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To carry out longitudinal stochastic cooling of charge particle beams at the Nuclotron of the Joint Institute for Nuclear Research (Dubna), a unique optical comb filter was designed and developed. The designed filter has space-saving size, low insertion losses, and small dispersion. The comb filter tuning was automated using a specially designed software, which made it possible to reduce the tuning time and increase tuning accuracy up to several hertz. The designed filter with automatic tuning was successfully tested in an experiment on deuteron beam cooling. In this work, characteristics of the designed filter are presented and an algorithm of its automatic tuning is considered. [ABSTRACT FROM AUTHOR]

Objectives: Exposure to extreme heat events increases the risk for negative birth outcomes, including preterm birth. This study sought to determine the presence and content of web-based heat health information for pregnant people provided by federal, state, and local government public health websites., Methods: This website content analysis consisted of 17 federal, 50 state, and 21 city websites, and noted which of 25 recognized pregnancy heat health data elements were included. Data for the analysis were collected from March 12, 2022, through March 16, 2022., Results: The search identified 17 federal websites, 38 state websites, and 19 city websites with heat health information. Within these, only seven websites listed pregnant people as a vulnerable or at-risk population, and only six websites provided information related to heat health specifically for pregnancy. Of the 25 themes recognized as important for pregnancy risk during extreme heat exposure, only 11 were represented within these 6 websites., Conclusion: The presence of web-based pregnancy heat health information is infrequent and limited in content. Boosting web-based publication of extreme heat and pregnancy risks could mitigate negative maternal and child health outcomes.

Background: Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal) are two pathogenic fungi that are a significant threat to amphibian communities worldwide. European populations are strongly impacted and the monitoring of the presence and spread of these pathogens is crucial for efficient decision-making in conservation management., Results: Here we proposed an environmental DNA (eDNA) monitoring of these two pathogenic agents through droplet digital PCR (ddPCR) based on water samples from 24 ponds in Luxembourg. In addition, amphibians were swabbed in eight of the targeted ponds in order to compare the two approaches at site-level detection. This study allowed the development of a new method taking below-Limit of Detection (LOD) results into account thanks to the statistical comparison of the frequencies of false positives in no template controls (NTC) and below-LOD results in technical replicates. In the eDNA-based approach, the use of this method led to an increase in Bd and Bsal detection of 28 and 50% respectively. In swabbing, this resulted in 8% more positive results for Bd. In some samples, the use of technical replicates allowed to recover above-LOD signals and increase Bd detection by 35 and 33% respectively for eDNA and swabbing, and Bsal detection by 25% for eDNA., Conclusions: These results confirmed the usefulness of technical replicates to overcome high levels of stochasticity in very low concentration samples even for a highly sensitive technique such as ddPCR. In addition, it showed that below-LOD signals could be consistently recovered and the corresponding amplification events assigned either to positive or negative detection via the method developed here. This methodology might be particularly worth pursuing in pathogenic agents' detection as false negatives could have important adverse consequences. In total, 15 ponds were found positive for Bd and four for Bsal. This study reports the first record of Bsal in Luxembourg., (© 2023. The Author(s).)

Purpose: Different studies have shown that weightbearing is safe in stable transsyndesmotic, isolated lateral simple ankle fractures. Despite this evidence, AO guidelines still recommend immobilization with above-the-knee cast for 4-6 weeks for these fractures. The objective of this study was to compare the outcomes of mobilization and weightbearing to those of immobilization and non-weightbearing in patients with stable transsyndesmotic, lateral isolated simple ankle fractures., Methods: Fifty patients were randomly assigned to permissive weightbearing in a walking boot or non-weightbearing immobilization using a below-the-knee cast. Primary outcome was ankle functionality as scored by the Olerud-Molander Ankle Score (OMAS). Secondary outcomes were radiological displacement of fracture, range of motion (ROM), calf circumference, and RAND 36-item health survey. Patients were in follow-up for 24 months., Results: Ankle functionality after six and twelve weeks was significantly higher for the intervention group, with respectively 30 points (p = 0.001) and 10 points (p = 0.015) of difference. ROM improved significantly in the intervention group after six weeks. All fractures showed radiological progression of fracture healing. RAND 36-item showed differences in both physical (60.3 vs. 46.3, p = 0.017) and mental (78.5 vs. 58.2, p = 0.034) components in favor of the intervention group. In 16% of patients who initially showed stable fractures on radiographic imaging, joint dislocation was identified on weightbearing radiographs prior to randomization, leading to exclusion., Conclusion: Weightbearing and mobilization using a walking boot may be a safe treatment for patients with stable Weber B fractures., (© 2023. The Author(s).)

Objective: Basic Calcium Phosphate (BCP) crystals play an active role in the progression of osteoarthritis (OA). However, the cellular consequences remain largely unknown. Therefore, we characterized for the first time the changes in the protein secretome of human OA articular chondrocytes as a result of BCP stimulation using two unbiased proteomic analysis methods., Method: Isolated human OA articular chondrocytes were stimulated with BCP crystals and examined by Quantitative Reverse Transcription PCR (RT-qPCR) and enzyme-linked immune sorbent assay (ELISA) after twenty-four and forty-eight hours. Forty-eight hours conditioned media were analyzed by label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) and an antibody array. The activity of BCP dependent Transforming Growth Factor Beta (TGF-β) signaling was analyzed by RT-qPCR and luciferase reporter assays. The molecular consequences regarding BCP-dependent TGF-β signaling on BCP-dependent Interleukin 6 (IL-6) were investigated using specific pathway inhibitors., Results: Synthesized BCP crystals induced IL-6 expression and secretion upon stimulation of human articular chondrocytes. Concomitant induction of catabolic gene expression was observed. Analysis of conditioned media revealed a complex and diverse response with a large number of proteins involved in TGF-β signaling, both in activation of latent TGF-β and TGF-β superfamily members, which were increased compared to non-stimulated OA chondrocytes. Activity of this BCP driven TGF-β signaling was confirmed by increased activity of expression of TGF-β target genes and luciferase reporters. Inhibition of BCP driven TGF-β signaling resulted in decreased IL-6 expression and secretion with a moderate effect on catabolic gene expression., Conclusion: BCP crystal stimulation resulted in a complex and diverse chondrocyte protein secretome response. An important role for BCP-dependent TGF-β signaling was identified in development of a pro-inflammatory environment., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: Ectopic calcification is an important contributor to chronic diseases, such as osteoarthritis. Currently, no effective therapies exist to counteract calcification. We developed peptides derived from the calcium binding domain of human Alpha-2-HS-Glycoprotein (AHSG/Fetuin A) to counteract calcification., Methods: A library of seven 30 amino acid (AA) long peptides, spanning the 118 AA Cystatin 1 domain of AHSG, were synthesized and evaluated in an in vitro calcium phosphate precipitation assay. The best performing peptide was modified (cyclic, retro-inverso and combinations thereof) and evaluated in cellular calcification models and the rat Medial Collateral Ligament Transection + Medial Meniscal Tear (MCLT + MMT) osteoarthritis model., Results: A cyclic peptide spanning AA 1-30 of mature AHSG showed clear inhibition of calcium phosphate precipitation in the nM-pM range that far exceeded the biological activity of the linear peptide variant or bovine Fetuin. Biochemical and electron microscopy analyses of calcium phosphate particles revealed a similar, but distinct, mode of action in comparison with bFetuin. A cyclic-inverso variant of the AHSG 1-30 peptide inhibited calcification of human articular chondrocytes, vascular smooth muscle cells and during osteogenic differentiation of bone marrow derived stromal cells. Lastly, we evaluated the effect of intra-articular injection of the cyclic-inverso AHSG 1-30 peptide in a rat osteoarthritis model. A significant improvement was found in histopathological osteoarthritis score and animal mobility. Serum levels of IFNγ were found to be lower in AHSG 1-30 peptide treated animals., Conclusions: The cyclic-inverso AHSG 1-30 peptide directly inhibits the calcification process and holds the potential for future application in osteoarthritis., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Develop simple and valid models for predicting mortality and need for intensive care unit (ICU) admission in patients who present at the emergency department (ED) with suspected COVID-19., Design: Retrospective., Setting: Secondary care in four large Dutch hospitals., Participants: Patients who presented at the ED and were admitted to hospital with suspected COVID-19. We used 5831 first-wave patients who presented between March and August 2020 for model development and 3252 second-wave patients who presented between September and December 2020 for model validation., Outcome Measures: We developed separate logistic regression models for in-hospital death and for need for ICU admission, both within 28 days after hospital admission. Based on prior literature, we considered quickly and objectively obtainable patient characteristics, vital parameters and blood test values as predictors. We assessed model performance by the area under the receiver operating characteristic curve (AUC) and by calibration plots., Results: Of 5831 first-wave patients, 629 (10.8%) died within 28 days after admission. ICU admission was fully recorded for 2633 first-wave patients in 2 hospitals, with 214 (8.1%) ICU admissions within 28 days. A simple model-COVID outcome prediction in the emergency department (COPE)-with age, respiratory rate, C reactive protein, lactate dehydrogenase, albumin and urea captured most of the ability to predict death. COPE was well calibrated and showed good discrimination for mortality in second-wave patients (AUC in four hospitals: 0.82 (95% CI 0.78 to 0.86); 0.82 (95% CI 0.74 to 0.90); 0.79 (95% CI 0.70 to 0.88); 0.83 (95% CI 0.79 to 0.86)). COPE was also able to identify patients at high risk of needing ICU admission in second-wave patients (AUC in two hospitals: 0.84 (95% CI 0.78 to 0.90); 0.81 (95% CI 0.66 to 0.95))., Conclusions: COPE is a simple tool that is well able to predict mortality and need for ICU admission in patients who present to the ED with suspected COVID-19 and may help patients and doctors in decision making., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and objectives: Persistent left bundle branch block (P-LBBB) has been associated with poor clinical outcomes of transcatheter aortic valve implantation (TAVI) procedures. We hypothesized that the distance from the aortic valve to the proximal conduction system, expressed as the effective distance between the aortic valve and conduction system (EDACS), can predict the occurrence of P-LBBB in patients undergoing a TAVI procedure. Materials and methods: In a retrospective study, data from 269 patients were analyzed. EDACS was determined using two longitudinal CT sections. Results: Sixty-four of the patients developed P-LBBB. EDACS ranged between -3 and +18 mm. EDACS was significantly smaller in P-LBBB than in non-P-LBBB patients (4.6 (2.2-7.1) vs. 8.0 (5.8-10.2) mm, median values (interquartile range); p < 0.05). Receiver operating characteristic analysis showed an area under the curve of 0.78 for predicting P-LBBB based on EDACS. In patients with EDACS of ≤3 mm and >10 mm, the chance of developing P-LBBB was ≥50% and <10%, respectively. Conclusions: A small EDACS increases the risk for the development of P-LBBB during TAVI by a factor of >25. As EDACS can be measured pre-procedurally, it may be a valuable additional factor to weigh the risks of transcatheter and surgical aortic valve replacement.

Objective: To systematically collect clinical data from patients with a proven COVID-19 infection in the Netherlands., Design: Data from 2579 patients with COVID-19 admitted to 10 Dutch centers in the period February to July 2020 are described. The clinical data are based on the WHO COVID case record form (CRF) and supplemented with patient characteristics of which recently an association disease severity has been reported., Methods: Survival analyses were performed as primary statistical analysis. These Kaplan-Meier curves for time to (early) death (3 weeks) have been determined for pre-morbid patient characteristics and clinical, radiological and laboratory data at hospital admission., Results: Total in-hospital mortality after 3 weeks was 22.2% (95% CI: 20.7% - 23.9%), hospital mortality within 21 days was significantly higher for elderly patients (> 70 years; 35, 0% (95% CI: 32.4% - 37.8%) and patients who died during the 21 days and were admitted to the intensive care (36.5% (95% CI: 32.1% - 41.3%)). Apart from that, in this Dutch population we also see a risk of early death in patients with co-morbidities (such as chronic neurological, nephrological and cardiac disorders and hypertension), and in patients with more home medication and / or with increased urea and creatinine levels., Conclusion: Early death due to a COVID-19 infection in the Netherlands appears to be associated with demographic variables (e.g. age), comorbidity (e.g. cardiovascular disease) but also disease char-acteristics at admission.

Human milk oligosaccharides (HMOS) are a complex mixture of bioactive components supporting the immune development of breastfed-infants. Dendritic cells (DCs) play a central role in the regulation of immune responses, being specialized in antigen presentation and driving T-cell priming as well as differentiation. However, little is known about the direct effects of HMOS on human DC phenotypes and functions. Here, we report that HMOS mixture isolated from pooled human milk, induced semi-maturation of human monocytes-derived DCs (moDCs), and elevated levels of IL-10, IL-27 and IL-6 but not IL-12p70 and TNF-α. Consistently, HMOS-conditioned human moDCs promoted Treg generation from naïve CD4 + T cells. Interestingly, HMOS limited LPS-induced maturation of human moDCs, while maintained IL-10 and IL-27 secretion and reduced LPS-induced production of IL-12p70, IL-6 and TNF-α. Furthermore, HMOS+LPS-stimulated DCs induced a higher frequency of Tregs and increased IL-10 production, while a reduction in Tbet+Th1 frequency and IFN-γ production was detected as compared to LPS-DCs. The regulatory effects of HMOS seemed to be mediated by interactions of HMOS with receptors, including but not limited to TLR4 and DC-SIGN on human moDCs. In conclusion, HMOS contain tolerogenic factors influencing human moDCs and thereby modulating the development of the neonatal immune system., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Exclusive measurements of the quasifree pp→ppπ^{+}π^{-} reaction have been carried out at WASA@COSY by means of pd collisions at T&#95;{p}=1.2  GeV. Total and differential cross sections have been extracted covering the energy region T&#95;{p}=1.08-1.36  GeV, which is the region of N^{*}(1440) and Δ(1232)Δ(1232) resonance excitations. Calculations describing these excitations by t-channel meson exchange are at variance with the measured differential cross sections and underpredict substantially the experimental total cross section. An isotensor ΔN dibaryon resonance with I(J^{P})=2(1^{+}) produced associatedly with a pion is able to overcome these deficiencies.

Taking advantage of the high acceptance and axial symmetry of the WASA-at-COSY detector, and the high polarization degree of the proton beam of COSY, the reaction p[over →]p→ppη has been measured close to threshold to explore the analyzing power A&#95;{y}. The angular distribution of A&#95;{y} is determined with the precision improved by more than 1 order of magnitude with respect to previous results, allowing a first accurate comparison with theoretical predictions. The determined analyzing power is consistent with zero for an excess energy of Q=15  MeV, signaling s-wave production with no evidence for higher partial waves. At Q=72  MeV the data reveal strong interference of Ps and Pp partial waves and cancellation of (Pp)^{2} and Ss^{*}Sd contributions. These results rule out the presently available theoretical predictions for the production mechanism of the η meson.

This Letter reports the successful use of feedback from a spin polarization measurement to the revolution frequency of a 0.97  GeV/c bunched and polarized deuteron beam in the Cooler Synchrotron (COSY) storage ring in order to control both the precession rate (≈121  kHz) and the phase of the horizontal polarization component. Real time synchronization with a radio frequency (rf) solenoid made possible the rotation of the polarization out of the horizontal plane, yielding a demonstration of the feedback method to manipulate the polarization. In particular, the rotation rate shows a sinusoidal function of the horizontal polarization phase (relative to the rf solenoid), which was controlled to within a 1 standard deviation range of σ=0.21  rad. The minimum possible adjustment was 3.7 mHz out of a revolution frequency of 753 kHz, which changes the precession rate by 26  mrad/s. Such a capability meets a requirement for the use of storage rings to look for an intrinsic electric dipole moment of charged particles.

We observe a deuteron beam polarization lifetime near 1000 s in the horizontal plane of a magnetic storage ring (COSY). This long spin coherence time is maintained through a combination of beam bunching, electron cooling, sextupole field corrections, and the suppression of collective effects through beam current limits. This record lifetime is required for a storage ring search for an intrinsic electric dipole moment on the deuteron at a statistical sensitivity level approaching 10^{-29}  e cm.

A new method to determine the spin tune is described and tested. In an ideal planar magnetic ring, the spin tune-defined as the number of spin precessions per turn-is given by ν(s)=γG (γ is the Lorentz factor, G the gyromagnetic anomaly). At 970  MeV/c, the deuteron spins coherently precess at a frequency of ≈120  kHz in the Cooler Synchrotron COSY. The spin tune is deduced from the up-down asymmetry of deuteron-carbon scattering. In a time interval of 2.6 s, the spin tune was determined with a precision of the order 10^{-8}, and to 1×10^{-10} for a continuous 100 s accelerator cycle. This renders the presented method a new precision tool for accelerator physics; controlling the spin motion of particles to high precision is mandatory, in particular, for the measurement of electric dipole moments of charged particles in a storage ring.

A new method for removal of aural foreign bodies is introduced, employing the injection of a semifluid impression material into the external auditory canal, and its removal after curing with the engulfed foreign matter. This technique obviated the need for a general anesthetic in some pediatric cases, while in others it was just a more pleasant experience.