| 1. |
- Buus, Terkild Brink, et al.
(författare)
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Single-cell heterogeneity in Sézary syndrome
- 2018
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 2:16, s. 2115-2126
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Tidskriftsartikel (refereegranskat)abstract
- Sezary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.
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| 2. |
- Christensen, Lise, et al.
(författare)
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Gravitationally lensed galaxies at 2 < z < 3.5 : direct abundance measurements of Ly alpha emitters
- 2012
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 427:3, s. 1973-1982
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Tidskriftsartikel (refereegranskat)abstract
- Strong gravitational lensing magnifies the flux from distant galaxies, allowing us to detect emission lines that would otherwise fall below the detection threshold for medium-resolution spectroscopy. Here we present the detection of temperature-sensitive oxygen emission lines from three galaxies at 2 ? z ? 3.5, which enables us to directly determine the oxygen abundances and thereby double the number of galaxies at z > 2 for which this has been possible. The three galaxies have similar to 10?per?cent solar oxygen abundances in agreement with strong emission-line diagnostics. Carbon and nitrogen ratios relative to oxygen are subsolar as expected for young metal-poor galaxies. Two of the galaxies are Lyman a (Lya) emitters with rest-frame equivalent widths of 20 and 40 angstrom, respectively, and their high magnification factors allow us for the first time to gain insight into the physical characteristics of high-redshift Lya emitters. Using constraints from the physical properties of the galaxies, we accurately reproduce their line profiles with radiative transfer models. The models show a relatively small outflow in agreement with the observed small velocity offsets between nebular emission and interstellar absorption lines.
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| 3. |
- Christensen, Lise Lotte, et al.
(författare)
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The association between genetic variants in hMLH1 and hMSH2 and the development of sporadic colorectal cancer in the Danish population
- 2008
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Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 9, s. 52-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Mutations in the mismatch repair genes hMLH1 and hMSH2 predispose to hereditary non-polyposis colorectal cancer (HNPCC). Genetic screening of more than 350 Danish patients with colorectal cancer (CRC) has led to the identification of several new genetic variants (e.g. missense, silent and non-coding) in hMLH1 and hMSH2. The aim of the present study was to investigate the frequency of these variants in hMLH1 and hMSH2 in Danish patients with sporadic colorectal cancer and in the healthy background population. The purpose was to reveal if any of the common variants lead to increased susceptibility to colorectal cancer. METHODS: Associations between genetic variants in hMLH1 and hMSH2 and sporadic colorectal cancer were evaluated using a case-cohort design. The genotyping was performed on DNA isolated from blood from the 380 cases with sporadic colorectal cancer and a sub-cohort of 770 individuals. The DNA samples were analyzed using Single Base Extension (SBE) Tag-arrays. A Bonferroni corrected Fisher exact test was used to test for association between the genotypes of each variant and colorectal cancer. Linkage disequilibrium (LD) was investigated using HaploView (v3.31). RESULTS: Heterozygous and homozygous changes were detected in 13 of 35 analyzed variants. Two variants showed a borderline association with colorectal cancer, whereas the remaining variants demonstrated no association. Furthermore, the genomic regions covering hMLH1 and hMSH2 displayed high linkage disequilibrium in the Danish population. Twenty-two variants were neither detected in the cases with sporadic colorectal cancer nor in the sub-cohort. Some of these rare variants have been classified either as pathogenic mutations or as neutral variants in other populations and some are unclassified Danish variants. CONCLUSION: None of the variants in hMLH1 and hMSH2 analyzed in the present study were highly associated with colorectal cancer in the Danish population. High linkage disequilibrium in the genomic regions covering hMLH1 and hMSH2, indicate that common genetic variants in the two genes in general are not involved in the development of sporadic colorectal cancer. Nevertheless, some of the rare unclassified variants in hMLH1 and hMSH2 might be involved in the development of colorectal cancer in the families where they were originally identified.
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| 4. |
- Christensen, Lise, et al.
(författare)
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The low-mass end of the fundamental relation for gravitationally lensed star-forming galaxies at 1 < z < 6
- 2012
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 427:3, s. 1953-1972
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Forskningsöversikt (refereegranskat)abstract
- We present Very Large Telescope/X-shooter spectra of 13 galaxies in the redshift range 1 ? z ? 6, which are strongly lensed by massive galaxy clusters. Spectroscopic redshifts are measured for nine galaxies, while three sources have redshifts determined from continuum breaks in their spectra. The stellar masses of the galaxies span four orders of magnitude between 107 and 1011?M? and have luminosities at 1500 angstrom rest frame between 0.004 and 9L* after correcting for the magnification. This allows us to probe a variety of galaxy types from young, low-mass starburst galaxies to massive evolved galaxies. The lensed galaxies with stellar masses less than 1010?M? have a large scatter compared to the fundamental relation between stellar mass, star formation rates and oxygen abundances. We provide a modified fit to the fundamental relation for low-mass, low-metallicity galaxies with a weaker dependence of the metallicity on either the star formation rate or stellar mass compared to low-redshift, high-mass and high-metallicity Sloan Digital Sky Survey galaxies.
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| 5. |
- Christensen, Sarah Friis, et al.
(författare)
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Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study
- 2022
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Ingår i: European Journal of Haematology. - : John Wiley & Sons. - 0902-4441 .- 1600-0609.
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Tidskriftsartikel (refereegranskat)abstract
- Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.
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| 6. |
- Christensen, Sarah Friis, et al.
(författare)
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Labor Market Attachment in Patients with Myeloproliferative Neoplasms: A Nationwide Matched Cohort Study
- 2021
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 138:Suppl 1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Myeloproliferative neoplasms (MPNs) are characterized by a substantial symptom burden, risk of debilitating complications (e.g., thrombosis), and increased comorbidity. Recently, three comprehensive questionnaire studies (Mesa 2016, Harrison 2017, Jingbo 2018) have reported a high impact of MPNs on patients' ability to work. However, no registry-based studies have assessed labor market attachment (LMA) of MPN patients and matched nonMPN comparisons.AIM: To assess the pre- and post-diagnostic LMA of MPN patients and matched nonMPN comparisons.METHODS: We conducted a descriptive, registry-based nationwide cohort study, using data from the Danish National Chronic Myeloid Neoplasia Registry including all Danish MPN patients diagnosed between January 2010 and December 2016. Population-based cohorts of nonMPN comparisons were constructed by 1:10 matching on age, sex, level of education, and region of residence. Data on LMA were retrieved from the Danish Register for Evaluation of Marginalization, which holds information on all public transfer payments in Denmark. Data were linked using the unique civil registration number, which identifies all Danish citizens. The LMA endpoints were defined for each individual as working (not receiving any type of transfer payment), unemployed, receiving transfer payment for either sick leave, disability pension, age pension, or other health-related benefits (e.g., wage-subsidized employment). We assessed LMA weekly for each individual from two years before diagnosis until death, emigration, or two years after the diagnosis. For each cohort, we presented LMA as proportions with 95% confidence intervals (CIs), as well as the proportion of individuals who died during follow-up.RESULTS: The study included 3,342 MPN patients (1,140 essential thrombocythemia [ET]; 1,109 polycythemia vera [PV]; 533 myelofibrosis [MF]; and 560 unspecified MPN [MPN-U]) and 32,737 nonMPN comparisons (11,181 nonET; 10,873 nonPV; 5,217 nonPMF; and 5,466 nonMPN-U). The median age at time of diagnosis was: ET 67 years (interquartile range [IQR], 55-76); PV, 69 years (IQR, 61-77); PMF, 73 years (IQR, 66-79); and MPN-U, 72 years (IQR, 63-80).At time of MPN diagnosis, the majority of MPN patients and nonMPN comparisons received age pension (range: ET, 52.1% [95% CI, 49.2-55.0] to nonMF, 70.3% [95% CI, 69.1-71.6]). The proportions working were: ET, 35.1% (95% CI, 32.3-37.9) vs. nonET, 37.3% (95% CI, 36.5-38.2); PV, 22.6% (95% CI, 20.2-25.1) vs. nonPV, 30.8% (95% CI, 29.9-31.7); MF, 23.8% (95% CI, 20.2-27.4) vs. nonMF, 23.6% (95% CI, 22.5-24.8); and MPN-U, 22.1% (95% CI,18.7- 25.6) vs. nonMPN-U, 27.8% (95% CI, 26.6-29.0). Across MPN subtypes, a larger proportion of patients than comparisons were on sick leave: ET, 3.5% (95% CI, 2.4-4.6) vs. nonET, 1.3% (95% CI, 1.1-1.5); PV, 5.5% (95% CI, 4.2-6.8) vs. nonPV, 0.9% (95% CI, 0.7-1.1); MF (not applicable due to small numbers) vs. nonMF, 0.6% (95% CI, 0.4-0.8); and MPN-U, 3.0% (95% CI, 1.6- 4.5) vs. nonMPN-U, 1.0% (95% CI, 0.7-1.3). Regarding disability pension, the proportions ranged from 4.1% (95% CI, 2.4-5.8) to 5.0% (95% CI, 3.7-6.3) among patients and from 3.1% (95% CI, 2.6-3.6) to 4.7% (95% CI, 4.3-5.1) among comparisons. For both MPN patients and nonMPN comparisons, few were unemployed (≤3.3%) or received other health-related benefits (≤1.6%).Two years preceding diagnosis, the proportion of PV and MPN-U patients working was slightly lower than the matched comparisons: PV, 31.0% (95% CI, 28.4-33.8) vs. nonPV, 34.3% (95% CI, 33.5-35.2) and MPN-U, 28.2% (95% CI, 24.6-32.1) vs. nonMPN-U, 32.0% (95% CI, 30.7-33.2), while this difference was not observed between ET and MF patients and their respective comparisons.From two years before to two years after diagnosis, we observed slightly larger reductions in the proportion working among MPN patients than among comparisons. Among MPN patients, the proportion on sick leave including other health-related benefits, increased during the study period, while it remained unchanged among comparisons. The proportion of patients and comparisons on disability pension remained stable.CONCLUSION: Overall, our findings showed that Danish patients with ET, PV, MF, and MPN-U had slightly impaired LMA already two years before diagnosis and up to two years after diagnosis. Thus, fewer patients were working and more patients transferred to sick leave compared with matched individuals without MPN.
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| 7. |
- Christensen, Sarah, et al.
(författare)
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Healthcare resource utilization in patients with myeloproliferative neoplasms: a nationwide matched cohort study
- 2021
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Ingår i: HemaSphere. - : Ovid Technologies (Wolters Kluwer Health). - 2572-9241. ; 5:S2, s. 529-530
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Tidskriftsartikel (refereegranskat)abstract
- Background: Myeloproliferative neoplasms (MPNs) are associated with severe complications and a substantial symptom burden – frequently emerging several years before diagnosis. Due to the chronic nature ofthe diseases, MPN patients have a lifelong need for treatment and care. However, only few studies have assessed MPN healthcare resource utilization (HRU) compared with matched cohorts, and no detailed assessments of HRU in the years preceding MPN diagnosis exist.Aims: To assess the pre- and post-diagnostic HRU of MPN patients compared with matched cohorts of nonMPN comparisons.Methods: We conducted this descriptive, register-based nationwide cohort study, utilizing data from the Danish National Chronic Myeloid Neoplasia Registry on all MPN patients diagnosed between January 2010 and December 2016, and data on HRU from the Danish National Patient Registry and the Danish National Health Service Registry. Populationbased cohorts of nonMPN comparisons were constructed by 1:10 matchingon age, sex, level of education, and region of residence. Data were linkedusing the unique civil registration number, which identifies all Danish citizens. HRU was summarized over each year for all cohorts from twoyears before date of MPN diagnosis and until emigration, death, or endof study (31 December 2017). HRU was calculated as annual number ofhealthcare contacts (inpatient days, outpatient consultations, treatmentsand examinations, and general practitioner [GP] visits) divided by person-years at risk and compared using rate ratios with 95% CI.Results: The study population included 3,342 MPN patients (1,140 essential thrombocythemia [ET]; 1,109 polycythemia vera [PV]; 533 primary myelofibrosis [PMF]; and 560 unspecified MPN [MPN-U]) and 32,737 nonMPN comparisons (11,181 nonET; 10,873 nonPV; 5,217 nonPMF; and 5,466 nonMPN-U). The median age was 67 (ET), 69 (PV), 73 (PMF), and 72 years (MPN-U), and the mean follow-up was 3.8 (ET), 3.8(PV), 3.1 (PMF), and 3.3 years (MPN-U). A total of 750 (22.4%) MPNpatients and 4,627 (14.1%) nonMPN comparisons died during follow-up.In nearly all years of follow-up, MPN patients had a higher HRU thannonMPN comparisons (Figure, rate ratio>1). Rate ratios for outpatientconsultations were largest at the time of diagnosis: ET, 2.7 (95%CI, 2.6-2.9); PV, 3.4 (95%CI, 3.2-3.6); PMF, 4.0 (95%CI, 3.7-4.4); and MPN-U,3.7 (95%CI, 3.4-4.0). For most MPN subtypes, rate ratios also peaked attime of diagnosis for treatment and examinations. In contrast, the largest rate ratio for PV was in the last year of follow-up: 3.5 (95%CI, 2.8-4.3). Across MPN subtypes, rate ratios for GP visits varied from 1.0 to1.5 during follow-up without any considerable fluctuations. Interestingly, increased rate ratios for inpatients days were evident 2 years before diagnosis: ET, 1.8 (95%CI, 1.7-1.9); PV, 1.3, (95%CI, 1.2-1.3); PMF, 1.4(95%CI, 1.2-1.5); and MPN-U, 1.7 (95%CI, 1.6-1.9). During follow-up,notable increases in rate ratios were observed, e.g., PMF 3.0 (95%CI 2.4-3.6) and PV 3.8 (95%CI 3.0-4.8) in year 5 and 7, respectively.Summary/Conclusion: Overall, compared with matched nonMPN comparisons, MPN patients had a higher HRU throughout the study period. This was consistent across MPN subtypes and HRU measures. Within the limitations of small numbers toward end of follow-up and lack ofmatching on comorbidity, our findings confirmed a consistent HRU burden after MPN diagnosis. Equally important, our study revealed substantial increases in HRU two years before MPN diagnosis, warrantingfurther exploration of the pre-diagnostic period, including the potentialbenefits of early detection.
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| 8. |
- de Lange, Annet H., et al.
(författare)
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Opportunities and challenges in designing and evaluating complex multilevel, multi-stakeholder occupational health interventions in practice
- 2024
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Ingår i: Work & Stress. - : Routledge. - 0267-8373 .- 1464-5335.
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Tidskriftsartikel (refereegranskat)abstract
- Extant research suggests the effectiveness of Occupational Health Psychology (OHP) interventions depends on their design in the broader organisational context. While the field recognises that pre- and posttest evaluation do not sufficiently capture the complex dynamics around OHP interventions, complex multi-level OHP interventions are still scarce in the literature. As established intervention implementation frameworks suggest, it remains difficult to address this complexity in practice. The present position paper re-evaluates lessons learned from two complex European OHP intervention projects, by applying the Integrated Process Evaluation Framework (IPEF) and related theories to bridge the gap between the theoretically recognised complexity and practical challenges. The re-evaluations emphasise that programme-multilevel theories rooted in OHP-perspectives contribute to adequately hypothesising around systemic factors and mechanisms relevant to OHP interventions. Concretely, middle range theories that outline how an intervention’s mechanisms work within a specific context to produce certain outcomes are crucial. Additionally, strategically and actively involving key stakeholders at all levels of the system and across the different intervention phases improves the embedding of OHP interventions in organisations. We elaborate on these insights with seven concrete recommendations for complex OHP intervention research.
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| 9. |
- de Lange, Annet H., et al.
(författare)
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Opportunities and challenges in designing and evaluating complex multilevel, multi-stakeholder occupational health interventions in practice
- 2024
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Ingår i: WORK AND STRESS. - : Routledge. - 0267-8373 .- 1464-5335.
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Tidskriftsartikel (refereegranskat)abstract
- Extant research suggests the effectiveness of Occupational Health Psychology (OHP) interventions depends on their design in the broader organisational context. While the field recognises that pre- and posttest evaluation do not sufficiently capture the complex dynamics around OHP interventions, complex multi-level OHP interventions are still scarce in the literature. As established intervention implementation frameworks suggest, it remains difficult to address this complexity in practice. The present position paper re-evaluates lessons learned from two complex European OHP intervention projects, by applying the Integrated Process Evaluation Framework (IPEF) and related theories to bridge the gap between the theoretically recognised complexity and practical challenges. The re-evaluations emphasise that programme-multilevel theories rooted in OHP-perspectives contribute to adequately hypothesising around systemic factors and mechanisms relevant to OHP interventions. Concretely, middle range theories that outline how an intervention's mechanisms work within a specific context to produce certain outcomes are crucial. Additionally, strategically and actively involving key stakeholders at all levels of the system and across the different intervention phases improves the embedding of OHP interventions in organisations. We elaborate on these insights with seven concrete recommendations for complex OHP intervention research.
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| 10. |
- Ferreras, Ignacio, et al.
(författare)
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FIGS : spectral fitting constraints on the star formation history of massive galaxies since the cosmic noon
- 2019
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 486:1, s. 1358-1376
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Tidskriftsartikel (refereegranskat)abstract
- We constrain the stellar population properties of a sample of 52 massive galaxies - with stellar mass log (M-s/M-circle dot) greater than or similar to 10.5 - over the redshift range 0.5 < z < 2 by use of observer-frame optical and near-infrared slitless spectra from Hubble Space Telescope's ACS and WFC3 grisms. The deep exposures (similar to 100 ks) allow us to target individual spectra of massive galaxies to F160W = 22.5AB. Our spectral fitting approach uses a set of six base models adapted to the redshift and spectral resolution of each observation, and fits the weights of the base models, including potential dust attenuation, via a Markov Chain Monte Carlo method. Our sample comprises a mixed distribution of quiescent (19) and star-forming galaxies (33). We quantify the width of the age distribution (Delta t) that is found to dominate the variance of the retrieved parameters according to principal component analysis. The population parameters follow the expected trend towards older ages with increasing mass, and Delta t appears to weakly anticorrelate with stellar mass, suggesting a more efficient star formation at the massive end. As expected, the redshift dependence of the relative stellar age (measured in units of the age of the Universe at the source) in the quiescent sample rejects the hypothesis of a single burst (aka monolithic collapse). Radial colour gradients within each galaxy are also explored, finding a wider scatter in the star-forming subsample, but no conclusive trend with respect to the population parameters.
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