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1.
  • Axfors, Cathrine, et al. (author)
  • Association between convalescent plasma treatment and mortality in COVID-19 : a collaborative systematic review and meta-analysis of randomized clinical trials
  • 2021
  • In: BMC Infectious Diseases. - : BioMed Central (BMC). - 1471-2334. ; 21:1
  • Research review (peer-reviewed)abstract
    • Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, ). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung-Knapp-Sidik-Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I-2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
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3.
  • Willeit, P., et al. (author)
  • Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients
  • 2020
  • In: Circulation. - 1524-4539. ; 142:7, s. 621-642
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 μm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.
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4.
  • Costello, David M., et al. (author)
  • Global patterns and controls of nutrient immobilization on decomposing cellulose in riverine ecosystems
  • 2022
  • In: Global Biogeochemical Cycles. - : John Wiley & Sons. - 0886-6236 .- 1944-9224. ; 36:3
  • Journal article (peer-reviewed)abstract
    • Microbes play a critical role in plant litter decomposition and influence the fate of carbon in rivers and riparian zones. When decomposing low-nutrient plant litter, microbes acquire nitrogen (N) and phosphorus (P) from the environment (i.e., nutrient immobilization), and this process is potentially sensitive to nutrient loading and changing climate. Nonetheless, environmental controls on immobilization are poorly understood because rates are also influenced by plant litter chemistry, which is coupled to the same environmental factors. Here we used a standardized, low-nutrient organic matter substrate (cotton strips) to quantify nutrient immobilization at 100 paired stream and riparian sites representing 11 biomes worldwide. Immobilization rates varied by three orders of magnitude, were greater in rivers than riparian zones, and were strongly correlated to decomposition rates. In rivers, P immobilization rates were controlled by surface water phosphate concentrations, but N immobilization rates were not related to inorganic N. The N:P of immobilized nutrients was tightly constrained to a molar ratio of 10:1 despite wide variation in surface water N:P. Immobilization rates were temperature-dependent in riparian zones but not related to temperature in rivers. However, in rivers nutrient supply ultimately controlled whether microbes could achieve the maximum expected decomposition rate at a given temperature. Collectively, we demonstrated that exogenous nutrient supply and immobilization are critical control points for decomposition of organic matter.
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5.
  • Kraemer, Benjamin M., et al. (author)
  • Climate change drives widespread shifts in lake thermal habitat
  • 2021
  • In: Nature Climate Change. - : Springer Science and Business Media LLC. - 1758-678X .- 1758-6798. ; 11:6, s. 521-529
  • Journal article (peer-reviewed)abstract
    • Lake surfaces are warming worldwide, raising concerns about lake organism responses to thermal habitat changes. Species may cope with temperature increases by shifting their seasonality or their depth to track suitable thermal habitats, but these responses may be constrained by ecological interactions, life histories or limiting resources. Here we use 32 million temperature measurements from 139 lakes to quantify thermal habitat change (percentage of non-overlap) and assess how this change is exacerbated by potential habitat constraints. Long-term temperature change resulted in an average 6.2% non-overlap between thermal habitats in baseline (1978-1995) and recent (1996-2013) time periods, with non-overlap increasing to 19.4% on average when habitats were restricted by season and depth. Tropical lakes exhibited substantially higher thermal non-overlap compared with lakes at other latitudes. Lakes with high thermal habitat change coincided with those having numerous endemic species, suggesting that conservation actions should consider thermal habitat change to preserve lake biodiversity. Using measurements from 139 global lakes, the authors demonstrate how long-term thermal habitat change in lakes is exacerbated by species' seasonal and depth-related constraints. They further reveal higher change in tropical lakes, and those with high biodiversity and endemism.
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6.
  • Pilla, Rachel M., et al. (author)
  • Global data set of long-term summertime vertical temperature profiles in 153 lakes
  • 2021
  • In: Scientific Data. - : Springer Nature. - 2052-4463. ; 8:1
  • Journal article (peer-reviewed)abstract
    • Climate change and other anthropogenic stressors have led to long-term changes in the thermal structure, including surface temperatures, deepwater temperatures, and vertical thermal gradients, in many lakes around the world. Though many studies highlight warming of surface water temperatures in lakes worldwide, less is known about long-term trends in full vertical thermal structure and deepwater temperatures, which have been changing less consistently in both direction and magnitude. Here, we present a globally-expansive data set of summertime in-situ vertical temperature profiles from 153 lakes, with one time series beginning as early as 1894. We also compiled lake geographic, morphometric, and water quality variables that can influence vertical thermal structure through a variety of potential mechanisms in these lakes. These long-term time series of vertical temperature profiles and corresponding lake characteristics serve as valuable data to help understand changes and drivers of lake thermal structure in a time of rapid global and ecological change.
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7.
  • Pilla, Rachel M., et al. (author)
  • Deeper waters are changing less consistently than surface waters in a global analysis of 102 lakes
  • 2020
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
  • Journal article (peer-reviewed)abstract
    • Globally, lake surface water temperatures have warmed rapidly relative to air temperatures, but changes in deepwater temperatures and vertical thermal structure are still largely unknown. We have compiled the most comprehensive data set to date of long-term (1970–2009) summertime vertical temperature profiles in lakes across the world to examine trends and drivers of whole-lake vertical thermal structure. We found significant increases in surface water temperatures across lakes at an average rate of + 0.37 °C decade−1, comparable to changes reported previously for other lakes, and similarly consistent trends of increasing water column stability (+ 0.08 kg m−3 decade−1). In contrast, however, deepwater temperature trends showed little change on average (+ 0.06 °C decade−1), but had high variability across lakes, with trends in individual lakes ranging from − 0.68 °C decade−1 to + 0.65 °C decade−1. The variability in deepwater temperature trends was not explained by trends in either surface water temperatures or thermal stability within lakes, and only 8.4% was explained by lake thermal region or local lake characteristics in a random forest analysis. These findings suggest that external drivers beyond our tested lake characteristics are important in explaining long-term trends in thermal structure, such as local to regional climate patterns or additional external anthropogenic influences.
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8.
  • Wannigama, D. L., et al. (author)
  • COVID-19 monitoring with sparse sampling of sewered and non-sewered wastewater in urban and rural communities
  • 2023
  • In: Iscience. ; 26:7
  • Journal article (peer-reviewed)abstract
    • Equitable SARS-CoV-2 surveillance in low-resource communities lacking centralized sewers is critical as wastewater-based epidemiology (WBE) progresses. However, large-scale studies on SARS-CoV-2 detection in wastewater from low-and middle-income countries is limited because of economic and technical reasons. In this study, wastewater samples were collected twice a month from 186 urban and rural subdistricts in nine provinces of Thailand mostly having decentralized and non-sewered sanitation infrastructure and analyzed for SARS-CoV-2 RNA variants using allele-specific RT-qPCR. Wastewater SARS-CoV-2 RNA concentration was used to estimate the real-time incidence and time-varying effective reproduction number (Re). Results showed an increase in SARS-CoV-2 RNA concentrations in wastewater from urban and rural areas 14-20 days earlier than infected individuals were officially reported. It also showed that community/food markets were ''hot spots'' for infected people. This approach offers an opportunity for early detection of transmission surges, allowing preparedness and potentially mitigating significant outbreaks at both spatial and temporal scales.
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9.
  • Biel, D., et al. (author)
  • Combining tau-PET and fMRI meta-analyses for patient-centered prediction of cognitive decline in Alzheimer's disease
  • 2022
  • In: Alzheimers Research & Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 14:1
  • Journal article (peer-reviewed)abstract
    • Background Tau-PET is a prognostic marker for cognitive decline in Alzheimer's disease, and the heterogeneity of tau-PET patterns matches cognitive symptom heterogeneity. Thus, tau-PET may allow precision-medicine prediction of individual tau-related cognitive trajectories, which can be important for determining patient-specific cognitive endpoints in clinical trials. Here, we aimed to examine whether tau-PET in cognitive-domain-specific brain regions, identified via fMRI meta-analyses, allows the prediction of domain-specific cognitive decline. Further, we aimed to determine whether tau-PET-informed personalized cognitive composites capture patient-specific cognitive trajectories more sensitively than conventional cognitive measures. Methods We included Alzheimer's Disease Neuroimaging Initiative (ADNI) participants classified as controls (i.e., amyloid-negative, cognitively normal, n = 121) or Alzheimer's disease-spectrum (i.e., amyloid-positive, cognitively normal to dementia, n = 140), plus 111 AVID-1451-A05 participants for independent validation (controls/Alzheimer's disease-spectrum=46/65). All participants underwent baseline F-18-flortaucipir tau-PET, amyloid-PET, and longitudinal cognitive testing to assess annual cognitive changes (i.e., episodic memory, language, executive functioning, visuospatial). Cognitive changes were calculated using linear mixed models. Independent meta-analytical task-fMRI activation maps for each included cognitive domain were obtained from the Neurosynth database and applied to tau-PET to determine tau-PET signal in cognitive-domain-specific brain regions. In bootstrapped linear regression, we assessed the strength of the relationship (i.e., partial R-2) between cognitive-domain-specific tau-PET vs. global or temporal-lobe tau-PET and cognitive changes. Further, we used tau-PET-based prediction of domain-specific decline to compose personalized cognitive composites that were tailored to capture patient-specific cognitive decline. Results In both amyloid-positive cohorts (ADNI [age = 75.99 +/- 7.69] and A05 [age = 74.03 +/- 9.03]), cognitive-domain-specific tau-PET outperformed global and temporal-lobe tau-PET for predicting future cognitive decline in episodic memory, language, executive functioning, and visuospatial abilities. Further, a tau-PET-informed personalized cognitive composite across cognitive domains enhanced the sensitivity to assess cognitive decline in amyloid-positive subjects, yielding lower sample sizes required for detecting simulated intervention effects compared to conventional cognitive endpoints (i.e., memory composite, global cognitive composite). However, the latter effect was less strong in A05 compared to the ADNI cohort. Conclusion Combining tau-PET with task-fMRI-derived maps of major cognitive domains facilitates the prediction of domain-specific cognitive decline. This approach may help to increase the sensitivity to detect Alzheimer's disease-related cognitive decline and to determine personalized cognitive endpoints in clinical trials.
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10.
  • Gillespie, S. A., et al. (author)
  • Identification of sub- μ s isomeric states in the odd-odd nucleus Au 178
  • 2021
  • In: Physical Review C. - 2469-9985. ; 103:4
  • Journal article (peer-reviewed)abstract
    • The neutron-deficient gold (Z=79) isotopes in the vicinity of the neutron midshell N=104 provide prolific examples of shape coexistence and isomerism at low excitation energy. They can be probed via a number of different experimental techniques. In this study, two new isomeric states with half-lives of 294(7) and 373(9) ns have been observed in the neutron-deficient odd-odd nuclide Au178 (N=99) in an experiment at the RITU gas-filled separator at JYFL, Jyväskylä. This result was achieved due to the use of a segmented planar germanium detector with a high efficiency at low energies. By applying the recoil-decay tagging technique, they were assigned to decay to two different long-lived α-decaying states in Au178.
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11.
  • Leshan, D., et al. (author)
  • Ca-EDTA restores the activity of ceftazidime- avibactam or aztreonam against carbapenemase- producing Klebsiella pneumoniae infections
  • 2023
  • In: iScience. - 2589-0042. ; 26:7
  • Journal article (peer-reviewed)abstract
    • Developing an effective therapy to overcome carbapenemase-positive Klebsiella pneumoniae (CPKp) is an important therapeutic challenge that must be ad-dressed urgently. Here, we explored a Ca-EDTA combination with aztreonam or ceftazidime-avibactam in vitro and in vivo against diverse CPKp clinical iso-lates. The synergy testing of this study demonstrated that novel aztreonam-Ca-EDTA or ceftazidime-avibactam-Ca-EDTA combination was significantly effective in eliminating planktonic and mature biofilms in vitro, as well as eradicating CPKp infections in vivo. Both combinations revealed significant therapeutic efficacies in reducing bacterial load in internal organs and protecting treated mice from mor-tality. Conclusively, this is the first in vitro and in vivo study to demonstrate that novel aztreonam-Ca-EDTA or ceftazidime-avibactam-Ca-EDTA combinations pro-vide favorable efficacy and safety for successful eradication of carbapenemase-producing Klebsiella pneumoniae planktonic and biofilm infections.
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  • Nagao-Kitamoto, H., et al. (author)
  • Interleukin-22-mediated host glycosylation prevents Clostridioides difficile infection by modulating the metabolic activity of the gut microbiota
  • 2020
  • In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 26, s. 608-617
  • Journal article (peer-reviewed)abstract
    • In germ-free mice colonized with human microbiota, mucosal IL-22 signaling promotes the growth of succinate-consuming commensal bacteria via host mucus glycosylation, and transplantation of these bacteria limits Clostridioides difficile infection. The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.
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  • Shein, A. M. S., et al. (author)
  • High prevalence of mgrB-mediated colistin resistance among carbapenem-resistant Klebsiella pneumoniae is associated with biofilm formation, and can be overcome by colistin-EDTA combination therapy
  • 2022
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
  • Journal article (peer-reviewed)abstract
    • The global prevalence of colistin-resistant Klebsiella pneumoniae (ColRkp) facilitated by chromosomal and plasmid-mediated Ara4N or PEtN-remodeled LPS alterations has steadily increased with increased colistin usage for treating carbapenem-resistant K. pneumoniae (CRkp). Our study demonstrated the rising trend of ColRkp showing extensively and pandrug-resistant characteristics among CRkp, with a prevalence of 28.5%, which was mediated by chromosomal mgrB, pmrB, or phoQ mutations (91.5%), and plasmid-mediated mcr-1.1, mcr-8.1, mcr-8.2 alone or in conjunction with R256G PmrB (8.5%). Several genetic alterations in mgrB (85.1%) with increased expressions of Ara4N-related phoPQ and pmrK were critical for establishing colistin resistance in our isolates. In this study, we discovered the significant associations between extensively drug-resistant bacteria (XDR) and pandrug-resistant bacteria (PDR) ColRkp in terms of moderate, weak or no biofilm-producing abilities, and altered expressions of virulence factors. These ColRkp would therefore be very challenging to treat, emphasizing for innovative therapy to combat these infections. Regardless of the underlying colistin-resistant mechanisms, colistin-EDTA combination therapy in this study produced potent synergistic effects in both in vitro and in vivo murine bacteremia, with no ColRkp regrowth and improved animal survival, implying the significance of colistin-EDTA combination therapy as systemic therapy for unlocking colistin resistance in ColRkp-associated bacteremia.
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  • Shein, A. M. S., et al. (author)
  • Novel intranasal phage-CaEDTA-ceftazidime/avibactam triple combination therapy demonstrates remarkable efficacy in treating Pseudomonas aeruginosa lung infection
  • 2023
  • In: Biomedicine & Pharmacotherapy. - 0753-3322. ; 168
  • Journal article (peer-reviewed)abstract
    • Given the rise of multidrug-resistant (MDR) Pseudomonas aeruginosa infections, alternative treatments are needed. Anti-pseudomonal phage therapy shows promise, but its clinical application is limited due to the development of resistance and a lack of biofilm penetration. Recently, adjuvants like CaEDTA have shown the ability to enhance the effectiveness of combined antimicrobial agents. Here, we tested a phage-adjuvant com-bination and demonstrated the effectiveness of intranasally inhaled phage (KKP10) + CaEDTA in addition to ceftazidime/avibactam (CZA) for chronic P. aeruginosa lung infections. The results emphasize that intranasal inhalation of phage along with CaEDTA can successfully re-sensitize MDR P. aeruginosa to CZA in a triple combination treatment. This promising approach shows potential as a therapy for chronic respiratory tract infections.
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  • Wannigama, D. L., et al. (author)
  • Multiple traces of monkeypox detected in non-sewered wastewater with sparse sampling from a densely populated metropolitan area in Asia
  • 2023
  • In: SCIENCE OF THE TOTAL ENVIRONMENT. - : Elsevier BV. - 0048-9697. ; 858
  • Journal article (peer-reviewed)abstract
    • The monkeypox virus is excreted in the feces of infected individuals. Therefore, there is an interest in using viral load detection in wastewater for sentinel early surveillance at a community level and as a complementary approach to syndromic surveillance. We collected wastewater from 63 sewered and non-sewered locations in Bangkok city center between May and August 2022. Monkeypox viral DNA copy numbers were quantified using real-time polymerase chain reaction (PCR) and confirmed positive by Sanger sequencing. Monkeypox viral DNA was first detected in waste-water from the second week of June 2022, with a mean copy number of 16.4 copies/ml (n = 3). From the first week of July, the number of viral DNA copies increased to a mean copy number of 45.92 copies/ml. Positive samples were Sanger sequenced and confirmed the presence of the monkeypox virus. Our study is the first to detect monkeypox viral DNA in wastewater from various locations within Thailand. Results suggest that this could be a complementary source for detecting viral DNA and predicting upcoming outbreaks.
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  • Al-Hallaq, Hania A., et al. (author)
  • AAPM task group report 302 : Surface-guided radiotherapy
  • 2022
  • In: Medical Physics. - : Wiley. - 0094-2405 .- 2473-4209. ; 49:4, s. 82-112
  • Journal article (peer-reviewed)abstract
    • The clinical use of surface imaging has increased dramatically, with demonstrated utility for initial patient positioning, real-time motion monitoring, and beam gating in a variety of anatomical sites. The Therapy Physics Subcommittee and the Imaging for Treatment Verification Working Group of the American Association of Physicists in Medicine commissioned Task Group 302 to review the current clinical uses of surface imaging and emerging clinical applications. The specific charge of this task group was to provide technical guidelines for clinical indications of use for general positioning, breast deep-inspiration breath hold treatment, and frameless stereotactic radiosurgery. Additionally, the task group was charged with providing commissioning and on-going quality assurance (QA) requirements for surface-guided radiation therapy (SGRT) as part of a comprehensive QA program including risk assessment. Workflow considerations for other anatomic sites and for computed tomography simulation, including motion management, are also discussed. Finally, developing clinical applications, such as stereotactic body radiotherapy (SBRT) or proton radiotherapy, are presented. The recommendations made in this report, which are summarized at the end of the report, are applicable to all video-based SGRT systems available at the time of writing.
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  • Casares, L., et al. (author)
  • The synthetic triterpenoids CDDO-TFEA and CDDO-Me, but not CDDO, promote nuclear exclusion of BACH1 impairing its activity
  • 2022
  • In: Redox Biology. - : Elsevier BV. - 2213-2317. ; 51
  • Journal article (peer-reviewed)abstract
    • The transcription factor BACH1 is a potential therapeutic target for a variety of chronic conditions linked to oxidative stress and inflammation, as well as cancer metastasis. However, only a few BACH1 degraders/inhibitors have been described. BACH1 is a transcriptional repressor of heme oxygenase 1 (HMOX1), which is positively regulated by transcription factor NRF2 and is highly inducible by derivatives of the synthetic oleanane triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO). Most of the therapeutic activities of these compounds are due to their anti-inflammatory and antioxidant properties, which are widely attributed to their ability to activate NRF2. However, with such a broad range of action, these compounds have other molecular targets that have not been fully identified and could also be of importance for their therapeutic profile. Herein we identified BACH1 as a target of two CDDO-derivatives (CDDO-Me and CDDO-TFEA), but not of CDDO. While both CDDO and CDDO-derivatives activate NRF2 similarly, only CDDO-Me and CDDO-TFEA inhibit BACH1, which explains the much higher potency of these CDDO-derivatives as HMOX1 inducers compared with unmodified CDDO. Notably, we demonstrate that CDDO-Me and CDDO-TFEA inhibit BACH1 via a novel mechanism that reduces BACH1 nuclear levels while accumulating its cytoplasmic form. In an in vitro model, both CDDO-derivatives impaired lung cancer cell invasion in a BACH1-dependent and NRF2-independent manner, while CDDO was inactive. Altogether, our study identifies CDDO-Me and CDDO-TFEA as dual KEAP1/BACH1 inhibitors, providing a rationale for further therapeutic uses of these drugs.
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20.
  • Hodgson, L., et al. (author)
  • Interassociation consensus recommendations for pitch-side emergency care and personal protective equipment for elite sport during the COVID-19 pandemic
  • 2021
  • In: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 55:10, s. 531-538
  • Journal article (peer-reviewed)abstract
    • The COVID-19 pandemic has necessitated many novel responses in healthcare including sport and exercise medicine. The cessation of elite sport almost globally has had significant economic implications and resulted in pressure to resume sport in very controlled conditions. This includes protecting pitch-side medical staff and players from infection. The ongoing prevalence of SARS-CoV-2 and the desire to resume professional sport required urgent best practice guidelines to be developed so that sport could be resumed as safely as possible. This set of best practice recommendations assembles early evidence for managing SARS-CoV-2 and integrates expert opinion to provide a uniform and pragmatic approach to enhance on-field and pitch-side safety for the clinician and player. The nature of SARS-CoV-2 transmission creates new hazards during resuscitation and emergency care and procedures. Recommendations for the use and type of personal protective equipment during on-field or pitch-side emergency medical care is provided based on the clinical scenario and projected risk of viral transmission.
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25.
  • Karah, Nabil, et al. (author)
  • The acinetobacter baumannii website (ab-web) : a multidisciplinary knowledge hub, communication platform, and workspace
  • 2023
  • In: FEMS Microbes. - : Oxford University Press. - 2633-6685. ; 4
  • Research review (peer-reviewed)abstract
    • Acinetobacter baumannii is a Gram-negative bacterium increasingly implicated in hospital-acquired infections and outbreaks. Effective prevention and control of such infections are commonly challenged by the frequent emergence of multidrug-resistant strains. Here we introduce Ab-web (https://www.acinetobacterbaumannii.no), the first online platform for sharing expertise on A. baumannii. Abweb is a species-centric knowledge hub, initially with 10 articles organized into two main sections, 'Overview' and 'Topics', and three themes, 'epidemiology', 'antibiotic resistance', and 'virulence'. The 'workspace' section provides a spot for colleagues to collaborate, build, and manage joint projects. Ab-web is a community-driven initiative amenable to constructive feedback and new ideas.
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26.
  • Shein, A. M. S., et al. (author)
  • Novel colistin-EDTA combination for successful eradication of colistin-resistant Klebsiella pneumoniae catheter-related biofilm infections
  • 2021
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Development of an effective therapy to overcome colistin resistance in Klebsiella pneumoniae, a common pathogen causing catheter-related biofilm infections in vascular catheters, has become a serious therapeutic challenge that must be addressed urgently. Although colistin and EDTA have successful roles for eradicating biofilms, no in vitro and in vivo studies have investigated their efficacy in catheter-related biofilm infections of colistin-resistant K. pneumoniae. In this study, colistin resistance was significantly reversed in both planktonic and mature biofilms of colistin-resistant K. pneumoniae by a combination of colistin (0.25-1 mu g/ml) with EDTA (12 mg/ml). This novel colistin-EDTA combination was also demonstrated to have potent efficacy in eradicating colistin-resistant K. pneumoniae catheter-related biofilm infections, and eliminating the risk of recurrence in vivo. Furthermore, this study revealed significant therapeutic efficacy of colistin-EDTA combination in reducing bacterial load in internal organs, lowering serum creatinine, and protecting treated mice from mortality. Altered in vivo expression of different virulence genes indicate bacterial adaptive responses to survive in hostile environments under different treatments. According to these data discovered in this study, a novel colistin-EDTA combination provides favorable efficacy and safety for successful eradication of colistin-resistant K. pneumonia catheter-related biofilm infections.
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27.
  • Srisakul, S., et al. (author)
  • Overcoming addition of phosphoethanolamine to lipid A mediated colistin resistance in Acinetobacter baumannii clinical isolates with colistin-sulbactam combination therapy
  • 2022
  • In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
  • Journal article (peer-reviewed)abstract
    • Overcoming colistin-resistant Acinetobacter baumannii (CoR-AB) has become a major concern due to the lack of effective antibiotics. This study aimed to explore the prevalence of CoR-AB clinical isolates in Thailand, their mechanisms of resistance, and test the efficacy of colistin plus sulbactam against CoR-AB isolates. The colistin resistance rate among carbapenem-resistant A. baumannii was 15.14%. The mcr gene or its variants were not detected in CoR-AB isolates by PCR screening. The lipid A mass spectra of CoR-AB isolates showed the additional [M-H](-) ion peak at m/z = 2034 that correlated to the phosphoethanolamine (pEtN) addition to lipid A (N = 27/30). The important amino acid substitutions were found at position S14P, A138T, A227V in PmrB that are associated with overexpression of the pEtN transferase (PmrC) and contributed the pEtN addition. The lipopolysacccharide production genes (lpxACD) were not related to lipid A mass spectra. A colistin plus sulbactam combination exhibited the synergy rate at 86.7% against CoR-AB isolates compare to sulbactam (85.89% resistance) or colistin (15.14% resistance) alone. The excellent synergistic activity of colistin plus sulbactam combination has the potential for the treatment of CoR-AB infections.
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28.
  • Zheng, L. K., et al. (author)
  • Combined Connectomics, MAPT Gene Expression, and Amyloid Deposition to Explain Regional Tau Deposition in Alzheimer Disease
  • 2024
  • In: Annals of Neurology. - 0364-5134. ; 95:2, s. 274-287
  • Journal article (peer-reviewed)abstract
    • Objective: We aimed to test whether region-specific factors, including spatial expression patterns of the tau-encoding gene MAPT and regional levels of amyloid positron emission tomography (PET), enhance connectivity-based modeling of the spatial variability in tau-PET deposition in the Alzheimer disease (AD) spectrum.Methods: We included 685 participants (395 amyloid-positive participants within AD spectrum and 290 amyloid-negative controls) with tau-PET and amyloid-PET from 3 studies (Alzheimer's Disease Neuroimaging Initiative, F-18-AV-1451-A05, and BioFINDER-1). Resting-state functional magnetic resonance imaging was obtained in healthy controls (n = 1,000) from the Human Connectome Project, and MAPT gene expression from the Allen Human Brain Atlas. Based on a brain-parcellation atlas superimposed onto all modalities, we obtained region of interest (ROI)-to-ROI functional connectivity, ROI-level PET values, and MAPT gene expression. In stepwise regression analyses, we tested connectivity, MAPT gene expression, and amyloid-PET as predictors of group-averaged and individual tau-PET ROI values in amyloid-positive participants.Results: Connectivity alone explained 21.8 to 39.2% (range across 3 studies) of the variance in tau-PET ROI values averaged across amyloid-positive participants. Stepwise addition of MAPT gene expression and amyloid-PET increased the proportion of explained variance to 30.2 to 46.0% and 45.0 to 49.9%, respectively. Similarly, for the prediction of patient-level tau-PET ROI values, combining all 3 predictors significantly improved the variability explained (mean adjusted R-2 range across studies = 0.118-0.148, 0.156-0.196, and 0.251-0.333 for connectivity alone, connectivity plus MAPT expression, and all 3 modalities combined, respectively).Interpretation: Across 3 study samples, combining the functional connectome and molecular properties substantially enhanced the explanatory power compared to single modalities, providing a valuable tool to explain regional susceptibility to tau deposition in AD.
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30.
  • Hofer, J., et al. (author)
  • High- Q Magnetic Levitation and Control of Superconducting Microspheres at Millikelvin Temperatures
  • 2023
  • In: Physical Review Letters. - 1079-7114 .- 0031-9007. ; 131:4
  • Journal article (peer-reviewed)abstract
    • We report the levitation of a superconducting lead-tin sphere with 100 μm diameter (corresponding to a mass of 5.6 μg) in a static magnetic trap formed by two coils in an anti-Helmholtz configuration, with adjustable resonance frequencies up to 240 Hz. The center-of-mass motion of the sphere is monitored magnetically using a dc superconducting quantum interference device as well as optically and exhibits quality factors of up to 2.6×107. We also demonstrate 3D magnetic feedback control of the motion of the sphere. The setup is housed in a dilution refrigerator operating at 15 mK. By implementing a cryogenic vibration isolation system, we can attenuate environmental vibrations at 200 Hz by approximately 7 orders of magnitude. The combination of low temperature, large mass, and high quality factor provides a promising platform for testing quantum physics in previously unexplored regimes with high mass and long coherence times.
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31.
  • Kanze, Dana, et al. (author)
  • The motivation of mission statements: How regulatory mode influences workplace discrimination
  • 2021
  • In: Organizational Behavior and Human Decision Processes. - : Elsevier. - 1095-9920 .- 0749-5978. ; 166, s. 84-103
  • Journal article (peer-reviewed)abstract
    • Despite concerted efforts to enforce ethical standards, transgressions continue to plague US corporations. This paper investigates whether the way in which an organization pursues its goals can influence ethical violations, manifested as involvement in discrimination. We test this hypothesis among franchises, which employ a considerable amount of low-income workers adversely affected by discrimination. Drawing upon Regulatory Mode Theory, we perform a linguistic analysis of franchise mission statements to determine their degree of locomotion and assessment language. EEOC archival data for the past decade reveals that regulatory mode predicts franchise involvement in discrimination. Discriminatory behavior is associated with franchises whose mission statements motivate employees to embrace urgent action (locomotion mode) over thoughtful consideration (assessment mode). Two experiments demonstrate that participants exposed to high locomotion mission statements tend to disregard ethical standards due to their need for expediency, making significantly more discriminatory managerial decisions than those exposed to high assessment mission statements.
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35.
  • Lourenço, José A. S., et al. (author)
  • Non-Hermitian dynamics and PT-symmetry breaking in interacting mesoscopic Rydberg platforms
  • 2022
  • In: Physical Review A: covering atomic, molecular, and optical physics and quantum information. - 2469-9926 .- 2469-9934. ; 106:2
  • Journal article (peer-reviewed)abstract
    • We simulate the dissipative dynamics of a mesoscopic system of long-range interacting particles which can be mapped into non-Hermitian spin models with a PT symmetry. We find rich PT phase diagrams with PT-symmetric and PT-broken phases. The dynamical regimes can be further enriched by modulating tunable parameters of the system. We outline how the PT symmetries of such systems may be probed by studying their dynamics. We note that systems of Rydberg atoms and systems of Rydberg ions with strong dipolar interactions are particularly well suited for such studies. We present a viable proposal for implementing non-Hermitian physics with PT symmetry in Rydberg systems. We show that for realistic parameters, long-range interactions allow the emergence of new PT-symmetric regions, generating new PT phase transitions. In addition, such PT-symmetry phase transitions are found by changing the configurations of the Rydberg atoms. We propose a post selection scheme on an ensemble of Rydberg ions described by an effective three-level system. Detecting the population dynamics, the system shows an oscillatory behavior in the PT-unbroken phase and a stationary population for long times in the PT-broken phase.
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36.
  • Malm, Lisa E., et al. (author)
  • Livestock grazing impacts components of the breeding productivity of a common upland insectivorous passerine : Results from a long-term experiment
  • 2020
  • In: Journal of Applied Ecology. - : John Wiley & Sons. - 0021-8901 .- 1365-2664. ; 57:8, s. 1514-1523
  • Journal article (peer-reviewed)abstract
    • 1. The intensity of pastoral management in areas of High Nature Value farming is declining in some regions of Europe but increasing in others. This affects open habitats of conservation concern, such as the British uplands, where bird species that benefit from low-intensity grazing may be most sensitive to such polarization. While experimental manipulations of livestock grazing intensities have improved our understanding of upland breeding bird responses in the short term, none have examined the long-term impacts of altered management on reproductive success.2. Using a replicated landscape-scale experiment that started in 2003, we investigated the effects of four grazing treatments (intensive sheep; low-intensity sheep; low-intensity mixed sheep and cattle; and no grazing) on the breeding productivity of meadow pipits Anthus pratensis, the most common upland passerine. Surveys were carried out systematically during early (2003 and 2004) and late (2015 and 2016) sampling periods of the experiment to compare the short- and long-term effects of grazing treatments on breeding density and productivity of pipits specifically, but also on the overall bird community.3. Pipit breeding density was lowest under low-intensity sheep grazing while the highest egg-stage nest survival was observed in the same treatment, although no significant treatment effects were detected on overall nest survival or fledgling output. There were no significant differences in treatment effects between the sampling periods on any breeding variable, but overall nest survival was lower in the later sampling period across all treatments.4. Breeding bird species richness differed between treatments in the later sampling period, with highest species richness in the ungrazed treatment.5. Synthesis and applications. Livestock grazing management can have different outcomes for different upland birds. Our results showed that, with time, meadow pipit breeding productivity tended to be higher when sheep grazing intensity was reduced and/or mixed with cattle, and lower when livestock were removed, but not significantly so. Removal of grazing, however, can significantly increase bird species richness. The long-term experiment showed an overall decline in fledglings regardless of grazing treatments, potentially a result of increased predator numbers harboured by nearby developing woodland, highlighting the importance of considering wider landscape processes in grazing management decisions.
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38.
  • Moreno, R., et al. (author)
  • Biotinylation of an acetylenic tricyclic bis(cyanoenone) lowers its potency as an NRF2 activator while creating a novel activity against BACH1
  • 2022
  • In: Free Radical Biology and Medicine. - : Elsevier BV. - 0891-5849. ; 191, s. 203-211
  • Journal article (peer-reviewed)abstract
    • The transcription factor BACH1 regulates the expression of a variety of genes including genes involved in oxidative stress responses, inflammation, cell motility, cancer cell invasion and cancer metabolism. Based on this, BACH1 has become a promising therapeutic target in cancer (as anti-metastatic target) and also in chronic conditions linked to oxidative stress and inflammation, where BACH1 inhibitors share a therapeutic space with activators of transcription factor NRF2. However, while there is a growing number of NRF2 activators, there are only a few described BACH1 inhibitors/degraders. The synthetic acetylenic tricyclic bis(cyanoenone), (+/-)-(4bS,8aR,10aS)-10a-ethynyl-4b,8,8-trimethyl-3,7-dioxo-3.4b,7,8,8a,9,10, 10a-octahydrophenanthrene-2,6-dicarbonitrile, TBE31 is a potent activator of NRF2 without any BACH1 activity. Herein we found that biotinylation of TBE31 greatly reduces its potency as NRF2 activator (50-75-fold less active) while acquiring a novel activity as a BACH1 degrader (100-200-fold more active). We demonstrate that TBE56, the biotinylated TBE31, interacts and promotes the degradation of BACH1 via a mechanism involving the E3 ligase FBXO22. TBE56 is a potent and sustained BACH1 degrader (50-fold more potent than hemin) and accordingly a powerful HMOX1 inducer. TBE56 degrades BACH1 in lung and breast cancer cells, impairing breast cancer cell migration and invasion in a BACH1-dependent manner, while TBE31 has no significant effect. Altogether, our study identifies that the biotinylation of TBE31 provides novel activities with potential therapeutic value, providing a rationale for further characterisation of this and related compounds.
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