| 1. |
- Campbell, PJ, et al.
(författare)
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Pan-cancer analysis of whole genomes
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 578:7793, s. 82-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1–3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10–18.
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| 2. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 3. |
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| 4. |
- Gao, YX, et al.
(författare)
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Mendelian randomization implies no direct causal association between leukocyte telomere length and amyotrophic lateral sclerosis
- 2020
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1, s. 12184-
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Tidskriftsartikel (refereegranskat)abstract
- We employed Mendelian randomization (MR) to evaluate the causal relationship between leukocyte telomere length (LTL) and amyotrophic lateral sclerosis (ALS) with summary statistics from genome-wide association studies (n = ~ 38,000 for LTL and ~ 81,000 for ALS in the European population; n = ~ 23,000 for LTL and ~ 4,100 for ALS in the Asian population). We further evaluated mediation roles of lipids in the pathway from LTL to ALS. The odds ratio per standard deviation decrease of LTL on ALS was 1.10 (95% CI 0.93–1.31, p = 0.274) in the European population and 0.75 (95% CI 0.53–1.07, p = 0.116) in the Asian population. This null association was also detected between LTL and frontotemporal dementia in the European population. However, we found that an indirect effect of LTL on ALS might be mediated by low density lipoprotein (LDL) or total cholesterol (TC) in the European population. These results were robust against extensive sensitivity analyses. Overall, our MR study did not support the direct causal association between LTL and the ALS risk in neither population, but provided suggestive evidence for the mediation role of LDL or TC on the influence of LTL and ALS in the European population.
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| 5. |
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| 6. |
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| 7. |
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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Yakneen, S, et al.
(författare)
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Butler enables rapid cloud-based analysis of thousands of human genomes
- 2020
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Ingår i: Nature biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 38:3, s. 288-
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Tidskriftsartikel (refereegranskat)abstract
- We present Butler, a computational tool that facilitates large-scale genomic analyses on public and academic clouds. Butler includes innovative anomaly detection and self-healing functions that improve the efficiency of data processing and analysis by 43% compared with current approaches. Butler enabled processing of a 725-terabyte cancer genome dataset from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project in a time-efficient and uniform manner.
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| 12. |
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| 13. |
- Sadaghiani, Shokufeh, et al.
(författare)
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Associations of phosphorylated tau pathology with whole-hemisphere ex vivo morphometry in 7 tesla MRI
- 2023
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:6, s. 2355-2364
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Neurodegenerative disorders are associated with different pathologies that often co-occur but cannot be measured specifically with in vivo methods. Methods: Thirty-three brain hemispheres from donors with an Alzheimer's disease (AD) spectrum diagnosis underwent T2-weighted magnetic resonance imaging (MRI). Gray matter thickness was paired with histopathology from the closest anatomic region in the contralateral hemisphere. Results: Partial Spearman correlation of phosphorylated tau and cortical thickness with TAR DNA-binding protein 43 (TDP-43) and α-synuclein scores, age, sex, and postmortem interval as covariates showed significant relationships in entorhinal and primary visual cortices, temporal pole, and insular and posterior cingulate gyri. Linear models including Braak stages, TDP-43 and α-synuclein scores, age, sex, and postmortem interval showed significant correlation between Braak stage and thickness in the parahippocampal gyrus, entorhinal cortex, and Broadman area 35. Conclusion: We demonstrated an association of measures of AD pathology with tissue loss in several AD regions despite a limited range of pathology in these cases. Highlights: Neurodegenerative disorders are associated with co-occurring pathologies that cannot be measured specifically with in vivo methods. Identification of the topographic patterns of these pathologies in structural magnetic resonance imaging (MRI) may provide probabilistic biomarkers. We demonstrated the correlation of the specific patterns of tissue loss from ex vivo brain MRI with underlying pathologies detected in postmortem brain hemispheres in patients with Alzheimer's disease (AD) spectrum disorders. The results provide insight into the interpretation of in vivo structural MRI studies in patients with AD spectrum disorders.
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| 14. |
- Acerbo, E, et al.
(författare)
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Focal non-invasive deep-brain stimulation with temporal interference for the suppression of epileptic biomarkers
- 2022
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Ingår i: Frontiers in neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 16, s. 945221-
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Tidskriftsartikel (refereegranskat)abstract
- Neurostimulation applied from deep brain stimulation (DBS) electrodes is an effective therapeutic intervention in patients suffering from intractable drug-resistant epilepsy when resective surgery is contraindicated or failed. Inhibitory DBS to suppress seizures and associated epileptogenic biomarkers could be performed with high-frequency stimulation (HFS), typically between 100 and 165 Hz, to various deep-seated targets, such as the Mesio-temporal lobe (MTL), which leads to changes in brain rhythms, specifically in the hippocampus. The most prominent alterations concern high-frequency oscillations (HFOs), namely an increase in ripples, a reduction in pathological Fast Ripples (FRs), and a decrease in pathological interictal epileptiform discharges (IEDs).Materials and methodsIn the current study, we use Temporal Interference (TI) stimulation to provide a non-invasive DBS (130 Hz) of the MTL, specifically the hippocampus, in both mouse models of epilepsy, and scale the method using human cadavers to demonstrate the potential efficacy in human patients. Simulations for both mice and human heads were performed to calculate the best coordinates to reach the hippocampus.ResultsThis non-invasive DBS increases physiological ripples, and decreases the number of FRs and IEDs in a mouse model of epilepsy. Similarly, we show the inability of 130 Hz transcranial current stimulation (TCS) to achieve similar results. We therefore further demonstrate the translatability to human subjects via measurements of the TI stimulation vs. TCS in human cadavers. Results show a better penetration of TI fields into the human hippocampus as compared with TCS.SignificanceThese results constitute the first proof of the feasibility and efficiency of TI to stimulate at depth an area without impacting the surrounding tissue. The data tend to show the sufficiently focal character of the induced effects and suggest promising therapeutic applications in epilepsy.
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| 15. |
- Gousias, K, et al.
(författare)
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Expertise in surgical neuro-oncology. Results of a survey by the EANS neuro-oncology section.
- 2024
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Ingår i: Brain & spine. - 2772-5294. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Technical advances and the increasing role of interdisciplinary decision-making may warrant formal definitions of expertise in surgical neuro-oncology.The EANS Neuro-oncology Section felt that a survey detailing the European neurosurgical perspective on the concept of expertise in surgical neuro-oncology might be helpful.The EANS Neuro-oncology Section panel developed an online survey asking questions regarding criteria for expertise in neuro-oncological surgery and sent it to all individual EANS members.Our questionnaire was completed by 251 respondents (consultants: 80.1%) from 42 countries. 67.7% would accept a lifetime caseload of >200 cases and 86.7% an annual caseload of >50 as evidence of neuro-oncological surgical expertise. A majority felt that surgeons who do not treat children (56.2%), do not have experience with spinal fusion (78.1%) or peripheral nerve tumors (71.7%) may still be considered experts. Majorities believed that expertise requires the use of skull-base approaches (85.8%), intraoperative monitoring (83.4%), awake craniotomies (77.3%), and neuro-endoscopy (75.5%) as well as continuing education of at least 1/year (100.0%), a research background (80.0%) and teaching activities (78.7%), and formal interdisciplinary collaborations (e.g., tumor board: 93.0%). Academic vs. non-academic affiliation, career position, years of neurosurgical experience, country of practice, and primary clinical interest had a minor influence on the respondents' opinions.Opinions among neurosurgeons regarding the characteristics and features of expertise in neuro-oncology vary surprisingly little. Large majorities favoring certain thresholds and qualitative criteria suggest a consensus definition might be possible.
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| 16. |
- Grossman, M., et al.
(författare)
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Frontotemporal lobar degeneration
- 2023
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Ingår i: Nature Reviews Disease Primers. - 2056-676X. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) is one of the most common causes of early-onset dementia and presents with early social-emotional-behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20-25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau (FTLD-tau) or TDP-43 (FTLD-TDP), although 5-10% of patients may have inclusions containing proteins from the FUS-Ewing sarcoma-TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise. Frontotemporal lobar degeneration is one of the most common causes of early-onset dementia. This Primer summarizes the epidemiology, pathophysiology, diagnosis, and treatment of frontotemporal dementia and discusses how this disorder affects patients' quality of life.
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| 17. |
- Hernández-Durán, S., et al.
(författare)
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European women in neurosurgery: I – A chronology of trailblazers
- 2021
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Ingår i: Journal of Clinical Neuroscience. - : Elsevier BV. - 0967-5868. ; 86, s. 316-323
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Tidskriftsartikel (refereegranskat)abstract
- Neurosurgery as a distinct speciality has been around for 100 years. Some of the earliest women neurosurgeons were European, emerging from the 1920′s onwards. Here we detail the rise of women in neurosurgery across Europe with a decade by decade account of big events and firsts across the continent. The emerging themes are seen in stories of pioneers with enormous resilience, camaraderie, trailblazing and triumphing in a system with great obstacles and challenges. Our journey through this chronology brings us to the modern day, where most European countries have or have had a woman neurosurgeon and the future for women in neurosurgery in the continent is very bright. © 2021
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| 18. |
- Murphy, M., et al.
(författare)
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European women in neurosurgery: II – Historical characters and living legends
- 2021
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Ingår i: Journal of Clinical Neuroscience. - : Elsevier BV. - 0967-5868. ; 86, s. 324-331
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Tidskriftsartikel (refereegranskat)abstract
- A collaborative global working group of women neurosurgeons in multiple countries at different stages of their neurosurgical careers undertook the task of researching the history of European women in neurosurgery. While doing so, we happened upon many remarkable female neurosurgeons who overcame great adversity, made tremendous contributions to society and institutional neurosurgery, and displayed numerous talents beyond the operating room. In the first part of this paper, we recounted a chronology of female neurosurgeons in Europe, highlighting the most remarkable achievements of women in every decade, from the 1920’s to 2020. In this paper, we honor fascinating women in European neurosurgery, both historical characters and living legends. These women have overcome great adversity and have also excelled in a huge variety of pursuits. While some were themselves refugees, we also have uncovered noteworthy examples of women who immersed themselves in humanitarian missions and who tried to better the world through political action. There are stories of women beating the odds, taking on biased institutions and proving their worth, in spite of the prevailing system. Most inspirational, we have discovered through our comprehensive research on the history of women in European neurosurgery that the future is increasingly female. © 2021 Elsevier Ltd
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| 19. |
- Nitschke, S., et al.
(författare)
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Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:7, s. 2361-2377
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Tidskriftsartikel (refereegranskat)abstract
- Longer glucan chains tend to precipitate. Glycogen, by far the largest mammalian glucan and the largest molecule in the cytosol with up to 55 000 glucoses, does not, due to a highly regularly branched spherical structure that allows it to be perfused with cytosol. Aberrant construction of glycogen leads it to precipitate, accumulate into polyglucosan bodies that resemble plant starch amylopectin and cause disease. This pathology, amylopectinosis, is caused by mutations in a series of single genes whose functions are under active study toward understanding the mechanisms of proper glycogen construction. Concurrently, we are characterizing the physicochemical particularities of glycogen and polyglucosans associated with each gene. These genes include GBE1, EPM2A and EPM2B, which respectively encode the glycogen branching enzyme, the glycogen phosphatase laforin and the laforin-interacting E3 ubiquitin ligase malin, for which an unequivocal function is not yet known. Mutations in GBE1 cause a motor neuron disease (adult polyglucosan body disease), and mutations in EPM2A or EPM2B a fatal progressive myoclonus epilepsy (Lafora disease). RBCK1 deficiency causes an amylopectinosis with fatal skeletal and cardiac myopathy (polyglucosan body myopathy 1, OMIM# 615895). RBCK1 is a component of the linear ubiquitin chain assembly complex, with unique functions including generating linear ubiquitin chains and ubiquitinating hydroxyl (versus canonical amine) residues, including of glycogen. In a mouse model we now show (i) that the amylopectinosis of RBCK1 deficiency, like in adult polyglucosan body disease and Lafora disease, affects the brain; (ii) that RBCK1 deficiency glycogen, like in adult polyglucosan body disease and Lafora disease, has overlong branches; (iii) that unlike adult polyglucosan body disease but like Lafora disease, RBCK1 deficiency glycogen is hyperphosphorylated; and finally (iv) that unlike laforin-deficient Lafora disease but like malin-deficient Lafora disease, RBCK1 deficiency's glycogen hyperphosphorylation is limited to precipitated polyglucosans. In summary, the fundamental glycogen pathology of RBCK1 deficiency recapitulates that of malin-deficient Lafora disease. Additionally, we uncover sex and genetic background effects in RBCK1 deficiency on organ-and brain-region specific amylopectinoses, and in the brain on consequent neuroinflammation and behavioural deficits. Finally, we exploit the portion of the basic glycogen pathology that is common to adult polyglucosan body disease, both forms of Lafora disease and RBCK1 deficiency, namely overlong branches, to show that a unified approach based on downregulating glycogen synthase, the enzyme that elongates glycogen branches, can rescue all four diseases.
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| 20. |
- Ravikumar, Sadhana, et al.
(författare)
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Ex vivo MRI atlas of the human medial temporal lobe : characterizing neurodegeneration due to tau pathology
- 2021
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.
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| 21. |
- Ravikumar, Sadhana, et al.
(författare)
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Improved Segmentation of Deep Sulci in Cortical Gray Matter Using a Deep Learning Framework Incorporating Laplace’s Equation
- 2023
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Ingår i: Information Processing in Medical Imaging - 28th International Conference, IPMI 2023, Proceedings. - 1611-3349 .- 0302-9743. - 9783031340475 ; 13939 LNCS, s. 692-704
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Konferensbidrag (refereegranskat)abstract
- When developing tools for automated cortical segmentation, the ability to produce topologically correct segmentations is important in order to compute geometrically valid morphometry measures. In practice, accurate cortical segmentation is challenged by image artifacts and the highly convoluted anatomy of the cortex itself. To address this, we propose a novel deep learning-based cortical segmentation method in which prior knowledge about the geometry of the cortex is incorporated into the network during the training process. We design a loss function which uses the theory of Laplace’s equation applied to the cortex to locally penalize unresolved boundaries between tightly folded sulci. Using an ex vivo MRI dataset of human medial temporal lobe specimens, we demonstrate that our approach outperforms baseline segmentation networks, both quantitatively and qualitatively.
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| 22. |
- Wisse, Laura E.M., et al.
(författare)
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Cross-sectional and longitudinal medial temporal lobe subregional atrophy patterns in semantic variant primary progressive aphasia
- 2021
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 98, s. 231-241
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Tidskriftsartikel (refereegranskat)abstract
- T1-magnetic resonance imaging (MRI) studies report early atrophy in the left anterior temporal lobe, especially the perirhinal cortex, in semantic variant primary progressive aphasia (svPPA). Improved segmentation protocols using high-resolution T2-MRI have enabled fine-grained medial temporal lobe (MTL) subregional measurements, which may provide novel information on the atrophy pattern and disease progression in svPPA. We aimed to investigate the MTL subregional atrophy pattern cross-sectionally and longitudinally in patients with svPPA as compared with controls and patients with Alzheimer's disease (AD). MTL subregional volumes were obtained using the Automated Segmentation for Hippocampal Subfields software from high-resolution T2-MRIs in 15 svPPA, 37 AD, and 23 healthy controls. All MTL volumes were corrected for intracranial volume and parahippocampal cortices for slice number. Longitudinal atrophy rates of all subregions were obtained using an unbiased deformation-based morphometry pipeline in 6 svPPA patients, 9 controls, and 12 AD patients. Cross-sectionally, significant volume loss was observed in svPPA compared with controls in the left MTL, right cornu ammonis 1 (CA1), Brodmann area (BA)35, and BA36 (subdivisions of the perirhinal cortex). Compared with AD patients, svPPA patients had significantly smaller left CA1, BA35, and left and right BA36 volumes. Longitudinally, svPPA patients had significantly greater atrophy rates of left and right BA36 than controls but not relative to AD patients. Fine-grained analysis of MTL atrophy patterns provides information about the evolution of atrophy in svPPA. These results indicate that MTL subregional measures might be useful markers to track disease progression or for clinical trials in svPPA.
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| 23. |
- Wisse, L. E.M., et al.
(författare)
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Downstream effects of polypathology on neurodegeneration of medial temporal lobe subregions
- 2021
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The medial temporal lobe (MTL) is a nidus for neurodegenerative pathologies and therefore an important region in which to study polypathology. We investigated associations between neurodegenerative pathologies and the thickness of different MTL subregions measured using high-resolution post-mortem MRI. Tau, TAR DNA-binding protein 43 (TDP-43), amyloid-β and α-synuclein pathology were rated on a scale of 0 (absent)—3 (severe) in the hippocampus and entorhinal cortex (ERC) of 58 individuals with and without neurodegenerative diseases (median age 75.0 years, 60.3% male). Thickness measurements in ERC, Brodmann Area (BA) 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare (SRLM) were derived from 0.2 × 0.2 × 0.2 mm3 post-mortem MRI scans of excised MTL specimens from the contralateral hemisphere using a semi-automated approach. Spearman’s rank correlations were performed between neurodegenerative pathologies and thickness, correcting for age, sex and hemisphere, including all four proteinopathies in the model. We found significant associations of (1) TDP-43 with thickness in all subregions (r = − 0.27 to r = − 0.46), and (2) tau with BA35 (r = − 0.31) and SRLM thickness (r = − 0.33). In amyloid-β and TDP-43 negative cases, we found strong significant associations of tau with ERC (r = − 0.40), BA35 (r = − 0.55), subiculum (r = − 0.42) and CA1 thickness (r = − 0.47). This unique dataset shows widespread MTL atrophy in relation to TDP-43 pathology and atrophy in regions affected early in Braak stageing and tau pathology. Moreover, the strong association of tau with thickness in early Braak regions in the absence of amyloid-β suggests a role of Primary Age-Related Tauopathy in neurodegeneration.
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| 24. |
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| 25. |
- Boudi, Zoubir, et al.
(författare)
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Association between boarding in the emergency department and in-hospital mortality : A systematic review
- 2020
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:4
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Forskningsöversikt (refereegranskat)abstract
- Importance: Boarding in the emergency department (ED) is a critical indicator of quality of care for hospitals. It is defined as the time between the admission decision and departure from the ED. As a result of boarding, patients stay in the ED until inpatient beds are available; moreover, boarding is associated with various adverse events.Study objective: The objective of our systematic review was to determine whether ED boarding (EDB) time is associated with in-hospital mortality (IHM).Methods: A systematic search was conducted in academic databases to identify relevant studies. Medline, PubMed, Scopus, Embase, Cochrane, Web of Science, Cochrane, CINAHL and PsychInfo were searched. We included all peer-reviewed published studies from all previous years until November 2018. Studies performed in the ED and focused on the association between EDB and IHM as the primary objective were included. Extracted data included study characteristics, prognostic factors, outcomes, and IHM. A search update in PubMed was performed in May 2019 to ensure the inclusion of recent studies before publishing.Results: From the initial 4,321 references found through the systematic search, the manual screening of reference lists and the updated search in PubMed, a total of 12 studies were identified as eligible for a descriptive analysis. Overall, six studies found an association between EDB and IHM, while five studies showed no association. The last remaining study included both ICU and non-ICU subgroups and showed conflicting results, with a positive association for non-ICU patients but no association for ICU patients. Overall, a tendency toward an association between EDB and IHM using the pool random effect was observed.Conclusion: Our systematic review did not find a strong evidence for the association between ED boarding and IHM but there is a tendency toward this association. Further well-controlled, international multicenter studies are needed to demonstrate whether this association exists and whether there is a specific EDB time cut-off that results in increased IHM.
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| 26. |
- Cousins, Katheryn A Q, et al.
(författare)
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ATN incorporating cerebrospinal fluid neurofilament light chain detects frontotemporal lobar degeneration.
- 2021
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 17:5, s. 822-830
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Tidskriftsartikel (refereegranskat)abstract
- The ATN framework provides an in vivo diagnosis of Alzheimer's disease (AD) using cerebrospinal fluid (CSF) biomarkers of pathologic amyloid plaques (A), tangles (T), and neurodegeneration (N). ATN is rarely evaluated in pathologically confirmed patients and its poor sensitivity to suspected non-Alzheimer's pathophysiologies (SNAP), including frontotemporal lobar degeneration (FTLD), leads to misdiagnoses. We compared accuracy of ATN (ATNTAU ) using CSF total tau (t-tau) to a modified strategy (ATNNfL ) using CSF neurofilament light chain (NfL) in an autopsy cohort.ATNTAU and ATNNfL were trained in an independent sample and validated in autopsy-confirmed AD (n=67) and FTLD (n=27).ATNNfL more accurately identified FTLD as SNAP (sensitivity=0.93, specificity=0.94) than ATNTAU (sensitivity=0.44, specificity=0.97), even in cases with co-occurring AD and FTLD. ATNNfL misclassified fewer AD and FTLD as "Normal" (2%) than ATNTAU (14%).ATNNfL is a promising diagnostic strategy that may accurately identify both AD and FTLD, even when pathologies co-occur.
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| 27. |
- de Flores, Robin, et al.
(författare)
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Characterization of hippocampal subfields using ex vivo MRI and histology data : Lessons for in vivo segmentation
- 2020
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Ingår i: Hippocampus. - : Wiley. - 1050-9631 .- 1098-1063. ; 30:6, s. 545-564
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Tidskriftsartikel (refereegranskat)abstract
- Hippocampal subfield segmentation on in vivo MRI is of great interest for cognition, aging, and disease research. Extant subfield segmentation protocols have been based on neuroanatomical references, but these references often give limited information on anatomical variability. Moreover, there is generally a mismatch between the orientation of the histological sections and the often anisotropic coronal sections on in vivo MRI. To address these issues, we provide a detailed description of hippocampal anatomy using a postmortem dataset containing nine specimens of subjects with and without dementia, which underwent a 9.4 T MRI and histological processing. Postmortem MRI matched the typical orientation of in vivo images and segmentations were generated in MRI space, based on the registered annotated histological sections. We focus on the following topics: the order of appearance of subfields, the location of subfields relative to macroanatomical features, the location of subfields in the uncus and tail and the composition of the dark band, a hypointense layer visible in T2-weighted MRI. Our main findings are that: (a) there is a consistent order of appearance of subfields in the hippocampal head, (b) the composition of subfields is not consistent in the anterior uncus, but more consistent in the posterior uncus, (c) the dark band consists only of the CA-stratum lacunosum moleculare, not the strata moleculare of the dentate gyrus, (d) the subiculum/CA1 border is located at the middle of the width of the hippocampus in the body in coronal plane, but moves in a medial direction from anterior to posterior, and (e) the variable location and composition of subfields in the hippocampal tail can be brought back to a body-like appearance when reslicing the MRI scan following the curvature of the tail. Our findings and this publicly available dataset will hopefully improve anatomical accuracy of future hippocampal subfield segmentation protocols.
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| 28. |
- Dominguez Perez, Sophia, et al.
(författare)
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Neuropsychological and Neuroanatomical Features of Patients with Behavioral/Dysexecutive Variant Alzheimer's Disease (AD) : A Comparison to Behavioral Variant Frontotemporal Dementia and Amnestic AD Groups
- 2022
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877. ; 89:2, s. 641-658
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Tidskriftsartikel (refereegranskat)abstract
- Background: An understudied variant of Alzheimer's disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. Objective: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. Methods: Subjects included 16 bvAD, 67 bvFTD, 18 aAD patients, and 26 healthy controls. Neuropsychological assessment and MRI data were compared between these groups. Results: Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. Conclusion: Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.
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| 29. |
- Lauque, Dominique, et al.
(författare)
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Length-of-Stay in the Emergency Department and In-Hospital Mortality : A Systematic Review and Meta-Analysis
- 2022
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 12:1
-
Forskningsöversikt (refereegranskat)abstract
- The effect of emergency department (ED) length of stay (EDLOS) on in-hospital mortality (IHM) remains unclear. The aim of this systematic review and meta-analysis was to determine the association between EDLOS and IHM. We searched the PubMed, Medline, Embase, Web of Science, Cochrane Controlled Register of Trials, CINAHL, PsycInfo, and Scopus databases from their inception until 14-15 January 2022. We included studies reporting the association between EDLOS and IHM. A total of 11,337 references were identified, and 52 studies (total of 1,718,518 ED patients) were included in the systematic review and 33 in the meta-analysis. A statistically significant association between EDLOS and IHM was observed for EDLOS over 24 h in patients admitted to an intensive care unit (ICU) (OR = 1.396, 95% confidence interval [CI]: 1.147 to 1.701; p < 0.001, I2 = 0%) and for low EDLOS in non-ICU-admitted patients (OR = 0.583, 95% CI: 0.453 to 0.745; p < 0.001, I2 = 0%). No associations were detected for the other cut-offs. Our findings suggest that there is an association between IHM low EDLOS and EDLOS exceeding 24 h and IHM. Long stays in the ED should not be allowed and special attention should be given to patients admitted after a short stay in the ED.
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| 30. |
- Nilsson, Johanna, 1993, et al.
(författare)
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Cerebrospinal fluid biomarker panel of synaptic dysfunction in Alzheimer's disease and other neurodegenerative disorders
- 2023
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Ingår i: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 19:5, s. 1775-1784
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Synaptic degeneration is a key part of the pathophysiology of neurodegenerative diseases, and biomarkers reflecting the pathological alterations are greatly needed. Method Seventeen synaptic proteins were quantified in a pathology-confirmed cerebrospinal fluid cohort of patients with Alzheimer's disease (AD; n = 63), frontotemporal lobar degeneration (FTLD; n = 53), and Lewy body spectrum of disorders (LBD; n = 21), as well as healthy controls (HC; n = 48). Results Comparisons revealed four distinct patterns: markers decreased across all neurodegenerative conditions compared to HC (the neuronal pentraxins), markers increased across all neurodegenerative conditions (14-3-3 zeta/delta), markers selectively increased in AD compared to other neurodegenerative conditions (neurogranin and beta-synuclein), and markers selectively decreased in LBD and FTLD compared to HC and AD (AP2B1 and syntaxin-1B). Discussion Several of the synaptic proteins may serve as biomarkers for synaptic dysfunction in AD, LBD, and FTLD. Additionally, differential patterns of synaptic protein alterations seem to be present across neurodegenerative diseases. Highlights A panel of synaptic proteins were quantified in the cerebrospinal fluid using mass spectrometry. We compared Alzheimer's disease, frontotemporal degeneration, and Lewy body spectrum of disorders. Pathology was confirmed by autopsy or familial mutations. We discovered synaptic biomarkers for synaptic degeneration and cognitive decline. We found differential patterns of synaptic proteins across neurodegenerative diseases.
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| 31. |
- Schwartz, B. E., et al.
(författare)
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Discovery and Targeting of the Signaling Controls of PNPLA3 to Effectively Reduce Transcription, Expression, and Function in Pre-Clinical NAFLD/NASH Settings
- 2020
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 9:10
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are emerging worldwide epidemics, projected to become the leading cause of liver transplants. The strongest genetic risk factor for NAFLD/NASH susceptibility and progression is a single-nucleotide polymorphism (SNP) in the patatin-like phospholipase domain-containing 3 gene (PNPLA3), rs738409, encoding the missense mutation I148M. This aminoacidic substitution interferes with the normal remodeling of lipid droplets in hepatocytes. It is also thought to play a key role in promoting liver fibrosis by inhibiting the release of retinol from hepatic stellate cells. Reducing PNPLA3 levels in individuals homozygous for 148M may be an effective treatment for the entire spectrum of NAFLD, based on gene dosage analysis in the human population, as well as the protective effect of another naturally occurring SNP (rs2294918) in PNPLA3 which, when co-inherited, reduces PNPLA3 mRNA levels to 50% and counteracts disease risk. By screening a clinical compound library targeting specific signaling pathways active in primary human hepatocytes, we identified momelotinib, a drug evaluated in clinical trials to treat myelofibrosis, as a potent down-regulator of PNPLA3 expression, across all genotypes. We found that momelotinib treatment yielded >80% reduction in PNPLA3 mRNA in human primary hepatocytes and stellate cells, as well as in vivo via acute and chronic treatment of WT mice. Using a human multilineage 3D spheroid model of NASH homozygous for the PNPLA3 mutant protein, we additionally show that it decreases PNPLA3 mRNA as well as intracellular lipid content. Furthermore, we show that the effects on PNPLA3 coincide with changes in chromatin accessibility within regulatory regions of the PNPLA3 locus, consistent with inhibition occurring at the level of transcription. In addition to its primary reported targets, the JAK kinases, momelotinib inhibits several non-JAK kinases, including ACVR1. Using a combination of targeted siRNA knockdowns and signaling pathway perturbations, we show that momelotinib reduces the expression of the PNPLA3 gene largely through the inhibition of BMP signaling rather than the JAK/STAT pathway. Overall, our work identified momelotinib as a potential NASH therapeutic and uncovered previously unrecognized connections between signaling pathways and PNPLA3. These pathways may be exploited by drug modalities to "tune down" the level of gene expression, and therefore offer a potential therapeutic benefit to a high at-risk subset of NAFLD/NASH patients.
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| 32. |
- Shen, Ting, et al.
(författare)
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Novel data-driven subtypes and stages of brain atrophy in the ALS–FTD spectrum
- 2023
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Ingår i: Translational Neurodegeneration. - 2047-9158. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: TDP-43 proteinopathies represent a spectrum of neurological disorders, anchored clinically on either end by amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD). The ALS–FTD spectrum exhibits a diverse range of clinical presentations with overlapping phenotypes, highlighting its heterogeneity. This study was aimed to use disease progression modeling to identify novel data-driven spatial and temporal subtypes of brain atrophy and its progression in the ALS–FTD spectrum. Methods: We used a data-driven procedure to identify 13 anatomic clusters of brain volume for 57 behavioral variant FTD (bvFTD; with either autopsy-confirmed TDP-43 or TDP-43 proteinopathy-associated genetic variants), 103 ALS, and 47 ALS–FTD patients with likely TDP-43. A Subtype and Stage Inference (SuStaIn) model was trained to identify subtypes of individuals along the ALS–FTD spectrum with distinct brain atrophy patterns, and we related subtypes and stages to clinical, genetic, and neuropathological features of disease. Results: SuStaIn identified three novel subtypes: two disease subtypes with predominant brain atrophy in either prefrontal/somatomotor regions or limbic-related regions, and a normal-appearing group without obvious brain atrophy. The limbic-predominant subtype tended to present with more impaired cognition, higher frequencies of pathogenic variants in TBK1 and TARDBP genes, and a higher proportion of TDP-43 types B, E and C. In contrast, the prefrontal/somatomotor-predominant subtype had higher frequencies of pathogenic variants in C9orf72 and GRN genes and higher proportion of TDP-43 type A. The normal-appearing brain group showed higher frequency of ALS relative to ALS–FTD and bvFTD patients, higher cognitive capacity, higher proportion of lower motor neuron onset, milder motor symptoms, and lower frequencies of genetic pathogenic variants. The overall SuStaIn stages also correlated with evidence for clinical progression including longer disease duration, higher King’s stage, and cognitive decline. Additionally, SuStaIn stages differed across clinical phenotypes, genotypes and types of TDP-43 pathology. Conclusions: Our findings suggest distinct neurodegenerative subtypes of disease along the ALS–FTD spectrum that can be identified in vivo, each with distinct brain atrophy, clinical, genetic and pathological patterns.
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| 33. |
- Wisse, L. E.M., et al.
(författare)
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Pathological drivers of neurodegeneration in suspected non-Alzheimer’s disease pathophysiology
- 2021
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 13
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Little is known about the heterogeneous etiology of suspected non-Alzheimer’s pathophysiology (SNAP), a group of subjects with neurodegeneration in the absence of β-amyloid. Using antemortem MRI and pathological data, we investigated the etiology of SNAP and the association of neurodegenerative pathologies with structural medial temporal lobe (MTL) measures in β-amyloid-negative subjects. Methods: Subjects with antemortem MRI and autopsy data were selected from ADNI (n=63) and the University of Pennsylvania (n=156). Pathological diagnoses and semi-quantitative scores of MTL tau, neuritic plaques, α-synuclein, and TDP-43 pathology and MTL structural MRI measures from antemortem T1-weighted MRI scans were obtained. β-amyloid status (A+/A−) was determined by CERAD score and neurodegeneration status (N+/N−) by hippocampal volume. Results: SNAP reflects a heterogeneous group of pathological diagnoses. In ADNI, SNAP (A−N+) had significantly more neuropathological diagnoses than A+N+. In the A− group, tau pathology was associated with hippocampal, entorhinal cortex, and Brodmann area 35 volume/thickness and TDP-43 pathology with hippocampal volume. Conclusion: SNAP had a heterogeneous profile with more mixed pathologies than A+N+. Moreover, a role for TDP-43 and tau pathology in driving MTL neurodegeneration in the absence of β-amyloid was supported.
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| 34. |
- Wu, Lijuan, et al.
(författare)
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The Association between Emergency Department Length of Stay and In-Hospital Mortality in Older Patients Using Machine Learning : An Observational Cohort Study
- 2023
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 12:14
-
Tidskriftsartikel (refereegranskat)abstract
- The association between emergency department (ED) length of stay (EDLOS) with in-hospital mortality (IHM) in older patients remains unclear. This retrospective study aims to delineate the relationship between EDLOS and IHM in elderly patients. From the ED patients (n = 383,586) who visited an urban academic tertiary care medical center from January 2010 to December 2016, 78,478 older patients (age ≥60 years) were identified and stratified into three age subgroups: 60-74 (early elderly), 75-89 (late elderly), and ≥90 years (longevous elderly). We applied multiple machine learning approaches to identify the risk correlation trends between EDLOS and IHM, as well as boarding time (BT) and IHM. The incidence of IHM increased with age: 60-74 (2.7%), 75-89 (4.5%), and ≥90 years (6.3%). The best area under the receiver operating characteristic curve was obtained by Light Gradient Boosting Machine model for age groups 60-74, 75-89, and ≥90 years, which were 0.892 (95% CI, 0.870-0.916), 0.886 (95% CI, 0.861-0.911), and 0.838 (95% CI, 0.782-0.887), respectively. Our study showed that EDLOS and BT were statistically correlated with IHM (p < 0.001), and a significantly higher risk of IHM was found in low EDLOS and high BT. The flagged rate of quality assurance issues was higher in lower EDLOS ≤1 h (9.96%) vs. higher EDLOS 7 h
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| 35. |
- Yushkevich, Paul A., et al.
(författare)
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Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe
- 2021
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2784-2797
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Tidskriftsartikel (refereegranskat)abstract
- Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.
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| 36. |
- Alexandraki, Krystallenia I., et al.
(författare)
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Changing biological behaviour of NETs during the evolution of the disease : progress on progression
- 2021
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Ingår i: Endocrine-Related Cancer. - : BioScientifica Ltd.. - 1351-0088 .- 1479-6821. ; 28:5, s. R121-R140
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Forskningsöversikt (refereegranskat)abstract
- Following improvements in the management and outcome of neuroendocrine neoplasms (NENs) in recent years, we see a subset, particularly of pancreatic NENs, which become more aggressive during the course of the disease. This is reflected by an increase in the Ki-67 labelling index, as a marker of proliferation, which may lead to an occasion of increase in grading, but generally does not appear to be correlated with histologically confirmed dedifferentiation. A systematic review of the literature was performed in PubMed, Cochrane Library, and Embase until May 2020 to identify cases that have behaved in such a manner. We screened 244 articles: only seven studies included cases in their cohort, or in a subset of the cohort studied, with a proven increase in the Ki-67 during follow-up through additional biopsy. In addition to these studies, we have also tried to identify possible pathophysiological mechanisms implicated in advanced NENs, although currently no studies appear to have addressed the mechanisms implicated in the switch to a more aggressive biological phenotype over the course of the disease. Such progression of the disease course may demand a change in the management. Summarising the overall evidence, we suggest that future studies should concentrate on changes in the molecular pathways during disease progression with sequential biopsies in order to shed light on the mechanisms that render a neoplasm more aggressive than its initial phenotype or genotype.
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| 37. |
- Alexandraki, Krystallenia I., et al.
(författare)
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Endocrinological Toxicity Secondary to Treatment of Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs)
- 2020
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Ingår i: Trends in endocrinology and metabolism. - : Elsevier. - 1043-2760 .- 1879-3061. ; 31:3, s. 239-255
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Tidskriftsartikel (refereegranskat)abstract
- Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are increasingly recognized, characterized by prolonged survival even with metastatic disease. Their medical treatment is complex involving various specialties, necessitating awareness of treatment-related adverse effects (AEs). As GEP-NENs express somatostatin receptors (SSTRs), long-acting somatostatin analogs (SSAs) that are used for secretory syndrome and tumor control may lead to altered glucose metabolism. Everolimus and sunitinib are molecular targeted agents that affect glucose and lipid metabolism and may induce hypothyroidism or hypocalcemia, respectively. Chemotherapeutic drugs can affect the reproductive system and water homeostasis, whereas immunotherapeutic agents can cause hypophysitis and thyroiditis or other immune-mediated disorders. Treatment with radiopeptides may temporarily lead to radiation-induced hormone disturbances. As drugs targeting GEP-NENs are increasingly introduced, recognition and management of endocrine-related AEs may improve compliance and the quality of life of these patients.
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| 38. |
- Alsabri, Mohamed, et al.
(författare)
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Impact of Teamwork and Communication Training Interventions on Safety Culture and Patient Safety in Emergency Departments : A Systematic Review
- 2022
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Ingår i: Journal of patient safety. - : Lippincott Williams & Wilkins. - 1549-8417 .- 1549-8425. ; 18:1, s. E351-E361
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Forskningsöversikt (refereegranskat)abstract
- Objectives: This study aimed to narratively summarize the literature reporting on the effect of teamwork and communication training interventions on culture and patient safety in emergency department (ED) settings.Methods: We searched PubMed, EMBASE, Psych Info CINAHL, Cochrane, Science Citation Inc, the Web of Science, and Educational Resources Information Centre for peer-reviewed journal articles published from January 1, 1988, to June 8, 2018, that assessed teamwork and communication interventions focusing on how they influence patient safety in the ED. One additional search update was performed in July 2019.Results: Sixteen studies were included from 8700 screened publications. The studies' design, interventions, and evaluation methods varied widely. The most impactful ED training interventions were End-of-Course Critique, Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), and crisis resource management (CRM)-based training. Crisis resource management and TeamSTEPPS CRM-based training curriculum were used in most of the studies. Multiple tools, including the Kirkpatrick evaluation model, the Agency for Healthcare Research and Quality Hospital Survey on Patient Safety Culture, the TeamSTEPPS Teamwork Attitudes Questionnaire, the Safety Attitudes Questionnaire, and the Communication and Teamwork Skills Assessment, were used to assess the impact of such interventions. Improvements in one of the domains of safety culture and related domains were found in all studies. Four empirical studies established improvements in patient health outcomes that occurred after simulation CRM training (Kirkpatrick 4), but there was no effect on mortality.Conclusions: Overall, teamwork and communication training interventions improve the safety culture in ED settings and may positively affect patient outcome. The implementation of safety culture programs may be considered to reduce incidence of medical errors and adverse events.
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| 39. |
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| 40. |
- Benatar, Michael, et al.
(författare)
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Preventing amyotrophic lateral sclerosis : insights from pre-symptomatic neurodegenerative diseases
- 2022
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 145:1, s. 27-44
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Forskningsöversikt (refereegranskat)abstract
- Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned - more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers - we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.
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| 41. |
- Dhanasekara, Chathurika S., et al.
(författare)
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A comparison of outcomes including bile duct injury of subtotal cholecystectomy versus open total cholecystectomy as bailout procedures for severe cholecystitis : A multicenter real-world study
- 2024
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Ingår i: Surgery. - : Elsevier. - 0039-6060 .- 1532-7361.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dense inflammation obscuring the hepatocystic anatomy can hinder the ability to perform a safe standard laparoscopic cholecystectomy in severe cholecystitis, requiring use of a bailout procedure. We compared clinical outcomes of laparoscopic and open subtotal cholecystectomy against the traditional standard of open total cholecystectomy to identify the optimal bailout strategy for the difficult gallbladder.METHODS: A multicenter, multinational retrospective cohort study of patients who underwent bailout procedures for severe cholecystitis. Procedures were compared using one-way analysis of variance/Kruskal-Wallis tests and χ2 tests with multiple pairwise comparisons, maintaining a family-wise error rate at 0.05. Multiple multivariate linear/logistical regression models were created.RESULTS: In 11 centers, 727 bailout procedures were conducted: 317 laparoscopic subtotal cholecystectomies, 172 open subtotal cholecystectomies, and 238 open cholecystectomies. Baseline characteristics were similar among subgroups. Bile leak was common in laparoscopic and open fenestrating subtotal cholecystectomies, with increased intraoperative drain placements and postoperative endoscopic retrograde cholangiopancreatography(P < .05). In contrast, intraoperative bleeding (odds ratio = 3.71 [1.9, 7.22]), surgical site infection (odds ratio = 2.41 [1.09, 5.3]), intensive care unit admission (odds ratio = 2.65 [1.51, 4.63]), and length of stay (Δ = 2 days, P < .001) were higher in open procedures. Reoperation rates were higher for open reconstituting subtotal cholecystectomies (odds ratio = 3.43 [1.03, 11.44]) than other subtypes. The overall rate of bile duct injury was 1.1% and was not statistically different between groups. Laparoscopic subtotal cholecystectomy had a bile duct injury rate of 0.63%.CONCLUSION: Laparoscopic subtotal cholecystectomy is a feasible surgical bailout procedure in cases of severe cholecystitis where standard laparoscopic cholecystectomy may carry undue risk of bile duct injury. Open cholecystectomy remains a reasonable option.
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| 42. |
- Giordano, Luca, et al.
(författare)
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Essential Role of Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 (Cox4i2) for Acute Pulmonary Oxygen Sensing
- 2022
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Ingår i: Biochimica et Biophysica Acta - Bioenergetics. - : Elsevier. - 0005-2728 .- 1879-2650. ; 1863:Supplement
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial Cytochrome c Oxidase Subunit 4 Isoform 2 (Cox4i2) is essential for acute oxygen sensing and signaling in pulmonary arterial smooth muscle cells (PASMCs) by triggering the production of superoxide during acute hypoxia [1]. However, the molecular mechanism underlying Cox4i2-dependent oxygen sensing remains elusive. We analysed oxygen-dependent respiration by high resolution respirometry, redox changes of the electron transport chain (ETC) by RAMAN spectroscopy, and supercomplex formation by blue native gel analysis of PASMCs isolated from wild type (WT) and Cox4i2-/- mice. To understand the role of Cox4i2-specific cysteine residues we determined hypoxia-induced superoxide production and oxygen affinity in a mouse epithelial cell line (CMT167 cells) overexpressing either Cox4i1, or WT Cox4i2, or Cox4i2 mutants (C41S, C55A, C109S). Respiration and supercomplex formation were similar in WT and Cox4i2-/- PASMCs. Interestingly, hypoxia-induced reduction of ETC components (NADH, ubiquinol, and reduced cytochrome c) was prevented in Cox4i2-/- PASMCs. CMT167 cells expressing either Cox4i1, or Cox4i2 mutants lacked hypoxia-induced superoxide release, which was detected only in cells expressing WT Cox4i2. In contrast, overexpression of Cox4i1, or Cox4i2, or Cox4i2 mutants did not affect oxygen affinity. Our findings suggest that Cox4i2 does not alter superoxide production by rearrangement of supercomplexes, whereas its specific cysteines are needed for the superoxide release. In conclusion, Cox4i2 plays a major role in the hypoxia-induced reduction of ETC components, likely mediated through its redox-active cysteine residues.
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| 43. |
- Goudzovski, Evgueni, et al.
(författare)
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New physics searches at kaon and hyperon factories
- 2023
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Ingår i: Reports on progress in physics (Print). - : Institute of Physics (IOP). - 0034-4885 .- 1361-6633. ; 86:1
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Forskningsöversikt (refereegranskat)abstract
- Rare meson decays are among the most sensitive probes of both heavy and light new physics. Among them, new physics searches using kaons benefit from their small total decay widths and the availability of very large datasets. On the other hand, useful complementary information is provided by hyperon decay measurements. We summarize the relevant phenomenological models and the status of the searches in a comprehensive list of kaon and hyperon decay channels. We identify new search strategies for under-explored signatures, and demonstrate that the improved sensitivities from current and next-generation experiments could lead to a qualitative leap in the exploration of light dark sectors.
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| 44. |
- Groff II, Louis C., et al.
(författare)
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Uncertainty estimation strategies for quantitative non-targeted analysis
- 2022
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Ingår i: Analytical and Bioanalytical Chemistry. - : Springer Science and Business Media LLC. - 1618-2642 .- 1618-2650. ; 414:17, s. 4919-4933
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Tidskriftsartikel (refereegranskat)abstract
- Non-targeted analysis (NTA) methods are widely used for chemical discovery but seldom employed for quantitation due to a lack of robust methods to estimate chemical concentrations with confidence limits. Herein, we present and evaluate new statistical methods for quantitative NTA (qNTA) using high-resolution mass spectrometry (HRMS) data from EPA’s Non-Targeted Analysis Collaborative Trial (ENTACT). Experimental intensities of ENTACT analytes were observed at multiple concentrations using a semi-automated NTA workflow. Chemical concentrations and corresponding confidence limits were first estimated using traditional calibration curves. Two qNTA estimation methods were then implemented using experimental response factor (RF) data (where RF = intensity/concentration). The bounded response factor method used a non-parametric bootstrap procedure to estimate select quantiles of training set RF distributions. Quantile estimates then were applied to test set HRMS intensities to inversely estimate concentrations with confidence limits. The ionization efficiency estimation method restricted the distribution of likely RFs for each analyte using ionization efficiency predictions. Given the intended future use for chemical risk characterization, predicted upper confidence limits (protective values) were compared to known chemical concentrations. Using traditional calibration curves, 95% of upper confidence limits were within ~tenfold of the true concentrations. The error increased to ~60-fold (ESI+) and ~120-fold (ESI−) for the ionization efficiency estimation method and to ~150-fold (ESI+) and ~130-fold (ESI−) for the bounded response factor method. This work demonstrates successful implementation of confidence limit estimation strategies to support qNTA studies and marks a crucial step towards translating NTA data in a risk-based context.
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| 45. |
- Hernández‑Morcillo, Monica, et al.
(författare)
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Scanning the solutions for the sustainable supply of forest ecosystem services in Europe
- 2022
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Ingår i: Sustainability Science. - : Springer Science and Business Media LLC. - 1862-4057 .- 1862-4065. ; 17:5, s. 2013-2029
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Tidskriftsartikel (refereegranskat)abstract
- Forests are key components of European multifunctional landscapes and supply numerous forest ecosystem services (FES) fundamental to human well-being. The sustainable provision of FES has the potential to provide responses to major societal challenges, such as climate change, biodiversity loss, or rural development. To identify suitable strategies for the future sustenance of FES, we performed a solution scanning exercise with a group of transdisciplinary forest and FES experts from diferent European regions. We identifed and prioritized ffteen major challenges hindering the balanced provision of multiple FES and identifed a series of potential solutions to tackle each of them. The most prominent challenges referred to the increased frequency and impacts of extreme weather events and the normative mindset regarding forest management. The respective solutions pointed to the promotion of forest resilience via climate-smart forestry and mainstreaming FES-orientedmanagement through a threefold strategy focusing on education, awareness raising, and networking. In a subsequent survey,most solutions were assessed as highly efective, transferable, monitorable, and with potential for being economically efcient. The implementation of the solutions could have synergistic efects when applying the notion of leverage points. Sevenemerging pathways towards the sustainable supply of FES have been identifed. These pathways build on each other and areorganized based on their potential for transformation: (1) shifting forest management paradigms towards pluralistic ecosystem valuation; (2) using integrated landscape approaches; (3) increasing forest resilience; (4) coordinating actions betweenforest-related actors; (5) increasing participation in forest planning and management; (6) continuous, open, and transparentknowledge integration; and (7) using incentive-based instruments to support regulating and cultural FES. These pathwayscan contribute to the implementation of the new EU Forestry Strategy to support the balanced supply of multiple FES.
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| 46. |
- Ho, Ken, et al.
(författare)
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Pituitary Neoplasm Nomenclature Workshop: Does Adenoma Stand the Test of Time?
- 2021
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 5:3
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Forskningsöversikt (refereegranskat)abstract
- The WHO Classification of Endocrine Tumours designates pituitary neoplasms as adenomas. A proposed nomenclature change to pituitary neuroendocrine tumors (PitNETs) has been met with concern by some stakeholder groups. The Pituitary Society coordinated the Pituitary Neoplasm Nomenclature (PANOMEN) workshop to address the topic. Experts in pituitary developmental biology, pathology, neurosurgery, endocrinology, and oncology, including representatives nominated by the Endocrine Society, European Society of Endocrinology, European Neuroendocrine Association, Growth Hormone Research Society, and International Society of Pituitary Surgeons. Clinical epidemiology, disease phenotype, management, and prognosis of pituitary adenomas differ from that of most NETs. The vast majority of pituitary adenomas are benign and do not adversely impact life expectancy. A nomenclature change to PitNET does not address the main challenge of prognostic prediction, assigns an uncertain malignancy designation to benign pituitary adenomas, and may adversely affect patients. Due to pandemic restrictions, the workshop was conducted virtually, with audiovisual lectures and written précis on each topic provided to all participants. Feedback was collated and summarized by Content Chairs and discussed during a virtual writing meeting moderated by Session Chairs, which yielded an evidence-based draft document sent to all participants for review and approval. There is not yet a case for adopting the PitNET nomenclature. The PANOMEN Workshop recommends that the term adenoma be retained and that the topic be revisited as new evidence on pituitary neoplasm biology emerges.
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| 47. |
- Quilico Cousins, Katheryn Alexandra, et al.
(författare)
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CSF Biomarkers of Alzheimer Disease in Patients With Concomitant alpha-Synuclein Pathology
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:20
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives CSF biomarkers beta-amyloid 1-42 (A beta(42)) phosphorylated tau 181 (p-tau(181)), total tau (t-tau), and neurogranin (Ng) can diagnose Alzheimer disease (AD) in life. However, it is unknown whether CSF concentrations, and thus their accuracies, are affected by concomitant pathologies common in AD, such as alpha-synuclein (alpha Syn). Our primary goal was to test whether biomarkers in patients with AD are altered by concomitant alpha Syn. We compared CSF A beta(42), p-tau(181), t-tau, and Ng levels across autopsy-confirmed AD and concomitant AD and alpha Syn (AD + alpha Syn). Antemortem CSF levels were related to postmortem accumulations of alpha Syn. Finally, we tested how concommitant AD + alpha Syn affected the diagnostic accuracy of 2 CSF-based strategies: the amyloid/tau/neurodegeneration (ATN) framework and the t-tau/A beta(42) ratio. Methods Inclusion criteria were neuropathologic diagnoses of AD, mixed AD + alpha Syn, and alpha Syn. A convenience sample of nonimpaired controls was selected with available CSF and a Mini-Mental State Examination (MMSE) >= 27. alpha Syn without AD and controls were included as reference groups. Analyses of covariance (ANCOVAs) tested planned comparisons were CSF A beta(42), t-tau, and Ng differences across AD and AD + alpha Syn. Linear models tested how biomarkers were altered by alpha Syn accumulation in AD, accounting for pathologic beta-amyloid and tau. Receiver operating characteristic and area under the curve (AUC), including 95% CI, evaluated diagnostic accuracy. Results Participants were 61 patients with AD, 39 patients with mixed AD + alpha Syn, 20 patients with alpha Syn, and 61 controls. AD had similar median age (73 [interquartile range {IQR} = 12] years), MMSE (23 [IQR = 9]), and sex distribution (male = 49%) compared with AD + alpha Syn age (70 [IQR = 13] years; p = 0.3), MMSE (25 [IQR = 9.5]; p = 0.19), and sex distribution (male = 69%; p = 0.077). ANCOVAs showed that AD + alpha Syn had lower p-tau(181) (F(1,94) = 17, p < 2.6e-16), t-tau (F(1,93) = 11, p = 0.0004), and Ng levels (F(1,50) = 12, p = 0.0004) than AD; there was no difference in A beta(42) = 0.44). Models showed increasing alpha Syn related to lower (beta = -0.26, SE = 0.092, p = 0.0065), t-tau (beta = -0.19, SE = 0.092, p = 0.041), and Ng levels (beta = -0.2, SE = 0.066, p = 0.0046); alpha Syn was not a significant factor for A beta(42) (p = 1). T-tau/A beta(42) had the highest accuracy when detecting AD, including mixed AD + alpha Syn cases (AUC = 0.95; CI 0.92-0.98). Discussion Findings demonstrate that concomitant alpha Syn pathology in AD is associated with lower CSF p-tau(181), t-tau, and Ng levels and can affect diagnostic accuracy in patients with AD.
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| 48. |
- Taïeb, David, et al.
(författare)
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Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants : an international expert Consensus statement
- 2024
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Ingår i: Nature Reviews Endocrinology. - : Springer Nature. - 1759-5029 .- 1759-5037. ; 20:3, s. 168-184
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Forskningsöversikt (refereegranskat)abstract
- Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.
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| 49. |
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| 50. |
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