| 1. |
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| 2. |
- Murari, A., et al.
(author)
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A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
- 2024
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In: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
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Journal article (peer-reviewed)abstract
- The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
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| 3. |
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| 7. |
- Blokland, G. A. M., et al.
(author)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Journal article (peer-reviewed)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 8. |
- Mullins, N., et al.
(author)
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Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology
- 2021
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53, s. 817-829
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Journal article (peer-reviewed)abstract
- Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies. Genome-wide association analyses of 41,917 bipolar disorder cases and 371,549 controls of European ancestry provide new insights into the etiology of this disorder and identify novel therapeutic leads and potential opportunities for drug repurposing.
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| 9. |
- Sliz, E., et al.
(author)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 10. |
- Stacchiotti, S., et al.
(author)
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Epithelioid hemangioendothelioma, an ultra-rare cancer : a consensus paper from the community of experts
- 2021
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In: ESMO Open. - : Elsevier BV. - 2059-7029. ; 6:3
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Research review (peer-reviewed)abstract
- Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
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| 11. |
- Jonsson, Lina, 1982, et al.
(author)
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Characterisation of age and polarity at onset in bipolar disorder
- 2021
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In: British Journal of Psychiatry. - : Royal College of Psychiatrists. - 0007-1250 .- 1472-1465. ; 219:6, s. 659-669
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Journal article (peer-reviewed)abstract
- Background Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. Aims To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. Method Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. Results Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (beta = -0.34 years, s.e. = 0.08), major depression (beta = -0.34 years, s.e. = 0.08), schizophrenia (beta = -0.39 years, s.e. = 0.08), and educational attainment (beta = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. Conclusions AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
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| 12. |
- Mullins, Niamh, et al.
(author)
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Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors
- 2022
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In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 91:3, s. 313-327
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Journal article (peer-reviewed)abstract
- BACKGROUND: Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.METHODS: We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.RESULTS: Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.CONCLUSIONS: Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.
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| 13. |
- Abdelhameed, A. H., et al.
(author)
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Cryogenic characterization of a LiAlO2 crystal and new results on spin-dependent dark matter interactions with ordinary matter: CRESST Collaboration
- 2020
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In: European Physical Journal C. - : Springer Science and Business Media LLC. - 1434-6044 .- 1434-6052. ; 80:9
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Journal article (peer-reviewed)abstract
- In this work, a first cryogenic characterization of a scintillating LiAlO2 single crystal is presented. The results achieved show that this material holds great potential as a target for direct dark matter search experiments. Three different detector modules obtained from one crystal grown at the Leibniz-Institut fur Kristallzuchtung (IKZ) have been tested to study different properties at cryogenic temperatures. Firstly, two 2.8 g twin crystals were used to build different detector modules which were operated in an above-ground laboratory at the Max Planck Institute for Physics (MPP) in Munich, Germany. The first detector module was used to study the scintillation properties of LiAlO2 at cryogenic temperatures. The second achieved an energy threshold of (213.02 +/- 1.48) eV which allows setting a competitive limit on the spin-dependent dark matter particle-proton scattering cross section for dark matter particle masses between 350 MeV/c2 and 1.50 GeV/c2. Secondly, a detector module with a 373 g LiAlO2 crystal as the main absorber was tested in an underground facility at the Laboratori Nazionali del Gran Sasso (LNGS): from this measurement it was possible to determine the radiopurity of the crystal and study the feasibility of using this material as a neutron flux monitor for low-background experiments.
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| 14. |
- Bertoldo, E., et al.
(author)
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Lithium-Containing Crystals for Light Dark Matter Search Experiments
- 2020
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In: Journal of Low Temperature Physics. - : Springer Science and Business Media LLC. - 0022-2291 .- 1573-7357. ; 199:1-2, s. 510-518
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Journal article (peer-reviewed)abstract
- In the current direct dark matter search landscape, the leading experiments in the sub-GeV mass region mostly rely on cryogenic techniques which employ crystalline targets. One attractive type of crystals for these experiments is those containing lithium, due to the fact that 7Li is an ideal candidate to study spin-dependent dark matter interactions in the low mass region. Furthermore, 6Li can absorb neutrons, a challenging background for dark matter experiments, through a distinctive signature which allows the monitoring of the neutron flux directly on site. In this work, we show the results obtained with three different detectors based on LiAlO 2, a target crystal never used before in cryogenic experiments.
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| 15. |
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| 16. |
- Davis, B, et al.
(author)
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Voices of chemical biology
- 2021
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In: Nature chemical biology. - : Springer Science and Business Media LLC. - 1552-4469 .- 1552-4450. ; 17:1, s. 1-4
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Journal article (peer-reviewed)
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| 17. |
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| 18. |
- Galluzzi, L, et al.
(author)
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Consensus guidelines for the definition, detection and interpretation of immunogenic cell death
- 2020
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In: Journal for immunotherapy of cancer. - : BMJ. - 2051-1426. ; 8:1
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Journal article (peer-reviewed)abstract
- Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation.
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| 19. |
- Kluck, H., et al.
(author)
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Latest results of CRESST-III's search for sub-GeV/c(2) dark matter
- 2020
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In: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6596 .- 1742-6588. ; 1468:1
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Conference paper (peer-reviewed)abstract
- The CRESST-III experiment searches for direct interactions of dark matter with ordinary matter. The main event signature would be a nuclear recoil inside one of the scintillating CaWO4 crystals. Operating the crystals as cryogenic calorimeters provides a phonon signal as measure of the deposited energy. The simultaneous readout of both signals is used to actively discriminate backgrounds. CRESST-III focuses on the sub-GeV/c(2) mass region where the sensitivity is driven by the threshold. In the first data taking campaign of CRESST-III from 2016-2018 an unprecedented low threshold of 30.1 eV for nuclear recoils was obtained. In this contribution, we will report the status of the experiment and the latest results. [GRAPHICS]
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| 20. |
- Mancuso, M., et al.
(author)
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Searches for Light Dark Matter with the CRESST-III Experiment
- 2020
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In: Journal of Low Temperature Physics. - : Springer Science and Business Media LLC. - 0022-2291 .- 1573-7357. ; 199:1-2, s. 547-555
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Journal article (peer-reviewed)abstract
- Cryogenic Rare Event Search with Superconducting Thermometers (CRESST) is a long-standing direct dark matter detection experiment with cryogenic detectors located at the underground facility Laboratori Nazionali del Gran Sasso in Italy. CRESST-III, the third generation of CRESST, was specifically designed to have a world-leading sensitivity for low-mass dark matter (DM) (less than 2 GeV/c 2) to probe the spin-independent DM-nucleus cross section. At present, a large part of the parameter space for spin-independent scattering off nuclei remains untested for dark matter particles with masses below few GeV/c 2 although many motivated theoretical models having been proposed. The CRESST-III experiment employs scintillating CaWO 4 crystals of ∼ 25 g as target material for dark matter interactions operated as cryogenic scintillating calorimeters at ∼ 10 mK. CRESST-III first data taking was successfully completed in 2018, achieving an unprecedented energy threshold for nuclear recoils. This result extended the present sensitivity to DM particles as light as ∼ 160 MeV/c 2. In this paper, an overview of the CRESST-III detectors and results will be presented.
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| 21. |
- Mishra, Umakant, et al.
(author)
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Spatial heterogeneity and environmental predictors of permafrost region soil organic carbon stocks
- 2021
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:9
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Journal article (peer-reviewed)abstract
- Large stocks of soil organic carbon (SOC) have accumulated in the Northern Hemisphere permafrost region, but their current amounts and future fate remain uncertain. By analyzing dataset combining >2700 soil profiles with environmental variables in a geospatial framework, we generated spatially explicit estimates of permafrost-region SOC stocks, quantified spatial heterogeneity, and identified key environmental predictors. We estimated that Pg C are stored in the top 3 m of permafrost region soils. The greatest uncertainties occurred in circumpolar toe-slope positions and in flat areas of the Tibetan region. We found that soil wetness index and elevation are the dominant topographic controllers and surface air temperature (circumpolar region) and precipitation (Tibetan region) are significant climatic controllers of SOC stocks. Our results provide first high-resolution geospatial assessment of permafrost region SOC stocks and their relationships with environmental factors, which are crucial for modeling the response of permafrost affected soils to changing climate.
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| 22. |
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| 23. |
- Shalom, Jonathan G, et al.
(author)
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Predicting sudden gains before treatment begins : An examination of pretreatment intraindividual variability in symptoms.
- 2020
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In: Journal of Consulting and Clinical Psychology. - : American Psychological Association (APA). - 0022-006X .- 1939-2117. ; 88:9, s. 809-817
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Journal article (peer-reviewed)abstract
- Objective: Sudden gains during psychotherapy have been found to be predictive of positive treatment outcomes. Previous attempts at predicting occurrence of sudden gains have yielded equivocal findings. Recently, intraindividual variability in symptoms during treatment was suggested as a trans-therapeutic and trans-diagnostic predictor of sudden gains. The goal of the present study was to examine this predictor in Internet-delivered treatment for social anxiety disorder (SAD) and to examine whether this predictor predicts sudden gains when measured before treatment begins. Method: We examined data from a preregistered randomized controlled trial (RCT) of Internet-delivered cognitive-behavioral therapy (CBT) for SAD (n = 101). We measured variability in symptoms both within-treatment and before treatment (i.e. during waitlist). Results: Intraindividual variability in symptoms significantly predicted sudden gains both when measured before treatment or within-treatment and correctly classified 84% and 83% of individuals to sudden gains versus non-sudden gains status, respectively. Conclusions: Intraindividual variability in symptoms can predict sudden gains in Internet-delivered treatment for SAD, thus supporting its trans-diagnostic and trans-therapeutic nature. Predicting sudden gains before treatment begins has implications for treatment planning and clinical decision making as well as for personalized tailoring of interventions. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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| 24. |
- Zalaznik, Dina, et al.
(author)
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Anxious Attachment Improves and Is Predicted by Anxiety Sensitivity in Internet-Based, Guided Self-Help Cognitive Behavioral Treatment for Panic Disorder
- 2022
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In: Journal of counseling psychology. - : AMER PSYCHOLOGICAL ASSOC. - 0022-0167 .- 1939-2168. ; 69:2, s. 211-221
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Journal article (peer-reviewed)abstract
- The purpose of this study was to examine whether anxious and avoidant attachment styles improve during guided internet-based cognitive behavioral treatment (ICBT) for panic disorder, and if so, to identify potential theoretically driven mechanisms related to the change. We examined changes in anxious and avoidant attachment and their time-lagged (1 week), longitudinal relationship with panic-related constructs in patients participating in ICBT (n = 79) in an open trial. Anxious attachment scores improved significantly with a medium effect during ICBT, d = 0.76 [0.45, 1.08]. According to benchmark analyses, changes were similar to the magnitude of change in face-to-face CBT and final scores to values of a nonclinical sample. Additionally, similar to findings in face-to-face CBT for panic disorder, longitudinal time analyses revealed that anxiety sensitivity scores predicted later improvement in anxious attachment scores, but not vice versa. Counter to our hypothesis, avoidant attachment did not significantly change during treatment, d = 0.15 [0.02, 0.46]; however, pretreatment level of avoidant attachment in ICBT was similar to the nonclinical sample. Also counter to our hypotheses, agoraphobic avoidant behaviors when alone did not predict changes in anxious attachment. These results suggest that anxious attachment can improve in ICBT for panic disorder even though the focus of the treatment is not on interpersonal relationships. These changes appear to follow changes in anxiety sensitivity. Public Significance Statement Results of this study suggest that anxious attachment improves following an internet-based intervention for panic disorder with minimal therapist contact (ICBT). This improvement appears to follow changes in anxiety sensitivity, or fear of ones bodily sensations, which are likely facilitated by self-driven techniques of cognitive restructuring and exposure. Thus, interpersonal factors can improve in psychotherapeutic interventions even when the involvement of the therapist is limited and the focus is on cognitive and behavioral change.
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| 25. |
- Bader, J. M., et al.
(author)
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Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease
- 2020
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In: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 16:6
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Journal article (peer-reviewed)abstract
- Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higherCSFlevels of tau, but we lack knowledge of systems-wide changes ofCSFprotein levels that accompanyAD. Here, we present a highly reproducible mass spectrometry (MS)-based proteomics workflow for the in-depth analysis ofCSFfrom minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins byADstatus (> 1,000 proteins,CV < 20%). Proteins with previous links to neurodegeneration such as tau,SOD1, andPARK7 differed most strongly byADstatus, providing strong positive controls for our approach.CSFproteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature.
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| 26. |
- Bianco, Federica B., et al.
(author)
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Optimization of the Observing Cadence for the Rubin Observatory Legacy Survey of Space and Time : A Pioneering Process of Community-focused Experimental Design
- 2022
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In: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 258:1
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Journal article (peer-reviewed)abstract
- Vera C. Rubin Observatory is a ground-based astronomical facility under construction, a joint project of the National Science Foundation and the U.S. Department of Energy, designed to conduct a multipurpose 10 yr optical survey of the Southern Hemisphere sky: the Legacy Survey of Space and Time. Significant flexibility in survey strategy remains within the constraints imposed by the core science goals of probing dark energy and dark matter, cataloging the solar system, exploring the transient optical sky, and mapping the Milky Way. The survey's massive data throughput will be transformational for many other astrophysics domains and Rubin's data access policy sets the stage for a huge community of potential users. To ensure that the survey science potential is maximized while serving as broad a community as possible, Rubin Observatory has involved the scientific community at large in the process of setting and refining the details of the observing strategy. The motivation, history, and decision-making process of this strategy optimization are detailed in this paper, giving context to the science-driven proposals and recommendations for the survey strategy included in this Focus Issue.
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| 27. |
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| 28. |
- Dominguez-Valentin, M, et al.
(author)
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Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database
- 2020
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In: Journal of clinical medicine. - : MDPI AG. - 2077-0383. ; 9:7
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Journal article (peer-reviewed)abstract
- Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35–55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.
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| 29. |
- Halaj, Asala, et al.
(author)
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Clinical and cognitive insight in panic disorder: phenomenology and treatment effects in internet cognitive behavior therapy
- 2024
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In: Journal of Psychiatric Research. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0022-3956 .- 1879-1379. ; 172, s. 164-170
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Journal article (peer-reviewed)abstract
- Clinical observations suggest that individuals with panic disorder (PD) vary in their beliefs about the causes of their panic attacks. Some attribute these attacks to psychological factors, while others to physiological or medical factors. These beliefs also extend to whether individuals perceive panic attacks as dangerous. In other areas of psychiatric nosology, these phenomena are commonly called clinical insight (recognition of disorder and the need for treatment) and cognitive insight (the ability to reflect on one's beliefs). Despite its importance, limited research exists on insight in PD and its relation to symptoms and treatment outcomes. This study examines clinical and cognitive insight in 83 patients with PD who received internet-based cognitive behavioral therapy, investigating their relationship with symptoms, treatment outcomes, and changes in insight. We assessed patients using interview and self-report measures of insight and symptoms. Clinical and cognitive insight were correlated and both constructs improved significantly during treatment. Good clinical insight pretreatment was positively correlated with more severe pretreatment symptoms. Pretreatment clinical and cognitive insight were not correlated with symptom change or attrition. Greater change in clinical and cognitive insight was related to greater change in symptoms. The findings highlight the significance of clinical and cognitive insight in PD, and the importance of distinguishing between them. This suggests the need to develop interventions according to patients' level of insight, particularly focusing on those lacking insight. Further research is essential to advance our understanding of the relationship between insight and the phenomenology and treatment of PD.
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| 30. |
- Halaj, Asala, et al.
(author)
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Examining the relationship between cognitive factors and insight in panic disorder before and during treatment
- 2023
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In: Cognitive Behaviour Therapy. - : ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD. - 1650-6073 .- 1651-2316. ; 52:4, s. 331-346
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Journal article (peer-reviewed)abstract
- Individuals with Panic Disorder (PD) often have impaired insight, which can impede their willingness to seek treatment. Cognitive processes, including metacognitive beliefs, cognitive flexibility, and jumping to conclusions (JTC) may influence the degree of insight. By understanding the relationship between insight and these cognitive factors in PD, we can better identify individuals with such vulnerabilities to improve their insight. The aim of this study is to examine the relationships between metacognition, cognitive flexibility, and JTC with clinical and cognitive insight at pretreatment. We investigate the association among those factors changes and changes in insight over treatment. Eighty-three patients diagnosed with PD received internet-based cognitive behavior therapy. Analyses revealed that metacognition was related to both clinical and cognitive insight, and cognitive flexibility was related to clinical insight at pre-treatment. Greater changes in metacognition were correlated with greater changes in clinical insight. Also, greater changes in cognitive flexibility were related to greater changes in cognitive insight. The current study extends previous studies suggesting potential relationships among insight, metacognition, and cognitive flexibility in PD. Determining the role of cognitive concepts in relation to insight may lead to new avenues for improving insight and can have implications for engagement and treatment-seeking behaviors.
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| 31. |
- Mairinoja, L., et al.
(author)
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Deep Learning-Based Image Analysis of Liver Steatosis in Mouse Models
- 2023
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In: American Journal of Pathology. - 0002-9440. ; 193:8, s. 1072-1080
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Journal article (peer-reviewed)abstract
- The incidence of nonalcoholic fatty liver disease is a continuously growing health problem worldwide, along with obesity. Therefore, novel methods to both efficiently study the manifestation of nonalco-holic fatty liver disease and to analyze drug efficacy in preclinical models are needed. The present study developed a deep neural network-based model to quantify microvesicular and macrovesicular steatosis in the liver on hematoxylin-eosin-stained whole slide images, using the cloud-based platform, Aiforia Create. The training data included a total of 101 whole slide images from dietary interventions of wild-type mice and from two genetically modified mouse models with steatosis. The algorithm was trained for the following: to detect liver parenchyma, to exclude the blood vessels and any artefacts generated during tissue processing and image acquisition, to recognize and differentiate the areas of micro-vesicular and macrovesicular steatosis, and to quantify the recognized tissue area. The results of the image analysis replicated well the evaluation by expert pathologists and correlated well with the liver fat content measured by EchoMRI ex vivo, and the correlation with total liver triglycerides was notable. In conclusion, the developed deep learning-based model is a novel tool for studying liver steatosis in mouse models on paraffin sections and, thus, can facilitate reliable quantification of the amount of steatosis in large preclinical study cohorts. (Am J Pathol 2023, 193: 1072-1080; https://doi.org/ 10.1016/j.ajpath.2023.04.014)
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| 32. |
- Mehta, N. H., et al.
(author)
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The Brain-Nose Interface: A Potential Cerebrospinal Fluid Clearance Site in Humans
- 2022
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In: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 12
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Journal article (peer-reviewed)abstract
- The human brain functions at the center of a network of systems aimed at providing a structural and immunological layer of protection. The cerebrospinal fluid (CSF) maintains a physiological homeostasis that is of paramount importance to proper neurological activity. CSF is largely produced in the choroid plexus where it is continuous with the brain extracellular fluid and circulates through the ventricles. CSF movement through the central nervous system has been extensively explored. Across numerous animal species, the involvement of various drainage pathways in CSF, including arachnoid granulations, cranial nerves, perivascular pathways, and meningeal lymphatics, has been studied. Among these, there is a proposed CSF clearance route spanning the olfactory nerve and exiting the brain at the cribriform plate and entering lymphatics. While this pathway has been demonstrated in multiple animal species, evidence of a similar CSF egress mechanism involving the nasal cavity in humans remains poorly consolidated. This review will synthesize contemporary evidence surrounding CSF clearance at the nose-brain interface, examining across species this anatomical pathway, and its possible significance to human neurodegenerative disease. Our discussion of a bidirectional nasal pathway includes examination of the immune surveillance in the olfactory region protecting the brain. Overall, we expect that an expanded discussion of the brain-nose pathway and interactions with the environment will contribute to an improved understanding of neurodegenerative and infectious diseases, and potentially to novel prevention and treatment considerations. Copyright © 2022 Mehta, Sherbansky, Kamer, Carare, Butler, Rusinek, Chiang, Li, Strauss, Saint-Louis, Theise, Suss, Blennow, Kaplitt and de Leon.
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| 33. |
- Obara, EAA, et al.
(author)
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SPT6-driven error-free DNA repair safeguards genomic stability of glioblastoma cancer stem-like cells
- 2020
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 4709-
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Journal article (peer-reviewed)abstract
- Glioblastoma cancer-stem like cells (GSCs) display marked resistance to ionizing radiation (IR), a standard of care for glioblastoma patients. Mechanisms underpinning radio-resistance of GSCs remain largely unknown. Chromatin state and the accessibility of DNA lesions to DNA repair machineries are crucial for the maintenance of genomic stability. Understanding the functional impact of chromatin remodeling on DNA repair in GSCs may lay the foundation for advancing the efficacy of radio-sensitizing therapies. Here, we present the results of a high-content siRNA microscopy screen, revealing the transcriptional elongation factor SPT6 to be critical for the genomic stability and self-renewal of GSCs. Mechanistically, SPT6 transcriptionally up-regulates BRCA1 and thereby drives an error-free DNA repair in GSCs. SPT6 loss impairs the self-renewal, genomic stability and tumor initiating capacity of GSCs. Collectively, our results provide mechanistic insights into how SPT6 regulates DNA repair and identify SPT6 as a putative therapeutic target in glioblastoma.
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| 34. |
- Petropoulos, Fotios, et al.
(author)
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Operational Research : methods and applications
- 2024
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In: Journal of the Operational Research Society. - : Taylor & Francis Group. - 0160-5682 .- 1476-9360. ; 75:3, s. 423-617
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Research review (peer-reviewed)abstract
- Throughout its history, Operational Research has evolved to include methods, models and algorithms that have been applied to a wide range of contexts. This encyclopedic article consists of two main sections: methods and applications. The first summarises the up-to-date knowledge and provides an overview of the state-of-the-art methods and key developments in the various subdomains of the field. The second offers a wide-ranging list of areas where Operational Research has been applied. The article is meant to be read in a nonlinear fashion and used as a point of reference by a diverse pool of readers: academics, researchers, students, and practitioners. The entries within the methods and applications sections are presented in alphabetical order. The authors dedicate this paper to the 2023 Turkey/Syria earthquake victims. We sincerely hope that advances in OR will play a role towards minimising the pain and suffering caused by this and future catastrophes.
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| 35. |
- Shalom, Jonathan G., et al.
(author)
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Mediation of social anxiety and depression during internet-delivered treatment for social anxiety disorder
- 2024
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In: Cognitive Behaviour Therapy. - : ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD. - 1650-6073 .- 1651-2316.
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Journal article (peer-reviewed)abstract
- Many individuals with social anxiety disorder (SAD) have depressive symptoms that meet criteria for major depressive disorder (MDD). In our study, we examined the temporal relationship between symptoms of social anxiety and symptoms of depression during the course of an 11-week internet-delivered cognitive behavioral treatment (ICBT) for SAD (n = 170). Specifically, we investigated whether weekly changes in social anxiety mediated changes in depression, changes in depression mediated changes in anxiety, both or neither. In addition, we compared individuals with SAD and MDD (n = 50) and individuals with SAD and no MDD (n = 120) to examine the role of MDD as a moderator of the social anxiety-depression relationship. Lower-level mediational modeling revealed that changes in social anxiety symptoms mediated changes in depression symptoms to a greater extent than vice versa. In addition, mediation among individuals with SAD and MDD was significantly greater compared to individuals with SAD and no MDD. Our findings suggest that ICBT is effective in treating individuals with SAD regardless of comorbid depression, and that focusing ICBT interventions on social anxiety can lead to significant reductions in depression among individuals with SAD.
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| 36. |
- Strauss-Riggs, Kandra, et al.
(author)
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Recommended Process Outcome Measures for Stop the Bleed Education Programs
- 2021
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In: AEM Education and Training. - : John Wiley and Sons Inc.. - 2472-5390. ; 5:1, s. 139-142
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Journal article (peer-reviewed)abstract
- Trauma is a critical public health issue as the lead-ing cause of death for Americans between theages of 1 and 44 years.1In response to this reality, anumber of Stop the Bleed educa tion programs arebeing implemented to teach the lay public how to stopexsanguinating hemorrhage in preventable deaths.2Todate, there are limited data available to compare effec-tiveness of these programs. Because there is limitedcapacity to track outcome measures at this time,authors offer direction to practitioners on 12 processmeasures that will best allow comparisons among pro-grams to make informed decisions when implement-ing Stop the Bleed education
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| 37. |
- Swain, S., et al.
(author)
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Clustering of comorbidities and associated outcomes in people with osteoarthritis - A UK Clinical Practice Research Datalink study
- 2022
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In: Osteoarthritis and Cartilage. - : Elsevier BV. - 1063-4584. ; 30:5, s. 702-713
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Journal article (peer-reviewed)abstract
- Objective: To examine the clusters of chronic conditions present in people with osteoarthritis and the associated risk factors and health outcomes. Methods: Clinical Practice Research Datalink (CPRD) GOLD was used to identify people diagnosed with incident osteoarthritis (n = 221,807) between 1997 and 2017 and age (±2 years), gender, and practice matched controls (no osteoarthritis, n = 221,807) from UK primary care. Clustering of people was examined for 49 conditions using latent class analysis. The associations between cluster membership and covariates were quantified by odds ratios (OR) using multinomial logistic regression. General practice (GP) consultations, hospitalisations, and all-cause mortality rates were compared across the clusters identified at the time of first diagnosis of osteoarthritis (index date). Results: In both groups, conditions largely grouped around five clusters: relatively healthy; cardiovascular (CV), musculoskeletal-mental health (MSK-MH), CV-musculoskeletal (CV-MSK) and metabolic (MB). In the osteoarthritis group, compared to the relatively healthy cluster, strong associations were seen for 1) age with all clusters; 2) women with the MB cluster (OR 5.55: 5.14–5.99); 3) obesity with the CV-MSK (OR 2.11: 2.03–2.20) and CV clusters (OR 2.03: 1.97–2.09). The CV-MSK cluster in the osteoarthritis group had the highest number of GP consultations and hospitalisations, and the mortality risk was 2.45 (2.33–2.58) times higher compared to the relatively healthy cluster. Conclusions: Of the five identified clusters, CV-MSK, CV, and MSK-MH are more common in OA and CV-MSK cluster had higher health utilisation. Further research is warranted to better understand the mechanistic pathways and clinical implications.
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| 38. |
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| 39. |
- Treat, Claire C., et al.
(author)
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Permafrost Carbon : Progress on Understanding Stocks and Fluxes Across Northern Terrestrial Ecosystems
- 2024
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In: Journal of Geophysical Research - Biogeosciences. - : American Geophysical Union (AGU). - 2169-8953 .- 2169-8961. ; 129:3
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Journal article (peer-reviewed)abstract
- Significant progress in permafrost carbon science made over the past decades include the identification of vast permafrost carbon stocks, the development of new pan-Arctic permafrost maps, an increase in terrestrial measurement sites for CO2 and methane fluxes, and important factors affecting carbon cycling, including vegetation changes, periods of soil freezing and thawing, wildfire, and other disturbance events. Process-based modeling studies now include key elements of permafrost carbon cycling and advances in statistical modeling and inverse modeling enhance understanding of permafrost region C budgets. By combining existing data syntheses and model outputs, the permafrost region is likely a wetland methane source and small terrestrial ecosystem CO2 sink with lower net CO2 uptake toward higher latitudes, excluding wildfire emissions. For 2002–2014, the strongest CO2 sink was located in western Canada (median: −52 g C m−2 y−1) and smallest sinks in Alaska, Canadian tundra, and Siberian tundra (medians: −5 to −9 g C m−2 y−1). Eurasian regions had the largest median wetland methane fluxes (16–18 g CH4 m−2 y−1). Quantifying the regional scale carbon balance remains challenging because of high spatial and temporal variability and relatively low density of observations. More accurate permafrost region carbon fluxes require: (a) the development of better maps characterizing wetlands and dynamics of vegetation and disturbances, including abrupt permafrost thaw; (b) the establishment of new year-round CO2 and methane flux sites in underrepresented areas; and (c) improved models that better represent important permafrost carbon cycle dynamics, including non-growing season emissions and disturbance effects.
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| 40. |
- Zalaznik, Dina, et al.
(author)
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Patient alliance with the program predicts treatment outcomes whereas alliance with the therapist predicts adherence in internet-based therapy for panic disorder
- 2021
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In: Psychotherapy Research. - : Routledge. - 1050-3307 .- 1468-4381. ; 31:8, s. 1022-1035
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Journal article (peer-reviewed)abstract
- Objective This study examines relationships among different aspects of therapeutic alliance with treatment outcome, adherence and attrition in internet delivered cognitive behavioral therapy (ICBT) for panic disorder. Methods: We examined alliance-outcome relationships in ICBT (N = 74) using a newly developed self-report alliance measure that disentangles alliance with program content (Internet Patients Experience of Attunement and Responsiveness with the program; I-PEARp) and with the therapist (I-PEARt). We compared ICBT outcomes of patient rated and therapist-rated alliance with conventional alliance scales (WAI-6 and WAI-T). Results: Consistent with our hypothesis, I-PEARp and I-PEARt distinguished between different aspects of the alliance and predicted outcomes better than standard alliance scales. Furthermore, higher ratings of I-PEARp were associated with subsequent lower symptoms and lower symptoms were associated with higher subsequent alliance. In contrast, I-PEARt predicted adherence, but not symptoms. Although therapists ratings of alliance (thI-PEAR) improved significantly during treatment, they did not predict subsequent symptoms, adherence, or dropout. Conclusion: Results indicate that the patient experience of the alliance in ICBT includes two aspects, each of which uniquely contributes to outcomes; patient connection to the program is related to symptom outcomes whereas the dyadic relationship with the therapist serves as the glue to allow the treatment to hold.
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| 41. |
- Zimmer, Christine L., et al.
(author)
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A biliary immune landscape map of primary sclerosing cholangitis reveals a dominant network of neutrophils and tissue-resident T cells
- 2021
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In: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:599
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Journal article (peer-reviewed)abstract
- The human biliary system, a mucosal barrier tissue connecting the liver and intestine, is an organ often affected by serious inflammatory and malignant diseases. Although these diseases are linked to immunological processes, the biliary system represents an unexplored immunological niche. By combining endoscopy-guided sampling of the biliary tree with a high-dimensional analysis approach, comprehensive mapping of the human biliary immunological landscape in patients with primary sclerosing cholangitis (PSC), a severe biliary inflammatory disease, was conducted. Major differences in immune cell composition in bile ducts compared to blood were revealed. Furthermore, biliary inflammation in patients with PSC was characterized by high presence of neutrophils and T cells as compared to control individuals without PSC. The biliary T cells displayed a CD103(+)CD69(+) effector memory phenotype, a combined gut and liver homing profile, and produced interleukin-17 (IL-17) and IL-22. Biliary neutrophil infiltration in PSC associated with CXCL8, possibly produced by resident T cells, and CXCL16 was linked to the enrichment of T cells. This study uncovers the immunological niche of human bile ducts, defines a local immune network between neutrophils and biliary-resident T cells in PSC, and provides a resource for future studies of the immune responses in biliary disorders.
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| 42. |
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