| 1. |
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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
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| 4. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 5. |
- Athan, E., et al.
(författare)
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Influence of vancomycin minimum inhibitory concentration on the outcome of methicillin-susceptible Staphylococcus aureus left-sided infective endocarditis treated with antistaphylococcal β-lactam antibiotics: a prospective cohort study by the International Collaboration on Endocarditis
- 2017
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Ingår i: Clinical Microbiology and Infection. - : Elsevier BV. - 1198-743X .- 1469-0691. ; 23, s. 544-549
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Tidskriftsartikel (refereegranskat)abstract
- © 2017 European Society of Clinical Microbiology and Infectious Diseases Objectives Left-sided methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis treated with cloxacillin has a poorer prognosis when the vancomycin minimum inhibitory concentration (MIC) is ≥1.5 mg/L. We aimed to validate this using the International Collaboration on Endocarditis cohort and to analyse whether specific genetic characteristics were associated with a high vancomycin MIC (≥1.5 mg/L) phenotype. Methods All patients with left-sided MSSA infective endocarditis treated with antistaphylococcal β-lactam antibiotics between 2000 and 2006 with available isolates were included. Vancomycin MIC was determined by Etest as either high (≥1.5 mg/L) or low (<1.5 mg/L). Isolates underwent spa typing to infer clonal complexes and multiplex PCR for identifying virulence genes. Univariate analysis was performed to evaluate the association between in-hospital and 1-year mortality, and vancomycin MIC phenotype. Results Sixty-two cases met the inclusion criteria. Vancomycin MIC was low in 28 cases (45%) and high in 34 cases (55%). No significant differences in patient demographic data or characteristics of infection were observed between patients with infective endocarditis due to high and low vancomycin MIC isolates. Isolates with high and low vancomycin MIC had similar distributions of virulence genes and clonal lineages. In-hospital and 1-year mortality did not differ significantly between the two groups (32% (9/28) vs. 27% (9/34), p 0.780; and 43% (12/28) vs. 29% (10/34), p 0.298, for low and high vancomycin MIC respectively). Conclusions In this international cohort of patients with left-sided MSSA endocarditis treated with antistaphylococcal β-lactams, vancomycin MIC phenotype was not associated with patient demographics, clinical outcome or virulence gene repertoire.
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| 6. |
- Jones, Benedict C, et al.
(författare)
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To which world regions does the valence-dominance model of social perception apply?
- 2021
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Ingår i: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
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Tidskriftsartikel (refereegranskat)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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| 7. |
- Arai, Sally, et al.
(författare)
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Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation : a report from the Center for International Blood and Marrow Transplant Research.
- 2015
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Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 21:2, s. 266-74
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Tidskriftsartikel (refereegranskat)abstract
- Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P < .0001), and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, nonrelapse mortality has decreased over time, but at 5 years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.
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| 8. |
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| 9. |
- Kupfer, Thomas, et al.
(författare)
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Year 1 of the ZTF high-cadence Galactic plane survey : strategy, goals, and early results on new single-mode hot subdwarf B-star pulsatos
- 2021
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Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 505:1, s. 1254-1267
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Tidskriftsartikel (refereegranskat)abstract
- We present the goals, strategy, and first results of the high-cadence Galactic plane survey using the Zwicky Transient Facility (ZTF). The goal of the survey is to unveil the Galactic population of short-period variable stars, including short-period binaries, and stellar pulsators with periods less than a few hours. Between 2018 June and 2019 January, we observed 64 ZTF fields resulting in 2990 deg2 of high stellar density in the ZTF-r band along the Galactic plane. Each field was observed continuously for 1.5 to 6 h with a cadence of 40 sec. Most fields have between 200 and 400 observations obtained over 2–3 continuous nights. As part of this survey, we extract a total of ≈230 million individual objects with at least 80 epochs obtained during the high-cadence Galactic plane survey reaching an average depth of ZTF–r ≈ 20.5 mag. For four selected fields with 2–10 million individual objects per field, we calculate different variability statistics and find that ≈1–2 per cent of the objects are astrophysically variable over the observed period. We present a progress report on recent discoveries, including a new class of compact pulsators, the first members of a new class of Roche lobe filling hot subdwarf binaries as well as new ultracompact double white dwarfs and flaring stars. Finally, we present a sample of 12 new single-mode hot subdwarf B-star pulsators with pulsation amplitudes between ZTF–r = 20–76 mmag and pulsation periods between P = 5.8–16 min with a strong cluster of systems with periods ≈6 min. All of the data have now been released in either ZTF Data Release 3 or Data Release 4.
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| 10. |
- Chu, V H, et al.
(författare)
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Coagulase-negative staphylococcal prosthetic valve endocarditis--a contemporary update based on the International Collaboration on Endocarditis: prospective cohort study.
- 2009
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Ingår i: Heart (British Cardiac Society). - : BMJ. - 1468-201X .- 1355-6037. ; 95:7, s. 570-6
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Tidskriftsartikel (refereegranskat)abstract
- To describe the contemporary features of coagulase-negative staphylococcal (CoNS) prosthetic valve endocarditis (PVE).Observational study of prospectively collected data from a multinational cohort of patients with infective endocarditis. Patients with CoNS PVE were compared to patients with Staphylococcus aureus and viridans streptococcal (VGS) PVE.The International Collaboration on Endocarditis-Prospective Cohort Study (ICE-PCS) is a contemporary cohort of patients with infective endocarditis from 61 centres in 28 countries.Adult patients in the ICE-PCS with definite PVE and no history of injecting drug use from June 2000 to August 2005 were included.None.Heart failure, intracardiac abscess, death.CoNS caused 16% (n = 86) of 537 cases of definite non-injecting drug use-associated PVE. Nearly one-half (n = 33/69, 48%) of patients with CoNS PVE presented between 60 days and 365 days of valve implantation. The rate of intracardiac abscess was significantly higher in patients with CoNS PVE (38%) than in patients with either S aureus (23%, p = 0.03) or VGS (20%, p = 0.05) PVE. The rate of abscess was particularly high in early (50%) and intermediate (52%) CoNS PVE. In-hospital mortality was 24% for CoNS PVE, 36% for S aureus PVE (p = 0.09) and 9.1% for VGS PVE (p = 0.08). Meticillin resistance was present in 68% of CoNS strains.Nearly one-half of CoNS PVE cases occur between 60 days and 365 days of prosthetic valve implantation. CoNS PVE is associated with a high rate of meticillin resistance and significant valvular complications.
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| 11. |
- McDonald, J R, et al.
(författare)
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Enterococcal endocarditis: 107 cases from the international collaboration on endocarditis merged database.
- 2005
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Ingår i: The American journal of medicine. - : Elsevier BV. - 0002-9343. ; 118:7, s. 759-66
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: To describe clinical features and outcomes of enterococcal left-sided native valve endocarditis and to compare it to endocarditis caused by other pathogens. SUBJECTS AND METHODS: Patients in the International Collaboration on Endocarditis-Merged Database were included if they had left-sided native valve endocarditis. Demographic characteristics, clinical features, and outcomes were analyzed. Multivariable analysis evaluated enterococcus as a predictor of mortality. RESULTS: Of 1285 patients with left-sided native valve endocarditis, 107 had enterococcal endocarditis. Enterococcal endocarditis was most frequently seen in elderly men, frequently involved the aortic valve, tended to produce heart failure rather than embolic events, and had relatively low short-term mortality. Compared to patients with non-enterococcal endocarditis, patients with enterococcal endocarditis had similar rates of nosocomial acquisition, heart failure, embolization, surgery, and mortality. Compared to patients with streptococcal endocarditis, patients with enterococcal endocarditis were more likely to be nosocomially acquired (9 of 59 [15%] vs 2 of 400 [1%]; P <.0001) and have heart failure (49 of 107 [46%] vs 234 of 666 [35%]; P = 0.03). Compared to patients with S. aureus endocarditis, patients with enterococcal endocarditis were less likely to embolize (28 of 107 [26%] vs 155 of 314 [49%]; P <.0001) and less likely to die (12 of 107 [11%] vs 83 of 313 [27%]; P = 0.001). Multivariable analysis of all patients with left-sided native valve endocarditis showed that enterococcal endocarditis was associated with lower mortality (odds ratio [OR] 0.49; 95% confidence interval [CI] 0.24 to 0.97). CONCLUSIONS: Enterococcal native valve endocarditis has a distinctive clinical picture with a good prognosis.
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| 12. |
- Mittal, S., et al.
(författare)
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The World-wide Randomized Antibiotic Envelope Infection Prevention (WRAP-IT) trial: Long-term follow-up
- 2020
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Ingår i: Heart Rhythm. - : Elsevier BV. - 1547-5271. ; 17:7, s. 1115-1122
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Tidskriftsartikel (refereegranskat)abstract
- Background: The World-wide Randomized Antibiotic Envelope Infection Prevention trial reported a 40% reduction in major cardiac implantable electronic device (CIED) infections within 12 months of the procedure with the use of an antibacterial-eluting envelope (TYRX Absorbable Antibacterial Envelope, Medtronic, Mounds View, MN). Objective: The purpose of this report was to describe the longer-term (>12 months) envelope effects on infection reduction and complications. Methods: All trial patients who underwent CIED replacement, upgrade, revision, or initial cardiac resynchronization therapy – defibrillator implantation received standard-of-care infection prophylaxis and were randomized in a 1:1 ratio to receive the envelope or not. CIED infection incidence and procedure and system-related complications were characterized through all follow-up (36 months) by using Cox proportional hazards regression modeling. Results: In total, 6800 patients received their intended randomized treatment (3371 envelope; 3429 control; mean follow-up period 21.0 ± 8.3 months). Major CIED-related infections occurred in 32 envelope patients and 51 control patients (Kaplan-Meier [KM] estimate 1.3% vs 1.9%; hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.41–0.99; P = .046). Any CIED-related infection occurred in 57 envelope patients and 84 control patients (KM estimate 2.1% vs 2.8%; HR 0.69; 95% CI 0.49–0.97; P = .030). System- or procedure-related complications occurred in 235 envelope patients and 252 control patients (KM estimate 8.0% vs 8.2%; HR 0.95; 95% CI 0.79–1.13; P < .001 for noninferiority); the most common were lead dislodgment (1.1%), device lead damage (0.5%), and implant site hematoma (0.4%). Implant site pain occurred less frequently in the envelope group (0.1% vs 0.4%; P = .067). There were no (0.0%) reports of allergic reactions to the components of the envelope (mesh, polymer, or antibiotics). Conclusion: The effects of the TYRX envelope on the reduction of the risk of CIED infection are sustained beyond the first year postprocedure, without an increased risk of complications. © 2020 The Authors
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| 13. |
- ODonnell, Michael, et al.
(författare)
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Registered Replication Report: Dijksterhuis and van Knippenberg (1998)
- 2018
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Ingår i: Perspectives on Psychological Science. - : SAGE PUBLICATIONS LTD. - 1745-6916 .- 1745-6924. ; 13:2, s. 268-294
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Tidskriftsartikel (refereegranskat)abstract
- Dijksterhuis and van Knippenberg (1998) reported that participants primed with a category associated with intelligence (professor) subsequently performed 13% better on a trivia test than participants primed with a category associated with a lack of intelligence (soccer hooligans). In two unpublished replications of this study designed to verify the appropriate testing procedures, Dijksterhuis, van Knippenberg, and Holland observed a smaller difference between conditions (2%-3%) as well as a gender difference: Men showed the effect (9.3% and 7.6%), but women did not (0.3% and -0.3%). The procedure used in those replications served as the basis for this multilab Registered Replication Report. A total of 40 laboratories collected data for this project, and 23 of these laboratories met all inclusion criteria. Here we report the meta-analytic results for those 23 direct replications (total N = 4,493), which tested whether performance on a 30-item general-knowledge trivia task differed between these two priming conditions (results of supplementary analyses of the data from all 40 labs, N = 6,454, are also reported). We observed no overall difference in trivia performance between participants primed with the professor category and those primed with the hooligan category (0.14%) and no moderation by gender.
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| 14. |
- Schott, Ryan K., et al.
(författare)
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Diversity and Evolution of Frog Visual Opsins : Spectral Tuning and Adaptation to Distinct Light Environments
- 2024
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Ingår i: Molecular biology and evolution. - 0737-4038. ; 41:4
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Tidskriftsartikel (refereegranskat)abstract
- Visual systems adapt to different light environments through several avenues including optical changes to the eye and neurological changes in how light signals are processed and interpreted. Spectral sensitivity can evolve via changes to visual pigments housed in the retinal photoreceptors through gene duplication and loss, differential and coexpression, and sequence evolution. Frogs provide an excellent, yet understudied, system for visual evolution research due to their diversity of ecologies (including biphasic aquatic-terrestrial life cycles) that we hypothesize imposed different selective pressures leading to adaptive evolution of the visual system, notably the opsins that encode the protein component of the visual pigments responsible for the first step in visual perception. Here, we analyze the diversity and evolution of visual opsin genes from 93 new eye transcriptomes plus published data for a combined dataset spanning 122 frog species and 34 families. We find that most species express the four visual opsins previously identified in frogs but show evidence for gene loss in two lineages. Further, we present evidence of positive selection in three opsins and shifts in selective pressures associated with differences in habitat and life history, but not activity pattern. We identify substantial novel variation in the visual opsins and, using microspectrophotometry, find highly variable spectral sensitivities, expanding known ranges for all frog visual pigments. Mutations at spectral-tuning sites only partially account for this variation, suggesting that frogs have used tuning pathways that are unique among vertebrates. These results support the hypothesis of adaptive evolution in photoreceptor physiology across the frog tree of life in response to varying environmental and ecological factors and further our growing understanding of vertebrate visual evolution.
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| 15. |
- Wilkoff, B. L., et al.
(författare)
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Impact of Cardiac Implantable Electronic Device Infection A Clinical and Economic Analysis of the WRAP-IT Trial
- 2020
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Ingår i: Circulation-Arrhythmia and Electrophysiology. - : Ovid Technologies (Wolters Kluwer Health). - 1941-3149 .- 1941-3084. ; 13:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Current understanding of the impact of cardiac implantable electronic device (CIED) infection is based on retrospective analyses from medical records or administrative claims data. The WRAP-IT (Worldwide Randomized Antibiotic Envelope Infection Prevention Trial) offers an opportunity to evaluate the clinical and economic impacts of CIED infection from the hospital, payer, and patient perspectives in the US healthcare system. Methods: This was a prespecified, as-treated analysis evaluating outcomes related to major CIED infections: mortality, quality of life, disruption of CIED therapy, healthcare utilization, and costs. Payer costs were assigned using medicare fee for service national payments, while medicare advantage, hospital, and patient costs were derived from similar hospital admissions in administrative datasets. Results: Major CIED infection was associated with increased all-cause mortality (12-month risk-adjusted hazard ratio, 3.41 [95% CI, 1.81-6.41]; P<0.001), an effect that sustained beyond 12 months (hazard ratio through all follow-up, 2.30 [95% CI, 1.29-4.07]; P=0.004). Quality of life was reduced (P=0.004) and did not normalize for 6 months. Disruptions in CIED therapy were experienced in 36% of infections for a median duration of 184 days. Mean costs were $55 547 +/-$45 802 for the hospital, $26 867 +/-$14 893, for medicare fee for service and $57 978 +/-$29 431 for Medicare Advantage (mean hospital margin of -$30 828 +/-$39 757 for medicare fee for service and -$6055 +/-$45 033 for medicare advantage). Mean out-of-pocket costs for patients were $2156 +/-$1999 for medicare fee for service, and $1658 +/-$1250 for medicare advantage. Conclusions: This large, prospective analysis corroborates and extends understanding of the impact of CIED infections as seen in real-world datasets. CIED infections severely impact mortality, quality of life, healthcare utilization, and cost in the US healthcare system.
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| 16. |
- Anderson, D J, et al.
(författare)
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Enterococcal prosthetic valve infective endocarditis: report of 45 episodes from the International Collaboration on Endocarditis-merged database.
- 2005
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Ingår i: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. - : Springer Science and Business Media LLC. - 0934-9723. ; 24:10, s. 665-70
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Tidskriftsartikel (refereegranskat)abstract
- Enterococcal prosthetic valve infective endocarditis (PVE) is an incompletely understood disease. In the present study, patients with enterococcal PVE were compared to patients with enterococcal native valve endocarditis (NVE) and other types of PVE to determine differences in basic clinical characteristics and outcomes using a large multicenter, international database of patients with definite endocarditis. Forty-five of 159 (29%) cases of definite enterococcal endocarditis were PVE. Patients with enterococcal PVE were demographically similar to patients with enterococcal NVE but had more intracardiac abscesses (20% vs. 6%; p=0.009), fewer valve vegetations (51% vs. 79%; p<0.001), and fewer cases of new valvular regurgitation (12% vs. 45%; p=0.01). Patients with either enterococcal PVE or NVE were elderly (median age, 73 vs. 69; p=0.06). Rates of in-hospital mortality, surgical intervention, heart failure, peripheral embolization, and stroke were similar in both groups. Patients with enterococcal PVE were also demographically similar to patients with other types of PVE, but mortality may be lower (14% vs. 26%; p=0.08). Notably, 93% of patients with enterococcal PVE came from European centers, as compared with only 79% of patients with enterococcal NVE (p=0.03). Thus, patients with enterococcal PVE have higher rates of myocardial abscess formation and lower rates of new regurgitation compared to patients with enterococcal NVE, but there are no differences between the groups with regard to surgical or mortality rates. In contrast, though patients with enterococcal PVE and patients with other types of PVE share similar characteristics, mortality is higher in the latter group. Importantly, the prevalence of enterococcal PVE was higher in the European centers in this study.
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| 17. |
- Chauhan, Ganesh, et al.
(författare)
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Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies
- 2016
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Ingår i: The Lancet Neurology. - 1474-4465 .- 1474-4422. ; 15:7, s. 695-707
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Tidskriftsartikel (refereegranskat)abstract
- Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq. © 2016 Elsevier Ltd
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| 18. |
- Nagle, Nick J., et al.
(författare)
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Chemical and Structural Changes in Corn Stover After Ensiling : Influence on Bioconversion
- 2020
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Ingår i: Frontiers in Bioengineering and Biotechnology. - : Frontiers Media SA. - 2296-4185. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Production of biofuels, bioproducts, and bioenergy requires a well-characterized, stable, and reasonably uniform biomass supply and well-established supply chains for shipping biomass from farm fields to biorefineries, while achieving year-round production targets. Preserving and stabilizing biomass feedstock during storage is a necessity for cost-effective and sustainable biofuel production. Ensiling is a common storage method used to preserve and even improve forage quality; however, the impact of ensiling on biomass physical and chemical properties that influence bioconversion processes has been variable. Our objective in this work was to determine the effects of ensiling on lignocellulosic feedstock physicochemical properties and how that influences bioconversion requirements. We observed statistically significant decreases (p < 0.05) in the content of two major structural carbohydrates (glucan and xylan) of 5 and 8%, respectively, between the ensiled and non-ensiled materials. We were unable to detect differences in sugar yields from structural carbohydrates after pretreatment and enzymatic hydrolysis of the ensiled materials compared to non-ensiled controls. Based on this work, we conclude that ensiling the corn stover did not change the bioconversion requirements compared to the control samples and incurred losses of structural carbohydrates. At the light microscopy level, ensiled corn stover exhibited little structural change or relocation of cell wall components as detected by immunocytochemistry. However, more subtle structural changes were revealed by electron microscopy, as ensiled cell walls exhibit ultrastructural characteristics such as wall delimitation intermediate between non-ensiled and dilute-acid-pretreated cell walls. These findings suggest that alternative methods of conversion, such as deacetylation and mechanical refining, could take advantage of lamellar defects and may be more effective than dilute acid or hot water pretreatment for biomass conversion of ensiled materials.
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| 19. |
- Turtelboom,, et al.
(författare)
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The TESS-Keck Survey. XI. Mass Measurements for Four Transiting Sub-Neptunes Orbiting K Dwarf TOI-1246
- 2022
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 163:6
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Tidskriftsartikel (refereegranskat)abstract
- Multiplanet systems are valuable arenas for investigating exoplanet architectures and comparing planetary siblings. TOI-1246 is one such system, with a moderately bright K dwarf (V = 11.6, K = 9.9) and four transiting sub-Neptunes identified by TESS with orbital periods of 4.31, 5.90, 18.66, and 37.92 days. We collected 130 radial velocity observations with Keck/HIRES and TNG/HARPS-N to measure planet masses. We refit the 14 sectors of TESS photometry to refine planet radii (2.97 +/- 0.06 R (circle plus), 2.47 +/- 0.08 R (circle plus), 3.46 +/- 0.09 R (circle plus), and 3.72 +/- 0.16 R (circle plus)) and confirm the four planets. We find that TOI-1246 e is substantially more massive than the three inner planets (8.1 +/- 1.1 M (circle plus), 8.8 +/- 1.2 M (circle plus), 5.3 +/- 1.7 M (circle plus), and 14.8 +/- 2.3 M (circle plus)). The two outer planets, TOI-1246 d and TOI-1246 e, lie near to the 2:1 resonance (P (e)/P ( d ) = 2.03) and exhibit transit-timing variations. TOI-1246 is one of the brightest four-planet systems, making it amenable for continued observations. It is one of only five systems with measured masses and radii for all four transiting planets. The planet densities range from 0.70 +/- 0.24 to 3.21 +/- 0.44 g cm(-3), implying a range of bulk and atmospheric compositions. We also report a fifth planet candidate found in the RV data with a minimum mass of 25.6 +/- 3.6 M (circle plus). This planet candidate is exterior to TOI-1246 e, with a candidate period of 93.8 days, and we discuss the implications if it is confirmed to be planetary in nature.
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| 20. |
- Weston, M. D., et al.
(författare)
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Myosin VIIA mutation screening in 189 Usher syndrome type 1 patients
- 1996
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Ingår i: American Journal of Human Genetics. - 0002-9297 .- 1537-6605. ; 59:5, s. 1074-1083
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Tidskriftsartikel (refereegranskat)abstract
- Usher syndrome type 1b (USH1B) is an autosomal recessive disorder characterized by congenital profound hearing loss, vestibular abnormalities, and retinitis pigmentosa. The disorder has recently been shown to be caused by mutations in the myosin VIIa gene (MYO7A) located on 11q14. In the current study, a panel of 189 genetically independent Usher I cases were screened for the presence of mutations in the N-terminal coding portion of the motor domain of MYO7A by heteroduplex analysis of 14 exons. Twenty-three mutations were found segregating with the disease in 20 families. Of the 23 mutations, 13 were unique, and 2 of the 13 unique mutations (Arg212His and Arg212Cys) accounted for the greatest percentage of observed mutant alleles (8/23, 31%). Six of the 13 mutations caused premature stop codons, 6 caused changes in the amino acid sequence of the myosin VIIa protein, and 1 resulted in a splicing defect. Three patients were homozygotes or compound heterozygotes for mutant alleles; these three cases were Tyr333Stop/Tyr333Stop, Arg212His-Arg302His/Arg212His-Arg302His, and IVS13nt-8c-->g/Glu450Gln. All the other USH1B mutations observed were simple heterozygotes, and it is presumed that the mutation on the other allele is present in the unscreened regions of the gene. None of the mutations reported here were observed in 96 unrelated control samples, although several polymorphisms were detected. These results add three patients to single case reported previously where mutations have been found in both alleles and raises the total number of unique mutations in MYO7A to 16.
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| 21. |
- Andersen, Casper W., et al.
(författare)
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OPTIMADE, an API for exchanging materials data
- 2021
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Ingår i: Scientific Data. - : Nature Portfolio. - 2052-4463. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- The Open Databases Integration for Materials Design (OPTIMADE) consortium has designed a universal application programming interface (API) to make materials databases accessible and interoperable. We outline the first stable release of the specification, v1.0, which is already supported by many leading databases and several software packages. We illustrate the advantages of the OPTIMADE API through worked examples on each of the public materials databases that support the full API specification.
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| 22. |
- Bartel, N., et al.
(författare)
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The Compact Radio Source 2021+614 : Simultaneous 2.3 and 8.3 GHz Mark III VLBI Observations
- 1984
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Ingår i: Astrophysical Journal. - Philadelphia, PA : Institute of Physics Publishing (IOPP). - 0004-637X .- 1538-4357. ; 279:1, s. 116-121
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Tidskriftsartikel (refereegranskat)abstract
- Second-epoch VLBI observations of the flat-spectrum radio source 2021+614 made simultaneously at 2.3 and 8.3 GHz with the Mark III system are reported. The maps derived from these observations reveal a complex, frequency-dependent radio structure on the milliarcsecond scale. The object has four nearly collinear components oriented at a position angle of about 35 degrees and embedded in an extended region. Two of these are optically thin, one has a flat spectrum, and the other appears to be synchrotron self-absorbed in the frequency range 2.3-8.3 GHz. No significant structural variation is found at either frequency between epochs separated by about three years. The formal estimate of the transverse velocity between two components, one with a flat and the other with an inverted spectrum, is v/c = 0.7 + or - 2.3. Remarkable similarities between 2021+614 and the unusual source 0316+413 are discussed.
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| 23. |
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| 24. |
- Bolton, Corey J, et al.
(författare)
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Sex and Education Modify the Association Between Subjective Cognitive Decline and Amyloid Pathology.
- 2023
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Ingår i: medRxiv : the preprint server for health sciences.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Subjective cognitive decline (SCD) may be an early risk factor for dementia, particularly in highly educated individuals and women. This study examined the effect of education and sex on the association between SCD and Alzheimer's disease (AD) biomarkers in non-demented older adults.Vanderbilt Memory and Aging Project participants free of clinical dementia or stroke (n=156, 72±6 years, 37% mild cognitive impairment, 33% female) completed fasting lumbar puncture, SCD assessment, and Wide Range Achievement Test-III Reading subtest to assess reading level at baseline as a a proxy for educational quality. Cerebrospinal fluid (CSF) biomarkers for AD (β-amyloid 42 (Aβ42), Aβ42/40 ratio, phosphorylated tau (p-tau), tau, and neurofilament light (NfL)) were analyzed in batch. Linear mixed effects models related SCD to CSF AD biomarkers and follow-up models assessed SCD x sex, SCD x reading level , and SCD x education interactions on AD biomarkers.In main effect models, higher SCD was associated with lower Aβ42 and Aβ42/40 ratio (p-values<0.004). SCD was not associated with tau, p-tau, or NfL levels ( p- values>0.38). SCD score interacted with sex on Aβ42/40 ratio ( p =0.03) but no other biomarkers ( p -values>0.10). In stratified models, higher SCD was associated with lower Aβ42/40 ratio in men ( p =0.0003) but not in women ( p =0.48). SCD score interacted with education on Aβ42 ( p =0.005) and Aβ42/40 ratio ( p =0.001) such that higher education was associated with a stronger negative association between SCD and amyloid levels. No SCD score x reading level interaction was found (p-values> 0.51) though significant associations between SCD and amyloid markers were seen in the higher reading level group (p-values<0.004) but not the lower reading level group (p-values>0.12) when stratified by a median split in reading level.Among community-dwelling older adults free of clinical dementia, higher SCD was associated with greater cerebral amyloid accumulation, one of the earliest pathological AD changes. SCD appears most useful in detecting early AD-related brain changes in men and individuals with higher quantity and quality of education. SCD was not associated with CSF markers of tau pathology or neurodegeneration. These findings suggest that considering sex and education is important when assessing SCD in older adults.
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| 25. |
- Cabell, Cristopher H, et al.
(författare)
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Use of surgery in patients with native valve infective endocarditis: results from the International Collaboration on Endocarditis Merged Database.
- 2005
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Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 150:5, s. 1092-8
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Early surgery has been shown to be beneficial for patients with infective endocarditis (IE), yet surgery is not used in most patients. Evidence of the uncertainty around the use of surgery can be found in the wide variations in the use of cardiac surgery in IE with few precise indications for cardiac surgery yet defined. The aim of the study was to characterize patients with native valve IE relative to surgery and to determine if patients who benefit from an early surgical intervention can be identified. METHODS: The International Collaboration on Endocarditis Merged Database was used to quantify the differences between patients with IE receiving medical and surgical intervention in 1516 patients with definite native valve IE. Propensity models were built to identify a group of patients that benefit from early surgery. RESULTS: Patients in the early surgical group were more likely to be male, younger, and with less comorbidities compared with the early medical group (P < .001 for all) and were less likely to have infection with Staphylococcus aureus or viridans group streptococci (P < .05 for all). Intracardiac abscess and heart failure were much more common in the surgical group (P < .001 for all). In an unadjusted comparison, there was no statistically significant survival advantage in the surgical group. However, in the propensity analysis, in the subgroup of patients with the most indications for surgery, there was a significant decrease in mortality associated with early surgery (11.2% vs 38.0%, P < .001). CONCLUSIONS: The benefits of surgery are not seen uniformly in all patients with native valve IE, but are most realized in a targeted population. This observation requires confirmation in other populations of patients with definite IE.
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| 26. |
- Carleo, Ilaria, et al.
(författare)
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The Multiplanet System TOI-421*
- 2020
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Ingår i: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 160:3
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Tidskriftsartikel (refereegranskat)abstract
- We report the discovery of a warm Neptune and a hot sub-Neptune transiting TOI-421 (BD-14 1137, TIC 94986319), a bright (V = 9.9) G9 dwarf star in a visual binary system observed by the Transiting Exoplanet Survey Satellite (TESS) space mission in Sectors 5 and 6. We performed ground-based follow-up observations-comprised of Las Cumbres Observatory Global Telescope transit photometry, NIRC2 adaptive optics imaging, and FIbre-fed Echelle Spectrograph, CORALIE, High Accuracy Radial velocity Planet Searcher, High Resolution echelle Spectrometer, and Planet Finder Spectrograph high-precision Doppler measurements-and confirmed the planetary nature of the 16 day transiting candidate announced by the TESS team. We discovered an additional radial velocity signal with a period of five days induced by the presence of a second planet in the system, which we also found to transit its host star. We found that the inner mini-Neptune, TOI-421 b, has an orbital period of P-b = 5.19672 +/- 0.00049 days, a mass of M-b = 7.17 +/- 0.66 M-circle plus, and a radius of R-b = R-circle plus, whereas the outer warm Neptune, TOI-421 c, has a period of P-c = 16.06819 +/- 0.00035 days, a mass of M-c = 16.42(-1.04)(+1.06)M(circle plus), a radius of R-c = 5.09(-0.15)(+0.16)R(circle plus), and a density of rho(c) = 0.685(-0.072)(+0.080) cm(-3). With its characteristics, the outer planet (rho(c) = 0.685(-0.0072)(+0.080) cm(-3)) is placed in the intriguing class of the super-puffy mini-Neptunes. TOI-421 b and TOI-421 c are found to be well-suited for atmospheric characterization. Our atmospheric simulations predict significant Ly alpha transit absorption, due to strong hydrogen escape in both planets, as well as the presence of detectable CH4 in the atmosphere of TOI-421 c if equilibrium chemistry is assumed.
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| 27. |
- Caron, Bénédicte, et al.
(författare)
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IOIBD Recommendations for Clinical Trials in Ulcerative Proctitis : the PROCTRIAL Consensus
- 2022
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Ingår i: Clinical Gastroenterology and Hepatology. - : Elsevier. - 1542-3565 .- 1542-7714. ; 20:11, s. 2169-2627.e1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Clinical trials evaluating biologics and small molecules in patients with ulcerative colitis are predominantly excluding ulcerative proctitis. The objective of the PROCTRIAL (Definition and endpoints for ulcerative PROCtitis in clinical TRIALs) initiative was to develop consensus statements for definitions, inclusion criteria, and endpoints for the evaluation of ulcerative proctitis in adults.METHODS: Thirty-five international experts held a consensus meeting to define ulcerative proctitis, and the endpoints to use in clinical trials. Based on a systematic review of the literature, statements were generated, discussed, and approved by the working group participants using a modified Delphi method. Consensus was defined as at least 75% agreement among voters.RESULTS: The group agreed that the diagnosis of ulcerative proctitis should be made by ileocolonoscopy and confirmed by histopathology, with the exclusion of infections, drug-induced causes, radiation, trauma, and Crohn's disease. Ulcerative proctitis was defined as macroscopic extent of lesions limited to 15 cm distance from the anal verge in adults. Primary and secondary endpoints were identified to capture response of ulcerative proctitis to therapy. A combined clinical and endoscopic primary endpoint for the evaluation of ulcerative proctitis disease activity is proposed. Secondary endpoints which should be evaluated include endoscopic remission, histological remission, mucosal healing, histologic endoscopic mucosal improvement, disability, fecal incontinence, urgency, constipation, and health-related quality of life.CONCLUSION: In response to the need for guidance on the design of clinical trials in patients with ulcerative proctitis, the PROCTRIAL consensus provides recommendations on the definition and endpoints for ulcerative proctitis clinical trials.
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| 28. |
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| 29. |
- Hanlon, Killian S., et al.
(författare)
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High levels of AAV vector integration into CRISPR-induced DNA breaks
- 2019
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Adeno-associated virus (AAV) vectors have shown promising results in preclinical models, but the genomic consequences of transduction with AAV vectors encoding CRISPR-Cas nucleases is still being examined. In this study, we observe high levels of AAV integration (up to 47%) into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in cultured murine neurons, mouse brain, muscle and cochlea. Genome-wide AAV mapping in mouse brain shows no overall increase of AAV integration except at the CRISPR/Cas9 target site. To allow detailed characterization of integration events we engineer a miniature AAV encoding a 465 bp lambda bacteriophage DNA (AAV-lambda 465), enabling sequencing of the entire integrated vector genome. The integration profile of AAV-465 lambda in cultured cells display both full-length and fragmented AAV genomes at Cas9 on-target sites. Our data indicate that AAV integration should be recognized as a common outcome for applications that utilize AAV for genome editing.
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| 30. |
- Hon, Marc, et al.
(författare)
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A close-in giant planet escapes engulfment by its star
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 618:7967, s. 917-920
-
Tidskriftsartikel (refereegranskat)abstract
- When main-sequence stars expand into red giants, they are expected to engulf close-in planets(1-5). Until now, the absence of planets with short orbital periods around post-expansion, core-helium-burning red giants(6-8) has been interpreted as evidence that short-period planets around Sun-like stars do not survive the giant expansion phase of their host stars(9). Here we present the discovery that the giant planet 8 Ursae Minoris b(10) orbits a core-helium-burning red giant. At a distance of only 0.5 au from its host star, the planet would have been engulfed by its host star, which is predicted by standard single-star evolution to have previously expanded to a radius of 0.7 au. Given the brief lifetime of helium-burning giants, the nearly circular orbit of the planet is challenging to reconcile with scenarios in which the planet survives by having a distant orbit initially. Instead, the planet may have avoided engulfment through a stellar merger that either altered the evolution of the host star or produced 8 Ursae Minoris b as a second-generation planet(11). This system shows that core-helium-burning red giants can harbour close planets and provides evidence for the role of non-canonical stellar evolution in the extended survival of late-stage exoplanetary systems.
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| 31. |
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| 32. |
- Marcaide, J. M., et al.
(författare)
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The quasars 1038+528 A and B
- 1985
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Ingår i: Astronomy and Astrophysics. - Les Ulis : EDP Sciences. - 0004-6361 .- 1432-0746. ; 142:1, s. 71-84
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Tidskriftsartikel (refereegranskat)abstract
- The results of VLBI observations of the quasars 1038 + 528 A and B at 2.8, 3.6, 13, and 18 cm at various times between November 1979 and March 1981 are reported. The observations and data calibration are described, as are the mapping and astrometric techniques applied in the study. Both quasars are found to have 'core-jet' morphologies. The core of the A quasar dominates its morphology at centrimetric wavelengths with the brightness temperature of its 400 pc long jet being about 1/100 that of the core. By contrast, the 'jet' in the B quasar is very short (about 70 pc); the tail of this jet has the steepest spectral index found to date in extragalactic compact sources, indicating that high electron losses are responsible for the shortness of the jet. No evidence for appreciable morphological change in the B quasar was found over the time span of the study, whereas a new feature may be emerging from the A quasar core at superluminal speed.
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| 33. |
- Meeter, Lieke H.H., et al.
(författare)
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Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia
- 2019
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Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:9, s. 997-1004
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Tidskriftsartikel (refereegranskat)abstract
- Background: Semantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD. Methods: This large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset). Results: CSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p<0.001). Higher CSF NfL levels were moderately associated with naming impairment as measured by the Boston Naming Test (rs=-0.32, p=0.002) and with smaller grey matter volume of the parahippocampal gyri (rs=-0.31, p=0.004). However, cross-sectional CSF NfL levels were not associated with progression of grey matter atrophy and did not predict survival. Conclusion: CSF NfL is a promising biomarker in the diagnostic process of SD, although it has limited cross-sectional monitoring or prognostic abilities.
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| 34. |
- Moen, Jon, et al.
(författare)
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Eye on the Taiga : Removing Global Policy Impediments to Safeguard the Boreal Forest
- 2014
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Ingår i: Conservation Letters. - : Wiley. - 1755-263X. ; 7:4, s. 408-418
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Tidskriftsartikel (refereegranskat)abstract
- The absence of boreal forests from global policy agendas on sustainable development and climate change mitigation represents a massive missed opportunity for environmental protection. The boreal zone contains some of the world's largest pools of terrestrial carbon that, if not safeguarded from a conversion to a net source of greenhouse gases, could seriously exacerbate global climate change. At the same time, boreal countries have a strong tradition of forest management-expertise that could be effectively leveraged toward global and national carbon mitigation targets and sustainable development. Current obstacles against such contributions include weak incentives for carbon sequestration and a reluctance to embrace change by forest managers and policy makers. We discuss possible solutions to overcome these obstacles, including the improvement of ineffective incentives, the development of alternative forest management strategies, and the need to maintain ecosystem resilience through the pursuit of policy and management options.
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| 35. |
- Murdoch, David R, et al.
(författare)
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Clinical presentation, etiology, and outcome of infective endocarditis in the 21st century: the International Collaboration on Endocarditis-Prospective Cohort Study.
- 2009
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Ingår i: Archives of internal medicine. - : American Medical Association (AMA). - 1538-3679 .- 0003-9926. ; 169:5, s. 463-73
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: We sought to provide a contemporary picture of the presentation, etiology, and outcome of infective endocarditis (IE) in a large patient cohort from multiple locations worldwide. METHODS: Prospective cohort study of 2781 adults with definite IE who were admitted to 58 hospitals in 25 countries from June 1, 2000, through September 1, 2005. RESULTS: The median age of the cohort was 57.9 (interquartile range, 43.2-71.8) years, and 72.1% had native valve IE. Most patients (77.0%) presented early in the disease (<30 days) with few of the classic clinical hallmarks of IE. Recent health care exposure was found in one-quarter of patients. Staphylococcus aureus was the most common pathogen (31.2%). The mitral (41.1%) and aortic (37.6%) valves were infected most commonly. The following complications were common: stroke (16.9%), embolization other than stroke (22.6%), heart failure (32.3%), and intracardiac abscess (14.4%). Surgical therapy was common (48.2%), and in-hospital mortality remained high (17.7%). Prosthetic valve involvement (odds ratio, 1.47; 95% confidence interval, 1.13-1.90), increasing age (1.30; 1.17-1.46 per 10-year interval), pulmonary edema (1.79; 1.39-2.30), S aureus infection (1.54; 1.14-2.08), coagulase-negative staphylococcal infection (1.50; 1.07-2.10), mitral valve vegetation (1.34; 1.06-1.68), and paravalvular complications (2.25; 1.64-3.09) were associated with an increased risk of in-hospital death, whereas viridans streptococcal infection (0.52; 0.33-0.81) and surgery (0.61; 0.44-0.83) were associated with a decreased risk. CONCLUSIONS: In the early 21st century, IE is more often an acute disease, characterized by a high rate of S aureus infection. Mortality remains relatively high.
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| 36. |
- Spotorno, Nicola, et al.
(författare)
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Diffusion tensor MRI to distinguish progressive supranuclear palsy from a-synucleinopathies
- 2019
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 0033-8419 .- 1527-1315. ; 293:3, s. 646-653
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Tidskriftsartikel (refereegranskat)abstract
- Background: The differential diagnosis of progressive supranuclear palsy (PSP) and Lewy body disorders, which include Parkinson disease and dementia with Lewy bodies, is often challenging due to the overlapping symptoms. Purpose: To develop a diagnostic tool based on diffusion tensor imaging (DTI) to distinguish between PSP and Lewy body disorders at the individual-subject level. Materials and Methods: In this retrospective study, skeletonized DTI metrics were extracted from two independent data sets: the discovery cohort from the Swedish BioFINDER study and the validation cohort from the Penn Frontotemporal Degeneration Center (data collected between 2010 and 2018). Based on previous neuroimaging studies and neuropathologic evidence, a combination of regions hypothesized to be sensitive to pathologic features of PSP were identified (ie, the superior cerebellar peduncle and frontal white matter) and fractional anisotropy (FA) was used to compute an FA score for each individual. Classification performances were assessed by using logistic regression and receiver operating characteristic analysis. Results: In the discovery cohort, 16 patients with PSP (mean age 6 standard deviation, 73 years 6 5; eight women, eight men), 34 patients with Lewy body disorders (mean age, 71 years 6 6; 14 women, 20 men), and 44 healthy control participants (mean age, 66 years 6 8; 26 women, 18 men) were evaluated. The FA score distinguished between clinical PSP and Lewy body disorders with an area under the curve of 0.97 6 0.04, a specificity of 91% (31 of 34), and a sensitivity of 94% (15 of 16). In the validation cohort, 34 patients with PSP (69 years 6 7; 22 women, 12 men), 25 patients with Lewy body disorders (70 years 6 7; nine women, 16 men), and 32 healthy control participants (64 years 6 7; 22 women, 10 men) were evaluated. The accuracy of the FA score was confirmed (area under the curve, 0.96 6 0.04; specificity, 96% [24 of 25]; and sensitivity, 85% [29 of 34]). Conclusion: These cross-validated findings lay the foundation for a clinical test to distinguish progressive supranuclear palsy from Lewy body disorders.
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| 37. |
- Stenmark Tullberg, Axel, et al.
(författare)
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Immune infiltrate in the primary tumor predicts effect of adjuvant radiotherapy in breast cancer; results from the randomized SweBCG91RT trial.
- 2021
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Ingår i: Clinical cancer research : an official journal of the American Association for Cancer Research. - 1078-0432. ; 27:3, s. 749-758
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Tidskriftsartikel (refereegranskat)abstract
- Tumor-infiltrating immune cells play a key role in tumor progression. The purpose of this study was to analyze if the immune infiltrate predicts benefit from postoperative radiotherapy (RT) in a large randomized breast cancer RT trial.In the SweBCG91RT trial, patients with stage I and II breast cancer were randomized to breast conserving surgery (BCS) and postoperative RT or to BCS only and followed for a median time of 15.2 years. The primary tumor immune infiltrate was quantified through two independent methods; immunohistochemistry (IHC) and gene expression profiling. For IHC analyses, the absolute stromal area occupied by CD8+ T cells and FOXP3+ T cells, respectively, was used to define the immune infiltrate. For gene expression analyses, immune cells found to be prognostic in independent datasets were pooled into two groups consisting of antitumoral- and protumoral immune cells, respectively.An antitumoral immune response in the primary tumor was associated with a reduced risk of breast cancer recurrence and predicted less benefit from adjuvant RT. The interaction between RT and immune phenotype was significant for any recurrence in both the IHC and gene expression analyses (p=0.039 and p=0.035) and was also significant for IBTR in the gene expression analyses (p=0.025).Patients with an antitumoral immune infiltrate in the primary tumor have a reduced risk of any recurrence and may derive less benefit from adjuvant RT. These results may impact decisions regarding postoperative RT in early breast cancer.
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| 38. |
- Wang, Andrew, et al.
(författare)
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The use and effect of surgical therapy for prosthetic valve infective endocarditis: a propensity analysis of a multicenter, international cohort.
- 2005
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Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 150:5, s. 1086-91
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although surgical intervention is often used in the treatment of prosthetic valve infective endocarditis (PVIE), an understanding of its effect on survival has been limited by the biases of observational studies and lack of controlled trials. METHODS: The International Collaboration on Endocarditis Merged Database is a large, multicenter, international registry of patients with definite endocarditis by Duke criteria, including 367 patients with PVIE. Clinical, microbiologic, and echocardiographic variables were analyzed to determine those factors associated with the use of surgery for PVIE. Logistic regression analysis was performed to create a propensity model of predictors of surgery use. Patients who underwent surgery during initial hospitalization were matched by propensity score with patients treated with medical therapy alone. Logistic regression analysis was performed to determine variables independently associated with inhospital mortality in this matched subset. RESULTS: Surgical therapy for PVIE was performed in 148 (42%) of 367 patients. Inhospital mortality was similar for patients treated with surgery compared with those treated with medical therapy alone (25.0% vs 23.4%, P = .729). Surgical therapy was independently associated with patient age, microorganism, intracardiac abscess, and congestive heart failure. After adjustment for these determinants, inhospital mortality was predicted by brain embolization (OR 11.12, 95% CI 4.16-29.73) and Staphylococcus aureus infection (OR 3.67, 95% CI 1.29-9.74), with a trend toward benefit for surgery (OR 0.56, 95% CI 0.23-1.36). CONCLUSIONS: Despite the frequent use of surgery for the treatment of PVIE, this condition continues to be associated with a high inhospital mortality rate in the contemporary era. After adjustment for factors related to surgical intervention, brain embolism and S aureus infection were independently associated with inhospital mortality and a trend toward a survival benefit of surgery was evident.
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| 39. |
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| 40. |
- Benatar, Michael, et al.
(författare)
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Preventing amyotrophic lateral sclerosis : insights from pre-symptomatic neurodegenerative diseases
- 2022
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Ingår i: Brain. - : Oxford University Press. - 0006-8950 .- 1460-2156. ; 145:1, s. 27-44
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Forskningsöversikt (refereegranskat)abstract
- Significant progress has been made in understanding the pre-symptomatic phase of amyotrophic lateral sclerosis. While much is still unknown, advances in other neurodegenerative diseases offer valuable insights. Indeed, it is increasingly clear that the well-recognized clinical syndromes of Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal muscular atrophy and frontotemporal dementia are also each preceded by a pre-symptomatic or prodromal period of varying duration, during which the underlying disease process unfolds, with associated compensatory changes and loss of inherent system redundancy. Key insights from these diseases highlight opportunities for discovery in amyotrophic lateral sclerosis. The development of biomarkers reflecting amyloid and tau has led to a shift in defining Alzheimer's disease based on inferred underlying histopathology. Parkinson's disease is unique among neurodegenerative diseases in the number and diversity of non-genetic biomarkers of pre-symptomatic disease, most notably REM sleep behaviour disorder. Huntington's disease benefits from an ability to predict the likely timing of clinically manifest disease based on age and CAG-repeat length alongside reliable neuroimaging markers of atrophy. Spinal muscular atrophy clinical trials have highlighted the transformational value of early therapeutic intervention, and studies in frontotemporal dementia illustrate the differential role of biomarkers based on genotype. Similar advances in amyotrophic lateral sclerosis would transform our understanding of key events in pathogenesis, thereby dramatically accelerating progress towards disease prevention. Deciphering the biology of pre-symptomatic amyotrophic lateral sclerosis relies on a clear conceptual framework for defining the earliest stages of disease. Clinically manifest amyotrophic lateral sclerosis may emerge abruptly, especially among those who harbour genetic mutations associated with rapidly progressive amyotrophic lateral sclerosis. However, the disease may also evolve more gradually, revealing a prodromal period of mild motor impairment preceding phenoconversion to clinically manifest disease. Similarly, cognitive and behavioural impairment, when present, may emerge gradually, evolving through a prodromal period of mild cognitive impairment or mild behavioural impairment before progression to amyotrophic lateral sclerosis. Biomarkers are critically important to studying pre-symptomatic amyotrophic lateral sclerosis and essential to efforts to intervene therapeutically before clinically manifest disease emerges. The use of non-genetic biomarkers, however, presents challenges related to counselling, informed consent, communication of results and limited protections afforded by existing legislation. Experiences from pre-symptomatic genetic testing and counselling, and the legal protections against discrimination based on genetic data, may serve as a guide. Building on what we have learned - more broadly from other pre-symptomatic neurodegenerative diseases and specifically from amyotrophic lateral sclerosis gene mutation carriers - we present a road map to early intervention, and perhaps even disease prevention, for all forms of amyotrophic lateral sclerosis.
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| 41. |
- Benatar, Michael, et al.
(författare)
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The Miami Framework for ALS and related neurodegenerative disorders : an integrated view of phenotype and biology
- 2024
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Ingår i: Nature Reviews Neurology. - : Springer Nature. - 1759-4758 .- 1759-4766. ; 20:6, s. 364-376
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Forskningsöversikt (refereegranskat)abstract
- Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.
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| 42. |
- Bhowmick, Asmit, et al.
(författare)
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Structural evidence for intermediates during O2 formation in photosystem II
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 617:7961, s. 629-636
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Tidskriftsartikel (refereegranskat)abstract
- In natural photosynthesis, the light-driven splitting of water into electrons, protons and molecular oxygen forms the first step of the solar-to-chemical energy conversion process. The reaction takes place in photosystem II, where the Mn4CaO5 cluster first stores four oxidizing equivalents, the S0 to S4 intermediate states in the Kok cycle, sequentially generated by photochemical charge separations in the reaction center and then catalyzes the O–O bond formation chemistry. Here, we report room temperature snapshots by serial femtosecond X-ray crystallography to provide structural insights into the final reaction step of Kok’s photosynthetic water oxidation cycle, the S3→[S4]→S0 transition where O2 is formed and Kok’s water oxidation clock is reset. Our data reveal a complex sequence of events, which occur over micro- to milliseconds, comprising changes at the Mn4CaO5 cluster, its ligands and water pathways as well as controlled proton release through the hydrogen-bonding network of the Cl1 channel. Importantly, the extra O atom Ox, which was introduced as a bridging ligand between Ca and Mn1 during the S2→S3 transition, disappears or relocates in parallel with Yz reduction starting at approximately 700 μs after the third flash. The onset of O2 evolution, as indicated by the shortening of the Mn1–Mn4 distance, occurs at around 1,200 μs, signifying the presence of a reduced intermediate, possibly a bound peroxide.
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| 43. |
- Bolla, Jani Reddy, et al.
(författare)
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A Mass-Spectrometry-Based Approach to Distinguish Annular and Specific Lipid Binding to Membrane Proteins
- 2020
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Ingår i: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 59:9, s. 3523-3528
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Tidskriftsartikel (refereegranskat)abstract
- Membrane proteins engage in a variety of contacts with their surrounding lipids, but distinguishing between specifically bound lipids, and non-specific, annular interactions is a challenging problem. Applying native mass spectrometry to three membrane protein complexes with different lipid-binding properties, we explore the ability of detergents to compete with lipids bound in different environments. We show that lipids in annular positions on the presenilin homologue protease are subject to constant exchange with detergent. By contrast, detergent-resistant lipids bound at the dimer interface in the leucine transporter show decreased k(off) rates in molecular dynamics simulations. Turning to the lipid flippase MurJ, we find that addition of the natural substrate lipid-II results in the formation of a 1:1 protein-lipid complex, where the lipid cannot be displaced by detergent from the highly protected active site. In summary, we distinguish annular from non-annular lipids based on their exchange rates in solution.
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| 44. |
- Boscaro, Vittorio, et al.
(författare)
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Microbiomes of microscopic marine invertebrates do not reveal signatures of phylosymbiosis
- 2022
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Ingår i: Nature Microbiology. - : Springer Science and Business Media LLC. - 2058-5276. ; 7:6, s. 810-819
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Tidskriftsartikel (refereegranskat)abstract
- Animals and microorganisms often establish close ecological relationships. However, much of our knowledge about animal microbiomes comes from two deeply studied groups: vertebrates and arthropods. To understand interactions on a broader scale of diversity, we characterized the bacterial microbiomes of close to 1,000 microscopic marine invertebrates from 21 phyla, spanning most of the remaining tree of metazoans. Samples were collected from five temperate and tropical locations covering three marine habitats (sediment, water column and intertidal macroalgae) and bacterial microbiomes were characterized using 16S ribosomal RNA gene sequencing. Our data show that, despite their size, these animals harbour bacterial communities that differ from those in the surrounding environment. Distantly related but coexisting invertebrates tend to share many of the same bacteria, suggesting that guilds of microorganisms preferentially associated with animals, but not tied to any specific host lineage, are the main drivers of the ecological relationship. Host identity is a minor factor shaping these microbiomes, which do not show the same correlation with host phylogeny, or ‘phylosymbiosis’, observed in many large animals. Hence, the current debate on the varying strength of phylosymbiosis within selected lineages should be reframed to account for the possibility that such a pattern might be the exception rather than the rule.
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| 45. |
- Bosque, Irene, et al.
(författare)
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Redox Catalysis Facilitates Lignin Depolymerization
- 2017
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Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7951 .- 2374-7943. ; 3:6, s. 621-628
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Tidskriftsartikel (refereegranskat)abstract
- Lignin is a recalcitrant and underexploited natural feedstock for aromatic commodity chemicals, and its degradation generally requires the use of high temperatures and harsh reaction conditions. Herein we present an ambient temperature one-pot process for the controlled oxidation and depolymerization of this potent resource. Harnessing the potential of electrocatalytic oxidation in conjugation with our photocatalytic cleavage methodology, we have developed an operationally simple procedure for selective fragmentation of β-O-4 bonds with excellent mass recovery, which provides a unique opportunity to expand the existing lignin usage from energy source to commodity chemicals and synthetic building block source.
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| 46. |
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| 47. |
- 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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| 48. |
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| 49. |
- Caram, L B, et al.
(författare)
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Leptotrichia endocarditis: report of two cases from the International Collaboration on Endocarditis (ICE) database and review of previous cases.
- 2008
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Ingår i: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. - : Springer Science and Business Media LLC. - 0934-9723. ; 27:2, s. 139-43
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Tidskriftsartikel (refereegranskat)abstract
- Leptotrichia species typically colonize the oral cavity and genitourinary tract. We report the first two cases of endocarditis secondary to L. goodfellowii sp. nov. Both cases were identified using 16S rRNA gene sequencing. Review of the English literature revealed only two other cases of Leptotrichia sp. endocarditis.
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| 50. |
- Chapuis, AG, et al.
(författare)
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HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 117:20, s. 5391-5402
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Tidskriftsartikel (refereegranskat)abstract
- Most HIV+ individuals require lifelong highly active antiretroviral therapy (HAART) to suppress HIV replication, but fail to eliminate the virus in part because of residual replication in gut-associated lymphoid tissues (GALT). Naturally elicited HIV-specific CD8+ T cells generated in the acute and chronic infectious phases exhibit antiviral activity, but decrease in number after HAART. Therapeutic vaccines represent a potential strategy to expand cellular responses, although previous efforts have been largely unsuccessful, conceivably because of a lack of responding HIV-specific central-memory CD8+ T cells (Tcm). To determine whether patients receiving HAART possess CD8+ T cells with Tcm qualities that are amenable to augmentation, HIV-specific CD8+ T-cell clones were derived from HIV-reactive CD28+CD8+ T-cell lines isolated from 7 HIV+ HAART-treated patients, expanded ex vivo, and reinfused into their autologous host. Tracking of the cells in vivo revealed that clones could persist for ≥ 84 days, maintain expression and/or re-express CD28, up-regulate CD62L, secrete IL-2, proliferate on cognate Ag encounter and localize to the rectal mucosa. These results suggest some infused cells exhibited phenotypic and functional characteristics shared with Tcm in vivo, and imply that more effective therapeutic vaccination strategies targeting CD8+ Tcm in patients on HAART might provide hosts with expanded, long-lasting immune responses not only systemically but also in GALT. This study is registered at www.clinicaltrials.gov as NCT00110578.
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