| 1. |
- Gusev, A, et al.
(författare)
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Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation
- 2016
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7, s. 10979-
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Tidskriftsartikel (refereegranskat)abstract
- Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.
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| 2. |
- Chalmers, J. R., et al.
(författare)
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Report from the fifth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)
- 2018
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Ingår i: British Journal of Dermatology. - : John Wiley & Sons. - 0007-0963 .- 1365-2133. ; 178:5, s. E332-E341
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Tidskriftsartikel (refereegranskat)abstract
- This is the report from the fifth meeting of the Harmonising Outcome Measures for Eczema initiative (HOME V). The meeting was held on 12-14 June 2017 in Nantes, France, with 81 participants. The main aims of the meeting were (i) to achieve consensus over the definition of the core domain of long-term control and how to measure it and (ii) to prioritize future areas of research for the measurement of the core domain of quality of life (QoL) in children. Moderated whole-group and small-group consensus discussions were informed by presentations of qualitative studies, systematic reviews and validation studies. Small-group allocations were performed a priori to ensure that each group included different stakeholders from a variety of geographical regions. Anonymous whole-group voting was carried out using handheld electronic voting pads according to pre-defined consensus rules. It was agreed by consensus that the long-term control domain should include signs, symptoms, quality of life and a patient global instrument. The group agreed that itch intensity should be measured when assessing long-term control of eczema in addition to the frequency of itch captured by the symptoms domain. There was no recommendation of an instrument for the core outcome domain of quality of life in children, but existing instruments were assessed for face validity and feasibility, and future work that will facilitate the recommendation of an instrument was agreed upon.
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| 3. |
- Chalmers, J. R., et al.
(författare)
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Report from the fourth international consensus meeting to harmonize core outcome measures for atopic eczema/dermatitis clinical trials (HOME initiative)
- 2016
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Ingår i: British Journal of Dermatology. - : Oxford University Press (OUP). - 0007-0963 .- 1365-2133. ; 175:1, s. 69-79
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Tidskriftsartikel (refereegranskat)abstract
- This article is a report of the fourth meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in Malmo, Sweden on 23-24 April 2015 (HOME IV). The aim of the meeting was to achieve consensus over the preferred outcome instruments for measuring patient-reported symptoms and quality of life for the HOME core outcome set for atopic eczema (AE). Following presentations, which included data from systematic reviews, consensus discussions were held in a mixture of whole group and small group discussions. Small groups were allocated a priori to ensure representation of different stakeholders and countries. Decisions were voted on using electronic keypads. For the patient-reported symptoms, the group agreed by vote that itch, sleep loss, dryness, redness/inflamed skin and irritated skin were all considered essential aspects of AE symptoms. Many instruments for capturing patient-reported symptoms were discussed [ including the Patient-Oriented SCOring Atopic Dermatitis index, Patient-Oriented Eczema Measure (POEM), Self-Administered Eczema Area and Severity Index, Itch Severity Scale, Atopic Dermatitis Quickscore and the Nottingham Eczema Severity Score] and, by consensus, POEM was selected as the preferred instrument to measure patient-reported symptoms. Further work is needed to determine the reliability and measurement error of POEM. Further work is also required to establish the importance of pain/soreness and the importance of collecting information regarding the intensity of symptoms in addition to their frequency. Much of the discussion on quality of life concerned the Dermatology Life Quality Index and Quality of Life Index for Atopic Dermatitis; however, consensus on a preferred instrument for measuring this domain could not be reached. In summary, POEM is recommended as the HOME core outcome instrument for measuring AE symptoms.
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| 4. |
- Khadjinova, A. I., et al.
(författare)
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Autoantibodies against the envelope proteins of endogenous retroviruses K102 and K108 in patients with systemic lupus erythematosus correlate with active disease
- 2022
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Ingår i: Clinical and Experimental Rheumatology. - : Clinical and Experimental Rheumatology. - 0392-856X .- 1593-098X. ; 40:7, s. 1306-1312
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Tidskriftsartikel (refereegranskat)abstract
- Objective To determine if patients with systemic lupus erythematosus (SLE), a disease characterised by elevated type I interferons reminiscent of anti-viral immunity, have expression of human endogenous retrovirus K (HERV-K) proviruses capable of producing envelope (Env) protein, as well as associated autoantibodies against the Env protein. Methods ELISAs were conducted with recombinant Env protein and sera from SLE patients with active (n=60) or inactive (n=49) disease, healthy controls (n=47), other rheumatic disorders (n=59), as well as plasma from paediatric lupus patients with active (n=30) or inactive (n=30) disease, and 17 healthy children. Antibody reactivity was evaluated for correlations with clinical and laboratory parameters of the patients. Expression of HERV-K transcripts were profiled in SLE leukocytes by RNA-Seq. Results Both adult and paediatric SLE patients had autoantibodies against HERV-K Env with higher titres than healthy controls or patients with Sjögren’s syndrome, small- or large-vessel vasculitis, or psoriatic arthritis. Transcripts from only two HERV-K loci capable of producing Env, HERV-K102 and -K108, were detected among the 10 expressed loci in SLE patients. Conclusion Our data reveal that HERV-K proviruses are expressed in SLE and that the HERV-K-encoded Env protein elicits an immune response in patients, particularly during active disease.
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| 5. |
- Mund, A., et al.
(författare)
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Deep Visual Proteomics defines single-cell identity and heterogeneity
- 2022
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Ingår i: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 40:8, s. 1231-1240
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Tidskriftsartikel (refereegranskat)abstract
- Despite the availabilty of imaging-based and mass-spectrometry-based methods for spatial proteomics, a key challenge remains connecting images with single-cell-resolution protein abundance measurements. Here, we introduce Deep Visual Proteomics (DVP), which combines artificial-intelligence-driven image analysis of cellular phenotypes with automated single-cell or single-nucleus laser microdissection and ultra-high-sensitivity mass spectrometry. DVP links protein abundance to complex cellular or subcellular phenotypes while preserving spatial context. By individually excising nuclei from cell culture, we classified distinct cell states with proteomic profiles defined by known and uncharacterized proteins. In an archived primary melanoma tissue, DVP identified spatially resolved proteome changes as normal melanocytes transition to fully invasive melanoma, revealing pathways that change in a spatial manner as cancer progresses, such as mRNA splicing dysregulation in metastatic vertical growth that coincides with reduced interferon signaling and antigen presentation. The ability of DVP to retain precise spatial proteomic information in the tissue context has implications for the molecular profiling of clinical samples.
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| 6. |
- Birkebaek, N. H., et al.
(författare)
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Impact of the COVID-19 pandemic on long-term trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes: an international multicentre study based on data from 13 national diabetes registries
- 2022
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Ingår i: Lancet Diabetes & Endocrinology. - : Elsevier BV. - 2213-8587. ; 10:11, s. 786-794
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Tidskriftsartikel (refereegranskat)abstract
- Background An increased prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes in children was observed in various diabetes centres worldwide during the COVID-19 pandemic. We aimed to evaluate trends in the prevalence of diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes before and during the COVID-19 pandemic, and to identify potential predictors of changes in diabetic ketoacidosis prevalence during the pandemic.Methods For this international multicentre study, we used data from 13 national diabetes registries (Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA [Colorado], and Wales). The study population comprised 104 290 children and adolescents aged 6 months to younger than 18 years, who were diagnosed with type 1 diabetes between Jan 1, 2006, and Dec 31, 2021. The observed diabetic ketoacidosis prevalence in 2020 and 2021 was compared to predictions based on trends over the pre-pandemic years 2006-19. Associations between changes in diabetic ketoacidosis prevalence and the severity of the COVID-19 pandemic and containment measures were examined with excess all-cause mortality in the whole population and the Stringency Index from the Oxford COVID-19 Government Response Tracker.Findings 87 228 children and adolescents were diagnosed with type 1 diabetes between 2006 and 2019, 8209 were diagnosed in 2020, and 8853 were diagnosed in 2021. From 2006 to 2019, diabetic ketoacidosis at diagnosis of type 1 diabetes was present in 23 775 (27middot3%) of 87 228 individuals and the mean annual increase in the prevalence of diabetic ketoacidosis in the total cohort from 2006 to 2019 was 1middot6% (95% CI 1middot3 to 1middot9). The adjusted observed prevalence of diabetic ketoacidosis at diagnosis of type 1 diabetes was 39middot4% (95% CI 34middot0 to 45middot6) in 2020 and 38middot9% (33middot6 to 45middot0) in 2021, significantly higher than the predicted prevalence of 32middot5% (27middot8 to 37middot9) for 2020 and 33middot0% (28middot3 to 38middot5) for 2021 (p<0middot0001 for both years). The prevalence of diabetic ketoacidosis was associated with the pandemic containment measures, with an estimated risk ratio of 1middot037 (95% CI 1middot024 to 1middot051; p<0middot0001) per ten-unit increase in the Stringency Index for 2020 and 1middot028 (1middot009 to 1middot047; p=0middot0033) for 2021, but was not significantly associated with excess all-cause mortality.Interpretation During the COVID-19 pandemic, there was a marked exacerbation of the pre-existing increase in diabetic ketoacidosis prevalence at diagnosis of type 1 diabetes in children. This finding highlights the need for early and timely diagnosis of type 1 diabetes in children and adolescents.Funding German Federal Ministry for Education and Research, German Robert Koch Institute, German Diabetes Association, German Diabetes Foundation, Slovenian Research Agency, Welsh Government, Central Denmark Region, and Swedish Association of Local Authorities and Regions.Copyright (c) 2022 Elsevier Ltd. All rights reserved.
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| 7. |
- Tschudin-Sutter, S., et al.
(författare)
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Guidance document for prevention of Clostridium difficile infection in acute healthcare settings
- 2018
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Ingår i: Clinical Microbiology and Infection. - : Blackwell Publishing. - 1198-743X .- 1469-0691. ; 24:10, s. 1051-1054
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Forskningsöversikt (refereegranskat)abstract
- SCOPE: Clostridium difficile infection (CDI) is the most important infective cause of healthcare-associated diarrhoea in high income countries and one of the most important healthcare-associated pathogens in both Europe and the United States. It is associated with high morbidity and mortality resulting in both societal and financial burden. A significant proportion of this burden is potentially preventable by a combination of targeted infection prevention and control measures and antimicrobial stewardship. The aim of this guidance document is to provide an update on recommendations for prevention of CDI in acute care settings to provide guidance to those responsible for institutional infection prevention and control programmes.METHODS: An expert group was set up by the European society of clinical microbiology and infectious diseases (ESCMID) Study Group for C. difficile (ESGCD), which performed a systematic review of the literature on prevention of CDI in adults hospitalized in acute care settings and derived respective recommendations according to the GRADE approach. Recommendations are stratified for both outbreak and endemic settings.QUESTIONS ADDRESSED BY THE GUIDELINE AND RECOMMENDATIONS: This guidance document provides thirty-six statements on strategies to prevent CDI in acute care settings, including 18 strong recommendations. No recommendation was provided for three questions.
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| 8. |
- Pichora-Fuller, Kathleen M., et al.
(författare)
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Hearing Impairment and Cognitive Energy: The Framework for Understanding Effortful Listening (FUEL)
- 2016
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Ingår i: Ear and Hearing. - : LIPPINCOTT WILLIAMS & WILKINS. - 0196-0202 .- 1538-4667. ; 37, s. 5S-27S
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Tidskriftsartikel (refereegranskat)abstract
- The Fifth Eriksholm Workshop on "Hearing Impairment and Cognitive Energy" was convened to develop a consensus among interdisciplinary experts about what is known on the topic, gaps in knowledge, the use of terminology, priorities for future research, and implications for practice. The general term cognitive energy was chosen to facilitate the broadest possible discussion of the topic. It goes back to Titchener (1908) who described the effects of attention on perception; he used the term psychic energy for the notion that limited mental resources can be flexibly allocated among perceptual and mental activities. The workshop focused on three main areas: (1) theories, models, concepts, definitions, and frameworks; (2) methods and measures; and (3) knowledge translation. We defined effort as the deliberate allocation of mental resources to overcome obstacles in goal pursuit when carrying out a task, with listening effort applying more specifically when tasks involve listening. We adapted Kahnemans seminal (1973) Capacity Model of Attention to listening and proposed a heuristically useful Framework for Understanding Effortful Listening (FUEL). Our FUEL incorporates the well-known relationship between cognitive demand and the supply of cognitive capacity that is the foundation of cognitive theories of attention. Our FUEL also incorporates a motivation dimension based on complementary theories of motivational intensity, adaptive gain control, and optimal performance, fatigue, and pleasure. Using a three-dimensional illustration, we highlight how listening effort depends not only on hearing difficulties and task demands but also on the listeners motivation to expend mental effort in the challenging situations of everyday life.
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| 9. |
- Zhang, Ruiyan, et al.
(författare)
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The sialic acid-dependent nematocyst discharge process in relation to its physical-chemical properties is a role model for nanomedical diagnostic and therapeutic tools
- 2019
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Ingår i: Marine Drugs. - : MDPI AG. - 1660-3397. ; 17:8
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Tidskriftsartikel (refereegranskat)abstract
- Formulas derived from theoretical physics provide important insights about the nematocyst discharge process of Cnidaria (Hydra, jellyfishes, box-jellyfishes and sea-anemones). Our model description of the fastest process in living nature raises and answers questions related to the material properties of the cell- and tubule-walls of nematocysts including their polysialic acid (polySia) dependent target function. Since a number of tumor-cells, especially brain-tumor cells such as neuroblastoma tissues carry the polysaccharide chain polySia in similar concentration as fish eggs or fish skin, it makes sense to use these findings for new diagnostic and therapeutic approaches in the field of nanomedicine. Therefore, the nematocyst discharge process can be considered as a bionic blue-print for future nanomedical devices in cancer diagnostics and therapies. This approach is promising because the physical background of this process can be described in a sufficient way with formulas presented here. Additionally, we discuss biophysical and biochemical experiments which will allow us to define proper boundary conditions in order to support our theoretical model approach. PolySia glycans occur in a similar density on malignant tumor cells than on the cell surfaces of Cnidarian predators and preys. The knowledge of the polySia-dependent initiation of the nematocyst discharge process in an intact nematocyte is an essential prerequisite regarding the further development of target-directed nanomedical devices for diagnostic and therapeutic purposes. The theoretical description as well as the computationally and experimentally derived results about the biophysical and biochemical parameters can contribute to a proper design of anti-tumor drug ejecting vessels which use a stylet-tubule system. Especially, the role of nematogalectins is of interest because these bridging proteins contribute as well as special collagen fibers to the elastic band properties. The basic concepts of the nematocyst discharge process inside the tubule cell walls of nematocysts were studied in jellyfishes and in Hydra which are ideal model organisms. Hydra has already been chosen by Alan Turing in order to figure out how the chemical basis of morphogenesis can be described in a fundamental way. This encouraged us to discuss the action of nematocysts in relation to morphological aspects and material requirements. Using these insights, it is now possible to discuss natural and artificial nematocyst-like vessels with optimized properties for a diagnostic and therapeutic use, e.g., in neurooncology. We show here that crucial physical parameters such as pressure thresholds and elasticity properties during the nematocyst discharge process can be described in a consistent and satisfactory way with an impact on the construction of new nanomedical devices.
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| 10. |
- Currow, David, et al.
(författare)
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A pragmatic, phase III, multisite, double-blind, placebo-controlled, parallel-Arm, dose increment randomised trial of regular, low-dose extended-release morphine for chronic breathlessness : Breathlessness, Exertion and Morphine Sulfate (BEAMS) study protocol
- 2017
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Chronic breathlessness is highly prevalent and distressing to patients and families. No medication is registered for its symptomatic reduction. The strongest evidence is for regular, low-dose, extended-release (ER) oral morphine. A recent large phase III study suggests the subgroup most likely to benefit have chronic obstructive pulmonary disease (COPD) and modified Medical Research Council breathlessness scores of 3 or 4. This protocol is for an adequately powered, parallel-Arm, placebo-controlled, multisite, factorial, block-randomised study evaluating regular ER morphine for chronic breathlessness in people with COPD. Methods and analysis The primary question is what effect regular ER morphine has on worst breathlessness, measured daily on a 0-10 numerical rating scale. Uniquely, the coprimary outcome will use a FitBit to measure habitual physical activity. Secondary questions include safety and, whether upward titration after initial benefit delivers greater net symptom reduction. Substudies include longitudinal driving simulation, sleep, caregiver, health economic and pharmacogenetic studies. Seventeen centres will recruit 171 participants from respiratory and palliative care. The study has five phases including three randomisation phases to increasing doses of ER morphine. All participants will receive placebo or active laxatives as appropriate. Appropriate statistical analysis of primary and secondary outcomes will be used. Ethics and dissemination Ethics approval has been obtained. Results of the study will be submitted for publication in peer-reviewed journals, findings presented at relevant conferences and potentially used to inform registration of ER morphine for chronic breathlessness. Trial registration number NCT02720822; Pre-results.
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