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| 2. |
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| 3. |
- Murari, A., et al.
(författare)
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A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
- 2024
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Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
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| 7. |
- Lumbers, R. T., et al.
(författare)
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The genomics of heart failure: design and rationale of the HERMES consortium
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:6, s. 5531-5541
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Tidskriftsartikel (refereegranskat)abstract
- Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure. Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model. Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.
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| 8. |
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| 9. |
- Winkler, TW, et al.
(författare)
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Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals
- 2022
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Ingår i: Communications biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1, s. 580-
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Tidskriftsartikel (refereegranskat)abstract
- Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.
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| 10. |
- McBride, D. A., et al.
(författare)
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Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis
- 2023
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Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naive T cells into anti-inflammatory regulatory T cells (T-reg) and suppression of T-reg destabilization. Sustained release poly-(lactic-co-glycolic) acid (PLGA)-based biodegradable microparticles encapsulating ATRA (PLGA-ATRA MP) are retained in arthritic mouse joints after intra-articular (IA) injection. IA PLGA-ATRA MP enhance migratory T-reg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of T-reg. PLGA-ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen-induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA-ATRA MP is not associated with generalized immune suppression. PLGA-ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.
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| 11. |
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| 12. |
- Prigge, R., et al.
(författare)
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International comparison of glycaemic control in people with type 1 diabetes: an update and extension
- 2022
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 39:5
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. Methods: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c(IQR) and proportions of individuals with HbA1c < 58mmol/mol (<7.5%), 58–74mmol/mol (7.5–8.9%) and ≥75mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15–24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58mmol/mol (<7.5%) relative to ≥58mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. Results: Median HbA1c varied from 55 to 79mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c< 58mmol/mol (<7.5%) were 0.91 (0.90–0.92) for women compared to men, 1.68 (1.65–1.71) for people aged <15years and 0.81 (0.79–0.82) aged15–24years compared to those aged ≥25years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c<58mmol/l (<7.5%) increased and proportions of people with HbA1c≥ 75mmol/mol (≥9.0%) decreased. Conclusions: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.
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| 13. |
- Shah, S, et al.
(författare)
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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 163-
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Tidskriftsartikel (refereegranskat)abstract
- Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.
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| 14. |
- Callaway, EM, et al.
(författare)
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A multimodal cell census and atlas of the mammalian primary motor cortex
- 2021
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 598:7879, s. 86-102
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Tidskriftsartikel (refereegranskat)abstract
- Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties and cellular resolution input–output mapping, integrated through cross-modal computational analysis. Our results advance the collective knowledge and understanding of brain cell-type organization1–5. First, our study reveals a unified molecular genetic landscape of cortical cell types that integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a consensus taxonomy of transcriptomic types and their hierarchical organization that is conserved from mouse to marmoset and human. Third, in situ single-cell transcriptomics provides a spatially resolved cell-type atlas of the motor cortex. Fourth, cross-modal analysis provides compelling evidence for the transcriptomic, epigenomic and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types. We further present an extensive genetic toolset for targeting glutamatergic neuron types towards linking their molecular and developmental identity to their circuit function. Together, our results establish a unifying and mechanistic framework of neuronal cell-type organization that integrates multi-layered molecular genetic and spatial information with multi-faceted phenotypic properties.
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| 15. |
- Orsini, S., et al.
(författare)
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Inner southern magnetosphere observation of Mercury via SERENA ion sensors in BepiColombo mission
- 2022
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Mercury’s southern inner magnetosphere is an unexplored region as it was not observed by earlier space missions. In October 2021, BepiColombo mission has passed through this region during its first Mercury flyby. Here, we describe the observations of SERENA ion sensors nearby and inside Mercury’s magnetosphere. An intermittent high-energy signal, possibly due to an interplanetary magnetic flux rope, has been observed downstream Mercury, together with low energy solar wind. Low energy ions, possibly due to satellite outgassing, were detected outside the magnetosphere. The dayside magnetopause and bow-shock crossing were much closer to the planet than expected, signature of a highly eroded magnetosphere. Different ion populations have been observed inside the magnetosphere, like low latitude boundary layer at magnetopause inbound and partial ring current at dawn close to the planet. These observations are important for understanding the weak magnetosphere behavior so close to the Sun, revealing details never reached before.
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| 16. |
- Alhilou, AM, et al.
(författare)
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Nerve growth factor and glutamate increase the density and expression of substance P-containing nerve fibers in healthy human masseter muscles
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 15673-
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Tidskriftsartikel (refereegranskat)abstract
- Nocifensive behavior induced by injection of glutamate or nerve growth factor (NGF) into rats masseter muscle is mediated, in part, through the activation of peripheral NMDA receptors. However, information is lacking about the mechanism that contributes to pain and sensitization induced by these substances in humans. Immunohistochemical analysis of microbiopsies obtained from human masseter muscle was used to investigate if injection of glutamate into the NGF-sensitized masseter muscle alters the density or expression of the NMDA receptor subtype 2B (NR2B) or NGF by putative sensory afferent (that express SP) fibers. The relationship between expression and pain characteristics was also examined. NGF and glutamate administration increased the density and expression of NR2B and NGF by muscle putative sensory afferent fibers (P < 0.050). This increase in expression was greater in women than in men (P < 0.050). Expression of NR2B receptors by putative sensory afferent fibers was positively correlated with pain characteristics. Results suggest that increased expression of peripheral NMDA receptors partly contributes to the increased pain and sensitivity induced by intramuscular injection of NGF and glutamate in healthy humans; a model of myofascial temporomandibular disorder (TMD) pain. Whether a similar increase in peripheral NMDA expression occurs in patients with painful TMDs warrants further investigation.
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| 17. |
- Alhilou, AM, et al.
(författare)
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Sex-related differences in response to masseteric injections of glutamate and nerve growth factor in healthy human participants
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 13873-
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Tidskriftsartikel (refereegranskat)abstract
- The neurophysiological mechanisms underlying NGF-induced masseter muscle sensitization and sex-related differences in its effect are not well understood in humans. Therefore, this longitudinal cohort study aimed to investigate the effect of NGF injection on the density and expression of substance P, NMDA-receptors and NGF by the nerve fibers in the human masseter muscle, to correlate expression with pain characteristics, and to determine any possible sex-related differences in these effects of NGF. The magnitude of NGF-induced mechanical sensitization and pain during oral function was significantly greater in women than in men (P < 0.050). Significant positive correlations were found between nerve fiber expression of NMDA-receptors and peak pain intensity (rs = 0.620, P = 0.048), and expression of NMDA-receptors by putative nociceptors and change in temporal summation pain after glutamate injection (rs = 0.561, P = 0.003). In women, there was a significant inverse relationship between the degree of NGF-induced mechanical sensitization and the change in nerve fiber expression of NMDA-receptors alone (rs = − 0.659, P = 0.013), and in combination with NGF (rs = − 0.764, P = 0.001). In conclusion, women displayed a greater magnitude of NGF-induced mechanical sensitization that also was associated with nerve fibers expression of NMDA-receptors, when compared to men. The present findings suggest that, in women, increased peripheral NMDA-receptor expression could be associated with masseter muscle pain sensitivity.
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| 18. |
- Anderzen, J., et al.
(författare)
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International benchmarking in type 1 diabetes: Large difference in childhood HbA1c between eight high-income countries but similar rise during adolescence-A quality registry study
- 2020
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 21:4, s. 621-627
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To identify differences and similarities in HbA1c levels and patterns regarding age and gender in eight high-income countries. Subjects 66 071 children and adolescents below18 years of age with type 1 diabetes for at least 3 months and at least one HbA1c measurement during the study period. Methods Pediatric Diabetes Quality Registry data from Austria, Denmark, England, Germany, Norway, Sweden, the United States, and Wales were collected between 2013 and 2014. HbA1c, gender, age, and duration were used in the analysis. Results Distribution of gender and age groups was similar in the eight participating countries. The mean HbA1c varied from 60 to 73 mmol/mol (7.6%-8.8%) between the countries. The increase in HbA1c between the youngest (0-9 years) to the oldest (15-17 years) age group was close to 8 mmol/mol (0.7%) in all countries (P < .001). Females had a 1 mmol/mol (0.1%) higher mean HbA1c than boys (P < .001) in seven out of eight countries. Conclusions In spite of large differences in the mean HbA1c between countries, a remarkable similarity in the increase of HbA1c from childhood to adolescence was found.
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| 19. |
- Cherubini, V., et al.
(författare)
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Temporal trends in diabetic ketoacidosis at diagnosis of paediatric type 1 diabetes between 2006 and 2016: results from 13 countries in three continents
- 2020
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 63, s. 1530-1541
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: The aim of this work was to evaluate geographical variability and trends in the prevalence of diabetic ketoacidosis (DKA), between 2006 and 2016, at the diagnosis of childhood-onset type 1 diabetes in 13 countries over three continents. Methods: An international retrospective study on DKA at diagnosis of diabetes was conducted. Data on age, sex, date of diabetes diagnosis, ethnic minority status and presence of DKA at diabetes onset were obtained from Australia, Austria, Czechia, Denmark, Germany, Italy, Luxembourg, New Zealand, Norway, Slovenia, Sweden, USA and the UK (Wales). Mean prevalence was estimated for the entire period, both overall and by country, adjusted for sex and age group. Temporal trends in annual prevalence of DKA were estimated using logistic regression analysis for each country, before and after adjustment for sex, age group and ethnic minority status. Results: During the study period, new-onset type 1 diabetes was diagnosed in 59,000 children (median age [interquartile range], 9.0years [5.5–11.7]; male sex, 52.9%). The overall adjusted DKA prevalence was 29.9%, with the lowest prevalence in Sweden and Denmark and the highest in Luxembourg and Italy. The adjusted DKA prevalence significantly increased over time in Australia, Germany and the USA while it decreased in Italy. Preschool children, adolescents and children from ethnic minority groups were at highest risk of DKA at diabetes diagnosis in most countries. A significantly higher risk was also found for females in Denmark, Germany and Slovenia. Conclusions/interpretation: DKA prevalence at type 1 diabetes diagnosis varied considerably across countries, albeit it was generally high and showed a slight increase between 2006 and 2016. Increased awareness of symptoms to prevent delay in diagnosis is warranted, especially in preschool children, adolescents and children from ethnic minority groups. © 2020, The Author(s).
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| 20. |
- Dierig, A., et al.
(författare)
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A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis
- 2023
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Ingår i: Trials. - : BMC. - 1745-6215. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin.Methods: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course.Discussion: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages.
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| 21. |
- Hjorth, Stephan, 1953, et al.
(författare)
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(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752)-a Novel Cortical-Preferring Catecholamine Transmission- and Cognition-Promoting Agent
- 2020
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Ingår i: Journal of Pharmacology and Experimental Therapeutics. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0022-3565 .- 1521-0103. ; 374:3, s. 404-419
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe for the first time the distinctive pharmacological profile for (35)-3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752), a new phenyl-pyrrolidine derivative with regioselective central nervous system transmission-enhancing properties. IRL752 (3.7-150 mu mol/kg, s.c.) was characterized through extensive in vivo studies using behavioral, tissue neurochemical, and gene expression as well as microdialysis methods. Behaviorally, the compound normalized tetrabenazine-induced hypo-activity, whereas it was unable to stimulate basal locomotion in normal animals or either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across noradrenaline (NA)- and dopamine (DA)-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related immediate early genes (IEGs), however, increased by 1.5-fold to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600%-750% above baseline, whereas striatal DA remained unaltered, and NA rose to similar to 250%; cortical and hippocampal dialysate acetylcholine (ACh) increased to similar to 250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also procognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data coupled to drug exposure support the hypothesis that 5-hydroxytryptannine 7 receptor and alpha 2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on cate-cholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease. SIGNIFICANCE STATEMENT This report describes the distinctive preclinical profile of (3S)3-(2,3-difluorophenyI)-3-nnethoxypyrrolidine (IRL752). Its in vivo neurochemical, behavioral, microdialysis, and gene expression properties are consistent with a cortically regioselective facilitatory impact on catecholaminergic and cholinergic neurotransmission accompanied by cognitive impairment-reversing features. The pharmacological characteristics of IRL752 are in line with the clinical usefulness of IRL752 in conditions wherein these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson disease.
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| 24. |
- Marin, Ida, et al.
(författare)
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Establishment of a clinical SPECT/CT protocol for imaging of(161)Tb
- 2020
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Ingår i: Ejnmmi Physics. - : Springer Science and Business Media LLC. - 2197-7364. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Background It has been proposed, and preclinically demonstrated, that(161)Tb is a better alternative to(177)Lu for the treatment of small prostate cancer lesions due to its high emission of low-energy electrons.Tb-161 also emits photons suitable for single-photon emission computed tomography (SPECT) imaging. This study aims to establish a SPECT protocol for(161)Tb imaging in the clinic. Materials and methods Optimal settings using various gamma-camera collimators and energy windows were explored by imaging a Jaszczak phantom, including hollow-sphere inserts, filled with(161)Tb. The collimators examined were extended low-energy general purpose (ELEGP), medium-energy general purpose (MEGP), and low-energy high resolution (LEHR), respectively. In addition, three ordered subset expectation maximization (OSEM) algorithms were investigated: attenuation-corrected OSEM (A-OSEM); attenuation and dual- or triple-energy window scatter-corrected OSEM (AS-OSEM); and attenuation, scatter, and collimator-detector response-corrected OSEM (ASC-OSEM), where the latter utilized Monte Carlo-based reconstruction. Uniformity corrections, using intrinsic and extrinsic correction maps, were also investigated. Image quality was assessed by estimated recovery coefficients (RC), noise, and signal-to-noise ratio (SNR). Sensitivity was determined using a circular flat phantom. Results The best RC and SNR were obtained at an energy window between 67.1 and 82.1 keV. Ring artifacts, caused by non-uniformity, were removed with extrinsic uniformity correction for the energy window between 67.1 and 82.1 keV, but not with intrinsic correction. Analyzing the lower energy window between 48.9 and 62.9 keV, the ring artifacts remained after uniformity corrections. The recovery was similar for the different collimators when using a specific OSEM reconstruction. Recovery and SNR were highest for ASC-OSEM, followed by AS-OSEM and A-OSEM. When using the optimized parameter setting, the resolution of(161)Tb was higher than for(177)Lu (8.4 +/- 0.7 vs. 10.4 +/- 0.6 mm, respectively). The sensitivities for(161)Tb and(177)Lu were 7.41 and 8.46 cps/MBq, respectively. Conclusion SPECT with high resolution is feasible with(161)Tb; however, extrinsic uniformity correction is recommended to avoid ring artifacts. The LEHR collimator was the best choice of the three tested to obtain a high-resolution image. Due to the complex emission spectrum of low-energy photons, window-based scatter correction had a minor impact on the image quality compared to using attenuation correction only. On the other hand, performing attenuation, scatter, and collimator-detector correction clearly improved image quality. Based on these data, SPECT-based dosimetry for(161)Tb-labeled radiopharmaceuticals is feasible.
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| 25. |
- Mortazavi, A. N., et al.
(författare)
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Exploring failure modes of alumina scales on FeCrAl and FeNiCrAl alloys in a nitriding environment
- 2020
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Ingår i: Acta Materialia. - : Elsevier BV. - 1359-6454. ; 201, s. 131-146
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Tidskriftsartikel (refereegranskat)abstract
- Two high-temperature FeCrAl and FeNiCrAl alloys were exposed in a strongly nitriding environment at 900 °C and the morphology of nitridation was studied. Quasi-in-situ experiments revealed that nitridation started at specific surface sites directly related to the alloy microstructure where the alumina scale was permeable to nitrogen. FeCrAl alloy grains with (112) orientation formed outward-growing alumina scales and were susceptible to nitridation. Outward-growing scales and substrate nitridation was also observed at chromium carbide precipitates in the FeNiCrAl alloy. Both alloys suffered nitridation at reactive element-rich (Y and Zr) inclusions larger than a certain critical size. The latter type of attack is caused by cracks and pores in the scale. The findings open new avenues of research for developing the next generation of high temperature alloys with superior properties.
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| 26. |
- Nilsen, M. S., et al.
(författare)
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3-Hydroxyisobutyrate, A Strong Marker of Insulin Resistance in Type 2 Diabetes and Obesity That Modulates White and Brown Adipocyte Metabolism
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 69:9, s. 1903-1916
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Tidskriftsartikel (refereegranskat)abstract
- Circulating branched-chain amino acids (BCAAs) associate with insulin resistance and type 2 diabetes. 3-Hydroxyisobutyrate (3-HIB) is a catabolic intermediate of the BCAA valine. In this study, we show that in a cohort of 4,942 men and women, circulating 3-HIB is elevated according to levels of hyperglycemia and established type 2 diabetes. In complementary cohorts with measures of insulin resistance, we found positive correlates for circulating 3-HIB concentrations with HOMA2 of insulin resistance, as well as a transient increase in 3-HIB followed by a marked decrease after bariatric surgery and weight loss. During differentiation, both white and brown adipocytes upregulate BCAA utilization and release increasing amounts of 3-HIB. Knockdown of the 3-HIB-forming enzyme 3-hydroxyisobutyryl-CoA hydrolase decreases release of 3-HIB and lipid accumulation in both cell types. Conversely, addition of 3-HIB to white and brown adipocyte cultures increases fatty acid uptake and modulated insulin-stimulated glucose uptake in a time-dependent manner. Finally, 3-HIB treatment decreases mitochondrial oxygen consumption and generation of reactive oxygen species in white adipocytes, while increasing these measures in brown adipocytes. Our data establish 3-HIB as a novel adipocyte-derived regulator of adipocyte subtype-specific functions strongly linked to obesity, insulin resistance, and type 2 diabetes.
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| 27. |
- Rossignol, P, et al.
(författare)
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NT-proBNP and stem cell factor plasma concentrations are independently associated with cardiovascular outcomes in end-stage renal disease hemodialysis patients
- 2022
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Ingår i: European Heart Journal Open. - : Oxford University Press. - 2752-4191. ; 2:6
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Tidskriftsartikel (refereegranskat)abstract
- Aimas: End-stage renal disease (ESRD) treated by chronic hemodialysis (HD) is associated with poor cardiovascular (CV) outcomes, with no available evidence-based therapeutics. A multiplexed proteomic approach may identify new pathophysiological pathways associated with CV outcomes, potentially actionable for precision medicine.Methods and Results: The AURORA trial was an international, multicentre, randomized, double-blind trial involving 2776 patients undergoing maintenance HD. Rosuvastatin vs. placebo had no significant effect on the composite primary endpoint of death from CV causes, nonfatal myocardial infarction or nonfatal stroke. We first compared CV risk-matched cases and controls (n = 410) to identify novel biomarkers using a multiplex proximity extension immunoassay (276 proteomic biomarkers assessed with OlinkTM). We replicated our findings in 200 unmatched cases and 200 controls. External validation was conducted from a multicentre real-life Danish cohort [Aarhus-Aalborg (AA), n = 331 patients] in which 92 OlinkTM biomarkers were assessed. In AURORA, only N-terminal pro-brain natriuretic peptide (NT-proBNP, positive association) and stem cell factor (SCF) (negative association) were found consistently associated with the trial's primary outcome across exploration and replication phases, independently from the baseline characteristics. Stem cell factor displayed a lower added predictive ability compared with NT-ProBNP. In the AA cohort, in multivariable analyses, BNP was found significantly associated with major CV events, while higher SCF was associated with less frequent CV deaths.Conclusions: Our findings suggest that NT-proBNP and SCF may help identify ESRD patients with respectively high and low CV risk, beyond classical clinical predictors and also point at novel pathways for prevention and treatment.
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| 28. |
- Rönnelid, Ylva, et al.
(författare)
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Norovirus and rotavirus in children hospitalised with diarrhoea after rotavirus vaccine introduction in Burkina Faso
- 2020
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Ingår i: Epidemiology and Infection. - : CAMBRIDGE UNIV PRESS. - 0950-2688 .- 1469-4409. ; 148
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Tidskriftsartikel (refereegranskat)abstract
- Several studies report norovirus as the new leading cause of severe gastroenteritis in children after the global introduction of rotavirus vaccines. Burkina Faso introduced general rotavirus vaccination with the oral pentavalent vaccine RotaTeq in November 2013 and quickly reached a vaccine coverage of >90%. This study describes detection rates, clinical profiles and the molecular epidemiology of norovirus and rotavirus infections in 146 children aged <5 years with severe acute gastroenteritis in Ouagadougou, consecutively enrolled from a hospital between January 2015 and December 2015. Virus detection was performed with an antigen test or real-time polymerase chain reaction (PCR) and genotyping was performed by nucleotide sequencing or multiplex PCR. Rotavirus was found in 14% and norovirus in 20% of faecal samples. Norovirus infection was significantly more associated with severe dehydration compared to rotavirus (P < 0.001). Among genotyped norovirus samples 48% (12/25) belonged to GII.4 which caused significantly more diarrhoeal episodes than non-GII.4 genotypes (P = 0.01). The most common rotavirus genotypes were G2P[4] (30%), G12P[6] (25%) and G12P[8] (20%). Fifty percent of the rotavirus positive children were infected with fully or partly heterotypic strains. In conclusion, this study found a higher proportion of norovirus causing more severe symptoms in children with diarrhoea in Burkina Faso after the introduction of rotavirus vaccination.
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| 29. |
- Trajtenberg, N., et al.
(författare)
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The heterogeneous effects of COVID-19 lockdowns on crime across the world
- 2024
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Ingår i: Crime Science. - : BioMed Central (BMC). - 2193-7680. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- There is a vast literature evaluating the empirical association between stay-at-home policies and crime during the COVID-19 pandemic. However, these academic efforts have primarily focused on the effects within specific cities or regions rather than adopting a cross-national comparative approach. Moreover, this body of literature not only generally lacks causal estimates but also has overlooked possible heterogeneities across different levels of stringency in mobility restrictions. This paper exploits the spatial and temporal variation of government responses to the pandemic in 45 cities across five continents to identify the causal impact of strict lockdown policies on the number of offenses reported to local police. We find that cities that implemented strict lockdowns experienced larger declines in some crime types (robbery, burglary, vehicle theft) but not others (assault, theft, homicide). This decline in crime rates attributed to more stringent policy responses represents only a small proportion of the effects documented in the literature.
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| 30. |
- Trkulja, C. L., et al.
(författare)
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Rational antibody design for undruggable targets using kinetically controlled biomolecular probes
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:16
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Tidskriftsartikel (refereegranskat)abstract
- Several important drug targets, e.g., ion channels and G protein-coupled receptors, are extremely difficult to approach with current antibody technologies. To address these targets classes, we explored kinetically controlled proteases as structural dynamics-sensitive druggability probes in native-state and disease-relevant proteins. By using low-Reynolds number flows, such that a single or a few protease incisions are made, we could identify antibody binding sites (epitopes) that were translated into short-sequence antigens for antibody production. We obtained molecular-level information of the epitope-paratope region and could produce high-affinity antibodies with programmed pharmacological function against difficult-to-drug targets. We demonstrate the first stimulus-selective monoclonal antibodies targeting the transient receptor potential vanilloid 1 (TRPV1) channel, a clinically validated pain target widely considered undruggable with antibodies, and apoptosis-inducing antibodies selectively mediating cytotoxicity in KRAS-mutated cells. It is our hope that this platform will widen the scope of antibody therapeutics for the benefit of patients.
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| 31. |
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| 32. |
- Ainsworth, Richard I, et al.
(författare)
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Systems-biology analysis of rheumatoid arthritis fibroblast-like synoviocytes implicates cell line-specific transcription factor function.
- 2022
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Rheumatoid arthritis (RA) is an immune-mediated disease affecting diarthrodial joints that remains an unmet medical need despite improved therapy. This limitation likely reflects the diversity of pathogenic pathways in RA, with individual patients demonstrating variable responses to targeted therapies. Better understanding of RA pathogenesis would be aided by a more complete characterization of the disease. To tackle this challenge, we develop and apply a systems biology approach to identify important transcription factors (TFs) in individual RA fibroblast-like synoviocyte (FLS) cell lines by integrating transcriptomic and epigenomic information. Based on the relative importance of the identified TFs, we stratify the RA FLS cell lines into two subtypes with distinct phenotypes and predicted activepathways. We biologically validate these predictions for the top subtype-specific TF RARα and demonstrate differential regulation of TGFβ signaling in the two subtypes. This study characterizes clusters of RA cell lines with distinctive TF biology by integrating transcriptomic and epigenomic data, which could pave the way towards a greater understanding of disease heterogeneity.
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| 33. |
- Alffenaar, J. W. C., et al.
(författare)
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Clinical standards for the dosing and management of TB drugs
- 2022
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Ingår i: The International Journal of Tuberculosis and Lung Disease. - Paris, France : International Union Against Tuberculosis and Lung Disease. - 1027-3719 .- 1815-7920. ; 26:6, s. 483-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Optimal drug dosing is important to ensure adequate response to treatment, prevent development of drug resistance and reduce drug toxicity. The aim of these clinical standards is to provide guidance on 'best practice' for dosing and management of TB drugs.Methods: A panel of 57 global experts in the fields of microbiology, pharmacology and TB care were identified; 51 participated in a Delphi process. A 5-point Likert scale was used to score draft standards. The final document represents the broad consensus and was approved by all participants.Results: Six clinical standards were defined: Standard 1, defining the most appropriate initial dose for TB treatment; Standard 2, identifying patients who may be at risk of sub-optimal drug exposure; Standard 3, identifying patients at risk of developing drug-related toxicity and how best to manage this risk; Standard 4, identifying patients who can benefit from therapeutic drug monitoring (TDM); Standard 5, highlighting education and counselling that should be provided to people initiating TB treatment; and Standard 6, providing essential education for healthcare professionals. In addition, consensus research priorities were identified.Conclusion: This is the first consensus-based Clinical Standards for the dosing and management of TB drugs to guide clinicians and programme managers in planning and implementation of locally appropriate measures for optimal person-centred treatment to improve patient care.
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| 34. |
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| 35. |
- Andersson, Magnus N., et al.
(författare)
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Prophylactic mastectomy – Correlation between skin flap thickness and residual glandular tissue evaluated postoperatively by imaging
- 2022
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Ingår i: Journal of Plastic, Reconstructive & Aesthetic Surgery. - : Elsevier. - 1748-6815 .- 1878-0539. ; 75:6, s. 1813-1819
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Tidskriftsartikel (refereegranskat)abstract
- Background: Women with an increased hereditary risk of breast cancer can undergo risk-reducing prophylactic mastectomy. However, there is a balance between how much subcutaneous tissue should be resected to achieve maximal reduction of glandular tissue, while leaving viable skin flaps.Methods: Forty-five women previously operated with prophylactic mastectomy underwent magnetic resonance tomography (MRT) and ultrasound (US) to investigate the correlation between skin flap thickness and residual glandular tissue. Residual glandular tissue was documented as being present or not present, but not quantified, as the amount of residual glandular tissue in many cases was considered too small to make reliable volume quantifications with available tools. Since a mastectomy skin flap thickness of 5 mm is discussed as an oncologically safe thickness in the literature, this was used as a cut-off.Results: Following prophylactic mastectomy, residual glandular tissue was detected in 39.3% of all breasts and 27.9% of all the breast quadrants examined by MRT, and 44.1% of all breasts and 21.7% of all the breast quadrants examined by US. Residual glandular tissue was detected in 6.9% of the quadrants in skin flaps ≤ 5 mm and in 37.5% of the quadrants in skin flaps > 5 mm (OR 3.07; CI = 1.41–6.67; p = 0.005). Furthermore, residual glandular tissue increased significantly already when the skin flap thickness exceeded 7 mm.Conclusions: This study highlights that complete removal of glandular breast tissue during a mastectomy is difficult and suggests that this is an unattainable goal. We demonstrate that residual glandular tissue is significantly higher in skin flaps > 5 mm in comparison to skin flaps ≤ 5 mm, and that residual glandular tissue increases significantly already when the flap thickness exceeds 7 mm.
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| 36. |
- Askri, Dalel, et al.
(författare)
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A blood test to monitor bee health across a European network of agricultural sites of different land-use by MALDI BeeTyping mass spectrometry
- 2024
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Ingår i: Science of the Total Environment. - 0048-9697 .- 1879-1026. ; 929
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Tidskriftsartikel (refereegranskat)abstract
- There are substantial concerns about impaired honey bee health and colony losses due to several poorly understood factors. We used MALDI profiling (MALDI BeeTyping®) analysis to investigate how some environmental and management factors under field conditions across Europe affected the honey bee haemolymph peptidome (all peptides in the circulatory fluid), as a profile of molecular markers representing the immune status of Apis mellifera. Honey bees were exposed to a range of environmental stressors in 128 agricultural sites across eight European countries in four biogeographic zones, with each country contributing eight sites each for two different cropping systems: oilseed rape (OSR) and apple (APP). The full haemolymph peptide profiles, including the presence and levels of three key immunity markers, namely the antimicrobial peptides (AMPs) Apidaecin, Abaecin and Defensin-1, allowed the honey bee responses to environmental variables to be discriminated by country, crop type and site. When considering just the AMPs, it was not possible to distinguish between countries by the prevalence of each AMP in the samples. However, it was possible to discriminate between countries on the amounts of the AMPs, with the Swedish samples in particular expressing high amounts of all AMPs. A machine learning model was developed to discriminate the haemolymphs of bees from APP and OSR sites. The model was 90.6 % accurate in identifying the crop type from the samples used to build the model. Overall, MALDI BeeTyping® of bee haemolymph represents a promising and cost-effective “blood test” for simultaneously monitoring dozens of peptide markers affected by environmental stressors at the landscape scale, thus providing policymakers with new diagnostic and regulatory tools for monitoring bee health.
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| 37. |
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| 38. |
- Bernhardt, Peter, 1966, et al.
(författare)
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Dosimetric analysis of the short-ranged particle emitter161 tb for radionuclide therapy of metastatic prostate cancer
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:9
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to analyze the required absorbed doses to detectable metastases (Dreq ) when using radionuclides with prostate specific membrane antigen (PSMA)-targeting radioligands to achieve a high probability for metastatic control. The Monte Carlo based analysis was performed for the clinically-used radionuclides yttrium-90, iodine-131, lutetium-177, and actinium-225, and the newly-proposed low-energy electron emitter terbium-161. It was demonstrated that metastatic formation rate highly influenced the metastatic distribution. Lower values generated few large detectable metastases, as in the case with oligo metastases, while high values generated a distribution of multiple small detectable metastases, as observed in patients with diffused visualized metastases. With equal number of detectable metastases, the total metastatic volume burden was 4–6 times higher in the oligo metastatic scenario compared to the diffusely visualized scenario. The Dreq was around 30% higher for the situations with 20 detectable metastases compared to one detectable metastasis. The Dreq for iodine-131 and yttrium-90 was high (920–3300 Gy). The Dreq for lutetium-177 was between 560 and 780 Gy and considerably lower Dreq were obtained for actinium-225 and terbium-161, with 240–330 Gy and 210–280 Gy, respectively. In conclusion, the simulations demonstrated that terbium-161 has the potential for being a more effective targeted radionuclide therapy for metastases using PSMA ligands. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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| 39. |
- Beygui, F, et al.
(författare)
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Pre-hospital management of patients with chest pain and/or dyspnoea of cardiac origin. A position paper of the Acute Cardiovascular Care Association (ACCA) of the ESC
- 2020
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Ingår i: European heart journal. Acute cardiovascular care. - : Oxford University Press (OUP). - 2048-8734 .- 2048-8726. ; 9:1_SUPPL1_suppl, s. 59-81
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Tidskriftsartikel (refereegranskat)abstract
- Chest pain and acute dyspnoea are frequent causes of emergency medical services activation. The pre-hospital management of these conditions is heterogeneous across different regions of the world and Europe, as a consequence of the variety of emergency medical services and absence of specific practical guidelines. This position paper focuses on the practical aspects of the pre-hospital treatment on board and transfer of patients taken in charge by emergency medical services for chest pain and dyspnoea of suspected cardiac aetiology after the initial assessment and diagnostic work-up. The objective of the paper is to provide guidance, based on evidence, where available, or on experts’ opinions, for all emergency medical services’ health providers involved in the pre-hospital management of acute cardiovascular care.
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| 40. |
- 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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| 41. |
- Bjornsdottir, H. H., et al.
(författare)
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A national observation study of cancer incidence and mortality risks in type 2 diabetes compared to the background population over time
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- We examined changing patterns in cancer incidence and deaths in diabetes compared to the background population. A total of 457,473 patients with type 2 diabetes, included between 1998 and 2014, were matched on age, sex, and county to five controls from the population. Incidence, trends in incidence and post-cancer mortality for cancer were estimated with Cox regression and standardised incidence rates. Causes of death were estimated using logistic regression. Relative importance of risk factors was estimated using Heller's relative importance model. Type 2 diabetes had a higher risk for all cancer, HR 1.10 (95% CI 1.09-1.12), with highest HRs for liver (3.31), pancreas (2.19) and uterine cancer (1.78). There were lesser increases in risk for breast (1.05) and colorectal cancers (1.20). Type 2 diabetes patients experienced a higher HR 1.23 (1.21-1.25) of overall post-cancer mortality and mortality from prostate, breast, and colorectal cancers. By the year 2030 cancer could become the most common cause of death in type 2 diabetes. Persons with type 2 diabetes are at greater risk of developing cancer and lower chance of surviving it. Notably, hazards for specific cancers (e.g. liver, pancreas) in type 2 patients cannot be explained by obesity alone.
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| 42. |
- Broom, M., et al.
(författare)
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Outcomes of adults with invasive meningococcal disease with reduced penicillin susceptibility in Auckland 2004-2017
- 2023
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Ingår i: Infection. - : Springer Science and Business Media LLC. - 0300-8126 .- 1439-0973. ; 51:2, s. 425-432
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Tidskriftsartikel (refereegranskat)abstract
- Purpose The purpose of this study was to assess the clinical outcomes of adults with invasive meningococcal disease (IMD) and to compare the outcomes of patients with IMD caused by a penicillin susceptible isolate (minimum inhibitory concentration (MIC) <= 0.06 mg/L) with patients with IMD caused by an isolate with reduced penicillin susceptibility (MIC > 0.06 mg/L). We also assessed the outcomes of patients with IMD caused by an isolate with reduced penicillin susceptibility who were treated exclusively with intravenous (IV) benzylpenicillin. Methods Retrospective study of all culture positive IMD in adult patients (age >= 15 years) in the Auckland region from 2004 to 2017. Results One hundred and thirty-nine patients were included; 94 had penicillin susceptible isolates (88 cured, 6 died), and 45 had an isolate with reduced penicillin susceptibility (41 cured, 1 possible relapse, 3 died). The median benzylpenicillin/ceftriaxone treatment duration was 3 days for both groups. There was no difference in the patient outcomes of both groups. Eighteen patients with IMD caused by an isolate with reduced penicillin susceptibility received benzylpenicillin alone and were cured. Conclusions This study provides further support to existing data that has shown that short duration IV beta-lactam treatment is effective for IMD in adults. Only a small number of patients with meningitis caused by an isolate with reduced penicillin susceptibility received benzylpenicillin alone, limiting its evaluation. For Neisseria meningitidis meningitis, we recommend ceftriaxone as empiric treatment and as definitive treatment when this is caused by an isolate with reduced penicillin susceptibility.
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| 43. |
- Cadrin-Tourigny, Julia, et al.
(författare)
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A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy
- 2022
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 43:32, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients. Methods and results: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.2 ± 15.5 years, 44.7% male, were enrolled from five registries in North America and Europe. Over 4.83 (interquartile range 2.44-9.33) years of follow-up, 146 (27.7%) experienced sustained VA, defined as SCD, aborted SCD, sustained ventricular tachycardia, or appropriate implantable cardioverter-defibrillator (ICD) therapy. A prediction model estimating annual VA risk was developed using Cox regression with internal validation. Eight potential predictors were pre-specified: Age, sex, cardiac syncope in the prior 6 months, non-sustained ventricular tachycardia, number of premature ventricular complexes in 24 h, number of leads with T-wave inversion, and right and left ventricular ejection fractions (LVEFs). All except LVEF were retained in the final model. The model accurately distinguished patients with and without events, with an optimism-corrected C-index of 0.77 [95% confidence interval (CI) 0.73-0.81] and minimal over-optimism [calibration slope of 0.93 (95% CI 0.92-0.95)]. By decision curve analysis, the clinical benefit of the model was superior to a current consensus-based ICD placement algorithm with a 20.3% reduction of ICD placements with the same proportion of protected patients (P < 0.001). Conclusion: Using the largest cohort of patients with ARVC and no prior VA, a prediction model using readily available clinical parameters was devised to estimate VA risk and guide decisions regarding primary prevention ICDs (www.arvcrisk.com).
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| 44. |
- Cadrin-Tourigny, Julia, et al.
(författare)
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Sudden Cardiac Death Prediction in Arrhythmogenic Right Ventricular Cardiomyopathy : A Multinational Collaboration
- 2021
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Ingår i: Circulation: Arrhythmia and Electrophysiology. - : Lippincott Williams & Wilkins. - 1941-3149 .- 1941-3084. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with ventricular arrhythmias (VA) and sudden cardiac death (SCD). A model was recently developed to predict incident sustained VA in patients with ARVC. However, since this outcome may overestimate the risk for SCD, we aimed to specifically predict life-threatening VA (LTVA) as a closer surrogate for SCD. Methods: We assembled a retrospective cohort of definite ARVC cases from 15 centers in North America and Europe. Association of 8 prespecified clinical predictors with LTVA (SCD, aborted SCD, sustained, or implantable cardioverter-defibrillator treated ventricular tachycardia >250 beats per minute) in follow-up was assessed by Cox regression with backward selection. Candidate variables included age, sex, prior sustained VA (≥30s, hemodynamically unstable, or implantable cardioverter-defibrillator treated ventricular tachycardia; or aborted SCD), syncope, 24-hour premature ventricular complexes count, the number of anterior and inferior leads with T-wave inversion, left and right ventricular ejection fraction. The resulting model was internally validated using bootstrapping. Results: A total of 864 patients with definite ARVC (40±16 years; 53% male) were included. Over 5.75 years (interquartile range, 2.77-10.58) of follow-up, 93 (10.8%) patients experienced LTVA including 15 with SCD/aborted SCD (1.7%). Of the 8 prespecified clinical predictors, only 4 (younger age, male sex, premature ventricular complex count, and number of leads with T-wave inversion) were associated with LTVA. Notably, prior sustained VA did not predict subsequent LTVA (P=0.850). A model including only these 4 predictors had an optimism-corrected C-index of 0.74 (95% CI, 0.69-0.80) and calibration slope of 0.95 (95% CI, 0.94-0.98) indicating minimal over-optimism. Conclusions: LTVA events in patients with ARVC can be predicted by a novel simple prediction model using only 4 clinical predictors. Prior sustained VA and the extent of functional heart disease are not associated with subsequent LTVA events.
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| 45. |
- Cagigi, Alberto, et al.
(författare)
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Airway antibodies emerge according to COVID-19 severity and wane rapidly but reappear after SARS-CoV-2 vaccination
- 2021
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Ingår i: JCI Insight. - : American Society for Clinical Investigation. - 2379-3708. ; 6:22
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Tidskriftsartikel (refereegranskat)abstract
- Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.
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| 46. |
- Callen, Michael, et al.
(författare)
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COVID-19 vaccine acceptance and hesitancy in low- and middle-income countries
- 2021
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Ingår i: Nature Medicine. - : Springer Nature. - 1546-170X .- 1078-8956. ; 27:8, s. 1385-1394
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Tidskriftsartikel (refereegranskat)abstract
- Widespread acceptance of COVID-19 vaccines is crucial for achieving sufficient immunization coverage to end the global pandemic, yet few studies have investigated COVID-19 vaccination attitudes in lower-income countries, where large-scale vaccination is just beginning. We analyze COVID-19 vaccine acceptance across 15 survey samples covering 10 low- and middle-income countries (LMICs) in Asia, Africa and South America, Russia (an upper-middle-income country) and the United States, including a total of 44,260 individuals. We find considerably higher willingness to take a COVID-19 vaccine in our LMIC samples (mean 80.3%; median 78%; range 30.1 percentage points) compared with the United States (mean 64.6%) and Russia (mean 30.4%). Vaccine acceptance in LMICs is primarily explained by an interest in personal protection against COVID-19, while concern about side effects is the most common reason for hesitancy. Health workers are the most trusted sources of guidance about COVID-19 vaccines. Evidence from this sample of LMICs suggests that prioritizing vaccine distribution to the Global South should yield high returns in advancing global immunization coverage. Vaccination campaigns should focus on translating the high levels of stated acceptance into actual uptake. Messages highlighting vaccine efficacy and safety, delivered by healthcare workers, could be effective for addressing any remaining hesitancy in the analyzed LMICs. © 2021, The Author(s).
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| 47. |
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| 48. |
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| 49. |
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| 50. |
- De Lima, Carlos, et al.
(författare)
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Convergent Communication, Sensing and Localization in 6G Systems: An Overview of Technologies, Opportunities and Challenges
- 2021
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Ingår i: IEEE Access. - 2169-3536 .- 2169-3536. ; 9, s. 26902-26925
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Forskningsöversikt (refereegranskat)abstract
- Herein, we focus on convergent 6G communication, localization and sensing systems by identifying key technology enablers, discussing their underlying challenges, implementation issues, and recommending potential solutions. Moreover, we discuss exciting new opportunities for integrated localization and sensing applications, which will disrupt traditional design principles and revolutionize the way we live, interact with our environment, and do business. Regarding potential enabling technologies, 6G will continue to develop towards even higher frequency ranges, wider bandwidths, and massive antenna arrays. In turn, this will enable sensing solutions with very fine range, Doppler, and angular resolutions, as well as localization to cm-level degree of accuracy. Besides, new materials, device types, and reconfigurable surfaces will allow network operators to reshape and control the electromagnetic response of the environment. At the same time, machine learning and artificial intelligence will leverage the unprecedented availability of data and computing resources to tackle the biggest and hardest problems in wireless communication systems. As a result, 6G will be truly intelligent wireless systems that will provide not only ubiquitous communication but also empower high accuracy localization and high-resolution sensing services. They will become the catalyst for this revolution by bringing about a unique new set of features and service capabilities, where localization and sensing will coexist with communication, continuously sharing the available resources in time, frequency, and space. This work concludes by highlighting foundational research challenges, as well as implications and opportunities related to privacy, security, and trust.
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