| 1. |
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| 2. |
- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 3. |
- Pulit, S. L., et al.
(författare)
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Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 x 10(-4) in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 x 10(-48)), explaining similar to 20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07,p = 0.004), but no other primary stroke subtypes (all p > 0.1). Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.
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| 5. |
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| 7. |
- Marini, S., et al.
(författare)
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Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis
- 2019
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Ingår i: Jama Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:4, s. 480-491
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Genetic studies of intracerebral hemorrhage (ICH) have focused mainly on white participants, but genetic risk may vary or could be concealed by differing nongenetic coexposures in nonwhite populations. Transethnic analysis of risk may clarify the role of genetics in ICH risk across populations. OBJECTIVE To evaluate associations between established differences in ICH risk by race/ethnicity and the variability in the risks of apolipoprotein E (APOE) epsilon 4 alleles, the most potent genetic risk factor for ICH. DESIGN, SETTING, AND PARTICIPANTS This case-control study of primary ICH meta-analyzed the association of APOE allele status on ICH risk, applying a 2-stage clustering approach based on race/ethnicity and stratified by a contributing study. A propensity score analysis was used to model the association of APOE with the burden of hypertension across race/ethnic groups. Primary ICH cases and controls were collected from 3 hospital- and population-based studies in the United States and 8 in European sites in the International Stroke Genetic Consortium. Participants were enrolled from January 1, 1999, to December 31, 2017. Participants with secondary causes of ICH were excluded from enrollment. Controls were regionally matched within each participating study. MAIN OUTCOMES AND MEASURES Clinical variables were systematically obtained from structured interviews within each site. APOE genotype was centrally determined for all studies. RESULTS In total, 13 124 participants (7153 [54.5%] male with a median [interquartile range] age of 66 [56-76] years) were included. In white participants, APOE epsilon 2 (odds ratio [OR], 1.49; 95% CI, 1.24-1.80; P < .001) and APOE epsilon 4 (OR, 1.51; 95% CI, 1.23-1.85; P < .001) were associated with lobar ICH risk; however, within self-identified Hispanic and black participants, no associations were found. After propensity score matching for hypertension burden, APOE epsilon 4 was associated with lobar ICH risk among Hispanic (OR, 1.14; 95% CI, 1.03-1.28; P = .01) but not in black (OR, 1.02; 95% CI, 0.98-1.07; P = .25) participants. APOE epsilon 2 and epsilon 4 did not show an association with nonlobar ICH risk in any race/ethnicity. CONCLUSIONS AND RELEVANCE APOE epsilon 4 and epsilon 2 alleles appear to affect lobar ICH risk variably by race/ethnicity, associations that are confirmed in white individuals but can be shown in Hispanic individuals only when the excess burden of hypertension is propensity score-matched; further studies are needed to explore the interactions between APOE alleles and environmental exposures that vary by race/ethnicity in representative populations at risk for ICH.
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| 8. |
- Pierre, M., et al.
(författare)
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The XXL survey : First results and future
- 2017
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Ingår i: Astronomical Notes - Astronomische Nachrichten. - : Wiley-VCH Verlagsgesellschaft. - 0004-6337 .- 1521-3994. ; 338:2-3, s. 334-341
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Tidskriftsartikel (refereegranskat)abstract
- The XXL survey currently covers two 25 deg(2) patches with XMM observations of similar to 10 ks. We summarize the scientific results associated with the first release of the XXL dataset, which occurred in mid-2016. We review several arguments for increasing the survey depth to 40 ks during the next decade of XMM operations. X-ray (z < 2) cluster, (z < 4) active galactic nuclei (AGN), and cosmic background survey science will then benefit from an extraordinary data reservoir. This, combined with deep multi-lambda observations, will lead to solid standalone cosmological constraints and provide a wealth of information on the formation and evolution of AGN, clusters, and the X-ray background. In particular, it will offer a unique opportunity to pinpoint the z > 1 cluster density. It will eventually constitute a reference study and an ideal calibration field for the upcoming eROSITA and Euclid missions.
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| 9. |
- Wang, HD, et al.
(författare)
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Global, regional, national, and selected subnational levels of stillbirths, neonatal, infant, and under-5 mortality, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: Lancet (London, England). - : Elsevier. - 1474-547X .- 0140-6736. ; 388:10053, s. 1725-1774
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Tidskriftsartikel (refereegranskat)
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| 10. |
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| 11. |
- Sawcer, Stephen, et al.
(författare)
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Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
- 2011
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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| 12. |
- Wang, Haidong, et al.
(författare)
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Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015 : a systematic analysis for the Global Burden of Disease Study 2015
- 2016
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 388:10053, s. 1459-1544
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures.METHODS: We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14 294 geography-year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER).FINDINGS: Globally, life expectancy from birth increased from 61·7 years (95% uncertainty interval 61·4-61·9) in 1980 to 71·8 years (71·5-72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7-17·4), to 62·6 years (56·5-70·2). Total deaths increased by 4·1% (2·6-5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0% (15·8-18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1% (12·6-16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1% (11·9-14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1%, 39·1-44·6), malaria (43·1%, 34·7-51·8), neonatal preterm birth complications (29·8%, 24·8-34·9), and maternal disorders (29·1%, 19·3-37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146 000 deaths, 118 000-183 000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393 000 deaths, 228 000-532 000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost [YLLs]) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death.INTERPRETATION: At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems.
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| 14. |
- Axfors, Cathrine, et al.
(författare)
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Association between convalescent plasma treatment and mortality in COVID-19 : a collaborative systematic review and meta-analysis of randomized clinical trials
- 2021
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Ingår i: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 21:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I-2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
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| 15. |
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| 16. |
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| 17. |
- DeAngelis, Nicola, et al.
(författare)
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2020 WSES guidelines for the detection and management of bile duct injury during cholecystectomy
- 2021
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Ingår i: World Journal of Emergency Surgery. - : BMC. - 1749-7922. ; 16:1
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Forskningsöversikt (refereegranskat)abstract
- Bile duct injury (BDI) is a dangerous complication of cholecystectomy, with significant postoperative sequelae for the patient in terms of morbidity, mortality, and long-term quality of life. BDIs have an estimated incidence of 0.4-1.5%, but considering the number of cholecystectomies performed worldwide, mostly by laparoscopy, surgeons must be prepared to manage this surgical challenge. Most BDIs are recognized either during the procedure or in the immediate postoperative period. However, some BDIs may be discovered later during the postoperative period, and this may translate to delayed or inappropriate treatments. Providing a specific diagnosis and a precise description of the BDI will expedite the decision-making process and increase the chance of treatment success. Subsequently, the choice and timing of the appropriate reconstructive strategy have a critical role in long-term prognosis. Currently, a wide spectrum of multidisciplinary interventions with different degrees of invasiveness is indicated for BDI management. These World Society of Emergency Surgery (WSES) guidelines have been produced following an exhaustive review of the current literature and an international expert panel discussion with the aim of providing evidence-based recommendations to facilitate and standardize the detection and management of BDIs during cholecystectomy. In particular, the 2020 WSES guidelines cover the following key aspects: (1) strategies to minimize the risk of BDI during cholecystectomy; (2) BDI rates in general surgery units and review of surgical practice; (3) how to classify, stage, and report BDI once detected; (4) how to manage an intraoperatively detected BDI; (5) indications for antibiotic treatment; (6) indications for clinical, biochemical, and imaging investigations for suspected BDI; and (7) how to manage a postoperatively detected BDI.
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| 18. |
- Beal, Jacob, et al.
(författare)
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Robust estimation of bacterial cell count from optical density
- 2020
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 19. |
- Björck, Svante, et al.
(författare)
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A Holocene lacustrine record in the central North Atlantic: proxies for volcanic activity, short-term NAO mode variability, and long-term precipitation changes
- 2006
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 25:1-2, s. 9-32
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Tidskriftsartikel (refereegranskat)abstract
- Lake and peat corings on three Azores islands in the central North Atlantic, resulted in the discovery of a 6000 year long lacustrine sequence in a small crater lake, Lake Caveiro, on the island of Pico. This island is dominated by Pico mountain (2351 m), Portugal's highest mountain, and the lake site is situated at 903 in asl. Two sediment profiles, one central and one littoral, were sampled. Due to large facial shifts and disconformities in the littoral cores the analyses were concentrated on the central core; only the earliest 1000 years of the littoral core were studied to complement the central profile. We used sedimentology, geochemistry, diatom analyses, magnetic properties, and multivariate statistics, together with C-14 and Pb-210 dating techniques, to analyse the environmental history of the lake. Volcanic activity seems to have had a dominating impact on sediment changes and partly also on the diatom assemblages; a large number of tephras are found and seem to be connected with large (diatom) inferred pH variations. However, by a combination of methods, including multivariate techniques, we infer that precipitation changes can be detected through the volcanic noise. In the youngest part of the record (AD 1600-2000), with its decadal resolution, these humidity variations seem partly related to shifts in dominating NAO mode. The more long-term precipitation changes further back in time (350-5100 cal yr BP) roughly correspond to the well-known North Atlantic drift-ice variations as well as other North Atlantic records; low precipitation during drift-ice periods. We think these alterations were driven by changes in the thermolialine circulation as large-scale equivalences to the Great Salt Anomaly; low sea surface A temperatures and changes in circulation patterns of the central North Atlantic decreased the regional precipitation. Cooler/drier periods occurred 400-800, 1300-1800, 2600-3000, 3300-3400 and possibly also 4400-4600 cal yr BP,. while 300-400, 900-1000, 2000-2400, 3100-3200, 3800-4000 and 4700-5000 cal yr BP seem to have been more humid phases on the Azores. (c) 2005 Elsevier Ltd. All rights reserved.
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| 20. |
- Childerhouse, Thomas, et al.
(författare)
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Machining performance and wear behaviour of polycrystalline diamond and coated carbide tools during milling of titanium alloy Ti-54M
- 2023
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Ingår i: Wear. - : Elsevier BV. - 0043-1648. ; 523
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Tidskriftsartikel (refereegranskat)abstract
- Polycrystalline diamond (PCD) is currently under development as a new generation of cutting tool material for titanium alloy machining applications. The unrivaled high temperature hardness possessed by PCD offers the potential for higher levels of productivity compared to tungsten carbide, the current industry standard tool material, through facilitating higher cutting speeds. This study investigates the performance of various PCD tool grades during square shoulder milling of Ti-54M. The influence of PCD grain size on dominant wear mechanism has been established, revealing that a smaller, sub 1 μm, grain size offers improvements in tool life due to superior fracture toughness compared to larger grained material. For fine grained PCD, loss of tool material through a cyclic process of workpiece adhesion followed by grain pull-out was identified to be the predominant wear mechanism, contrasting the mechanical fracture dominated wear observed for the larger grained PCD grades. The influence of insert microgeometry was also investigated through honing of the cutting edge radii. An increased tendency for edge fracture was demonstrated when machining with larger radii tooling which was attributed to increased cutting forces. Finally, the study has compared the surface integrity response of the workpiece following PCD and carbide machining, revealing considerably lower levels of microstructural damage and cutting forces when machining with PCD. This highlights the potential benefits of PCD in finishing applications, whereby high speed machining can be employed to reduce the impact on component surface integrity.
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| 21. |
- Coelho, Teresa, et al.
(författare)
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Eplontersen for Hereditary Transthyretin Amyloidosis with Polyneuropathy
- 2023
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 330:15, s. 1448-1458
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis.Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy.Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group.Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60).Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights.Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P <.001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P <.001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P <.001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group.Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo.Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.
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| 22. |
- Commowick, Olivier, et al.
(författare)
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Objective Evaluation of Multiple Sclerosis Lesion Segmentation using a Data Management and Processing Infrastructure
- 2018
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- We present a study of multiple sclerosis segmentation algorithms conducted at the international MICCAI 2016 challenge. This challenge was operated using a new open-science computing infrastructure. This allowed for the automatic and independent evaluation of a large range of algorithms in a fair and completely automatic manner. This computing infrastructure was used to evaluate thirteen methods of MS lesions segmentation, exploring a broad range of state-of-theart algorithms, against a high-quality database of 53 MS cases coming from four centers following a common definition of the acquisition protocol. Each case was annotated manually by an unprecedented number of seven different experts. Results of the challenge highlighted that automatic algorithms, including the recent machine learning methods (random forests, deep learning,.), are still trailing human expertise on both detection and delineation criteria. In addition, we demonstrate that computing a statistically robust consensus of the algorithms performs closer to human expertise on one score (segmentation) although still trailing on detection scores.
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| 23. |
- DeSouza, Nandita M., et al.
(författare)
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Standardised lesion segmentation for imaging biomarker quantitation : a consensus recommendation from ESR and EORTC
- 2022
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Ingår i: Insights into Imaging. - : Springer. - 1869-4101. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Lesion/tissue segmentation on digital medical images enables biomarker extraction, image-guided therapy delivery, treatment response measurement, and training/validation for developing artificial intelligence algorithms and workflows. To ensure data reproducibility, criteria for standardised segmentation are critical but currently unavailable. Methods A modified Delphi process initiated by the European Imaging Biomarker Alliance (EIBALL) of the European Society of Radiology (ESR) and the European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group was undertaken. Three multidisciplinary task forces addressed modality and image acquisition, segmentation methodology itself, and standards and logistics. Devised survey questions were fed via a facilitator to expert participants. The 58 respondents to Round 1 were invited to participate in Rounds 2-4. Subsequent rounds were informed by responses of previous rounds. Results/conclusions Items with >= 75% consensus are considered a recommendation. These include system performance certification, thresholds for image signal-to-noise, contrast-to-noise and tumour-to-background ratios, spatial resolution, and artefact levels. Direct, iterative, and machine or deep learning reconstruction methods, use of a mixture of CE marked and verified research tools were agreed and use of specified reference standards and validation processes considered essential. Operator training and refreshment were considered mandatory for clinical trials and clinical research. Items with a 60-74% agreement require reporting (site-specific accreditation for clinical research, minimal pixel number within lesion segmented, use of post-reconstruction algorithms, operator training refreshment for clinical practice). Items with <= 60% agreement are outside current recommendations for segmentation (frequency of system performance tests, use of only CE-marked tools, board certification of operators, frequency of operator refresher training). Recommendations by anatomical area are also specified.
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| 24. |
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| 25. |
- Fournier, Laure, et al.
(författare)
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Incorporating radiomics into clinical trials : expert consensus endorsed by the European Society of Radiology on considerations for data-driven compared to biologically driven quantitative biomarkers
- 2021
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Ingår i: European Radiology. - : SPRINGER. - 0938-7994 .- 1432-1084. ; 31:8, s. 6001-6012
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Tidskriftsartikel (refereegranskat)abstract
- Existing quantitative imaging biomarkers (QIBs) are associated with known biological tissue characteristics and follow a well-understood path of technical, biological and clinical validation before incorporation into clinical trials. In radiomics, novel data-driven processes extract numerous visually imperceptible statistical features from the imaging data with no a priori assumptions on their correlation with biological processes. The selection of relevant features (radiomic signature) and incorporation into clinical trials therefore requires additional considerations to ensure meaningful imaging endpoints. Also, the number of radiomic features tested means that power calculations would result in sample sizes impossible to achieve within clinical trials. This article examines how the process of standardising and validating data-driven imaging biomarkers differs from those based on biological associations. Radiomic signatures are best developed initially on datasets that represent diversity of acquisition protocols as well as diversity of disease and of normal findings, rather than within clinical trials with standardised and optimised protocols as this would risk the selection of radiomic features being linked to the imaging process rather than the pathology. Normalisation through discretisation and feature harmonisation are essential pre-processing steps. Biological correlation may be performed after the technical and clinical validity of a radiomic signature is established, but is not mandatory. Feature selection may be part of discovery within a radiomics-specific trial or represent exploratory endpoints within an established trial; a previously validated radiomic signature may even be used as a primary/secondary endpoint, particularly if associations are demonstrated with specific biological processes and pathways being targeted within clinical trials.
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| 26. |
- Lamarca, Angela, et al.
(författare)
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Tumour Growth Rate as a validated early radiological biomarker able to reflect treatment-induced changes in Neuroendocrine Tumours : the GREPONET-2 study
- 2019
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 15:25, s. 6692-6699
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: TGR represents the percentage change in tumour volume per month (%/m). Previous results from the GREPONET study showed that TGR measured after 3 months (TGR3m) of starting systemic treatment (ST) or watch and wait (WW) was an early biomarker predicting progression-free survival (PFS) in NETs.EXPERIMENTAL DESIGN: Pts from7 centres with advanced grade(G) 1/2 NETs from the pancreas(P)/small bowel(SB) initiating ST/WW were eligible. Computed tomography (CT) / magnetic resonance imaging (MRI) performed at pre-baseline, baseline and 3(+/-1) months of study entry were retrospectively reviewed. Aim-1: explore treatment-induced changes in TGR (ΔTGR3m-BL) (paired T-test) and Aim-2: validate TGR3m (<0.8%/m vs ≥0.8%/m) as an early biomarker in an independent cohort (Kaplan-Meier/Cox Regression).RESULTS: Out of 785 pts screened, 127 were eligible. Mean (SD) TGR0 and TGR3m were 5.4%/m (14.9) and -1.4%/m (11.8), respectively. Mean(SD) ΔTGR3m-BL paired-difference was -6.8%/m(19.3) (p<0.001). Most marked ΔTGR3m-BL (mean (SD);p) were identified with targeted therapies (-11.3%/m(4.7);0.0237) and chemotherapy (-7.9%/m(3.4);0.0261). Multivariable analysis confirmed the absence of previous treatment (Odds Ratio (OR) 4.65 (95%CI 1.31-16.52); p-value0.018) and low TGR3m (continuous variable; OR 1.09 (95%CI 1.01-1.19); p-value0.042) to be independent predictors of radiological objective response. When the multivariable Cox Regression was adjusted to grade (p-value 0.004) and stage (p-value0.017), TGR3m≥0.8 (vs.<0.8) maintained its significance (p<0.001), while TGR0 and ΔTGR3m-BL did not. TGR3m was confirmed as an independent prognosis factor for PFS (external validation; Aim-2) (multivariable HR 2.21 (95%CI 1.21-3.70); p-value0.003).CONCLUSIONS: TGR has a role as biomarker for monitoring response to therapy for early prediction of PFS and radiological objective response.
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| 27. |
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| 28. |
- Levis, Brooke, et al.
(författare)
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Comparison of major depression diagnostic classification probability using the SCID, CIDI, and MINI diagnostic interviews among women in pregnancy or postpartum : An individual participant data meta-analysis
- 2019
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Ingår i: International Journal of Methods in Psychiatric Research. - : WILEY. - 1049-8931 .- 1557-0657. ; 28:4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: A previous individual participant data meta-analysis (IPDMA) identified differences in major depression classification rates between different diagnostic interviews, controlling for depressive symptoms on the basis of the Patient Health Questionnaire-9. We aimed to determine whether similar results would be seen in a different population, using studies that administered the Edinburgh Postnatal Depression Scale (EPDS) in pregnancy or postpartum.Methods: Data accrued for an EPDS diagnostic accuracy IPDMA were analysed. Binomial generalised linear mixed models were fit to compare depression classification odds for the Mini International Neuropsychiatric Interview (MINI), Composite International Diagnostic Interview (CIDI), and Structured Clinical Interview for DSM (SCID), controlling for EPDS scores and participant characteristics.Results Among fully structured interviews, the MINI (15 studies, 2,532 participants, 342 major depression cases) classified depression more often than the CIDI (3 studies, 2,948 participants, 194 major depression cases; adjusted odds ratio [aOR] = 3.72, 95% confidence interval [CI] [1.21, 11.43]). Compared with the semistructured SCID (28 studies, 7,403 participants, 1,027 major depression cases), odds with the CIDI (interaction aOR = 0.88, 95% CI [0.85, 0.92]) and MINI (interaction aOR = 0.95, 95% CI [0.92, 0.99]) increased less as EPDS scores increased.Conclusion Different interviews may not classify major depression equivalently.
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| 29. |
- Maastrup, Ragnhild, et al.
(författare)
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Compliance with the Baby-friendly Hospital Initiative for Neonatal Wards (Neo-BFHI) : A cross-sectional study in 36 countries
- 2019
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Ingår i: Maternal and Child Nutrition. - : Blackwell Science Ltd.. - 1740-8695 .- 1740-8709. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- In 2012, the Baby-friendly Hospital Initiative for Neonatal Wards (Neo-BFHI) began providing recommendations to improve breastfeeding support for preterm and ill infants. This cross-sectional survey aimed to measure compliance on a global level with the Neo-BFHI’s expanded Ten steps to Successful Breastfeeding and three Guiding Principles in neonatal wards. In 2017 the Neo-BFHI Self-Assessment questionnaire was used in 15 languages to collect data from neonatal wards of all levels of care. Answers were summarized into compliance scores ranging from 0 to 100 at the ward, country and international levels. A total of 917 neonatal wards from 36 low, middle and high-income countries from all continents participated. The median international overall score was 77, and median country overall scores ranged from 52 to 91. Guiding Principle 1 (respect for mothers), Step 5 (breastfeeding initiation and support), and Step 6 (human milk use) had the highest scores, 100, 88, and 88, respectively. Steps 3 (antenatal information) and 7 (rooming-in) had the lowest scores, 63 and 67, respectively. High-income countries had significantly higher scores for Guiding principle 2 (family-centered care), Step 4 (skin-to-skin contact) and Step 5. Neonatal wards in hospitals ever-designated Baby-friendly had significantly higher scores than those never designated. Sixty percent of managers stated they would like to obtain Neo-BFHI designation. Currently, Neo-BFHI recommendations are partly implemented in many countries. The high number of participating wards indicates international readiness to expand Baby-friendly standards to neonatal settings. Hospitals and governments should increase their efforts to better support breastfeeding in neonatal wards.
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| 30. |
- Macerol, Nastja, 1988, et al.
(författare)
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A lapping-based test method to investigate wear behaviour of bonded-abrasive tools
- 2022
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Ingår i: CIRP Annals - Manufacturing Technology. - : Elsevier BV. - 1726-0604 .- 0007-8506. ; 71:1, s. 305-308
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Tidskriftsartikel (refereegranskat)abstract
- Grinding-wheel wear is a critical factor affecting grinding performance and tool cost. Unfortunately, wear tests – particularly with superabrasives – can be notoriously time-consuming. Therefore, a novel lapping-based method is proposed for investigating wear behaviour of the grit-bond system. Wear tests were performed in (i) lapping, (ii) surface grinding, and (iii) cylindrical grinding for a range of grit-shape aspect ratios and grit-toughness values for the same grit-bond systems. Results showed that all three methods yielded similar trends. This indicates that the lapping tests could be a viable substitute for lengthy grinding tests, resulting in shorter testing times and smaller specimen sizes.
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| 31. |
- Macerol, Nastja, 1988, et al.
(författare)
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Effect of the grit shape on the performance of vitrified-bonded CBN grinding wheel
- 2020
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Ingår i: Journal of Materials Processing Technology. - : Elsevier BV. - 0924-0136. ; 277
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Tidskriftsartikel (refereegranskat)abstract
- This paper deals with the effect of the CBN grit shape on the grindability of a low alloy chrome steel, 100Cr6. Firstly, a simple wheel-workpiece interaction model is introduced to investigate the grinding response. The formulation considers the global grinding forces, which embodies all the properties of the wheel acting at the interface. The use of this approach eliminates the need to consider the interaction of each individual grit with the workpiece during the grinding process. Next, a series of tailored grinding tests conducted with a creep-feed grinding machine are used to evaluate the grinding performance and the wheel wear. The results have shown that the specific grinding energy (ue) is affected by the CBN grit shape, and the wheel wear is proportional to the ratio of the CBN shape factor (Aspect Ratio) and the overall bearing surface of the wheel-workpiece contact area (af).
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| 32. |
- Macerol, Nastja, 1988, et al.
(författare)
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The effects of grit properties and dressing on grinding mechanics and wheel performance: Analytical assessment framework
- 2022
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Ingår i: International Journal of Machine Tools and Manufacture. - : Elsevier BV. - 0890-6955. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- This paper introduces an analytical assessment framework for evaluating grinding wheel performance derived from the model of cutting and sliding grinding force components. Four new parameters are proposed based on wheel topography. These parameters are normalized through the aggressiveness number, which circumvents the influences of grinding geometry and kinematics. The framework is validated through experiments with different wheel topographies obtained by changing dressing conditions and grit properties (toughness, thermal stability and shape). The framework and experiments quantify how wheel wear flat area influences the sliding component and how grit protrusion influences the intrinsic specific grinding energy. This framework provides a rational basis for evaluating grinding-wheel performance and abrasive-grit selection.
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| 33. |
- Morozov, Konstantin M., et al.
(författare)
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Efficient UV Luminescence from Organic-Based Tamm Plasmon Structures Emitting in the Strong-Coupling Regime
- 2020
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Ingår i: The Journal of Physical Chemistry C. - : AMER CHEMICAL SOC. - 1932-7447 .- 1932-7455. ; 124:39, s. 21656-21663
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Tidskriftsartikel (refereegranskat)abstract
- Excitons in organic semiconductors possessing a large oscillator strength demonstrate strong coupling with cavity modes at room temperature. A large Stokes shift in some organic semiconductors enriches and complicates the picture of the emission in strongly coupled systems of organic excitons and light. Here, we demonstrate strong coupling of excitons in 4,4-bis(N-carbazolyl)-1,1-biphenyl (CBP) and Tamm plasmons in the ultraviolet (UV) band, accompanied by a bright emission from the structure. Reflection measurements demonstrate the pronounced formation of the lower and upper polariton modes with Rabi splitting of the magnitude of 0.3 eV, and the emission peak experiences a substantial red shift with respect to the lower polariton mode. Both radiative and nonradiative decay rates in the Tamm plasmon CBP structure are increased with respect to a bare CBP. Such peculiar behavior is attributed to the simultaneous manifestation of strong coupling and weak coupling of the CBP molecule emitters to the Tamm plasmons.
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| 34. |
- Morozov, Konstantin M., et al.
(författare)
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Opposite Sign of Polarization Splitting in Ultrastrongly Coupled Organic Tamm Plasmon Structures
- 2021
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Ingår i: The Journal of Physical Chemistry C. - : AMER CHEMICAL SOC. - 1932-7447 .- 1932-7455. ; 125:15, s. 8376-8381
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Tidskriftsartikel (refereegranskat)abstract
- The properties of the ultrastrongly coupled Tamm plasmon cavity filled with a high-oscillator-strength organic material DPAVBi (4,4-bis[4-(di-p-tolylamino)styryl]biphenyl) are studied using theoretical and experimental methods. An analytical model predicts the opposite sign of polarization splitting for the lower and upper polariton cases and a giant absolute value of the splitting. A set of organic Tamm plasmon cavities with different detuning parameters are fabricated. We demonstrate that all structures are operating in the ultrastrong coupling regime: the values of the Rabi splitting are close to a 20% fraction of the exciton energy. The measured angle-dependent reflectivity spectra structure for both transverse electric (TE) and transverse magnetic (TM) polarizations confirm the predicted theoretical model. We obtained a giant value of the polarization splitting of up to 180 meV for both polariton branches. We believe that it is the first demonstration of such peculiar polarization splitting behavior of polaritons in the ultrastrong coupling regime.
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| 35. |
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| 36. |
- Porpino, Suenia K. P., et al.
(författare)
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Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension
- 2016
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 173:14, s. 2290-2302
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Tidskriftsartikel (refereegranskat)abstract
- Background and PurposeNO deficiency and oxidative stress are crucially involved in the development or progression of cardiovascular disease, including hypertension and stroke. We have previously demonstrated that acute treatment with the newly discovered organic nitrate, 2-nitrate-1,3-dibuthoxypropan (NDBP), is associated with NO-like effects in the vasculature. This study aimed to further characterize the mechanism(s) and to elucidate the therapeutic potential in a model of hypertension and oxidative stress. Experimental ApproachA combination of ex vivo, in vitro and in vivo approaches was used to assess the effects of NDBP on vascular reactivity, NO release, NADPH oxidase activity and in a model of hypertension. Key ResultsEx vivo vascular studies demonstrated NDBP-mediated vasorelaxation in mesenteric resistance arteries, which was devoid of tolerance. In vitro studies using liver and kidney homogenates revealed dose-dependent and sustained NO generation by NDBP, which was attenuated by the xanthine oxidase inhibitor febuxostat. In addition, NDBP reduced NADPH oxidase activity in the liver and prevented angiotensin II-induced activation of NADPH oxidase in the kidney. In vivo studies showed that NDBP halted the progression of hypertension in mice with chronic angiotensin II infusion. This was associated with attenuated cardiac hypertrophy, and reduced NADPH oxidase-derived oxidative stress and fibrosis in the kidney and heart. Conclusion and ImplicationsThe novel organic nitrate NDBP halts the progression of angiotensin II-mediated hypertension. Mechanistically, our findings suggest that NDBP treatment is associated with sustained NO release and attenuated activity of NADPH oxidase, which to some extent requires functional xanthine oxidase.
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