| 1. |
- Ahlner, Alexandra, 1984-, et al.
(författare)
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Conformational Dynamics and Multimerization of Active Forms of the EphrinB Receptor 2 Kinase Domain
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Active and autoinhibited forms of the ephrinB receptor 2 (EphB2) kinase domain have been studied using NMR spectroscopy. The project was initiated because of the finding that the crystal structures of active forms of the kinase domain and previous NMR studies suggested that a change in inter-lobe flexibility and the sampling of catalytically competent excited states conformations are responsible for activity. Using Carr-Purcell-Meiboom-Gill relaxation dispersion experiments, we have measured millisecond dynamics to identify such states. We have also performed concentration dependent relaxation experiments and analytical ultracentrifugation experiments that report on the effective protein size to look for possible differences in self-association for active and autoinhibited forms of the EphB2 kinase domain. We show that the active but not autoinhibited forms exchange between a ground state and an excited state at a rate of 1900 s-1. Similar results were found for the S677/680A mutant of the protein. The nature and importance of the excited state is still unknown. Our most important finding is that active forms of the kinase domain self-associate in a concentration dependent manner and form tetramers and possibly larger oligomers. Multimerization of the kinase domain may enable the assembly of complexes of downstream proteins and could be important for Eph signaling.
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| 2. |
- Andrésen, Cecilia, et al.
(författare)
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Transient structure and dynamics in the disordered c-Myc transactivation domain affect Bin1 binding
- 2012
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP): Policy C / Oxford University Press. - 0305-1048 .- 1362-4962. ; 40:13, s. 6353-6366
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Tidskriftsartikel (refereegranskat)abstract
- The crucial role of Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of Myc function. The N-terminal region of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of Myc-1-88, where hierarchical phosphorylation of S62 and T58 regulates activation and destruction of the Myc protein. By nuclear magnetic resonance (NMR) chemical shift analysis, relaxation measurements and NOE analysis, we show that although Myc occupies a very heterogeneous conformational space, we find transiently structured regions in residues 22-33 and in the Myc homology box I (MBI; residues 45-65); both these regions are conserved in other members of the Myc family. Binding of Bin1 to Myc-1-88 as assayed by NMR and surface plasmon resonance (SPR) revealed primary binding to the S62 region in a dynamically disordered and multivalent complex, accompanied by population shifts leading to altered intramolecular conformational dynamics. These findings expand the increasingly recognized concept of intrinsically disordered regions mediating transient interactions to Myc, a key transcriptional regulator of major medical importance, and have important implications for further understanding its multifaceted role in gene regulation.
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| 3. |
- Andrésen, Cecilia, et al.
(författare)
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Transient structure and intrinsic disorder in the c-Myc transactivation domain and its effects on ligand binding
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The crucial role of c-Myc as an oncoprotein and as a key regulator of cell growth makes it essential to understand the molecular basis of c-Myc function. The transactivation domain of c-Myc coordinates a wealth of protein interactions involved in transformation, differentiation and apoptosis. We have characterized in detail the intrinsically disordered properties of c-Myc-1-88, where hierarchical phosphorylation of T58 and S62 regulates activation and destruction of the c-Myc protein. By NMR chemical shift analysis, relaxation measurements and NOE analysis, we show that both the MBI region (residues 45-65) and residues 22-33 are transiently structured regions, conserved also in other members of the Myc family. Binding of Bin1-SH3 to c-Myc-1-88 as assayed by NMR and SPR revealed primary binding to the S62 region, but also a dynamically disordered and multivalent complex in which intrinsic disorder of c-Myc-1-88 was retained while releasing transient intramolecular interactions. Our findings describe a novel mode of regulatory recognition of c-Myc that is in agreement with the increasingly recognized capability of intrinsically disordered regions to efficiently mediate transient interactions with a wide range of targets, with important implications towards understanding the unique multifaceted biological functions of c-Myc.
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| 4. |
- Csizmok, Veronika, et al.
(författare)
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Multivalent Interactions with Fbw7 and Pin1 Facilitate Recognition of c-Jun by the SCFFbw7 Ubiquitin Ligase
- 2018
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Ingår i: Structure. - : CELL PRESS. - 0969-2126 .- 1878-4186. ; 26:1, s. 28-
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Tidskriftsartikel (refereegranskat)abstract
- Many regulatory proteins, including the transcription factor c-Jun, are highly enriched in disordered protein regions that govern growth, division, survival, differentiation, and response to signals. The stability of c-Jun is controlled by poorly understood regulatory interactions of its disordered region with both the E3 ubiquitin ligase SCFFbw7 and prolyl cis-trans isomerase Pin1. We use nuclear magnetic resonance and fluorescence studies of c-Jun to demonstrate that multisite c-Jun phosphorylation is required for high-affinity interaction with Fbw7. We show that the Pin1 WW and PPIase domains interact in a dynamic complex with multiply phosphorylated c-Jun. Importantly, Pin1 isomerizes a pSer-Pro peptide bond at the c-Jun N terminus that affects binding to Fbw7 and thus modulates the ubiquitin-mediated degradation of c-Jun. Our findings support the general principle that multiple weak binding motifs within disordered regions can synergize to yield high-affinity interactions and provide rapidly evolvable means to build and fine-tune regulatory events.
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| 5. |
- Greve, Anders M., et al.
(författare)
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Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study)
- 2018
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Ingår i: American Journal of Cardiology. - : Elsevier. - 0002-9149 .- 1879-1913. ; 121:6, s. 739-745
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Tidskriftsartikel (refereegranskat)abstract
- Observational studies indicate that low-density lipoprotein (LDL) cholesterol acts as a primary contributor to an active process leading to aortic stenosis (AS) development. However, randomized clinical trials have failed to demonstrate an effect of lipid lowering on impeding AS progression. This study explored if pretreatment LDL levels and AS severity altered the efficacy of lipid-lowering therapy. The study goal was evaluated in the analysis of surviving patients with baseline data in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 asymptomatic patients with mild-to-moderate AS. Serially measured peak aortic jet velocity was the primary effect estimate. Linear mixed model analysis adjusted by baseline peak jet velocity and pretreatment LDL levels was used to assess effect modifications of treatment. Data were available in 1,579 (84%) patients. In adjusted analyses, lower baseline peak aortic jet velocity and higher pretreatment LDL levels increased the effect of randomized treatment (p >= 0.04 for interaction). As such, treatment impeded progression of AS in the highest quartile of LDL among patients with mild AS at baseline (0.06 m/s per year slower progression vs placebo in peak aortic jet velocity, 95% confidence interval 0.01 to 0.11, p = 0.03), but not in the 3 other quartiles of LDL. Conversely, among patients with moderate AS, there was no detectable effect of treatment in any of the pretreatment LDL quartiles (all p In conclusion, in a non prespecified post hoc analysis, the efficacy of lipid-lowering therapy on impeding AS progression increased with higher pretreatment LDL and lower peak aortic jet velocity (SEAS study: NCT00092677).
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| 6. |
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| 7. |
- Hodges, Gethin W., et al.
(författare)
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Effect of simvastatin and ezetimibe on suPAR levels and outcomes
- 2018
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Ingår i: Atherosclerosis. - : ELSEVIER IRELAND LTD. - 0021-9150 .- 1879-1484. ; 272, s. 129-136
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with cardiovascular disease. Statins lower both low-density lipoprotein (LDL)-cholesterol and C-reactive protein (CRP), resulting in improved outcomes. However, whether lipid-lowering therapy also lowers suPAR levels is unknown.& para;& para;Methods: We investigated whether treatment with Simvastatin 40 mg and Ezetimibe 10 mg lowered plasma suPAR levels in 1838 patients with mild-moderate, asymptomatic aortic stenosis, included in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, using a pattern mixture model. A 1-year Cox analysis, adjusted for established cardiovascular risk factors, allocation to study treatment, peak aortic valve velocity and baseline suPAR, was performed to evaluate relationships between change in suPAR with all-cause mortality and the composite endpoint of major cardiovascular events (MCE) composed of ischemic cardiovascular events (ICE) and aortic valve related events (AVE).& para;& para;Results: After 4.3 years of follow-up, suPAR levels had increased by 9.2% (95% confidence interval [CI]: 7.0%-11.5%) in the placebo group, but only by 4.1% (1.9%-6.2%) in the group with lipid-lowering treatment (p<0.001). In a multivariate 1-year analysis, 1-year suPAR was strongly associated with all-cause mortality, hazard ratio (HR) = 2.05 (1.17-3.61); MCE 1.40 (1.01-1.92); and AVE 1.42 (1.02-1.99) (all p<0.042) for each doubling of suPAR; but was not associated with ICE.& para;& para;Conclusions: Simvastatin and Ezetimibe treatment impeded the progression of the time-related increase in plasma suPAR levels. Year-1 suPAR was associated with all-cause mortality, MCE, and AVE irrespective of baseline levels (SEAS study: NCT00092677). (C) 2018 Elsevier B.V. All rights reserved.
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| 8. |
- Knorr, Ulla, et al.
(författare)
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Alzheimer's disease related biomarkers in bipolar disorder - A longitudinal one-year case-control study.
- 2022
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Ingår i: Journal of affective disorders. - : Elsevier BV. - 1573-2517 .- 0165-0327. ; 297, s. 623-633
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Tidskriftsartikel (refereegranskat)abstract
- Bipolar disorder (BD) is a heterogeneous mental disorder characterized by recurrent relapses of affective episodes: Subgroups of patients with BD have cognitive deficits, and an increased risk of dementia.This prospective, longitudinal, one-year follow-up, case-control study investigated biomarkers for AD and neurodegenerative diseases, namely: cerebrospinal fluid (CSF) amyloid beta (Aβ) isoforms and ratios (Aβ42, Aβ40, Aβ38), CSF soluble amyloid precursor protein (sAPP) α and β, CSF total (t-tau) and phosphorylated tau (p-tau), CSF neurofilament-light (NF-L), CSF neurogranin (NG), plasma-isoforms Aβ42 and Aβ40, plasma-tau, plasma-NF-L, and serum S100B, in patients with BD (N=62, aged 18-60) and gender-and-age-matched healthy control individuals (N=40). CSF and plasma/serum samples were collected at baseline, during and after an affective episode, if it occurred, and after a year. Data were analyzed in mixed models.Levels of CSF Aβ42 decreased in patients with BD who had an episode during follow-up (BD-E) (N=22) compared to patients without an episode (BD-NE) (N=25) during follow-up (P=0.002). Stable levels were seen for all other markers in BD-E compared to BD-NE during the one-year follow-up. We found no statistically significant differences between patients with BD and HC at T0 and T3 for Aβ42, Aβ40, Aβ38, Aβ42/38, Aβ42/40, sAPPα, sAPPβ, t-tau, p-tau, p-tau /t-tau, NF-L, NG in CSF and further Aβ40, Aβ42, Aβ42/40, t-tau, NF-L in plasma, S100B in serum, and APOE-status. Furthermore, all 18 biomarkers were stable in HC during the one-year follow-up from T0 to T3.A panel of biomarkers of Alzheimer's and neurodegeneration show no differences between patients with BD and HC. There were abnormalities of amyloid production/clearance during an acute BD episode. The abnormalities mimic the pattern seen in AD namely decreasing CSF Aβ42 and may suggest an association with brain amyloidosis.
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| 9. |
- Knorr, Ulla, et al.
(författare)
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Biomarkers for neurodegeneration impact cognitive function: a longitudinal 1-year case–control study of patients with bipolar disorder and healthy control individuals
- 2024
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Ingår i: International Journal of Bipolar Disorders. - 2194-7511. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Abnormalities in cerebrospinal fluid (CSF)-amyloid-beta (Aβ)42, CSF-Aβ40, CSF-Aβ38, CSF-soluble amyloid precursor proteins α and β, CSF-total-tau, CSF-phosphorylated-tau, CSF-neurofilament light protein (NF-L), CSF-neurogranin, plasma-Aβ42, plasma-Aβ40, plasma-total-tau, plasma-NF-L and, serum-S100B during affective episodes may reflect brain changes that could impact cognitive function in patients with bipolar disorder (BD). The study aimed to investigate the association between these biomarkers indicative of Alzheimer’s disease and those reflecting neurodegeneration alongside their impact on cognitive function in patients with BD and healthy control individuals (HC). The primary hypothesis was that GL and VL would increase with increasing levels of CSF-Aβ42 based on data from T0 and T3 in BD and HC jointly. Methods: In a prospective, longitudinal case–control study euthymic patients with BD (N = 85) and HC (N = 44) were evaluated with clinical assessment and neuropsychological testing at baseline (T0) and during euthymia after a year (T3). Patients’ affective states were recorded weekly as euthymic, subthreshold level, major depression, or (hypo)mania. If an episode occurred during follow-up, the patient was also assessed in post-episode euthymia. Cognitive performance was measured as a global cognitive score (GL) for four cognitive domains including verbal learning and memory (VL). Results: Estimated in a linear mixed model GL increased with 0.001 for each increase of 1pg/ml of CSF-Aβ42 (97.5%, CI 0.00043–0.0018, adjusted-p = 0.0005) while VL increased by 0.00089 (97.5%, CI 0.00015–0.0018, adjusted-p = 0.045) in BD and HC jointly. The association was weak, however stronger in patients with BD compared to HC. Associations between other biomarkers including CSF-neurogranin, and cognitive domains were overall weak, and none remained significant after adjustment for multiple testing. Limitations: Modest sample size. A complete data set regarding both CSF-AB-42 and cognitive test scores was obtained from merely 61 patients with BD and 38 HC individuals. Conclusion: CSF-Aβ42 may be associated with cognitive dysfunction in patients with BD and HC individuals. The association appeared to be stronger in BD but with overlapping confidence intervals. Hence it remains uncertain whether the association is a general phenomenon or driven by BD.
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| 10. |
- Knorr, Ulla, et al.
(författare)
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Cerebrospinal fluid synaptic biomarker changes in bipolar disorder - A longitudinal case-control study.
- 2024
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Ingår i: Journal of affective disorders. - 1573-2517. ; 358, s. 250-259
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Tidskriftsartikel (refereegranskat)abstract
- This exploratory study investigated cerebrospinal fluid (CSF) synaptic protein biomarkers in bipolar disorder (BD), aiming to highlight the neurobiological basis of the disorder. With shared cognitive impairment features between BD and Alzheimer's disease, and considering increased dementia risk in BD patients, the study explores potential connections.Fifty-nine well-characterized patients with BD and thirty-seven healthy control individuals were examined and followed for one year. Synaptic proteins encompassing neuronal pentraxins (NPTX)1, NPTX2, and NPTX-receptor, 14-3-3 protein family epsilon, and zeta/delta, activating protein-2 complex subunit beta, synucleins beta-synuclein and gamma-synuclein, complexin-2, phosphatidylethanolamine-binding protein 1, rab GDP dissociation inhibitor alpha, and syntaxins 1B and 7 were measured in CSF using a microflow liquid chromatography-mass spectrometric multiple reaction monitoring set-up. Biomarker levels were compared between BD and HC and in BD before, during, and after mood episodes.The synaptic proteins revealed no statistically significant differences between BD and HC, neither at baseline, one-year follow-up, or in terms of changes from baseline to follow-up. Moreover, the CSF synaptic protein levels in patients with BD were unaltered compared to baseline when they stabilized in euthymia following an affective episode and at one-year follow-up.It is uncertain what the CSF biomarker concentrations reflect since we yet do not know the mechanisms of release of these proteins, and we are uncertain of what increased or decreased levels reflect.This first-ever investigation of a panel of CSF protein biomarkers of synaptic dysfunction in patients with BD and HC individuals found no statistically significant differences cross-sectionally or longitudinally.
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| 11. |
- Kyhl, Frederik, et al.
(författare)
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The risk of Type 1 diabetes in children born after ART: a Nordic cohort study from the CoNARTaS group
- 2024
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Ingår i: HUMAN REPRODUCTION OPEN. - 2399-3529. ; 2024:2
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION Do children born after ART have a higher risk of developing Type 1 diabetes (DM1) than children conceived without ART?SUMMARY ANSWER The risk of DM1 was similar for children conceived with and without ART, and there were no clear differences in risk according to method of fertility treatment.WHAT IS KNOWN ALREADY ART is associated with a higher risk of adverse perinatal outcomes, and the risk depends on the method of ART. The Developmental Origins of Health and Disease theory proposes that prenatal stress can provoke changes in endocrine processes which impact health later in life.STUDY DESIGN, SIZE, DURATION A Nordic register-based cohort study was carried out, including all children born in Denmark (birth years 1994-2014), Finland (1990-2014), and Norway (1984-2015). The study included 76 184 liveborn singletons born after ART and 4 403 419 born without ART. Median follow-up was 8.3 and 13.7 years in the ART and non-ART group, respectively.PARTICIPANTS/MATERIALS, SETTING, METHODS The cohort, initiated by the Committee of Nordic Assisted Reproductive Technology and Safety (CoNARTaS), was established by linking national registry data from the medical birth registries and national patient registries available in the Nordic countries. We performed multivariable logistic regression analyses for the birth year intervals 1984-1990, 1991-1995, 1996-2000, 2001-2005, 2006-2010, and 2011-2015, while adjusting for year of birth within each interval, sex of the child, parity, maternal age, maternal diabetes, and maternal smoking during pregnancy as potential confounders.MAIN RESULTS AND THE ROLE OF CHANCE During follow-up, 259 (3.4 parts per thousand) children born after ART were diagnosed with DM1, while this was the case for 22 209 (5.0 parts per thousand) born without ART, corresponding to an adjusted odds ratio of 0.98 (95% CI: 0.861.11). Within the different birth year intervals, no significant difference in risk of DM1 between the two groups was found, except for the youngest cohort of children born 2011-2015 where ART was associated with a higher risk of DM1. We found no significant differences in risk of DM1 when comparing children born after IVF versus ICSI or fresh versus frozen embryo transfer, but with only few cases in each group.LIMITATIONS, REASONS FOR CAUTION The main limitation of the study is the relatively short follow-up time. The incidence rate of DM1 peaks during ages 10-14 years, hence a longer follow-up would benefit all analyses and, in particular, the subgroup analyses.WIDER IMPLICATIONS OF THE FINDINGS Overall, our findings are reassuring especially considering the concomitantly increasing number of children born from ART and the increasing incidence of DM1 globally.STUDY FUNDING/COMPETING INTEREST(S) This Nordic registry study has been supported by the Nordic Trial Alliance/NORDFORSK and Rigshospitalets Research Foundation. The funding sources had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. None of the authors has any conflicts of interest to declare regarding this study.TRIAL REGISTRATION NUMBER ISRCTN11780826.
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| 12. |
- Lazar, Tamas, et al.
(författare)
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PED in 2021 : A major update of the protein ensemble database for intrinsically disordered proteins
- 2021
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 49:D1, s. 404-411
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Tidskriftsartikel (refereegranskat)abstract
- The Protein Ensemble Database (PED) (https://proteinensemble.org), which holds structural ensembles of intrinsically disordered proteins (IDPs), has been significantly updated and upgraded since its last release in 2016. The new version, PED 4.0, has been completely redesigned and reimplemented with cutting-edge technology and now holds about six times more data (162 versus 24 entries and 242 versus 60 structural ensembles) and a broader representation of state of the art ensemble generation methods than the previous version. The database has a completely renewed graphical interface with an interactive feature viewer for region-based annotations, and provides a series of descriptors of the qualitative and quantitative properties of the ensembles. High quality of the data is guaranteed by a new submission process, which combines both automatic and manual evaluation steps. A team of biocurators integrate structured metadata describing the ensemble generation methodology, experimental constraints and conditions. A new search engine allows the user to build advanced queries and search all entry fields including cross-references to IDP-related resources such as DisProt, MobiDB, BMRB and SASBDB. We expect that the renewed PED will be useful for researchers interested in the atomic-level understanding of IDP function, and promote the rational, structure-based design of IDP-targeting drugs.
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| 13. |
- Picchini, Umberto, 1977, et al.
(författare)
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Accelerating delayed-acceptance Markov chain Monte Carlo algorithms
- 2019
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Delayed-acceptance Markov chain Monte Carlo (DA-MCMC) samples from a probability distribution via a two-stages version of the Metropolis-Hastings algorithm, by combining the target distribution with a "surrogate" (i.e. an approximate and computationally cheaper version) of said distribution. DA-MCMC accelerates MCMC sampling in complex applications, while still targeting the exact distribution. We design a computationally faster, albeit approximate, DA-MCMC algorithm. We consider parameter inference in a Bayesian setting where a surrogate likelihood function is introduced in the delayed-acceptance scheme. When the evaluation of the likelihood function is computationally intensive, our scheme produces a 2-4 times speed-up, compared to standard DA-MCMC. However, the acceleration is highly problem dependent. Inference results for the standard delayed-acceptance algorithm and our approximated version are similar, indicating that our algorithm can return reliable Bayesian inference. As a computationally intensive case study, we introduce a novel stochastic differential equation model for protein folding data.
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| 14. |
- Picchini, Umberto, et al.
(författare)
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Accelerating inference for diffusions observed with measurement error and large sample sizes using approximate Bayesian computation
- 2016
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Ingår i: Journal of Statistical Computation and Simulation. - : Informa UK Limited. - 1563-5163 .- 0094-9655. ; 86:1, s. 195-213
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, dynamical modelling has been provided with a range of breakthrough methods to perform exact Bayesian inference. However, it is often computationally unfeasible to apply exact statistical methodologies in the context of large data sets and complex models. This paper considers a nonlinear stochastic differential equation model observed with correlated measurement errors and an application to protein folding modelling. An approximate Bayesian computation (ABC)-MCMC algorithm is suggested to allow inference for model parameters within reasonable time constraints. The ABC algorithm uses simulations of subsamples' from the assumed data-generating model as well as a so-called early-rejection' strategy to speed up computations in the ABC-MCMC sampler. Using a considerate amount of subsamples does not seem to degrade the quality of the inferential results for the considered applications. A simulation study is conducted to compare our strategy with exact Bayesian inference, the latter resulting two orders of magnitude slower than ABC-MCMC for the considered set-up. Finally, the ABC algorithm is applied to a large size protein data. The suggested methodology is fairly general and not limited to the exemplified model and data.
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| 15. |
- Picchini, Umberto, 1977, et al.
(författare)
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Bayesian inference for stochastic differential equation mixed effects models of a tumor xenography study
- 2019
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Ingår i: Journal of the Royal Statistical Society. Series C: Applied Statistics. - : Oxford University Press (OUP). - 1467-9876 .- 0035-9254. ; 68:4, s. 887-913
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Tidskriftsartikel (refereegranskat)abstract
- We consider Bayesian inference for stochastic differential equation mixed effects models (SDEMEMs) exemplifying tumour response to treatment and regrowth in mice. We produce an extensive study on how an SDEMEM can be fitted by using both exact inference based on pseudo‐marginal Markov chain Monte Carlo sampling and approximate inference via Bayesian synthetic likelihood (BSL). We investigate a two‐compartments SDEMEM, corresponding to the fractions of tumour cells killed by and survived on a treatment. Case‐study data consider a tumour xenography study with two treatment groups and one control, each containing 5–8 mice. Results from the case‐study and from simulations indicate that the SDEMEM can reproduce the observed growth patterns and that BSL is a robust tool for inference in SDEMEMs. Finally, we compare the fit of the SDEMEM with a similar ordinary differential equation model. Because of small sample sizes, strong prior information is needed to identify all model parameters in the SDEMEM and it cannot be determined which of the two models is the better in terms of predicting tumour growth curves. In a simulation study we find that with a sample of 17 mice per group BSL can identify all model parameters and distinguish treatment groups.
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| 16. |
- Slidsborg, Carina, et al.
(författare)
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Experts do not agree when to treat retinopathy of prematurity based on plus disease
- 2012
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Ingår i: British Journal of Ophthalmology. - London, United Kingdom : B M J Publishing Group. - 0007-1161 .- 1468-2079. ; 96:4, s. 549-553
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To investigate inter-reader agreement on five severity levels of central vascular changes (none, mild, moderate, severe pre-plus disease, plus disease) and aggressive posterior retinopathy of prematurity (ROP), and to see whether an unintended shift in indication for treatment occurred.Methods: Four international ROP readers participated. Before the grading of the photographs, the readers were informed that a high proportion of advanced ROP cases were included. In total, 243 photographs/948 quadrants were available from 136 infants. As a standard series of photographs was available, grading was performed under optimised conditions.Results: The four readers agreed on the quadrant scores of only 70 (7.38%) of the 948 quadrants-that is, on 1, 5, 15, 4 and 45 quadrants for scores 0, 1, 2, 3 and 4, respectively. The mean scores differed systematically between the readers (permutation test, p<0.0001). Agreement on presence of aggressive posterior ROP from all four readers was not obtained for any of the photographs. Readers scored plus disease in at least two quadrants in 95.5% of the eyes for which treatment was indicated. All four readers agreed on the scoring of indication for treatment for 195 eyes (80.2%); however, treatment was only recommended in 18 (7.4%) eyes. One reader was found to differ systematically from the others in indicating treatment (Rasch analysis; p=0.0001). Finally, a significant shift in indication for treatment occurred between birth period 2000-2002 and 2003-2006 (Mann-Whitney rank sum test, p<0.001).Conclusions: Inter-reader agreement on central vascular changes is poor, especially when based on more than two rating categories. The subjective nature of diagnosing such vascular changes possibly resulted in earlier treatment of preterm infants in Denmark over the entire study period (1997-2006). The recent increased incidence of treated infants in Denmark is, at least in part, explained by a significant shift in indication for treatment.
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| 17. |
- Spangmose, Anne Lærke, et al.
(författare)
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Cerebral palsy in ART children has declined substantially over time: a Nordic study from the CoNARTaS group
- 2021
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Ingår i: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 36:8, s. 2358-2370
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Tidskriftsartikel (refereegranskat)abstract
- STUDY QUESTION: Are the decreasing multiple birth rates after ART associated with a simultaneous drop in the incidence of cerebral palsy (CP) in ART children over time? SUMMARY ANSWER: The relative odds of CP in ART children have declined in the Nordic countries over the past two decades concurrently with declining multiple birth rates. WHAT IS KNOWN ALREADY: In the Nordic countries, the rate of twin pregnancies after ART has decreased from 30% in the early 1990s to 4-13% in 2014, following the implementation of elective single embryo transfer (SET). Consequently, preterm birth rates have declined substantially in ART pregnancies. However, whether the risk of CP, a known consequence of preterm birth, has decreased correspondingly is still unknown. STUDY DESIGN, SIZE, DURATION: Retrospective register-based cohort study based on data on all singletons, twins, and higher-order multiples born in Denmark (birth year 1994-2010), Finland (1990-2010), and Sweden (1990-2014), corresponding to 111 844 ART children and 4 679 351 spontaneously conceived children. PARTICIPANTS/MATERIAL, SETTING, METHODS: Data were obtained from a large Nordic cohort of children born after ART and spontaneous conception initiated by the Committee of Nordic ART and Safety-CoNARTaS. The CoNARTaS cohort was established by cross-linking national register data using the unique personal identification number, allocated to every citizen in the Nordic countries. Data from the National Medical Birth Registers, where information on maternal, obstetric, and perinatal outcomes is recorded, were cross-linked to data from the National ART- and Patients Registers to obtain information on fertility treatments and CP diagnoses. Relative risks of CP for ART compared to spontaneous conception were estimated as odds ratios from multivariate logistic regression analyses across all birth years, as well as for the following birth year categories: 1990-1993, 1994-1998, 1999-2002, 2003-2006, 2007-2010, and 2011-2014. Analyses were made for all children and for singletons and twins, separately. MAIN RESULTS AND THE ROLE OF CHANCE: The main outcome measure was the relative odds of CP in different time periods for ART versus spontaneously conceived children. CP was diagnosed in 661 ART children and 16 478 spontaneously conceived children born between 1990 and 2014. In 1990-1993, the relative odds of CP were substantially higher in all ART children (adjusted odds ratio (aOR) 2.76 (95% CI 2.03-3.67)) compared with all spontaneously conceived children, while in 2011-2014, it was only moderately higher (aOR 1.39 (95% CI 1.01-1.87)). In singletons, the higher relative odds of CP in ART children diminished over time from 1990 to 1993 (aOR 2.02 (95% CI 1.22-3.14)) to 2003-2006 (aOR 1.18 (95% CI 0.91-1. 49)) and was not significantly increased for birth cohorts 2007-2010 and 2011-2014. For ART twins versus spontaneously conceived twins, the relative odds of CP was not statistically significantly increased throughout the study period. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study was a shorter follow-up time and younger age at first CP diagnosis for ART children compared with spontaneously conceived children. However, analyses ensuring a minimum of bias from differences in age at CP diagnosis and follow-up time confirmed the results, hence, we do not consider this to cause substantial bias. WIDER IMPLICATIONS OF THE FINDINGS: A SET policy in ART treatments has the potential to reduce the increased risk of cerebral palsy in the ART population due to lower rates of multiple deliveries. At a time with high survival rates of frozen/thawed embryos, this study provides a strong argument against the continued use of multiple embryo transfer in most ART settings. Larger cohort studies including also the number of gestational sacs in early pregnancy will be preferable to show an effect of vanishing twins on the risk of CP in the ART population. STUDY FUNDING/COMPETING INTEREST(S): The study was financed by grants from NordForsk (grant number 71450), Elsass Foundation (19-3-0444), the ALF-agreement (ALFGBG 70940), and The Research Fund of Rigshospitalet, Copenhagen University Hospital. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: ISRCTN11780826.
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- Stormlund, Sacha, et al.
(författare)
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The prevalence of late-follicular phase progesterone elevation and impact on the ongoing pregnancy rate after fresh and frozen blastocyst transfer. Sub-study of an RCT
- 2024
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Ingår i: HUMAN FERTILITY. - 1464-7273 .- 1742-8149. ; 27:1
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Tidskriftsartikel (refereegranskat)abstract
- The effect of late-follicular phase progesterone elevation (LFPE) during ovarian stimulation on reproductive outcomes in ART treatment remains controversial, but recent studies indicate lower pregnancy rates with rising progesterone levels. This study aims to investigate the prevalence of late-follicular phase progesterone elevation (LFPE) and possible impact on ongoing pregnancy rate after fresh or frozen blastocyst transfer in a sub-study setting of a randomised controlled trial. A total of 288 women were included (n=137 and n=151 in the fresh transfer and freeze-all group, respectively). Among these 11(3.8%) had a progesterone level >= 1.5 ng/ml, and 20(6.9%) had a progesterone level >= 1.2 ng/ml on trigger day. Spline regression analysis showed no significant effect of late follicular phase progesterone levels on ongoing pregnancy. In the multivariate regression analysis (n = 312) only age, but not progesterone level on trigger day was significantly associated with ongoing pregnancy. In conclusion, in a clinical setting with moderate gonadotrophin stimulation and well-defined trigger and fresh transfer cancellation criteria, the prevalence of women with LFPE >= 1.5 ng/ml was low and did not indicate the clinical value of routine measurement of progesterone in the late follicular phase.
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