pain. The combination of TnI results and findings from the admission ECG improves prognostic assessment and allows early and reliable risk stratification in this patient population.
29.	Engberg, Hedvig, et al. (författare) Congenital adrenal hyperplasia and risk for psychiatric disorders in girls and women born between 1915 and 2010: A total population study. 2015 Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 60, s. 195-205 Tidskriftsartikel (refereegranskat)abstract Congenital adrenal hyperplasia (CAH) is a chronic condition and individuals are exposed to elevated androgen levels in utero as a result of the endogenous cortisol deficiency. Prenatal androgen exposure has been suggested to influence mental health, but population based studies on psychiatric morbidity among girls and women with CAH are lacking. Therefore, we performed a cohort study based on Swedish nationwide registers linked with the national CAH register. Girls and women with CAH due to 21-hydroxylase deficiency (n=335) born between January 1915 and January 2010 were compared with aged-matched female (n=33500) and male controls (n=33500). Analyses were stratified by phenotype [salt wasting (SW), simple virilizing (SV), and non-classical type (NC)] and by CYP21A2 genotype subgroups (null, I2splice, I172N, and P30L). Results are presented as estimated risks (OR, 95%CI) of psychiatric disorders among girls and women with CAH compared with age-matched controls. Any psychiatric diagnoses were more common in CAH females compared with female and male population controls [1.9 (1.4-2.5), and 2.2 (1.7-2.9)]. In particular, the risk of alcohol misuse was increased compared with female and male population controls [2.8 (1.7-4.7) and 2.1 (1.2-3.5)], and appeared most common among the girls and women with the most severe null genotype [6.7 (2.6-17.8)]. The risk of stress and adjustment disorders was doubled compared with female population controls [2.1 (1.3-3.6)]. Girls and women with CAH have an increased risk of psychiatric disorders in general and substance use disorders in particular compared with unexposed females, with the highest risk among those with the most severe genotype. Prenatal androgen exposure and deficient endogenous cortisol and/or adrenaline production may provide explanations for these findings, but other factors related to CAH cannot be excluded.
30.	Fadista, João, et al. (författare) Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus. 2018 Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 26:4, s. 561-569 Tidskriftsartikel (refereegranskat)abstract ; 322 cases and 4893 controls). The conditional signal was, however, not replicated in two HSCR cohorts from USA and Finland, leading to the hypothesis that rs144432435 tags a rare haplotype present in Denmark and Sweden. Using the genome-wide complex trait analysis method, we estimated the SNP heritability of HSCR to be 88%, close to estimates based on classical family studies. Moreover, by using Lasso (least absolute shrinkage and selection operator) regression we were able to construct a genetic HSCR predictor with a area under the receiver operator characteristics curve of 76% in an independent validation set. In conclusion, we combined the largest collection of sporadic Hirschsprung cases to date (586 cases) to further elucidate HSCR's genetic architecture.
31.	Falhammar, Henrik, et al. (författare) Increased cardiovascular and metabolic morbidity in patients with 21-hydroxylase deficiency : a Swedish population-based national cohort study 2015 Ingår i: The Journal of Clinical Endocrinology & Metabolism. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-972X. ; 100:9, s. 3520-3528 Tidskriftsartikel (refereegranskat)abstract CONTEXT: Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity. OBJECTIVE: This study aimed to study cardiovascular and metabolic morbidity in CAH. DESIGN, SETTING, AND PARTICIPANTS: Patients with CAH due to 21-hydroxylase deficiency (n = 588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n = 58 800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt wasting, simple virilizing, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age groups, and nonobesity. MAIN OUTCOME MEASURES: To study cardiovascular and metabolic morbidity in CAH. RESULTS: In CAH, both any cardiovascular and metabolic disorders (OR [odds ratio], 3.9; 95% CI [confidence interval], 3.1-5.0), and cardiovascular disease (OR, 2.7; 95% CI, 1.9-3.9) were increased. Separate analyses of the individual diseases showed higher frequencies in CAH of hypertension, hyperlipidemia, atrial fibrillation, venous thromboembolism, obesity, diabetes (mainly type 2), obstructive sleep disorder, thyrotoxicosis, and hypothyroidism. Similar results were seen in the stratified groups. On the subgroup level, females were generally more affected (especially I172N and the nonclassic group), as were males with the null genotype. CONCLUSIONS: CAH was associated with excess cardiovascular and metabolic morbidity but the mechanism is not certain as the glucocorticoids were not assessed. Hypothyroidism and obesity may be an effect of close observation. However, more severe conditions were presumably detected equally in patients and controls. Screening for diabetes and other metabolic disorders that increase cardiovascular risk is important.
32.	Falhammar, Henrik, et al. (författare) Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency 2014 Ingår i: The Journal of Clinical Endocrinology & Metabolism. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0021-972X .- 1945-7197. Tidskriftsartikel (refereegranskat)abstract Context: Reports on mortality in patients with congenital adrenal hyperplasia (CAH) are lacking. Objective: To study mortality and causes of death in CAH. Design, Setting and Participants: We studied patients with CAH (21-hydroxylase deficiency, n=588; CYP21A2 mutations known, >80%), and compared them with controls (n=58800). Data were derived through linkage of national population-based registers. Main Outcome Measures: Mortality and causes of death. Results: The mean age of death was 41.2±26.9 years in CAH patients and 47.7±27.7 years in controls (P<0.001). Among CAH patients 23 (3.9%) had deceased compared to 942 (1.6%) of controls. The hazard ratio (and 95% confidence interval) of death was 2.3(1.2-4.3) in CAH males and 3.5(2.0-6.0) in CAH females. Including only patients born 1952-2009, gave similar total results but only patients with salt-wasting or with unclear phenotype had an increased mortality. The causes of death in CAH patients were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). There were seven additional deaths in CAH individuals with incomplete or reused personal identification number that could not be analyzed using linkage of registers. Of the latter all except one were deceased before the introduction of neonatal screening in 1986 and most of them in the first weeks of life, probably in an adrenal crisis. Conclusions: CAH is a potentially lethal condition and was associated with excess mortality due to adrenal crisis. The salt-wasting phenotype seemed to have worse outcome also in children and adults due to adrenal crisis and not only before the introduction of neonatal screening.
33.	Falhammar, Henrik, et al. (författare) Increased Prevalence of Accidents and Injuries in Congenital Adrenal Hyperplasia : A Population-Based Cohort Study 2024 Ingår i: Journal of Clinical Endocrinology and Metabolism. - : Oxford University Press. - 0021-972X .- 1945-7197. ; 109:3, s. e1175-e1184 Tidskriftsartikel (refereegranskat)abstract CONTEXT: It has been suggested that injuries and accidents are increased in females with congenital adrenal hyperplasia (CAH), but the prevalence is unclear.OBJECTIVE: To study the prevalence of injuries and accidents in females and males with CAH.DESIGN, SETTING, AND PARTICIPANTS: Patients with CAH (n = 714, all 21-hydroxylase deficiency) were compared with matched controls (n = 71,400). Data were derived by linking National Population-Based Registers.MAIN OUTCOME MEASURES: Prevalence of injuries and accidents.RESULTS: Mean age was 29.8 ± 18.4 years. Injuries were more prevalent in patients with CAH than in controls (RR 1.34, 95%CI 1.24-1.44), and this was found in both sexes (females: 1.43, 1.29-1.58; males: 1.25, 1.12-1.38). In the classical phenotype, the prevalence of injuries was higher, especially in females but not in the non-classic phenotype. In the genotype groups, injuries were mainly increased in females. Head injuries were increased in all patients with CAH and in the different phenotypes and were mainly driven by females. More patients with CAH born before the introduction of neonatal screening had had an injury compared to controls (1.48, 1.35-1.62), this was seen in both sexes. In patients with CAH born after the introduction of screening, the prevalence of injuries was overall increased (1.20, 1.07-1.35), and in females with CAH but not in males. Accidents showed a similar pattern to injuries in all comparisons.CONCLUSIONS: Patients with CAH had an increased prevalence of both injuries and accidents, especially in females and in those born before the neonatal screening program. Patients with NC phenotype were hardly affected.
34.	Falhammar, Henrik, et al. (författare) Increased psychiatric morbidity in men with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. 2014 Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 99:3 Tidskriftsartikel (refereegranskat)abstract Context:Reports on psychiatric morbidity in males with congenital adrenal hyperplasia (CAH) are lacking.Objective:To study psychiatric disorders in CAH males.Design, Setting and Participants:We studied males with CAH (21-hydroxylase deficiency, n=253; CYP21A2 mutations known, n=185), and compared them with controls (n=25300). Data were derived through linkage of national population-based registers. We assessed the subgroups of CYP21A2 genotype separately (null, I2splice, I172N, P30L and NC), as well as outcomes before and after the introduction of national neonatal screening in 1986.Main Outcome Measures:Psychiatric disorders including attempted and completed suicide (suicidality).Results:Psychiatric disorders (suicidality not included), suicidality and alcohol misuse were increased in CAH males compared with controls (OR 1.5, 2.3, and 1.9; 95%CI 1.1-2.2, 1.1-5.0, and 1.0-3.5). In the null genotype group, no increased rates were seen; in the I2splice group, psychiatric disorders, personality disorders and alcohol misuse were increased; in the I172N group suicide attempt and drug misuse were increased; and in the P30L and NC group psychotic disorders were increased. In CAH males born before the neonatal screening, the rate of psychiatric disorders and suicidality were increased, but only psychotic disorders in those born after. There was no increased risk for any neurodevelopmental disorder.Conclusions:CAH males have an increased psychiatric morbidity. Psychiatric morbidity was not raised in the most severe genotype group. Late diagnosis of CAH may explain some of the findings. Those born before the introduction of neonatal screening were more affected, which may be explained by the higher age.
35.	Frisén, Lars, et al. (författare) Gender role behavior, sexuality, and psychosocial adaptation in women with congenital adrenal hyperplasia due to CYP21A2 deficiency 2009 Ingår i: J Clin Endocrinol Metab. - : The Endocrine Society. ; 94:9, s. 3432-9 Tidskriftsartikel (refereegranskat)abstract CONTEXT: Gender-atypical behavior has been described in young girls as well as in women with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency. OBJECTIVE: The aim of the study was to assess health-related, psychosexual, and psychosocial parameters and correlate the results to CYP21A2 genotype. DESIGN AND PARTICIPANTS: Sixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire and a validated quality of life instrument [psychological general well-being (PGWB) formula] to identify psychosexual and psychosocial parameters. The patients were divided into four CYP21A2 genotype groups. RESULTS: The women with CAH held more male-dominant occupations (30%) compared to controls (13%) (P = 0.04), especially those in the null genotype group (55%) (P = 0.006). They also reported a greater interest in rough sports (74%) compared to controls (50%) (P = 0.007). Eight women with CAH (14%) reported a prime interest in motor vehicles, compared to none of the controls (P = 0.002). Non-heterosexual orientation was reported by 19% of women with CAH (P = 0.005), 50% in the null genotype group (P = 0.0001), 30% in I2 splice (NS), and 5% in I172N (NS). PGWB total score did not differ between patients and controls. CONCLUSION: We identified increased gender-atypical behavior in women with CAH that could be correlated to the CYP21A2 genotype. This speaks in favor of dose-dependent effects of prenatal androgens on the development of higher brain functions. The impact of the disease on upbringing and interpersonal relationships did not correlate with disease severity, indicating that other factors, such as coping strategies, are important for psychosocial adaptation. This illustrates the need for psychological support to parents and patients.
36.	Giwercman, Yvonne, et al. (författare) An androgen receptor gene mutation (E653K) in a family with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency as well as in partial androgen insensitivity. 2002 Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 87:6, s. 2623-2628 Tidskriftsartikel (refereegranskat)
37.	Gotby, A. O., et al. (författare) Congenital Adrenal Hyperplasia, Polycystic Ovary Syndrome and criminal behavior: A Swedish population based study 2015 Ingår i: Psychiatry Research. - : Elsevier BV. - 0165-1781 .- 1872-7123. ; 229:3, s. 953-959 Tidskriftsartikel (refereegranskat)abstract Both prenatal and circulating testosterone and other androgens have been suggested to influence the individual's propensity to commit crime, but empirical evidence is limited and inconsistent. Congenital Adrenal Hyperplasia (CAH) and Polycystic Ovary Syndrome (PCOS) are both hyperandrogenic conditions but with an important difference; whereas subjects with CAH are exposed to high concentrations of androgens in utero, women with PCOS are subjected to high androgens in adulthood. Comparing these groups can therefore yield important insights of androgenic effects on behavior. In the current study, information on medical diagnoses and convicted crimes were gathered from Swedish population-based registers. The associations between diagnoses of CAH or PCOS and any crime, violent crime or sex crime were estimated with conditional logistic regression. Results showed that CAH in women and men did not predict criminality, whereas an increased risk for any crime and violent crime was found in PCOS women. Our findings indicate that female hyperandrogenism in adulthood, but not prenatal hyperandrogenism, is associated with risk for criminal behavior. Further research into hyperandrogenic conditions holds opportunities to deepen our understanding of the etiology of crime and psychopathology. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
38.	Göthlin Eremo, Anna, 1980-, et al. (författare) Wwox expression may predict benefit from adjuvant tamoxifen in randomized breast cancer patients 2013 Ingår i: Oncology Reports. - Athens, Greece : Spandidos Publications. - 1021-335X .- 1791-2431. ; 29:4, s. 1467-1474 Tidskriftsartikel (refereegranskat)abstract Reduced or absent Wwox expression has recently been associated with tamoxifen resistance in breast cancer and has also been proposed as a candidate predictive marker for treatment. We aimed to investigate the correlation of Wwox expression with the outcome of tamoxifen treatment by examining tissues from 912 randomized breast cancer patients. Paraffin-embedded tissues from patient tumors were arranged on tissue microarray, and Wwox protein was stained using immunohistochemistry. After microscopic examination, the results were analyzed with Cox regression, Kaplan-Meier survival curves and the log-rank test. In the group of cases having a tumor absent for Wwox expression, there was no difference in recurrence-free survival between treated and untreated patients (P=0.81). For treated cases with a tumor expressing moderate or strong Wwox protein, recurrence-free survival was improved (P=0.001 and P=0.003, respectively). The test for interaction between Wwox and treatment response demonstrated a decreased risk of recurrence for treated patients with a moderate or strong Wwox expression (HR=0.31, 95% CI 0.10-0.98 and HR=0.28, 95% CI 0.08-0.97, respectively). Our results indicate that patients with high expression of Wwox may gain more benefit from treatment with tamoxifen.
39.	Hammar, Per, et al. (författare) Unrecognized myocardial infarctions assessed by cardiovascular magnetic resonance are associated with the severity of the stenosis in the supplying coronary artery 2015 Ingår i: Journal of Cardiovascular Magnetic Resonance. - : BioMed Central. - 1097-6647 .- 1532-429X. ; 17 Tidskriftsartikel (refereegranskat)abstract Background: A previous study has shown an increased prevalence of late gadolinium enhancement cardiovascular magnetic resonance (LGE CMR) detected unrecognized myocardial infarction (UMI) with increasing extent and severity of coronary artery disease. However, the coronary artery disease was evaluated on a patient level assuming normal coronary anatomy. Therefore, the aims of the present study were to investigate the prevalence of UMI identified by LGE CMR imaging in patients with stable angina pectoris and no known previous myocardial infarction; and to investigate whether presence of UMI is associated with stenotic lesions in the coronary artery supplying the segment of the myocardium in which the UMI is located, using coronary angiography to determine the individual coronary anatomy in each patient.Methods: In this prospective multicenter study, we included patients with stable angina pectoris and without prior myocardial infarction, scheduled for coronary angiography. A LGE CMR examination was performed prior to the coronary angiography. The study cohort consisted of 235 patients (80 women, 155 men) with a mean age of 64.8 years.Results: UMIs were found in 25 % of patients. There was a strong association between stenotic lesions (>= 70 % stenosis) in a coronary artery and the presence of an UMI in the myocardial segments supplied by the stenotic artery; it was significantly more likely to have an UMI downstream a stenosis >= 70 % as compared to <70 % (OR 5.1, CI 3.1-8.3, p < 0.0001). 56 % of the UMIs were located in the inferior and infero-lateral myocardial segments, despite predominance for stenotic lesions in the left anterior descending artery.Conclusion: UMI is common in patients with stable angina and the results indicate that the majority of the UMIs are of ischemic origin due to severe coronary atherosclerosis. In contrast to what is seen in recognized myocardial infarctions, UMIs are predominately located in the inferior and infero-lateral myocardial segments.
40.	Hedna, Khedidja, et al. (författare) Suicidal behavior and all-cause mortality in depressed older adults aged 75+ treated with electroconvulsive therapy : A Swedish register-based comparison study 2024 Ingår i: International Journal of Geriatric Psychiatry. - : John Wiley & Sons. - 0885-6230 .- 1099-1166. ; 39:5 Tidskriftsartikel (refereegranskat)abstract OBJECTIVES: Electroconvulsive therapy (ECT) is effective in treating late-life depression. There is limited research on suicidal behavior and all-cause mortality in the oldest old after ECT.METHODS: Older adults aged 75 years and above who had been inpatients for moderate to severe depression between January 1, 2011, and December 31, 2017, were included in the study. We used exact and propensity score matching to balance groups. We compared suicidal behavior (fatal and non-fatal) and all-cause mortality in those who had received ECT and those with other depression treatments.RESULTS: Of the study population, 1802 persons who received ECT were matched to 4457 persons with other treatments. There were no significant differences in the risk of suicidal behavior between groups, (within 3 months: odds ratio 0.73; 95% confidence intervals (CI), 0.44-1.23, within 4 months to 1 year: aOR 1.34; 95% CI, 0.84-2.13). All-cause mortality was lower among ECT recipients compared to those who had received other treatments, both within 3 months (aOR, 0.35; 95% CI, 0.23-0.52), and within 4 months to 1 year (aOR 0.65; 95% CI, 0.50-0.83).CONCLUSIONS: Compared to other depression treatments, ECT is not associated with a higher risk of suicidal behavior in patients aged 75 and above. ECT is associated with lower all-cause mortality in this age group, but we advise caution regarding causal inferences.
41.	Hofmeister, Wolfgang, et al. (författare) CTNND2-a candidate gene for reading problems and mild intellectual disability. 2015 Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:2, s. 111-22 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.METHODS AND RESULTS: Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.CONCLUSIONS: Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.
42.	Johansson, A., et al. (författare) Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial 2022 Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 40:35, s. 4071-4082 Tidskriftsartikel (refereegranskat)abstract PURPOSETo assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer.METHODSSecondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.RESULTSIn estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.CONCLUSIONThis study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor-positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical.
43.	Karlsson, Elin, et al. (författare) The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer : a retrospective study including patients from the randomised Stockholm tamoxifen trials. 2013 Ingår i: Breast Cancer Research. - : BioMed Central. - 1465-5411 .- 1465-542X. ; 15:5, s. R96- Tidskriftsartikel (refereegranskat)abstract INTRODUCTION: mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.METHODS: The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.RESULTS: S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.CONCLUSION: This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.
44.	Larsson, E., et al. (författare) Evaluation of the ImmuView RSV Test for Rapid Detection of Respiratory Syncytial Virus in Adult Patients with Influenza-Like Symptoms 2021 Ingår i: Microbiology Spectrum. - : American Society for Microbiology. - 2165-0497. ; 9:3 Tidskriftsartikel (refereegranskat)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.
45.	Laurell, Tobias, et al. (författare) Identification of three novel FGF16 mutations in X-linked recessive fusion of the fourth and fifth metacarpals and possible correlation with heart disease. 2014 Ingår i: Molecular Genetics & Genomic Medicine. - : Wiley. - 2324-9269. ; 2:5, s. 402-411 Tidskriftsartikel (refereegranskat)abstract Nonsense mutations in FGF16 have recently been linked to X-linked recessive hand malformations with fusion between the fourth and the fifth metacarpals and hypoplasia of the fifth digit (MF4; MIM#309630). The purpose of this study was to perform careful clinical phenotyping and to define molecular mechanisms behind X-linked recessive MF4 in three unrelated families. We performed whole-exome sequencing, and identified three novel mutations in FGF16. The functional impact of FGF16 loss was further studied using morpholino-based suppression of fgf16 in zebrafish. In addition, clinical investigations revealed reduced penetrance and variable expressivity of the MF4 phenotype. Cardiac disorders, including myocardial infarction and atrial fibrillation followed the X-linked FGF16 mutated trait in one large family. Our findings establish that a mutation in exon 1, 2 or 3 of FGF16 results in X-linked recessive MF4 and expand the phenotypic spectrum of FGF16 mutations to include a possible correlation with heart disease.
46.	Lindahl, Bertil, 1957-, et al. (författare) Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease 2017 Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 135:16, s. 1481-1489 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) occurs in 5% to 10% of all patients with myocardial infarction. Clinical trials of secondary prevention treatment in MINOCA patients are lacking. Therefore, the aim of this study was to examine the associations between treatment with statins, renin-angiotensin system blockers, β-blockers, dual antiplatelet therapy, and long-term cardiovascular events.METHODS: This is an observational study of MINOCA patients recorded in the SWEDEHEART registry (the Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapy) between July 2003 and June 2013 and followed until December 2013 for outcome events in the Swedish Cause of Death Register and National Patient Register. Of 199 162 myocardial infarction admissions, 9466 consecutive unique patients with MINOCA were identified. Among those, the 9136 patients surviving the first 30 days after discharge constituted the study population. Mean age was 65.3 years, and 61% were women. No patient was lost to follow-up. A stratified propensity score analysis was performed to match treated and untreated groups. The association between treatment and outcome was estimated by comparing between treated and untreated groups by using Cox proportional hazards models. The exposures were treatment at discharge with statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dual antiplatelet therapy. The primary end point was major adverse cardiac events defined as all-cause mortality, hospitalization for myocardial infarction, ischemic stroke, and heart failure.RESULTS: At discharge, 84.5%, 64.1%, 83.4%, and 66.4% of the patients were on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, β-blockers, and dual antiplatelet therapy, respectively. During the follow-up of a mean of 4.1 years, 2183 (23.9%) patients experienced a major adverse cardiac event. The hazard ratios (95% confidence intervals) for major adverse cardiac events were 0.77 (0.68-0.87), 0.82 (0.73-0.93), and 0.86 (0.74-1.01) in patients on statins, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and β-blockers, respectively. For patients on dual antiplatelet therapy followed for 1 year, the hazard ratio was 0.90 (0.74-1.08).CONCLUSIONS: The results indicate long-term beneficial effects of treatment with statins and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on outcome in patients with MINOCA, a trend toward a positive effect of β-blocker treatment, and a neutral effect of dual antiplatelet therapy. Properly powered randomized clinical trials to confirm these results are warranted.
47.	Lindahl, Bertil, 1957-, et al. (författare) Response by Lindahl et al to Letter Regarding Article, "Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease" 2017 Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 136:11, s. 1082-1083 Tidskriftsartikel (refereegranskat)
48.	Lundin, Johanna, et al. (författare) 22q11.2 microduplication in two patients with bladder exstrophy and hearing impairment 2010 Ingår i: European Journal of Medical Genetics. - : Elsevier BV. - 1769-7212 .- 1878-0849. ; 53:2, s. 61-65 Tidskriftsartikel (refereegranskat)abstract Bladder exstrophy is a congenital malformation of the bladder and urethra. The genetic basis of this malformation is unknown however it is well known that chromosomal aberrations can lead to defects in organ development. A few bladder exstrophy patients have been described to carry chromosomal aberrations. Chromosomal rearrangements of 22q11.2 are implicated in several genomic disorders i.e. DiGeorge/velocardiofacial- and cat-eye syndrome. Deletions within this chromosomal region are relatively common while duplications of 22q11.2 are much less frequently observed. An increasing number of reports of microduplications of this region describe a highly variable phenotype. We have performed array-CGH analysis of 36 Swedish bladder exstrophy patients. The analysis revealed a similar and approximately 3 Mb duplication, consistent with the recently described 22q11.2 microduplication syndrome, in two unrelated cases with bladder exstrophy and hearing impairment. This finding was confirmed by multiplex ligation-dependent probe amplification (MLPA) and FISH analysis. Subsequent MLPA analysis of this chromosomal region in 33 bladder exstrophy patients did not reveal any deletion/duplication within this region. MLPA analysis of 171 anonymous control individuals revealed one individual carrying this microduplication. This is the first report of 22q11.2 microduplication associated with bladder exstrophy and hearing impairment. Furthermore the finding of one carrier among a cohort of normal controls further highlights the variable phenotype linked to this microduplication syndrome.
49.	Lundin, Johanna, et al. (författare) Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene 2019 Ingår i: Molecular Genetics and Genomic Medicine. - : Wiley. - 2324-9269. ; 7:6 Tidskriftsartikel (refereegranskat)abstract Background: The bladder exstrophy-epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases. Methods: We performed array comparative genomic hybridization (array-CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies. Results: We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10−4). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1wt and Lztr1mut, indicating a potential functional effect of the LZTR1mut. Conclusion: Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation.
50.	Nordenskjöld, Anna, 1969, et al. (författare) Breast cancer survival trends in different stages and age groups - a population-based study 1989-2013 2019 Ingår i: Acta Oncologica. - : TAYLOR & FRANCIS LTD. - 0284-186X .- 1651-226X. ; 58:1, s. 45-51 Tidskriftsartikel (refereegranskat)abstract Background: During the recent decades, breast cancer survival has gradually improved but there is limited knowledge on the improvement in population-based studies of patients diagnosed with different stages of the disease and in different age groups.Patients and methods: In two Swedish health care regions a total of 42,220 female breast cancer patients below 90years of age were diagnosed between 1989 and 2013. They were treated and followed according to national and regional guidelines and formed a population-based cohort.Results: Using patients diagnosed in 1989-1993 as a reference to the relative risk, 5-year mortality decreased with 49% for patients diagnosed at the end of the observation period (CI 95% 45-58). The mortality tended to decrease for patients with all stages of breast cancer and test for trend resulted in a statistically significant improvement over time in 5-year relative survival in stage III and IV and in 10-year survival in stage I and III. For each operable stage of disease, patients aged below 40years or more than 70years when diagnosed tended to have less favorable survival than patients diagnosed between 40-69years of age. Test for trend resulted in statistically significant improvements over time for patients diagnosed at ages below 40, 40-54 and 54-69, but less marked improvements for patients older than 70 when diagnosed.Conclusions: During the period 1989-2013 the relative risk of 5-year mortality decreased with 49%. Improvements were seen in all age groups but were unevenly distributed between stages and age groups pointing to the need for further improvements for younger and elderly patients.

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