| 1. |
- Adediran, Gbotemi, et al.
(författare)
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Micro and nano sized particles in leachates from agricultural soils: Phosphorus and sulfur speciation by X-ray micro-spectroscopy
- 2021
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Ingår i: Water Research. - : Elsevier BV. - 0043-1354 .- 1879-2448. ; 189
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Tidskriftsartikel (refereegranskat)abstract
- Colloids and nanoparticles leached from agricultural land are major carriers of potentially bioavailable nutrients with high mobility in the environment. Despite significant research efforts, accurate knowledge of macronutrients in colloids and nanoparticles is limited. We used multi-elemental synchrotron X-ray fluorescence (XRF) microscopy with multivariate spatial analysis and X-ray atomic absorption near-edge structure (XANES) spectroscopy at the P and S K-edges, to study the speciation of P and S in two fractions of leached particles, >0.45 and <0.45 mu m respectively, collected from four tile-drained agricultural sites in Sweden. P K-edge XANES showed that organic P, followed by P adsorbed to surfaces of aluminum-bearing particles were the most common forms of leached P. Iron-bound P (Fe-P) forms were generally less abundant (0-30 % of the total P). S K-edge XANES showed that S was predominantly organic, and a relatively high abundance of reduced S species suggests that redox conditions were adverse to the persistence of P bound to Fe-bearing colloids in the leachates. Acid ammonium-oxalate extractions suggested that P associated with Al and Fe (Al-P and Fe-P) in most cases could be explained by the adsorption capacity of non-crystalline (oxalate-extractable) oxides of Al and Fe. These results improve our understanding of particulate P and S speciation in the vadose zone and helps in developing effective technologies for mitigating colloidal driven eutrophication of water bodies near agricultural land. (C) 2020 The Author(s). Published by Elsevier Ltd.
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| 2. |
- Aranzana-Climent, Vincent, et al.
(författare)
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Translational in vitro and in vivo PKPD modelling for apramycin against Gram-negative lung pathogens to facilitate prediction of human efficacious dose in pneumonia
- 2022
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Ingår i: Clinical Microbiology and Infection. - : Elsevier B.V.. - 1198-743X .- 1469-0691. ; 28:10, s. 1367-1374
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: New drugs and methods to efficiently fight carbapenem-resistant gram-negative pathogens are sorely needed. In this study, we characterized the preclinical pharmacokinetics (PK) and pharmacodynamics of the clinical stage drug candidate apramycin in time kill and mouse lung infection models. Based on in vitro and in vivo data, we developed a mathematical model to predict human efficacy. Methods: Three pneumonia-inducing gram-negative species Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied. Bactericidal kinetics were evaluated with time-kill curves; in vivo PK were studied in healthy and infected mice, with sampling in plasma and epithelial lining fluid after subcutaneous administration; in vivo efficacy was measured in a neutropenic mouse pneumonia model. A pharmacokinetic-pharmacodynamic model, integrating all the data, was developed and simulations were performed. Results: Good lung penetration of apramycin in epithelial lining fluid (ELF) was shown (area under the curve (AUC)ELF/AUCplasma = 88%). Plasma clearance was 48% lower in lung infected mice compared to healthy mice. For two out of five strains studied, a delay in growth (∼5 h) was observed in vivo but not in vitro. The mathematical model enabled integration of lung PK to drive mouse PK and pharmacodynamics. Simulations predicted that 30 mg/kg of apramycin once daily would result in bacteriostasis in patients. Discussion: Apramycin is a candidate for treatment of carbapenem-resistant gram-negative pneumonia as demonstrated in an integrated modeling framework for three bacterial species. We show that mathematical modelling is a useful tool for simultaneous inclusion of multiple data sources, notably plasma and lung in vivo PK and simulation of expected scenarios in a clinical setting, notably lung infections. © 2022 The Author(s)
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| 3. |
- Arrazuria, Rakel, et al.
(författare)
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Expert workshop summary : Advancing toward a standardized murine model to evaluate treatments for antimicrobial resistance lung infections
- 2022
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Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The rise in antimicrobial resistance (AMR), and increase in treatment-refractory AMR infections, generates an urgent need to accelerate the discovery and development of novel anti-infectives. Preclinical animal models play a crucial role in assessing the efficacy of novel drugs, informing human dosing regimens and progressing drug candidates into the clinic. The Innovative Medicines Initiative-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium is establishing a validated and globally harmonized preclinical model to increase reproducibility and more reliably translate results from animals to humans. Toward this goal, in April 2021, COMBINE organized the expert workshop "Advancing toward a standardized murine model to evaluate treatments for AMR lung infections". This workshop explored the conduct and interpretation of mouse infection models, with presentations on PK/PD and efficacy studies of small molecule antibiotics, combination treatments (beta -lactam/beta -lactamase inhibitor), bacteriophage therapy, monoclonal antibodies and iron sequestering molecules, with a focus on the major Gram-negative AMR respiratory pathogens Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii. Here we summarize the factors of variability that we identified in murine lung infection models used for antimicrobial efficacy testing, as well as the workshop presentations, panel discussions and the survey results for the harmonization of key experimental parameters. The resulting recommendations for standard design parameters are presented in this document and will provide the basis for the development of a harmonized and bench-marked efficacy studies in preclinical murine pneumonia model.
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| 4. |
- Arrazuria, Rakel, et al.
(författare)
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Variability of murine bacterial pneumonia models used to evaluate antimicrobial agents
- 2022
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Ingår i: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 13
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Forskningsöversikt (refereegranskat)abstract
- Antimicrobial resistance has become one of the greatest threats to human health, and new antibacterial treatments are urgently needed. As a tool to develop novel therapies, animal models are essential to bridge the gap between preclinical and clinical research. However, despite common usage of in vivo models that mimic clinical infection, translational challenges remain high. Standardization of in vivo models is deemed necessary to improve the robustness and reproducibility of preclinical studies and thus translational research. The European Innovative Medicines Initiative (IMI)-funded "Collaboration for prevention and treatment of MDR bacterial infections" (COMBINE) consortium, aims to develop a standardized, quality-controlled murine pneumonia model for preclinical efficacy testing of novel anti-infective candidates and to improve tools for the translation of preclinical data to the clinic. In this review of murine pneumonia model data published in the last 10 years, we present our findings of considerable variability in the protocols employed for testing the efficacy of antimicrobial compounds using this in vivo model. Based on specific inclusion criteria, fifty-three studies focusing on antimicrobial assessment against Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii were reviewed in detail. The data revealed marked differences in the experimental design of the murine pneumonia models employed in the literature. Notably, several differences were observed in variables that are expected to impact the obtained results, such as the immune status of the animals, the age, infection route and sample processing, highlighting the necessity of a standardized model.
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| 5. |
- Budtz-Lilly, Jacob, et al.
(författare)
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European Multicentric Experience With Fenestrated-branched ENDOvascular Stent Grafting After Previous FAILed Infrarenal Aortic Repair The EU-FBENDO-FAIL Registry
- 2023
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Ingår i: Annals of Surgery. - : Ovid Technologies (Wolters Kluwer Health). - 0003-4932 .- 1528-1140. ; 278:2, s. E389-E395
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Tidskriftsartikel (refereegranskat)abstract
- Objective:To report the mid-term outcomes of fenestrated-branched endovascular aneurysm repair (F-BEVAR) following a failed previous endovascular aneurysm repair (pEVAR) or previous open aneurysm repair (pOAR).Methods:Data from consecutive patients who underwent F-BEVAR for pEVAR or pOAR from 2006 to 2021 from 17 European vascular centers were analyzed. Endpoints included technical success, major adverse events, 30-day mortality, and 5-year estimates of survival, target vessel primary patency, freedom from reinterventions, type I/III endoleaks, and sac growth >5 mm.Background:Treatment of a failed previous abdominal aortic aneurysm repair is a complex undertaking. F-BEVAR is becoming an increasingly attractive option, although comparative data are limited regarding associated risk factors, indications for treatment, and various outcomes.Results:There were 526 patients included, 268 pOAR and 258 pEVAR. The median time from previous repair to F-BEVAR was 7 (interquartile range, 4-12) years, 5 (3-8) for pEVAR, and 10 (6-14) for pOAR, P<0.001. Predominant indication for treatment was type Ia endoleak for pEVAR and progression of the disease for pOAR. Technical success was 92.8%, pOAR (92.2%), and pEVAR (93.4%), P=0.58. The 30-day mortality was 6.5% overall, 6.7% for pOAR, and 6.2% for pEVAR, P=0.81. There were 1853 treated target vessels with 5-year estimates of primary patency of 94.4%, pEVAR (95.2%), and pOAR (94.4%), P=0.03. Five-year estimates for freedom from type I/III endoleaks were similar between groups; freedom from reintervention was lower for pEVAR (38.3%) than for pOAR (56.0%), P=0.004. The most common indication for reinterventions was for type I/III endoleaks (37.5%).Conclusions:Repair of a failed pEVAR or pOARis safe and feasible with comparable technical success and survival rates. While successful treatment can be achieved, significant rates of reintervention should be anticipated, particularly for issues related to instability of target vessels/bridging stents.
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| 6. |
- Carvalho, Lucas Rannier Ribeiro Antonino, et al.
(författare)
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Antibacterial mouthwash alters gut microbiome, reducing nutrient absorption and fat accumulation in Western diet-fed mice
- 2024
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Prolonged use of antibacterial mouthwash is linked to an increased risk of systemic disease. We aimed to investigate if disturbing the oral microbiota would impact the lower gut microbiome with functional effects in diet-induced obesity. Mice were exposed to oral chlorhexidine and fed a Western diet (WD). Food intake and weight gain were monitored, and metabolic function, blood pressure, and microbiota were analyzed. Chlorhexidine reduced the number of viable bacteria in the mouth and lowered species richness in the gut but with proportional enrichment of some bacteria linked to metabolic pathways. In mice fed a Western diet, chlorhexidine reduced weight gain, body fat, steatosis, and plasma insulin without changing caloric intake, while increasing colon triglycerides and proteins, suggesting reduced absorption of these nutrients. The mechanisms behind these effects as well as the link between the oral microbiome and small intestinal function need to be pinpointed. While the short-term effects of chlorhexidine in this model appear beneficial, potential long-term disruptions in the oral and gut microbiota and possible malabsorption should be considered.
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| 7. |
- D'Oria, Mario, et al.
(författare)
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Comparison of early and mid-term outcomes after fenestrated-branched endovascular aortic repair in patients with or without prior infrarenal repair
- 2021
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Ingår i: Journal of Endovascular Therapy. - : Sage Publications. - 1526-6028 .- 1545-1550. ; 29:4, s. 544-554
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The purpose of this study was to compare short- and mid-term outcomes of fenestrated-branched endovascular repair (F-BEVAR) of pararenal (PRAA)/thoracoabdominal (TAAA) aortic aneurysms in patients with or without prior endovascular/open (EVAR/OAR) infrarenal aortic repair.Methods: Data from consecutive F-BEVAR (2010-2019) at two high-volume aortic centers were retrospectively reviewed. Primary endpoints were technical success, 30-day mortality, and overall survival. Secondary endpoints included 30-day major adverse events (MAE), freedom from type I/III endoleaks, reinterventions, sac expansion, and target vessel (TV) primary patency.Results: A total of 222 consecutive patients were included for analysis; of these 58 (26.1%) had prior infrarenal repair (EVAR=33, OAR=25) and 164 (73.9%) had native PRAA/TAAA. At baseline, patients with prior infrarenal repair were older (mean age=75.1 vs 71.6 years, p=.005) and the proportion of females was lower (8.6% vs 29.3%, p=.002). Technical success was 97.8% (n=217) in the entire cohort, without any significant differences between study groups (94.8% vs 98.8%, p=.08). At 30 days, there were no significant differences between patients with prior infrarenal repair as compared with those without in rate of MAE (44.8% vs 54.9%, p=.59). The 5-year estimate of survival for those who underwent native aortic repair was 61.6%, versus 61.3% for those who had a previous repair (p=.67). The 5-year freedom from endoleaks I/III estimates were significantly lower in patients who had prior infrarenal repair as compared with patients undergoing treatment of native aneurysms (57.1% vs 66.1%, p=.03), mainly owing to TV-related endoleaks (ie, type IC and/or IIIC endoleaks). No significant differences were found between study groups in rates of reinterventions and TV primary patency. Five-year estimates of freedom from sac increase >5mm were significantly lower in patients who received F-BEVAR after previous infrarenal repair as compared with those who underwent treatment of native aneurysms (48.6% vs 77.5%, p=.002).Conclusions: F-BEVAR is equally safe and feasible for treatment of patients with prior infrarenal repair as compared with those undergoing treatment for native aneurysms. Increased rates of TV-related endoleaks were observed which could lead to lower freedom from aneurysm sac shrinkage during follow-up. Nevertheless, the 5-year rates of reinterventions and TV patency were similar, thereby indicating that overall effectiveness of treatment remained satisfactory at mid-term.
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| 8. |
- Edqvist, Jon, 1988, et al.
(författare)
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Severe COVID-19 Infection in Type 1 and Type 2 Diabetes During the First Three Waves in Sweden.
- 2023
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Ingår i: Diabetes care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 46:3, s. 570-578
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes is an established risk factor for hospitalization and death in COVID-19 infection, while findings with respect to type 1 diabetes have been diverging.Using nationwide health registries, we identified all patients aged ≥18 years with type 1 and type 2 diabetes in Sweden. Odds ratios (ORs) describe the general and age-specific risk of being hospitalized, need for intensive care, or dying, adjusted for age, socioeconomic factors, and coexisting conditions, compared with individuals without diabetes. Machine learning models were used to find predictors of outcomes among individuals with diabetes positive for COVID-19.Until 30 June 2021, we identified 365 (0.71%) and 11,684 (2.31%) hospitalizations in 51,402 and 504,337 patients with type 1 and 2 diabetes, respectively, with 67 (0.13%) and 2,848 (0.56%) requiring intensive care unit (ICU) care and 68 (0.13%) and 4,020 (0.80%) dying (vs 7,824,181 individuals without diabetes [41,810 hospitalizations (0.53%), 8,753 (0.11%) needing ICU care, and 10,160 (0.13%) deaths). Although those with type 1 diabetes had moderately raised odds of being hospitalized (multiple-adjusted OR 1.38 [95% CI 1.24-1.53]), there was no independent effect on ICU care or death (OR of 1.21 [95% CI 0.94-1.52] and 1.13 [95% CI 0.88-1.48], respectively). Age and socioeconomic factors were the dominating features for predicting hospitalization and death in both types of diabetes.Type 2 diabetes was associated with increased odds for all outcomes, whereas patients with type 1 diabetes had moderately increased odds of hospitalization but not ICU care and death.
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| 9. |
- Kleschyov, Andrei L., et al.
(författare)
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NO-ferroheme is a signaling entity in the vasculature
- 2023
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Ingår i: Nature Chemical Biology. - 1552-4450 .- 1552-4469. ; 19:10, s. 1267-1275
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Tidskriftsartikel (refereegranskat)abstract
- Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity. While free NO-induced relaxations are abolished by an NO scavenger and in the presence of red blood cells or blood plasma, a model compound, NO-ferroheme-myoglobin preserves its vasoactivity suggesting the physiological relevance of NO-ferroheme species. We conclude that NO-ferroheme behaves as a signaling entity in the vasculature. Questions remain on the nature of the bioactivity of nitric oxide (NO) synthase signaling despite its wide appreciation. Here the authors describe NO-ferroheme as a vascular signaling species, whose biological activity is unrelated to the release of free nitric oxide, but allows it to travel protected to its main target guanylyl cyclase.
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| 10. |
- Lundberg, Christina, et al.
(författare)
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Age and sex differences in cause-specific excess mortality and years of life lost associated with COVID-19 infection in the Swedish population
- 2023
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Ingår i: European Journal of Public Health. - : OXFORD UNIV PRESS. - 1101-1262 .- 1464-360X. ; 33:5, s. 916-22
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Tidskriftsartikel (refereegranskat)abstract
- Background Estimating excess mortality and years of life lost (YLL) attributed to coronavirus disease 19 (COVID-19) infection provides a comprehensive picture of the mortality burden on society. We aimed to estimate the impact of the COVID-19 pandemic on age- and sex-specific excess mortality and YLL in Sweden during the first 17 months of the pandemic. Methods In this population-based observational study, we calculated age- and sex-specific excess all-cause mortality and excess YLL during 2020 and the first 5 months of 2021 and cause-specific death [deaths from cardiovascular disease (CVD), cancer, other causes and deaths excluding COVID-19] in 2020 compared with an average baseline for 2017-19 in the whole Swedish population. Results COVID-19 deaths contributed 9.9% of total deaths (98 441 deaths, 960 305 YLL) in 2020, accounting for 75 151 YLL (7.7 YLL/death). There were 2672 (5.7%) and 1408 (3.0%) excess deaths, and 19 141 (3.8%) and 3596 (0.8%) excess YLL in men and women, respectively. Men aged 65-110 years and women aged 75-110 years were the greatest contributors. Fewer deaths and YLL from CVD, cancer and other causes were observed in 2020 compared with the baseline adjusted to the population size in 2020. Conclusions Compared with the baseline, excess mortality and YLL from all causes were experienced in Sweden during 2020, with a higher excess observed in men than in women, indicating that more men died at a younger age while more women died at older ages than expected. A notable reduction in deaths and YLL due to CVD suggests a displacement effect from CVD to COVID-19.
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