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EUFOREUM Berlin 2023: Optimizing care for type 2 inflammatory diseases from clinic to AI: A pediatric focus.
Get PDFThe European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual forum EUFOREUM in Berlin in November 2023. The aim of EUFOREUM 2023 was to highlight pediatric action plans for prevention and optimizing care for type 2 inflammatory conditions starting in childhood, with a focus on early-stage diagnosis, ensuring neither under- nor overdiagnosis, optimal care, and suggestions for improvement of care. EUFOREA is an international not-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic respiratory diseases through the implementation of optimal patient care via educational, research, and advocacy activities. The inclusive and multidisciplinary approach of EUFOREA was reflected in the keynote lectures and faculty of the virtual EUFOREUM 2023 (www.euforea.eu/euforeum) coming from the pediatric, allergology, pulmonology, ENT, dermatology, primary health care fields and patients around the central theme of type 2 inflammation. As most type 2 inflammatory conditions may start in childhood or adolescence, and most children have type 2 inflammation when suffering from a respiratory or skin disease, the moment has come to raise the bar of ambitions of care, including prevention, remission and disease modification at an early stage. The current report provides a comprehensive overview of key statements by the faculty of the EUFOREUM 2023 and the ambitions of EUFOREA allowing all stakeholders in the respiratory field to be updated and ready to join forces in Europe and beyond
Time-calibrated phylogenetic and chromosomal mobilome analyses of Staphylococcus aureus CC398 reveal geographical and host-related evolution.
Get PDFAn international collection of Staphylococcus aureus of clonal complex (CC) 398 from diverse hosts spanning all continents and a 30 year-period is studied based on whole-genome sequencing (WGS) data. The collection consists of publicly available genomic data from 2994 strains and 134 recently sequenced Swiss methicillin-resistant S. aureus (MRSA) CC398 strains. A time-calibrated phylogeny reveals the presence of distinct phylogroups present in Asia, North and South America and Europe. European MRSA diverged from methicillin-susceptible S. aureus (MSSA) at the beginning of the 1950s. Two major European phylogroups (EP4 and EP5), which diverged approximately 1974, are the main drivers of MRSA CC398 spread in Europe. Within EP5, an emergent MRSA lineage spreading among the European horse population (EP5-Leq) diverged approximately 1996 from the pig lineage (EP5-Lpg), and also contains human-related strains. EP5-Leq is characterized by staphylococcal cassette chromosome mec (SCCmec) IVa and spa type t011 (CC398-IVa-t011), and EP5-Lpg by CC398-SCCmecVc-t011. The lineage-specific antibiotic resistance and virulence gene patterns are mostly mediated by the acquisition of mobile genetic elements like SCCmec, S. aureus Genomic Islands (SaGIs), prophages and transposons. Different combinations of virulence factors are present on S. aureus pathogenicity islands (SaPIs), and novel antimicrobial resistance gene containing elements are associated with certain lineages expanding in Europe. This WGS-based analysis reveals the actual evolutionary trajectory and epidemiological trend of the international MRSA CC398 population considering host, temporal, geographical and molecular factors. It provides a baseline for global WGS-based One-Health studies of adaptive evolution of MRSA CC398 as well as for local outbreak investigations
Cameo and intaglio surface stability and variability of additively, subtractively, and conventionally manufactured occlusal devices after long-term storage.
No full textSTATEMENT OF PROBLEM
Additive and subtractive manufacturing have become alternative technologies for fabricating occlusal devices. However, knowledge of the long-term stability of occlusal devices fabricated using these recent technologies is limited.
PURPOSE
The purpose of this in vitro study was to evaluate the cameo and intaglio surface stability and variability of additively, subtractively, and conventionally manufactured occlusal devices after 18 months of storage.
MATERIAL AND METHODS
A standard tessellation language (STL) file of a dentate maxillary typodont was used to design a master occlusal device. The STL file of this design was used to fabricate occlusal devices additively either with a digital light processing (AM-1) or a continuous liquid interface production (AM-2) printer, subtractively with 2 different 5-axis milling units (SM-1 and SM-2), and conventionally (TM-HP) (n=10). STL files of each device's cameo and intaglio surfaces were generated using a laboratory scanner after fabrication and after 18 months of storage in a moist environment. These generated files were imported into an analysis software program (Geomagic Control X) to analyze the dimensional stability of tested devices by using the root mean square method. The average deviation values defined the variability of measured changes over time. Cameo and intaglio surface deviations were analyzed using the Kruskal-Wallis and Dunn tests, while the variability of measured deviations was analyzed with 1-way analysis of variance and the Tukey HSD tests (α=.05).
RESULTS
Significant differences were observed among tested devices when the intaglio surface deviations and the cameo surface variability were considered (P<.001). SM-2 had significantly higher intaglio surface deviations than AM-1, SM-1, and AM-2 (P≤.036). Among the test groups, AM-1 had the greatest cameo surface variability (P≤.004).
CONCLUSIONS
SM-2 resulted in lower intaglio surface stability than the additive and the other subtractive manufacturing technologies, while AM-1 led to the highest cameo surface variability among the test groups
Genetic underpinning of historical afforestation with allochthonous Pinus cembra in the northwestern Swiss Alps
Get PDFThroughout the last centuries, the structure and genetic composition of forests have been strongly affected by forest management. Over 30% of European forests are artificially regenerated, very often using translocated forest reproductive material, among these species the Swiss stone pine (Pinus cembra L.). In the late nineteenth and early twentieth centuries, the species was largely used for artificial afforestation in the northern Alps. However, only a few planted trees have survived. Therefore, we aimed to evaluate if the historical afforestation of P. cembra in the northwestern Swiss Alps relied on allochthonous material. We sampled 12 sites, genotyping 11 nuclear microsatellites, to infer the spatial genetic structure of regional populations, to test for genetic differences between natural and planted stands, and to infer potential source regions of planted stands using reference samples covering the entire Alps. Population genetic structure analysis allowed us to distinguish planted from natural stands and to determine that forest reproductive material used for plantations was not of regional origin. We found similar levels of genetic diversity between natural and planted stands. Assignment tests revealed that reproductive material for planting was translocated to the study area from two source regions, i.e., near the border of Switzerland and Austria, and further to the East, between Austria and Italy. Our study shows how genetic tools may inform about historical transfer of forest reproductive material, which still may affect the population genetic make-up of regional occurrences, e.g., because of reduced natural regeneration
E2F1-associated purine synthesis pathway is a major component of the MET-DNA damage response network.
No full textVarious lines of investigation support a signaling interphase shared by receptor tyrosine kinases and the DNA damage response. However, the underlying network nodes and their contribution to the maintenance of DNA integrity remain unknown. We explored MET-related metabolic pathways whose interruption compromises proper resolution of DNA damage. Discovery metabolomics combined with transcriptomics identified changes in pathways relevant to DNA repair following MET inhibition (METi). METi by tepotinib was associated with formation of γH2AX foci and with significant alterations in major metabolic circuits such as glycolysis, gluconeogenesis, and purine, pyrimidine, amino acids, and lipids metabolism. 5'-Phosphoribosyl-N-formylglycinamide (FGAR), a de novo purine synthesis pathway metabolite, was consistently decreased in in vitro and in vivo MET-dependent models, and a METi-related depletion of dNTPs was observed. METi instigated the downregulation of critical purine synthesis enzymes including phosphoribosylglycinamide formyltransferase (GART) which catalyzes FGAR synthesis. Genes encoding these enzymes are regulated through E2F1, whose levels decrease upon METi in MET-driven cells and xenografts. Transient E2F1 overexpression prevented dNTPs depletion and the concomitant METi-associated DNA damage in MET-driven cells. We conclude that DNA damage following METi results from dNTPs reduction via downregulation of E2F1 and a consequent decline of de novo purine synthesis
Tamoxifen may contribute to preserve cardiac function in Duchenne muscular dystrophy.
Get PDFUNLABELLED
Duchenne muscular dystrophy is life-limiting. Cardiomyopathy, which mostly ensues in the second decade of life, is the main cause of death. Treatment options are still limited. The TAMDMD (NCT03354039) trial assessed motor function, muscle strength and structure, laboratory biomarkers, and safety in 79 ambulant boys with genetically confirmed Duchenne muscular dystrophy, 6.5-12 years of age, receiving either daily tamoxifen 20 mg or placebo for 48 weeks. In this post-hoc analysis, available echocardiographic data of ambulant patients recruited at one study centre were retrieved and compared before and after treatment. Data from 14 patients, median 11 (interquartile range, IQR, 11-12) years of age was available. Baseline demographic characteristics were similar in participants assigned to placebo (n = 7) or tamoxifen (n = 7). Left ventricular end-diastolic diameter in the placebo group (median and IQR) was 39 (38-41) mm at baseline and 43 (38-44) mm at study end, while it was 44 (41-46) mm at baseline and 41 (37-46) mm after treatment in the tamoxifen group. Left ventricular fractional shortening in the placebo group was 35% (32-38%) before and 33% (32-36%) after treatment, while in the tamoxifen group it was 34% (33-34%) at baseline and 35% (33-35%) at study end. No safety signals were detected.
CONCLUSION
This hypothesis-generating post-hoc analysis suggests that tamoxifen over 48 weeks is well tolerated and may help preserving cardiac structure and function in Duchenne muscular dystrophy. Further studies are justified.
CLINICALTRIALS
gov Identifier: EudraCT 2017-004554-42, NCT03354039 What is known: • Duchenne muscular dystrophy (DMD) is life-limiting. Cardiomyopathy ensues in the second decade of life and is the main cause of death. Treatment options are still limited. • Tamoxifen reduced cardiac fibrosis in mice and improved cardiomyocyte function in human-induced pluripotent stem cell-derived cardiomyocytes.
WHAT IS NEW
• In this post-hoc analysis of the TAMDMD trial among 14 boys, median 11 years of age, treated with either tamoxifen or placebo for 48 weeks, treatment was well-tolerated. • A visual trend of improved left-ventricular dimensions and better systolic function preservation generates the hypothesis of a potential beneficial effect of tamoxifen in DMD cardiomyopathy
Extracting very small amounts of potassium from iron meteorites for the analysis of potassium isotope ratios
Get PDFKeel bone fractures affect laying hens' mobility, but no evidence for reciprocal effects.
Get PDFKeel bone fractures (KBF) are prevalent in commercial laying hens and are considered one of the greatest welfare concerns in the egg-production industry. While clear associations exist between KBF and animal mobility, suggesting that KBF impair mobility, the effect of mobility on KBF remains unclear. We combined data from three studies that assessed keel bone fracture severity through radiographs and monitored hens' transitions between different zones of a multi-tier aviary system (the three tiers, a littered floor, and a winter garden) the week prior to radiograph. For each hen, we extracted two daily movement behaviours: the vertical distance travelled and the mean number of zones crossed within one transition; and two daily space-use behaviours: the time spent in the top tier and the unevenness of time spent across zones. We used hierarchical Bayesian continuous time dynamic modelling to estimate how a change in a behaviour predicted a later change in keel bone fracture severity, and vice versa. Increased fracture severity did not predict later changes in space-use behaviours, but it did predict changes in movement behaviours. Specifically, increased fracture severity led to decreased vertical travelled distance and a tendency to cross more zones within one transition, suggesting impaired mobility in hens with increased fracture severity. In contrast, we found no evidence that movement or space-use behaviours predict later change in fracture severity, challenging previous literature suggesting that vertical locomotion through jumping and flying may exacerbate keel bone fractures in complex three-dimensional systems due to increased risk of collisions. However, similar efforts accounting for the location of fractures on the keel could unveil the potential influence of movement and space-use behaviours in the formation and change (healing or worsening) of KBF and increase our ability to mitigate their effects
Time profiles of energy balance in dairy cows in association with metabolic status, inflammatory status, and disease.
Get PDFThe early lactation period in dairy cows is characterized by complex interactions among energy balance (EB), disease, and alterations in metabolic and inflammatory status. The objective of this study was to cluster cows based on EB time profiles in early lactation and investigate the association between EB clusters and inflammatory status, metabolic status, oxidative stress, and disease. Holstein-Friesian dairy cows (n = 153) were selected and monitored for disease treatments during wk 1 to 6 in lactation. Weekly EB was calculated based on energy intake and energy requirements for maintenance and milk yield in wk 1 to 6 in lactation. Weekly plasma samples were analyzed for metabolic variables in wk 1 to 6, and inflammatory and oxidative stress variables in wk 1, 2, and 4 in lactation. Liver activity index (LAI) was computed from plasma albumin, cholesterol, and retino-binding protein concentration. First, cows were clustered based on time profiles of EB, resulting in 4 clusters (SP: stable positive; MN: mild negative; IN: intermediate negative; SN: severe negative). Cows in the SN cluster had higher plasma nonesterified fatty acids and β-hydroxybutyrate concentrations, compared with cows in the SP cluster, with the MN and IN cluster being intermediate. Cows in the SN cluster had a higher milk yield, lower dry matter intake in wk 1, lower insulin concentration compared with cows in the SP cluster, and lower glucose and IGF-1 concentration compared with cows in the SP and MN clusters. Energy balance clusters were not related with plasma haptoglobin, cholesterol, albumin, paraoxonase, and liver activity index (LAI). Second, cows were grouped based on health status [IHP: cows with treatment for inflammatory health problem (endometritis, fever, clinical mastitis, vaginal discharge or retained placenta); OHP: cows with no IHP but treatment for other health problem (milk fever, cystic ovaries, claw, and leg problems, rumen and intestine problems or other diseases); NHP: cows with no treatments, in the first 6 weeks after calving]. Energy balance was not different among health status groups. The IHP cows had lower nonesterified fatty acids and greater insulin concentration in plasma compared with OHP. The IHP cows had lower plasma albumin concentration, lower LAI and higher haptoglobin concentration compared with OHP and NHP. Overall, EB time profiles were associated with the metabolic status of dairy cows in early lactation, but were only limitedly related with markers of inflammation and oxidative stress status. Inflammatory and metabolic status were related to disease events in early lactation and caused prolonged effects on liver metabolism
Clinical Efficacy of Permanent Internal Mammary Artery Occlusion in Chronic Coronary Syndrome: a Double-Blind, Randomized, Sham-Controlled Trial.
Get PDFThe CLIMACCS trial, a randomized, sham-controlled trial tested the CLinical efficacy of permanent internal mammary artery (IMA) device occlusion on symptoms in patients with chronic coronary syndrome (CCS), on coronary artery occlusive blood supply, and on myocardial ischemia. This was a prospective trial in 101 patients with CCS randomly allocated (1:1) to IMA device occlusion (verum group) or to IMA sham intervention (placebo group). The primary study endpoint was the change in treadmill exercise time (ΔET in seconds, s) at 6 weeks after trial intervention. Secondary study endpoints were the changes in collateral flow index (CFI), and angina pectoris during a simultaneous 1-minute proximal balloon occlusion of a coronary artery. CFI is the ratio between simultaneous mean coronary occlusive divided by mean aortic pressure both subtracted by central venous pressure. In the verum and placebo group, exercise time changed from 398±176s to 421±198s in the verum group (p=0.1745), and from 426±162s to 430±166s in the placebo group (p=0.55); DET amounted to +23±116s and +4±120s, respectively (p=0.44). CFI change during follow-up equalled +0.022±0.061 in the verum and-0.039±0.072 in the placebo group (p<0.0001). Angina pectoris at follow-up during the coronary balloon occlusion for CFI measurement had decreased or disappeared in 20/48 patients of the verum, and in 9/47 patients of the placebo group (p=0.0242). In conclusion, permanent IMA device occlusion tends to augment treadmill exercise time in response to heightened coronary artery occlusive blood supply, the fact of which is reflected by mitigated symptoms and signs of myocardial ischemia
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