| 1. |
- Tabiri, S, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 2. |
- Bravo, L, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 3. |
|
|
| 4. |
- Abel, I, et al.
(författare)
-
Overview of the JET results with the ITER-like wall
- 2013
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 53:10, s. 104002-
-
Tidskriftsartikel (refereegranskat)abstract
- Following the completion in May 2011 of the shutdown for the installation of the beryllium wall and the tungsten divertor, the first set of JET campaigns have addressed the investigation of the retention properties and the development of operational scenarios with the new plasma-facing materials. The large reduction in the carbon content (more than a factor ten) led to a much lower Z(eff) (1.2-1.4) during L- and H-mode plasmas, and radiation during the burn-through phase of the plasma initiation with the consequence that breakdown failures are almost absent. Gas balance experiments have shown that the fuel retention rate with the new wall is substantially reduced with respect to the C wall. The re-establishment of the baseline H-mode and hybrid scenarios compatible with the new wall has required an optimization of the control of metallic impurity sources and heat loads. Stable type-I ELMy H-mode regimes with H-98,H-y2 close to 1 and beta(N) similar to 1.6 have been achieved using gas injection. ELM frequency is a key factor for the control of the metallic impurity accumulation. Pedestal temperatures tend to be lower with the new wall, leading to reduced confinement, but nitrogen seeding restores high pedestal temperatures and confinement. Compared with the carbon wall, major disruptions with the new wall show a lower radiated power and a slower current quench. The higher heat loads on Be wall plasma-facing components due to lower radiation made the routine use of massive gas injection for disruption mitigation essential.
|
|
| 5. |
- Romanelli, F, et al.
(författare)
-
Overview of the JET results
- 2011
-
Ingår i: Nuclear Fusion. - : IOP Publishing. - 1741-4326 .- 0029-5515. ; 51:9
-
Tidskriftsartikel (refereegranskat)abstract
- Since the last IAEA Conference JET has been in operation for one year with a programmatic focus on the qualification of ITER operating scenarios, the consolidation of ITER design choices and preparation for plasma operation with the ITER-like wall presently being installed in JET. Good progress has been achieved, including stationary ELMy H-mode operation at 4.5 MA. The high confinement hybrid scenario has been extended to high triangularity, lower ρ*and to pulse lengths comparable to the resistive time. The steady-state scenario has also been extended to lower ρ*and ν*and optimized to simultaneously achieve, under stationary conditions, ITER-like values of all other relevant normalized parameters. A dedicated helium campaign has allowed key aspects of plasma control and H-mode operation for the ITER non-activated phase to be evaluated. Effective sawtooth control by fast ions has been demonstrated with3He minority ICRH, a scenario with negligible minority current drive. Edge localized mode (ELM) control studies using external n = 1 and n = 2 perturbation fields have found a resonance effect in ELM frequency for specific q95values. Complete ELM suppression has, however, not been observed, even with an edge Chirikov parameter larger than 1. Pellet ELM pacing has been demonstrated and the minimum pellet size needed to trigger an ELM has been estimated. For both natural and mitigated ELMs a broadening of the divertor ELM-wetted area with increasing ELM size has been found. In disruption studies with massive gas injection up to 50% of the thermal energy could be radiated before, and 20% during, the thermal quench. Halo currents could be reduced by 60% and, using argon/deuterium and neon/deuterium gas mixtures, runaway electron generation could be avoided. Most objectives of the ITER-like ICRH antenna have been demonstrated; matching with closely packed straps, ELM resilience, scattering matrix arc detection and operation at high power density (6.2 MW m-2) and antenna strap voltages (42 kV). Coupling measurements are in very good agreement with TOPICA modelling. © 2011 IAEA, Vienna.
|
|
| 6. |
|
|
| 7. |
- Abe, O, et al.
(författare)
-
Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
-
Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
-
Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
- Kim, Jae-Young, et al.
(författare)
-
Event Horizon Telescope imaging of the archetypal blazar 3C 279 at an extreme 20 microarcsecond resolution
- 2020
-
Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 640
-
Tidskriftsartikel (refereegranskat)abstract
- 3C 279 is an archetypal blazar with a prominent radio jet that show broadband flux density variability across the entire electromagnetic spectrum. We use an ultra-high angular resolution technique - global Very Long Baseline Interferometry (VLBI) at 1.3mm (230 GHz) - to resolve the innermost jet of 3C 279 in order to study its fine-scale morphology close to the jet base where highly variable-ray emission is thought to originate, according to various models. The source was observed during four days in April 2017 with the Event Horizon Telescope at 230 GHz, including the phased Atacama Large Millimeter/submillimeter Array, at an angular resolution of ∼20 μas (at a redshift of z = 0:536 this corresponds to ∼0:13 pc ∼ 1700 Schwarzschild radii with a black hole mass MBH = 8 × 108 M⊙). Imaging and model-fitting techniques were applied to the data to parameterize the fine-scale source structure and its variation.We find a multicomponent inner jet morphology with the northernmost component elongated perpendicular to the direction of the jet, as imaged at longer wavelengths. The elongated nuclear structure is consistent on all four observing days and across diffierent imaging methods and model-fitting techniques, and therefore appears robust. Owing to its compactness and brightness, we associate the northern nuclear structure as the VLBI "core". This morphology can be interpreted as either a broad resolved jet base or a spatially bent jet.We also find significant day-to-day variations in the closure phases, which appear most pronounced on the triangles with the longest baselines. Our analysis shows that this variation is related to a systematic change of the source structure. Two inner jet components move non-radially at apparent speeds of ∼15 c and ∼20 c (∼1:3 and ∼1:7 μas day-1, respectively), which more strongly supports the scenario of traveling shocks or instabilities in a bent, possibly rotating jet. The observed apparent speeds are also coincident with the 3C 279 large-scale jet kinematics observed at longer (cm) wavelengths, suggesting no significant jet acceleration between the 1.3mm core and the outer jet. The intrinsic brightness temperature of the jet components are ≤1010 K, a magnitude or more lower than typical values seen at ≥7mm wavelengths. The low brightness temperature and morphological complexity suggest that the core region of 3C 279 becomes optically thin at short (mm) wavelengths.
|
|
| 12. |
- Akiyama, Kazunori, et al.
(författare)
-
First Sagittarius A* Event Horizon Telescope Results. II. EHT and Multiwavelength Observations, Data Processing, and Calibration
- 2022
-
Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Tidskriftsartikel (refereegranskat)abstract
- We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5-11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of similar to 50 mu as, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*'s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior.
|
|
| 13. |
- Watson, Hunna J., et al.
(författare)
-
Common Genetic Variation and Age of Onset of Anorexia Nervosa
- 2022
-
Ingår i: BIOLOGICAL PSYCHIATRY: GLOBAL OPEN SCIENCE. - : Elsevier BV. - 2667-1743. ; 2:4, s. 368-378
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Genetics and biology may influence the age of onset of anorexia nervosa (AN). The aims of this study were to determine whether common genetic variation contributes to age of onset of AN and to investigate the genetic associations between age of onset of AN and age at menarche.METHODS: A secondary analysis of the Psychiatric Genomics Consortium genome-wide association study (GWAS) of AN was performed, which included 9335 cases and 31,981 screened controls, all from European ancestries. We conducted GWASs of age of onset, early-onset AN (,13 years), and typical-onset AN, and genetic correlation, genetic risk score, and Mendelian randomization analyses.RESULTS: Two loci were genome-wide significant in the typical-onset AN GWAS. Heritability estimates (single nucleotide polymorphism-h2) were 0.01-0.04 for age of onset, 0.16-0.25 for early-onset AN, and 0.17-0.25 for typical-onset AN. Early-and typical-onset AN showed distinct genetic correlation patterns with putative risk factors for AN. Specifically, early-onset AN was significantly genetically correlated with younger age at menarche, and typical-onset AN was significantly negatively genetically correlated with anthropometric traits. Genetic risk scores for age of onset and early-onset AN estimated from independent GWASs significantly predicted age of onset. Mendelian randomization analysis suggested a causal link between younger age at menarche and early -onset AN.CONCLUSIONS: Our results provide evidence consistent with a common variant genetic basis for age of onset and implicate biological pathways regulating menarche and reproduction.
|
|
| 14. |
- Ade, Peter, et al.
(författare)
-
The Simons Observatory : science goals and forecasts
- 2019
-
Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
-
Tidskriftsartikel (refereegranskat)abstract
- The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
|
|
| 15. |
- McCarrick, Heather, et al.
(författare)
-
The Simons Observatory Microwave SQUID Multiplexing Detector Module Design
- 2021
-
Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 922:1
-
Tidskriftsartikel (refereegranskat)abstract
- Advances in cosmic microwave background (CMB) science depend on increasing the number of sensitive detectors observing the sky. New instruments deploy large arrays of superconducting transition-edge sensor (TES) bolometers tiled densely into ever larger focal planes. High multiplexing factors reduce the thermal loading on the cryogenic receivers and simplify their design. We present the design of focal-plane modules with an order of magnitude higher multiplexing factor than has previously been achieved with TES bolometers. We focus on the novel cold readout component, which employs microwave SQUID multiplexing (μmux). Simons Observatory will use 49 modules containing 70,000 bolometers to make exquisitely sensitive measurements of the CMB. We validate the focal-plane module design, presenting measurements of the readout component with and without a prototype detector array of 1728 polarization-sensitive bolometers coupled to feedhorns. The readout component achieves a 95% yield and a 910 multiplexing factor. The median white noise of each readout channel is 65 pA √Hz . This impacts the projected SO mapping speed by <8%, which is less than is assumed in the sensitivity projections. The results validate the full functionality of the module. We discuss the measured performance in the context of SO science requirements, which are exceeded.
|
|
| 16. |
- Beal, Jacob, et al.
(författare)
-
Robust estimation of bacterial cell count from optical density
- 2020
-
Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
-
Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
|
|
| 17. |
- Green, Jonathan M. H., et al.
(författare)
-
Research priorities for managing the impacts and dependencies of business upon food, energy, water and the environment
- 2017
-
Ingår i: Sustainability Science. - : Springer Science and Business Media LLC. - 1862-4065 .- 1862-4057. ; 12:2, s. 319-331
-
Tidskriftsartikel (refereegranskat)abstract
- Delivering access to sufficient food, energy and water resources to ensure human wellbeing is a major concern for governments worldwide. However, it is crucial to account for the 'nexus' of interactions between these natural resources and the consequent implications for human wellbeing. The private sector has a critical role in driving positive change towards more sustainable nexus management and could reap considerable benefits from collaboration with researchers to devise solutions to some of the foremost sustainability challenges of today. Yet opportunities are missed because the private sector is rarely involved in the formulation of deliverable research priorities. We convened senior research scientists and influential business leaders to collaboratively identify the top forty questions that, if answered, would best help companies understand and manage their food-energy-water-environment nexus dependencies and impacts. Codification of the top order nexus themes highlighted research priorities around development of pragmatic yet credible tools that allow businesses to incorporate nexus interactions into their decision-making; demonstration of the business case for more sustainable nexus management; identification of the most effective levers for behaviour change; and understanding incentives or circumstances that allow individuals and businesses to take a leadership stance. Greater investment in the complex but productive relations between the private sector and research community will create deeper and more meaningful collaboration and cooperation.
|
|
| 18. |
- Strom, Nora I., et al.
(författare)
-
Meta-analysis of genome-wide association studies of hoarding symptoms in 27,537 individuals
- 2022
-
Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- Hoarding Disorder (HD) is a mental disorder characterized by persistent difficulties discarding or parting with possessions, often resulting in cluttered living spaces, distress, and impairment. Its etiology is largely unknown, but twin studies suggest that it is moderately heritable. In this study, we pooled phenotypic and genomic data from seven international cohorts (N = 27,537 individuals) and conducted a genome wide association study (GWAS) meta-analysis of parent- or self-reported hoarding symptoms (HS). We followed up the results with gene-based and gene-set analyses, as well as leave-one-out HS polygenic risk score (PRS) analyses. To examine a possible genetic association between hoarding symptoms and other phenotypes we conducted cross-trait PRS analyses. Though we did not report any genome-wide significant SNPs, we report heritability estimates for the twin-cohorts between 26-48%, and a SNP-heritability of 11% for an unrelated sub-cohort. Cross-trait PRS analyses showed that the genetic risk for schizophrenia and autism spectrum disorder were significantly associated with hoarding symptoms. We also found suggestive evidence for an association with educational attainment. There were no significant associations with other phenotypes previously linked to HD, such as obsessive-compulsive disorder, depression, anxiety, or attention-deficit hyperactivity disorder. To conclude, we found that HS are heritable, confirming and extending previous twin studies but we had limited power to detect any genome-wide significant loci. Much larger samples will be needed to further extend these findings and reach a "gene discovery zone". To move the field forward, future research should not only include genetic analyses of quantitative hoarding traits in larger samples, but also in samples of individuals meeting strict diagnostic criteria for HD, and more ethnically diverse samples.
|
|
| 19. |
- Betts, Marissa, J., et al.
(författare)
-
Early Cambrian chronostratigraphy and geochronology of South Australia
- 2018
-
Ingår i: Earth-Science Reviews. - : Elsevier BV. - 0012-8252 .- 1872-6828. ; 185, s. 498-543
-
Tidskriftsartikel (refereegranskat)abstract
- The most successful chronostratigraphic correlation methods enlist multiple proxies such as biostratigraphy and chemostratigraphy to constrain the timing of globally important bio- and geo-events. Here we present the first regional, high-resolution shelly fossil biostratigraphy integrated with δ13C chemostratigraphy (and corresponding δ18O data) from the traditional lower Cambrian (Terreneuvian and provisional Cambrian Series 2) of South Australia. The global ZHUCE, SHICE, positive excursions II and III and the CARE are captured in lower Cambrian successions from the Arrowie and Stansbury basins. The South Australian shelly fossil biostratigraphy has a consistent relationship with the δ13C results, bolstering interpretation, identification and correlation of the excursions. Positive excursion II straddles the boundary between the Kulparina rostrata and Micrina etheridgei zones, and the CARE straddles the boundary between the M. etheridgei and Dailyatia odyssei zones, peaking in the lower parts of the latter zone. New CA-TIMS zircon dates from the upper Hawker Group and Billy Creek Formation provide geochronologic calibration points for the upper D. odyssei Zone and corresponding chemostratigraphic curve, embedding the lower Cambrian successions from South Australia into a global chronostratigraphic context. This multi-proxy investigation demonstrates the power of integrated methods for developing regional biostratigraphic schemes and facilitating robust global correlation of lower Cambrian successions from South Australia (part of East Gondwana) with coeval terranes on other Cambrian palaeocontinents, including South and North China, Siberia, Laurentia, Avalonia and West Gondwana.
|
|
| 20. |
- Chen, Long Long, et al.
(författare)
-
Genomics of severe and treatment-resistant obsessive–compulsive disorder treated with deep brain stimulation : a preliminary investigation
- 2024
-
Ingår i: American Journal of Medical Genetics Part B. - : John Wiley & Sons. - 1552-4841 .- 1552-485X.
-
Tidskriftsartikel (refereegranskat)abstract
- Individuals with severe and treatment-resistant obsessive-compulsive disorder (trOCD) represent a small but severely disabled group of patients. Since trOCD cases eligible for deep brain stimulation (DBS) probably comprise the most severe end of the OCD spectrum, we hypothesize that they may be more likely to have a strong genetic contribution to their disorder. Therefore, while the worldwide population of DBS-treated cases may be small (~300), screening these individuals with modern genomic methods may accelerate gene discovery in OCD. As such, we have begun to collect DNA from trOCD cases who qualify for DBS, and here we report results from whole exome sequencing and microarray genotyping of our first five cases. All participants had previously received DBS in the bed nucleus of stria terminalis (BNST), with two patients responding to the surgery and one showing a partial response. Our analyses focused on gene-disruptive rare variants (GDRVs; rare, predicted-deleterious single-nucleotide variants or copy number variants overlapping protein-coding genes). Three of the five cases carried a GDRV, including a missense variant in the ion transporter domain of KCNB1, a deletion at 15q11.2, and a duplication at 15q26.1. The KCNB1 variant (hg19 chr20-47991077-C-T, NM_004975.3:c.1020G>A, p.Met340Ile) causes substitution of methionine for isoleucine in the trans-membrane region of neuronal potassium voltage-gated ion channel KV2.1. This KCNB1 substitution (Met340Ile) is located in a highly constrained region of the protein where other rare missense variants have previously been associated with neurodevelopmental disorders. The patient carrying the Met340Ile variant responded to DBS, which suggests that genetic factors could potentially be predictors of treatment response in DBS for OCD. In sum, we have established a protocol for recruiting and genomically characterizing trOCD cases. Preliminary results suggest that this will be an informative strategy for finding risk genes in OCD.
|
|
| 21. |
- Mataix-Cols, David, et al.
(författare)
-
A total-population multigenerational family clustering study of autoimmune diseases in obsessive-compulsive disorder and Tourette’s/chronic tic disorders
- 2017
-
Ingår i: Molecular Psychiatry. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 1359-4184 .- 1476-5578.
-
Tidskriftsartikel (refereegranskat)abstract
- The association between obsessive-compulsive disorder (OCD) and Tourette's/chronic tic disorders (TD/CTD) with autoimmune diseases (ADs) is uncertain. In this nationwide study, we sought to clarify the patterns of comorbidity and familial clustering of a broad range of ADs in individuals with OCD, individuals with TD/CTD and their biological relatives. From a birth cohort of 7 465 455 individuals born in Sweden between 1940 and 2007, we identified 30 082 OCD and 7279 TD/CTD cases in the National Patient Register and followed them up to 31 December 2013. The risk of 40 ADs was evaluated in individuals with OCD, individuals with TD/CTD and their first- (siblings, mothers, fathers), second- (half siblings) and third-degree (cousins) relatives, compared with population controls. Individuals with OCD and TD/CTD had increased comorbidity with any AD (43% and 36%, respectively) and many individual ADs. The risk of any AD and several individual ADs was consistently higher among first-degree relatives than among second- and third-degree relatives of OCD and TD/CTD probands. The risk of ADs was very similar in mothers, fathers and siblings of OCD probands, whereas it tended to be higher in mothers and fathers of TD/CTD probands (compared with siblings). The results suggest a familial link between ADs in general (that is, not limited to Streptococcus-related conditions) and both OCD and TD/CTD. Additional mother-specific factors, such as the placental transmission of antibodies, cannot be fully ruled out, particularly in TD/CTD.
|
|
| 22. |
- Slama, Jiri, et al.
(författare)
-
Plesovice zircon : A new natural reference material for U-Pb and Hf isotopic microanalysis
- 2008
-
Ingår i: Chemical Geology. - : Elsevier BV. - 0009-2541 .- 1872-6836. ; 249:02-jan, s. 1-35
-
Tidskriftsartikel (refereegranskat)abstract
- Matrix-matched calibration by natural zircon standards and analysis of natural materials as a reference are the principle methods for achieving accurate results in inicrobeam U-Pb dating and Hf isotopic analysis. We describe a new potential zircon reference material for laser ablation ICP-MS that was extracted from a potassic granulite facies rock collected in the southern part of the Bohemian Massif (Plesovice, Czech Republic). Data from different techniques (ID-TIMS, SIMS and LA ICP-MS) and several laboratories suggest that this zircon has a concordant U-Pb age with a weighted mean Pb-206/U-238 date of 337.13 +/- 0.37 Ma (ID-TIMS, 95% confidence limits, including tracer calibration uncertainty) and U-Pb age homogeneity on the scale used in LA ICP-MS dating. Inhomogeneities in trace element composition due to primary growth zoning prevent its use as a calibration standard for trace element analysis. The content of U varies from 465 ppm in pristine parts of the grains to similar to 3000 ppm in actinide-rich sectors that correspond to pyramidal faces with a high degree of metamictization (present in ca. 30% of the grains). These domains are easily recognized from high intensities on BSE images and should be avoided during the analysis. Hf isotopic composition of the Plesovice zircon (>0.9 wt.% Hf) is homogenous within and between the grains with a mean Hf-176/Hf-177 value of 0.282492 +/- 0.000013 (2SD). The age and Hf isotopic homogeneity of the Plesovice zircon together with its relatively high U and Pb contents make it an ideal calibration and reference material for laser ablation ICP-MS measurements, especially when using low laser energies and/or small diameters of laser beam required for improved spatial resolution.
|
|
| 23. |
- Strom, Nora I., et al.
(författare)
-
Genome-Wide Association Study of Obsessive-Compulsive Symptoms including 33,943 individuals from the general population
- 2024
-
Ingår i: Molecular Psychiatry. - : Springer Nature. - 1359-4184 .- 1476-5578.
-
Tidskriftsartikel (refereegranskat)abstract
- While 1-2% of individuals meet the criteria for a clinical diagnosis of obsessive-compulsive disorder (OCD), many more (~13-38%) experience subclinical obsessive-compulsive symptoms (OCS) during their life. To characterize the genetic underpinnings of OCS and its genetic relationship to OCD, we conducted the largest genome-wide association study (GWAS) meta-analysis of parent- or self-reported OCS to date (N = 33,943 with complete phenotypic and genome-wide data), combining the results from seven large-scale population-based cohorts from Sweden, the Netherlands, England, and Canada (including six twin cohorts and one cohort of unrelated individuals). We found no genome-wide significant associations at the single-nucleotide polymorphism (SNP) or gene-level, but a polygenic risk score (PRS) based on the OCD GWAS previously published by the Psychiatric Genetics Consortium (PGC-OCD) was significantly associated with OCS (Pfixed = 3.06 × 10-5). Also, one curated gene set (Mootha Gluconeogenesis) reached Bonferroni-corrected significance (Ngenes = 28, Beta = 0.79, SE = 0.16, Pbon = 0.008). Expression of genes in this set is high at sites of insulin mediated glucose disposal. Dysregulated insulin signaling in the etiology of OCS has been suggested by a previous study describing a genetic overlap of OCS with insulin signaling-related traits in children and adolescents. We report a SNP heritability of 4.1% (P = 0.0044) in the meta-analyzed GWAS, and heritability estimates based on the twin cohorts of 33-43%. Genetic correlation analysis showed that OCS were most strongly associated with OCD (rG = 0.72, p = 0.0007) among all tested psychiatric disorders (N = 11). Of all 97 tested phenotypes, 24 showed a significant genetic correlation with OCS, and 66 traits showed concordant directions of effect with OCS and OCD. OCS have a significant polygenic contribution and share genetic risk with diagnosed OCD, supporting the hypothesis that OCD represents the extreme end of widely distributed OCS in the population.
|
|
| 24. |
- Andersson, Evelyn, et al.
(författare)
-
Genetics of response to cognitive behavior therapy in adults with major depression : a preliminary report
- 2019
-
Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 24:4, s. 484-490
-
Tidskriftsartikel (refereegranskat)abstract
- Major depressive disorder is heritable and a leading cause of disability. Cognitive behavior therapy is an effective treatment for major depression. By quantifying genetic risk scores based on common genetic variants, the aim of this report was to explore the utility of psychiatric and cognitive trait genetic risk scores, for predicting the response of 894 adults with major depressive disorder to cognitive behavior therapy. The participants were recruited in a psychiatric setting, and the primary outcome score was measured using the Montgomery Asberg Depression Rating Scale-Self Rated. Single-nucleotide polymorphism genotyping arrays were used to calculate the genomic risk scores based on large genetic studies of six phenotypes: major depressive disorder, bipolar disorder, attention-deficit/hyperactivity disorder, autism spectrum disorder, intelligence, and educational attainment. Linear mixed-effect models were used to test the relationships between the six genetic risk scores and cognitive behavior therapy outcome. Our analyses yielded one significant interaction effect (B = 0.09, p < 0.001): the autism spectrum disorder genetic risk score correlated with Montgomery Asberg Depression Rating Scale-Self Rated changes during treatment, and the higher the autism spectrum disorder genetic load, the less the depressive symptoms decreased over time. The genetic risk scores for the other psychiatric and cognitive traits were not related to depressive symptom severity or change over time. Our preliminary results indicated, as expected, that the genomics of the response of patients with major depression to cognitive behavior therapy were complex and that future efforts should aim to maximize sample size and limit subject heterogeneity in order to gain a better understanding of the use of genetic risk factors to predict treatment outcome.
|
|
| 25. |
- Beckham, Gregg T., et al.
(författare)
-
The O-Glycosylated Linker from the Trichoderma reesei Family 7 Cellulase Is a Flexible, Disordered Protein
- 2010
-
Ingår i: Biophysical Journal. - : Elsevier BV. - 0006-3495 .- 1542-0086. ; 99:11, s. 3773-3781
-
Tidskriftsartikel (refereegranskat)abstract
- Fungi and bacteria secrete glycoprotein cocktails to deconstruct cellulose Cellulose degrading enzymes (cellulases) are often modular with catalytic domains for cellulose hydrolysis and carbohydrate binding modules connected by linkers rich in serine and threonine with O-glycosylation Few studies have probed the role that the linker and O-glycans play in catalysis Since different expression and growth conditions produce different glycosylation patterns that affect enzyme activity the structure function relationships that glycosylation imparts to linkers are relevant for understanding cellulase mechanisms Here the linker of the Trichoderma reesei Family 7 cellobiohydrolase (Cel7A) is examined by simulation Our results suggest that the Cel7A linker is an intrinsically disordered protein with and without glycosylation Contrary to the predominant view the O-glycosylation does not change the stiffness of the linker as measured by the relative fluctuations in the end to end distance rather it provides a 16 A extension thus expanding the operating range of Cel7A We explain observations from previous biochemical experiments in the light of results obtained here and compare the Cel7A linker with linkers from other cellulases with sequence based tools to predict disorder This preliminary screen indicates that linkers from Family 7 enzymes from other genera and other cellulases within T reesei may not be as disordered warranting further study
|
|
| 26. |
- Boberg, Julia, et al.
(författare)
-
Swedish multimodal cohort of patients with anxiety or depression treated with internet-delivered psychotherapy (MULTI-PSYCH)
- 2023
-
Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:10
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Depression and anxiety afflict millions worldwide causing considerable disability. MULTI-PSYCH is a longitudinal cohort of genotyped and phenotyped individuals with depression or anxiety disorders who have undergone highly structured internet-based cognitive-behaviour therapy (ICBT). The overarching purpose of MULTI-PSYCH is to improve risk stratification, outcome prediction and secondary preventive interventions. MULTI-PSYCH is a precision medicine initiative that combines clinical, genetic and nationwide register data.Participants MULTI-PSYCH includes 2668 clinically well-characterised adults with major depressive disorder (MDD) (n=1300), social anxiety disorder (n=640) or panic disorder (n=728) assessed before, during and after 12 weeks of ICBT at the internet psychiatry clinic in Stockholm, Sweden. All patients have been blood sampled and genotyped. Clinical and genetic data have been linked to several Swedish registers containing a wide range of variables from patient birth up to 10 years after the end of ICBT. These variable types include perinatal complications, school grades, psychiatric and somatic comorbidity, dispensed medications, medical interventions and diagnoses, healthcare and social benefits, demographics, income and more. Long-term follow-up data will be collected through 2029.Findings to date Initial uses of MULTI-PSYCH include the discovery of an association between PRS for autism spectrum disorder and response to ICBT, the development of a machine learning model for baseline prediction of remission status after ICBT in MDD and data contributions to genome wide association studies for ICBT outcome. Other projects have been launched or are in the planning phase.Future plans The MULTI-PSYCH cohort provides a unique infrastructure to study not only predictors or short-term treatment outcomes, but also longer term medical and socioeconomic outcomes in patients treated with ICBT for depression or anxiety. MULTI-PSYCH is well positioned for research collaboration.
|
|
| 27. |
- Brander, Gustaf, et al.
(författare)
-
A population-based family clustering study of tic-related obsessive-compulsive disorder
- 2021
-
Ingår i: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 26:4, s. 1224-1233
-
Tidskriftsartikel (refereegranskat)abstract
- In the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), obsessive-compulsive disorder (OCD) included a new "tic-related" specifier. However, strong evidence supporting tic-related OCD as a distinct subtype of OCD is lacking. This study investigated whether, at the population level, tic-related OCD has a stronger familial load than non-tic-related OCD. From a cohort of individuals born in Sweden between 1967 and 2007 (n = 4,085,367; 1257 with tic-related OCD and 20,975 with non-tic-related OCD), we identified all twins, full siblings, maternal and paternal half siblings, and cousins. Sex- and birth year-adjusted hazard ratios (aHR) were calculated to estimate the risk of OCD in relatives of individuals with OCD with and without comorbid tics, compared with relatives of unaffected individuals. We found that OCD is a familial disorder, regardless of comorbid tic disorder status. However, the risk of OCD in relatives of individuals with tic-related OCD was considerably greater than the risk of OCD in relatives of individuals with non-tic-related OCD (e.g., risk for full siblings: aHR = 10.63 [95% CI, 7.92-14.27] and aHR = 4.52 [95% CI, 4.06-5.02], respectively; p value for the difference < 0.0001). These differences remained when the groups were matched by age at first OCD diagnosis and after various sensitivity analyses. The observed familial patterns of OCD in relation to tics were not seen in relation to other neuropsychiatric comorbidities. Tic-related OCD is a particularly familial subtype of OCD. The results have important implications for ongoing gene-searching efforts.
|
|
| 28. |
- Fielding, Christopher R., et al.
(författare)
-
A multidisciplinary approach to resolving the end-Guadalupian extinction
- 2023
-
Ingår i: Evolving Earth. - : Elsevier. - 2950-1172. ; 1
-
Tidskriftsartikel (refereegranskat)abstract
- The transition from the middle to late Permian (Guadalupian–Lopingian) is claimed to record one or more extinction events that rival the ‘Big Five’ in terms of depletion of biological diversity and reorganization of ecosystem structure. Yet many questions remain as to whether the events recorded in separate regions were synchronous, causally related, or were of a magnitude rivaling other major crises in Earth’s history. In this paper, we survey some major unresolved issues related to the Guadalupian–Lopingian transition and offer a multidisciplinary approach to advance understanding of this under-appreciated biotic crisis by utilizing records in Southern Hemisphere high-palaeolatitude settings. We focus on the Bowen-Gunnedah-Sydney Basin System (BGSBS) as a prime site for analyses of biotic and physical environmental change at high palaeolatitudes in the middle and terminal Capitanian. Preliminary data suggest the likely position of the mid-Capitanian event is recorded in regressive deposits at the base of the Tomago Coal Measures (northern Sydney Basin) and around the contact between the Broughton Formation and the disconformably overlying Pheasants Nest Formation (southern Sydney Basin). Initial data suggest that the end-Capitanian event roughly correlates to the transgressive “Kulnura Marine Tongue” in the middle of the Tomago Coal Measures (northern Sydney Basin) and strata bearing dispersed, ice-rafted gravel in the Erins Vale Formation (southern Sydney Basin). Preliminary observations suggest that few plant genera or species disappeared in the transition from the Guadalupian to Lopingian, and the latter interval saw an increase in floristic diversity.
|
|
| 29. |
- Halvorsen, Matthew, et al.
(författare)
-
Increased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1, s. 1842-
-
Tidskriftsartikel (refereegranskat)abstract
- Despite considerable progress in schizophrenia genetics, most findings have been for large rare structural variants and common variants in well-imputed regions with few genes implicated from exome sequencing. Whole genome sequencing (WGS) can potentially provide a more complete enumeration of etiological genetic variation apart from the exome and regions of high linkage disequilibrium. We analyze high-coverage WGS data from 1162 Swedish schizophrenia cases and 936 ancestry-matched population controls. Our main objective is to evaluate the contribution to schizophrenia etiology from a variety of genetic variants accessible to WGS but not by previous technologies. Our results suggest that ultra-rare structural variants that affect the boundaries of topologically associated domains (TADs) increase risk for schizophrenia. Alterations in TAD boundaries may lead to dysregulation of gene expression. Future mechanistic studies will be needed to determine the precise functional effects of these variants on biology.
|
|
| 30. |
- Mahjani, Behrang, et al.
(författare)
-
The Genetic Architecture of Obsessive-Compulsive Disorder: Contribution of Liability to OCD From Alleles Across the Frequency Spectrum.
- 2022
-
Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 179:3, s. 216-225
-
Tidskriftsartikel (refereegranskat)abstract
- Obsessive-compulsive disorder (OCD) is known to be substantially heritable; however, the contribution of genetic variation across the allele frequency spectrum to this heritability remains uncertain. The authors used two new homogeneous cohorts to estimate the heritability of OCD from inherited genetic variation and contrasted the results with those of previous studies.The sample consisted of 2,090 Swedish-born individuals diagnosed with OCD and 4,567 control subjects, all genotyped for common genetic variants, specifically >400,000 single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) ≥0.01. Using genotypes of these SNPs to estimate distant familial relationships among individuals, the authors estimated the heritability of OCD, both overall and partitioned according to MAF bins.Narrow-sense heritability of OCD was estimated at 29% (SE=4%). The estimate was robust, varying only modestly under different models. Contrary to an earlier study, however, SNPs with MAF between 0.01 and 0.05 accounted for 10% of heritability, and estimated heritability per MAF bin roughly followed expectations based on a simple model for SNP-based heritability.These results indicate that common inherited risk variation (MAF ≥0.01) accounts for most of the heritable variation in OCD. SNPs with low MAF contribute meaningfully to the heritability of OCD, and the results are consistent with expectation under the "infinitesimal model" (also referred to as the "polygenic model"), where risk is influenced by a large number of loci across the genome and across MAF bins.
|
|
| 31. |
- Mataix-Cols, David, et al.
(författare)
-
In search of environmental risk factors for obsessive-compulsive disorder : study protocol for the OCDTWIN project
- 2023
-
Ingår i: BMC Psychiatry. - 1471-244X. ; 23:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The causes of obsessive-compulsive disorder (OCD) remain unknown. Gene-searching efforts are well underway, but the identification of environmental risk factors is at least as important and should be a priority because some of them may be amenable to prevention or early intervention strategies. Genetically informative studies, particularly those employing the discordant monozygotic (MZ) twin design, are ideally suited to study environmental risk factors. This protocol paper describes the study rationale, aims, and methods of OCDTWIN, an open cohort of MZ twin pairs who are discordant for the diagnosis of OCD. Methods: OCDTWIN has two broad aims. In Aim 1, we are recruiting MZ twin pairs from across Sweden, conducting thorough clinical assessments, and building a biobank of biological specimens, including blood, saliva, urine, stool, hair, nails, and multimodal brain imaging. A wealth of early life exposures (e.g., perinatal variables, health-related information, psychosocial stressors) are available through linkage with the nationwide registers and the Swedish Twin Registry. Blood spots stored in the Swedish phenylketonuria (PKU) biobank will be available to extract DNA, proteins, and metabolites, providing an invaluable source of biomaterial taken at birth. In Aim 2, we will perform within-pair comparisons of discordant MZ twins, which will allow us to isolate unique environmental risk factors that are in the causal pathway to OCD, while strictly controlling for genetic and early shared environmental influences. To date (May 2023), 43 pairs of twins (21 discordant for OCD) have been recruited. Discussion: OCDTWIN hopes to generate unique insights into environmental risk factors that are in the causal pathway to OCD, some of which have the potential of being actionable targets.
|
|
| 32. |
- Mataix-Cols, David, et al.
(författare)
-
Nordic OCD & Related Disorders Consortium : Rationale, design, and methods.
- 2020
-
Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 183:1, s. 38-50
-
Tidskriftsartikel (refereegranskat)abstract
- Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder, yet its etiology is unknown and treatment outcomes could be improved if biological targets could be identified. Unfortunately, genetic findings for OCD are lagging behind other psychiatric disorders. Thus, there is a pressing need to understand the causal mechanisms implicated in OCD in order to improve clinical outcomes and to reduce morbidity and societal costs. Specifically, there is a need for a large-scale, etiologically informative genetic study integrating genetic and environmental factors that presumably interact to cause the condition. The Nordic countries provide fertile ground for such a study, given their detailed population registers, national healthcare systems and active specialist clinics for OCD. We thus formed the Nordic OCD and Related Disorders Consortium (NORDiC, www.crowleylab.org/nordic), and with the support of NIMH and the Swedish Research Council, have begun to collect a large, richly phenotyped and genotyped sample of OCD cases. Our specific aims are geared toward answering a number of key questions regarding the biology, etiology, and treatment of OCD. This article describes and discusses the rationale, design, and methodology of NORDiC, including details on clinical measures and planned genomic analyses.
|
|
| 33. |
- Mataix-Cols, David, et al.
(författare)
-
Operational Definitions of Treatment Response and Remission in Obsessive-Compulsive Disorder Capture Meaningful Improvements in Everyday Life
- 2022
-
Ingår i: Psychotherapy and Psychosomatics. - : S. Karger AG. - 0033-3190 .- 1423-0348. ; 91:6, s. 424-430
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: The operational definitions of treatment response, partial response, and remission in obsessive-compulsive disorder (OCD) are widely used in clinical trials and regular practice. However, the clinimetric sensitivity of these definitions, that is, whether they identify patients that experience meaningful changes in their everyday life, remains unexplored.Objective: The objective was to examine the clinimetric sensitivity of the operational definitions of treatment response, partial response, and remission in children and adults with OCD.Methods: Pre- and post-treatment data from five clinical trials and three cohort studies of children and adults with OCD (n = 1,528; 55.3% children, 61.1% female) were pooled. We compared (1) responders, partial responders, and non-responders and (2) remitters and non-remitters on self-reported OCD symptoms, clinician-rated general functioning, and self-reported quality of life. Remission was also evaluated against post-treatment diagnostic interviews.Results: Responders and remitters experienced large improvements across validators. Responders had greater improvements than partial responders and non-responders on self-reported OCD symptoms (Cohen’s d 0.65–1.13), clinician-rated functioning (Cohen’s d 0.53–1.03), and self-reported quality of life (Cohen’s d 0.63–0.73). Few meaningful differences emerged between partial responders and non-responders. Remitters had better outcomes across most validators than non-remitters. Remission criteria corresponded well with absence of post-treatment diagnosis (sensitivity/specificity: 93%/83%). Using both the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and the Clinical Global Impression Scale yielded more conservative results and more robust changes across validators, compared to only using the Y-BOCS.Conclusions: The current definitions of treatment response and remission capture meaningful improvements in the everyday life of individuals with OCD, whereas the concept of partial response has dubious clinimetric sensitivity.
|
|
| 34. |
- Murray, Ewan J, et al.
(författare)
-
Targeting Staphylococcus aureus Quorum Sensing with Nonpeptidic Small Molecule Inhibitors.
- 2014
-
Ingår i: Journal of medicinal chemistry. - : American Chemical Society (ACS). - 1520-4804 .- 0022-2623. ; 57:6, s. 2813-2819
-
Tidskriftsartikel (refereegranskat)abstract
- A series of 3-oxo-C12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus. Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.
|
|
| 35. |
- Nordsletten, Ashley E., et al.
(författare)
-
Evaluating the Impact of Nonrandom Mating : Psychiatric Outcomes Among the Offspring of Pairs Diagnosed With Schizophrenia and Bipolar Disorder.
- 2020
-
Ingår i: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 87:3, s. 253-262
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Nonrandom mating has been shown for psychiatric diagnoses, with hypothesized-but not quantified-implications for offspring liability. This national cohort study enumerated the incidence of major psychiatric disorders among the offspring of parent pairs affected with schizophrenia (SCZ) and/or bipolar disorder (BIP) (i.e., dual-affected pairs).METHODS: Participants were all Swedish residents alive or born between 1968 and 2013 (n = 4,255,196 unique pairs and 8,343,951 offspring). Offspring with dual-affected, single-affected, and unaffected parents were followed (1973-2013) for incidence of broad psychiatric disorders. Primary outcomes included hazard ratio (HR) and cumulative incidence for SCZ and BIP in the offspring. Additional outcomes included any neuropsychiatric, anxiety, depressive, personality, or substance use disorders. Cumulative incidences of SCZ and BIP were used to inform heritability models for these disorders.RESULTS: Hazards were highest within disorder (e.g., offspring of dual-SCZ pairs had sharply raised hazards for SCZ [HR = 55.3]); however, they were significantly raised for all diagnoses (HR range = 2.89-11.84). Incidences were significantly higher for the majority of outcomes, with 43.4% to 48.5% diagnosed with "any" disorder over follow-up. Risks were retained, with modest attenuations, for the offspring of heterotypic pairs. The estimated heritability of liability for SCZ (h2 = 0.62, 95% confidence interval = 0.55-0.70) and BIP (h2 = 0.52, 95% confidence interval = 0.46-0.58) did not differ significantly from estimates derived from single-affected parents.CONCLUSIONS: Risks for a broad spectrum of psychiatric diagnoses are significantly raised in the offspring of dual-affected parents, in line with expectations from a polygenic model of liability to disease risk. How these risks may contribute to population maintenance of these disorders is considered.
|
|
| 36. |
|
|
| 37. |
- Nordsletten, Ashley E., et al.
(författare)
-
Patterns of Nonrandom Mating Within and Across 11 Major Psychiatric Disorders
- 2016
-
Ingår i: JAMA psychiatry. - Chicago, USA : American Medical Association. - 2168-6238 .- 2168-622X. ; 73:4, s. 354-361
-
Tidskriftsartikel (refereegranskat)abstract
- Importance: Psychiatric disorders are heritable, polygenic traits, which often share risk alleles and for which nonrandom mating has been suggested. However, despite the potential etiological implications, the scale of nonrandom mating within and across major psychiatric conditions remains unclear.Objective: To quantify the nature and extent of nonrandom mating within and across a broad range of psychiatric conditions at the population level.Design, setting and participants: Population-based cohort using Swedish population registers. Participants were all Swedish residents with a psychiatric diagnosis of interest (attention-deficit/hyperactivity disorder, autism spectrum disorder, schizophrenia, bipolar disorder, major depression, generalized anxiety disorder, agoraphobia, social phobia, obsessive-compulsive disorder, anorexia, or substance abuse), along with their mates. Individuals with select nonpsychiatric disorders (Crohn's disease, type 1 and type 2 diabetes mellitus, multiple sclerosis, or rheumatoid arthritis) were included for comparison. General population samples were also derived and matched 1:5 with each case proband. Inpatient and outpatient diagnostic data were derived from the Swedish National Patient Register (1973-2009), with analyses conducted between June 2014 and May 2015.MAIN OUTCOMES AND MEASURES: Correlation in the diagnostic status of mates both within and across disorders. Conditional logistic regression was used to quantify the odds of each diagnosis in the mates of cases relative to matched population controls.RESULTS: Across cohorts, data corresponded to 707 263 unique case individuals, with women constituting 45.7% of the full population. Positive correlations in diagnostic status were evident between mates. Within-disorder correlations were marginally higher (range, 0.11-0.48) than cross-disorder correlations (range, 0.01-0.42). Relative to matched populations, the odds of psychiatric case probands having an affected mate were significantly elevated. Differences in the magnitude of observed relationships were apparent by disorder (odds ratio range, 0.8-11.4). The number of comorbidities in a case proband was associated with the proportion of affected mates. These relationships were not apparent or weaker in magnitude among nonpsychiatric conditions (correlation range, -0.03 to 0.17).CONCLUSIONS AND RELEVANCE: Nonrandom mating is evident in psychiatric populations both within specific disorders and across the spectrum of psychiatric conditions. This phenomenon may hold important implications for how we understand the familial transmission of these disorders and for psychiatric genetic research.
|
|
| 38. |
- Sidorchuk, Anna, et al.
(författare)
-
One versus two biological parents with mental disorders : Relationship to educational attainment in the next generation
- 2023
-
Ingår i: Psychological Medicine. - : Cambridge University Press. - 0033-2917 .- 1469-8978. ; 53:15, s. 7025-7041
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Both maternal and, separately, paternal mental illness are associated with diminished academic attainment among children. However, the differential impacts of diagnostic type and degree of parental burden (e.g. one v. both parents affected) on these functional outcomes are unknown.METHODS: Using the Swedish national patient (NPR) and multi-generation (MGR) registers, 2 226 451 children (1 290 157 parental pairs), born 1 January 1973-31 December 1997, were followed through 31 December 2013. Diagnostic status of all cohort members was defined for eleven psychiatric disorders, and families classed by exposure: (1) parents affected with any disorder, (2) parents affected with a disorder group (e.g. neuropsychiatric disorders), and (3) parents affected with a specific disorder (e.g. ADHD). Pairs were further defined as 'unaffected,' 'single-affected,', or 'dual-affected.' Among offspring, the study evaluated fulfillment of four academic milestones, from compulsory (primary) school through University (college). Sensitivity analyses considered the impact of child's own mental health, as well as parental education, on main effects.RESULTS: Marked reductions in the odds of achievement were observed, emerging at the earliest levels of schooling for both single-affected [adjusted odds ratio (aOR), 0.50; 95% CI 0.49-0.51] and dual-affected (aOR 0.29, 95% CI 0.28-0.30) pairs and persisting thereafter [aOR range (single), 0.52-0.65; aOR range (dual), 0.30-0.40]. This pattern was repeated for analyses within diagnosis/diagnostic group. Main results were robust to adjustment for offspring mental health and parent education level.CONCLUSIONS: Parental mental illness is associated with profound reductions in educational attainment in the subsequent generation, with children from dual-affected families at uniquely high risk.
|
|
| 39. |
- Szatkiewicz, Jin, et al.
(författare)
-
The genomics of major psychiatric disorders in a large pedigree from Northern Sweden
- 2019
-
Ingår i: Translational Psychiatry. - : Nature Publishing Group. - 2158-3188. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- We searched for genetic causes of major psychiatric disorders (bipolar disorder, schizoaffective disorder, and schizophrenia) in a large, densely affected pedigree from Northern Sweden that originated with three pairs of founders born around 1650. We applied a systematic genomic approach to the pedigree via karyotyping (N = 9), genome-wide SNP arrays (N = 418), whole-exome sequencing (N = 26), and whole-genome sequencing (N = 10). Comprehensive analysis did not identify plausible variants of strong effect. Rather, pedigree cases had significantly higher genetic risk scores compared to pedigree and community controls.
|
|
| 40. |
- Wallert, John, et al.
(författare)
-
Predicting remission after internet-delivered psychotherapy in patients with depression using machine learning and multi-modal data
- 2022
-
Ingår i: Translational Psychiatry. - : Springer Nature. - 2158-3188. ; 12:1
-
Tidskriftsartikel (refereegranskat)abstract
- This study applied supervised machine learning with multi-modal data to predict remission of major depressive disorder {MDD) after psychotherapy. Genotyped adult patients (n = 894, 65.5% women, age 18-75 years) diagnosed with mild-to-moderate MDD and treated with guided Internet-based Cognitive Behaviour Therapy (ICBT) at the Internet Psychiatry Clinic in Stockholm were included (2008-2016). Predictor types were demographic, clinical, process (e.g., time to complete online questionnaires), and genetic (polygenic risk scores). Outcome was remission status post ICBT (cut-off <= 10 on MADRS-S). Data were split into train (60%) and validation (40%) given ICBT start date. Predictor selection employed human expertise followed by recursive feature elimination. Model derivation was internally validated through cross-validation. The final random forest model was externally validated against a (i) null, (ii) logit, (iii) XGBoost, and {iv) blended meta-ensemble model on the hold-out validation set. Feature selection retained 45 predictors representing all four predictor types. With unseen validation data, the final random forest model proved reasonably accurate at classifying post ICBT remission (Accuracy 0.656 [0.604, 0.705], P vs null model = 0.004; AUC 0.687 [0.631, 0.743]), slightly better vs logit (bootstrap D = 1.730, P = 0.084) but not vs XGBoost (D = 0.463, P = 0.643). Transparency analysis showed model usage of all predictor types at both the group and individual patient level. A new, multi-modal classifier for predicting MDD remission status after ICBT treatment in routine psychiatric care was derived and empirically validated. The multi-modal approach to predicting remission may inform tailored treatment, and deserves further investigation to attain clinical usefulness.
|
|
