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International audience; Underground nuclear explosions generate non-isothermal two-phase flow, heat and mass transfer, and tracer transport through fractured porous media. The governing equations of these coupled phenomena on the Darcy scale are presented and the corresponding numerical code is briefly described. Two configurations are considered. In the first one, the damaged zone generated by the explosion is replaced by equivalent macroscopic boundary conditions at the bottom of the medium. Vapor condensation at distance from this zone plays a crucial role and slows down the tracer transport to the ground surface, while the presence of hot liquid water and of hot rubble particles in it accelerates it. In the second configuration, the damaged zone itself is treated as a porous medium with specific properties and is integrated in the simulation domain. Several regions can be distinguished with different properties, such as the chimney, the cavity, the solidified magma, the fractured porous medium, and the intact porous medium. Phase change, heat transfer and tracer transport can be detailed in these regions and at the boundaries between them. Among the most important conclusions, the role of phase change, of the thermal properties and therefore of the temperature, is pointed out.

Miniature devices are becoming increasingly demanded as fifth-generation (5G) technology is been deployed. This has necessitated the need to miniaturize all the various components of 5G enabling systems. It is a well-known fact that without the antenna, there is no wireless communication as it forms the link between the space and the wired network. Hence, the miniaturization of the antenna will contribute to the miniaturization of the entire wireless system. In this work, a miniature dual-band ultracompact antenna based on an opened-B-shaped (OBS) patch, a partial ground, and a ground protruding stub is presented. The antenna size is 0.14 × 0.07 λ o λ o @ 1.85 G H z . The proposed antenna is etched on a rogers (RT5880) substrate and fed with a 50 Ω asymmetric microstrip feedline. The proposed OBS antenna is fabricated and measured. In addition, the equivalent circuit of the proposed OBS antenna is designed and analyzed using AWR®. The antenna operates at a center frequency of 1.85 GHz and 5.89 GHz with an impedance bandwidth of 10.41% and 36.29%, respectively, which means that the first and second bands are narrow and wide bands, respectively. Furthermore, the mean peak gain of the proposed OBS antenna at lower and upper bands are 4.1 dB and 3.95 dB, respectively. More so, the radiation pattern antenna shows a quasiomnidirectional at E-plane and omnidirectional at H-plane. There is a good agreement between simulated and measured results. Therefore, the proposed OBS antenna is a suitable candidate for future portable mobile devices.

Salt weathering is a main cause of damage in building heritage materials. Despite the large amount of research on this topic, the mechanism of damaging processes remains not fully understood in particular at the pore scale where the salt crystallization and dissolution occur. For this reason, we propose an innovative approach combining damage proxy measurements at pore-scale using Atomic Force Microscopy (AFM), Raman spectrometry and multi-scale numerical modelling, performed during weathering cycles. Imbibition-evaporation cycles are performed on carbonate stones (Savonnières and Saint Maximin limestones) with a 0.1 mol/L sodium sulfate solution at controlled room temperature and relative humidity. The stone samples are especially designed for the measurements at the pore-scale. Cylinder of 1.6 cm diameter and 1.5 cm thickness have been coated with very viscous epoxy resin. Then the two sides of the cylinder have been polished to obtained two free surfaces that allow the fluid circulation in the sample and the measurements. After each weathering cycle, nanoindentation experiments are performed on representative areas of several hundreds of square micrometers in order to monitor the mechanical properties evolution. A force of the µN order is applied in order to stay in the elastic deformation regime. Young modulus values can be then deduced from the slope of the force curves that occurs during the cantilever deflection. With this method, the effect of salt weathering on the mechanical properties of stone minerals is investigated at the pore scale and with no impact of the measurement on the phases structure (reversible indentations). The AFM results are then coupled with chemical Raman mapping to identify the present phases and assign them their mechanical properties. The obtained experimental data are then used in numerical modeling, to generate a numerical Young modulus field with the same properties than the experimental field. Finally, a new medium with higher dimensions will be generated to compare the results with the macro-scale observations on building heritage stones. AFM characterization shows that changes occurred on the topography of the samples between the first and the third alteration cycles. They are of the order of several tens of nanometers and correspond either to salt crystals deposits or in some cases to the loss of material that took place between the second and the third cycle. A decrease of the Young modulus is observed after each cycle that is of the order of 2 GPa between the first and the second cycles. More significant changes are observed after the third cycle especially in some areas where a decrease up to 3 to 4 GPa is estimated.

Supplementary Methods, Figures, and Tables

Thalidomide analogues exert their therapeutic effects by binding to the CRL4CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2–FGFR1 and ZMYM2–FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment.Significance:We extend the potential clinical scope of thalidomide analogues by the identification of a novel avadomide-dependent CRL4CRBN substrate, ZMYM2. Avadomide induces ubiquitination and degradation of ZMYM2–FGFR1 and ZMYM2–FLT3, two chimeric oncoproteins involved in hematologic malignancies, providing a proof of concept for drug-induced degradation of transcription factor fusion proteins by thalidomide analogues.

Supplementary Table 1. Proteomic data

Sixteen geosterane derivatives were synthesized in up to 57 % overall yields in four steps harnessing the olefin cross-metathesis (OCM) and Metal hydride H atom transfer (MHAT) or homogeneous hydrogenation reactions as key steps. Drawing on this strategy, the diastereomeric ratio (d. r.) reached up to 24 : 1 for the thermodynamic isomer and 7 : 1 for the other isomer in the hydrogenation step. In a geological sample from northeast Brazil, we confirmed the putative structures previously assumed as methyl 2-(3α-5αH-cholestan) acetate, methyl 2-(3β-5αH-cholestan)acetate, and methyl 6-(3β-5αH-cholestan)hexanoate, as well three new molecular fossils of approximately 120 million years old. We also proved the migration marking ability of those carboxylic acids derived from forerunner geosteranes during an oil migration event, which suggests their aptitudes as molecular odometers. Our approach demonstrated swiftness and effectiveness in preparing a molecular library of geological biomarkers would also be appropriate to generate stereochemical diversity in molecular libraries for medicinal chemistry and natural product anticipation.

The aim of this study was to determine the outcome of dogs with soft tissue sarcoma (STS) within the region of the ischiatic tuberosity (ITSTS) treated surgically. This was a multi-institutional retrospective study. Fifty-two dogs met the inclusion criteria, which were: histologically confirmed STS in the region of the IT treated with surgical resection between March 1st, 2009 and March 1st, 2021 with a minimum follow-up time of 6 months. Data collected included patient signalment, preoperative diagnostics, surgical intent/method, surgical complications, histopathology, margins, outcome and cause of death. Statistical analyses were performed to determine significant factors in the treatment and prognosis of ITSTS. Overall survival time (OST) and disease progression were negatively associated with tumour grade, while recurrence was positively associated with grade and incomplete margins. Of the 52 included dogs, there were 24 grade I, 20 grade II and 7 grade III tumours. Forty dogs had reported histopathologic margins of which 26 were reported to be complete and 14 were incomplete. OST and progression-free survival was not reached for tumours graded as I or II and was 255 and 268 days respectively, for grade III. Median time to recurrence was not reached for tumours excised with complete margins and was 398 days for those with incomplete margins. The surgical complication rate was 25%. ITSTS was not found to be a unique clinical entity in dogs as tumour behavior, treatment recommendations, and prognosis were similar to STS in other locations, with overall outcome and prognosis influenced by histologic grade and margins. While surgical complications were common, none resulted in significant morbidity or mortality.

Heparin is widely used in the intensive care unit despite the risk of bleeding it can cause. Although it is rarely reported, hyperkalemia is one of the side effects associated with heparin therapy (unfractionated or fractionated heparin). It would be secondary to hypoaldosteronism by blocking the biosynthesis of aldosterone in the adrenal gland and often appears in context of prolonged heparin therapy or inappropriate renin production in elderly, diabetic, and kidney insufficiency patients. We report a case of persistent hyperkalemia in a diabetic COVID-19 patient treated with curative heparin in the context of severe COVID-19.

Delayed single- and few-electron emissions plague dual-phase time projection chambers, limiting their potential to search for light-mass dark matter. This paper examines the origins of these events in the XENON1T experiment. Characterization of the intensity of delayed electron backgrounds shows that the resulting emissions are correlated, in time and position, with high-energy events and can effectively be vetoed. In this work we extend previous S2-only analyses down to a single electron. From this analysis, after removing the correlated backgrounds, we observe rates < 30 events/(electron*kg*day) in the region of interest spanning 1 to 5 electrons. We derive 90% confidence upper limits for dark matter-electron scattering, first direct limits on the electric dipole, magnetic dipole, and anapole interactions, and bosonic dark matter models, where we exclude new parameter space for dark photons and solar dark photons., 20 pages, 17 figures

Ferrocene-based porous organic polymers (FPOPs) were prepared from phenol-formaldehyde polymer (Bakelite) and phenol as starting materials; and two possible mechanisms for polymerization were discussed. Solid-state 13C CP-MAS NMR, FTIR, powder XRD, elemental analysis and ICP (Fe, Na, B) were performed to characterize the prepared materials. The two synthetic approaches produced polymers with different pore sizes: the FPOP synthesized through Bakelite presented a higher surface area (52 m2 g−1) when compared to the one obtained by the bottom-up polymerization from phenol (only 5 m2 g−1). Thermogravimetric analysis confirmed the thermal stability of the material, which decomposed at 350 °C. Furthermore, cyclic voltammetry (CV) of the new FPOP on modified electrodes, in ACN and 0.1 M TBAP as an electrolyte, showed fully reversible electron transfer, which is similar to that observed for the ferrocene probe dissolved in the same electrolyte. As a proof-of-concept for an electrochromic device, this novel material was also tested, with a color change detected between yellow/brownish coloration (reduced form) and green/blue coloration (oxidized form). The new hybrid FPOP seems very promising for material science, energy storage and electrochromic applications, as well as for plastic degradation.

Objective. The insulin tolerance test (ITT) is the gold standard endocrine test used to assess the integrity of the growth hormone (GH) and cortisol axes. The ITT has potential risks, and severe hypoglycaemia may necessitate intravenous glucose rescue. There is no clear consensus as to the optimal insulin dose for the ITT. Therefore, we sought to compare the standard dose (0.15 U/kg) and a low-dose ITT (0.1 U/kg). Design. Single-centre audit of ITT data (2012–2021). Patients and Measurements. Patients who underwent an ITT to assess possible GH deficiency/adrenal insufficiency were included. Glucose, GH, and cortisol were measured at baseline and 30, 45, 60, 90, and 120 minutes following I.V. insulin bolus (0.15 U/kg or 0.10 U/kg). Results. Of the ITTs performed, only 3/177 (1.7%) did not achieve adequate hypoglycaemia (≤2.2 mmol/L) with a single insulin dose. In total, 174 patients (43.5 ± 12.1 yrs, mean ± standard deviation) were included for analysis (0.15 U/kg: n = 113, 0.10 U/kg: n = 61). All 174 subjects had adequate hypoglycaemia regardless of baseline fasting blood glucose level or insulin dose. Neither nadir glucose nor glucose delta (i.e., baseline minus nadir) differed between insulin doses. Trends in both cortisol and GH responses over time were similar between groups, and a greater proportion of patients receiving the standard dose had an adequate cortisol response (77/106 (72.6%) vs. 32/60 (53.3%), p = 0.01 ). The rates of glucose rescue did not differ in a subset of 79 patients, with on-demand glucose rescue in 4/35 (11%) for the standard dose and 2/44 (5%) for the low dose ( p = 0.25 ). Conclusions. Our results suggest that the low-dose ITT produces comparable glucose, cortisol, and GH responses to the higher dose. Given the risks associated with hypoglycaemia, the low dose appears to be preferable to the standard dose ITT in most circumstances.

The discovery of caspase homologs in bacteria highlighted the relationship between programmed cell death (PCD) evolution and eukaryogenesis. However, the origin of PCD genes in prokaryotes themselves (bacteria and archaea) is poorly understood and a source of controversy. Whether archaea also contain C14 peptidase enzymes and other death domains is largely unknown because of a historical dearth of genomic data. Archaeal genomic databases have grown significantly in the last decade, which allowed us to perform a detailed comparative study of the evolutionary histories of PCD-related death domains in major archaeal phyla, including the deepest branching phyla of Candidatus Aenigmarchaeota, Candidatus Woesearchaeota, and Euryarchaeota. We identified death domains associated with executioners of PCD, like the caspase homologs of the C14 peptidase family, in 321 archaea sequences. Of these, 15.58% were metacaspase type I orthologues and 84.42% were orthocaspases. Maximum likelihood phylogenetic analyses revealed a scattered distribution of orthocaspases and metacaspases in deep-branching bacteria and archaea. The tree topology was incongruent with the prokaryote 16S phylogeny suggesting a common ancestry of PCD genes in prokaryotes and subsequent massive horizontal gene transfer coinciding with the divergence of archaea and bacteria. Previous arguments for the origin of PCD were philosophical in nature with two popular propositions being the "addiction" and 'original sin' hypotheses. Our data support the 'original sin' hypothesis, which argues for a pleiotropic origin of the PCD toolkit with pro-life and pro-death functions tracing back to the emergence of cellular life-the Last Universal Common Ancestor State.

In north Greenland, which holds more than 2.7 m of sea level equivalent, the ice flows through ice shelves, as in Antarctica. These floating platforms are the most vulnerable parts of the ice sheets as the advection of warm, salty ocean waters increases basal melting, which can trigger an increase in ice flow into the ocean. Here we study the recent dynamic and geometric changes of all present and former ice shelves along the north coast of Greenland. We document the evolution of the surface elevation using data from the GIMP project, from NASA's instruments (ICESat-1/2, ATM, LVIS, GLISTIN-A) and generate DEMs using ASTER imagery between 2000-present. We also monitor changes in surface ice velocity and grounding zone evolution using a combination of optical and radar data. We use the elevation time series to monitor the temporal evolution of the ice shelves volumes and combine them with the surface flow velocity to calculate basal melt rates in a Lagrangian framework at unprecedented level of resolution. Finally, we compare our observations with nearby CTD measurements, the TOPAZ4b reanalysis of Arctic ocean physics provided by Copernicus Marine Service and model outputs from the Modèle Atmosphérique Régoinal. We show that basal melting, grounding line retreat and fracturing are rapidly increasing and is followed by an increase in ice discharge into the ocean. These observations demonstrate that significant changes are occuring in a region that has long been considered stable, which may have dramatic consequences for the ice sheet contribution to sea level rise., The 28th IUGG General Assembly (IUGG2023) (Berlin 2023)

Contains fulltext : 290914.pdf (Publisher’s version ) (Open Access) BACKGROUND: In node-negative breast cancer (NNBC), a high risk of recurrence is determined by clinico-pathological or tumor-biological assessment. Taxanes may improve adjuvant chemotherapy. METHODS: NNBC 3-Europe, the first randomized phase-3 trial in node-negative breast cancer (BC) with tumor-biological risk assessment, recruited 4146 node-negative breast cancer patients from 2002 to 2009 in 153 centers. Risk assessment was performed by clinico-pathological factors (43%) or biomarkers (uPA/PAI-1, urokinase-type plasminogen activator/its inhibitor PAI-1). High-risk patients received six courses 5-fluorouracil (500 mg/m(2)), epirubicin (100 mg/m(2)), cyclophosphamide (500 mg/m(2)) (FEC), or three courses FEC followed by three courses docetaxel 100 mg/m(2) (FEC-Doc). Primary endpoint was disease-free survival (DFS). RESULTS: In the intent-to-treat population, 1286 patients had received FEC-Doc, and 1255 received FEC. Median follow-up was 45 months. Tumor characteristics were equally distributed; 90.6% of tested tumors had high uPA/PAI-1-concentrations. Planned courses were given in 84.4% (FEC-Doc) and 91.5% (FEC). Five-year-DFS was 93.2% (95% C.I. 91.1-94.8) with FEC-Doc and 93.7% (91.7-95.3) with FEC. Five-year-overall survival was 97.0% (95.4-98.0) for FEC-Doc and 96.6% % (94.9-97.8) for FEC. CONCLUSIONS: With adequate adjuvant chemotherapy, even high-risk node-negative breast cancer patients have an excellent prognosis. Docetaxel did not further reduce the rate of early recurrences and led to significantly more treatment discontinuations.

These files are the inputs and outputs of the scripts described in this GitHub repository: pierrj/moryzae_pav_manuscript_code (github.com) The organization and names of the files uploaded here match those within the code repository

BACKGROUND: Interpatient variability in cytochrome P450 2D6 (CYP2D6) enzyme activity alters the serum concentrations of most psychotropics, which often have narrow therapeutic indices. Therefore, preemptive knowledge of CYP2D6 activity is desired. However, accessible indicators for deficient CYP2D6 activity are necessary because genotyping all patients prescribed CYP2D6 metabolized drugs is often not feasible or cost-effective. METHODS: In this study, the predictive value of the ratio between a CYP2D6 substrate and its metabolite, known as the metabolic ratio (MR), the dose-corrected serum concentration of substrate (CDR), and the dose-corrected sum concentration of substrate and metabolite (Sum CDR) of venlafaxine, risperidone, aripiprazole, and nortriptyline were determined to predict the CYP2D6 poor metabolizer (PM) phenotype. The area-under-the-receiver operator characteristic curve, as well as the sensitivity, specificity, and positive and negative predictive values of the optimal thresholds, were calculated. RESULTS: Although the MR, CDR, and Sum CDR all predicted the CYP2D6 PM phenotype, the predictive value of the MR was most robust for venlafaxine and aripiprazole, and the Sum CDR was inferior for all 3 psychotropics. MRs of venlafaxine, risperidone, and aripiprazole, and CDR of nortriptyline showed an area-under-the-receiver operator characteristics (95% confidence interval) of 97.2% (94.7%-99.6%), 93.0% (88.8%-97.2%), 97.8% (95.4%-100.0%), and 85.6% (78.0%-93.1%), respectively. Thresholds of the log(MR) of ≥0.1 for venlafaxine, ≥0.0 for risperidone, and ≥1.5 for aripiprazole, and log(CDR) ≥0.5 for nortriptyline produced >92% sensitivity and >64% specificity. CONCLUSIONS: If therapeutic drug monitoring is available, the thresholds presented here could serve as a diagnostic tool for the CYP2D6 PM phenotype of psychiatric patients prescribed the aforementioned psychotropic medications.

Background Numerous vaccines have been evaluated and approved for coronavirus disease 2019 (COVID-19). Since pregnant persons have been excluded from most clinical trials of COVID-19 vaccines, sufficient data regarding safety of these vaccines for the pregnant persons and their fetus have rarely been available at the time of product licensure. However, as COVID-19 vaccines have been deployed, data on the safety, efficacy or effectiveness, reactogenicity, and immunogenicity of COVID-19 vaccines for pregnant persons and neonates are becoming increasingly available. A living systematic review (LSR) of the safety and effectiveness of COVID-19 vaccines for pregnant persons and newborns could provide information necessary to help guide vaccine policy decisions. Methods We aim to conduct a LSR based on biweekly searches of medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries to systematically identify relevant studies of COVID-19 vaccines for pregnant persons. Pairs of reviewers will independently select, extract data, and conduct risk of bias assessments. We will include randomized clinical trials, quasi-experimental studies, cohort, case-control, cross-sectional studies, and case reports. Primary outcomes will be the safety (i.e., impacts on obstetric and neonatal outcomes), efficacy or effectiveness of COVID-19 vaccines in pregnant persons. Secondary outcomes will be immunogenicity and reactogenicity. We will conduct paired meta-analyses, including pre-specified subgroup and sensitivity analyses, and will use the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to evaluate the certainty of evidence. Conclusion This will be the first living systematic review (LSR) and meta-analysis assessing the safety, reactogenicity, immunogenicity, and effectiveness of COVID-19 vaccines for pregnant persons. An online interactive dashboard for data visualization using Microsoft Power BI will be developed to regularly update and disseminate the latest findings (an in-progress version is available at https://safeinpregnancy.org/lsr/). In addition, the findings will be disseminated through publications and presentations.

In Rwanda, cattle and milk hold a cultural and historical significance, providing an opportunity for pro-dairy governmental policies aimed to alleviate food insecurity, malnutrition, and improve livelihoods. The government of Rwanda has identified strategies to grow the dairy sector through strategic investment to achieve these goals. It is estimated two-thirds of lactating cows in Rwanda have clinical or subclinical mastitis, which reduces milk production and increases the risk of milk as a source for zoonotic disease if the milk is consumed undercooked or unpasteurized. This case study outlines the implementation of a One Health framework that integrates education, research, and outreach in Rwanda to improve food safety and food security, for the social, economic, and health benefit of Rwandans and their livestock. Twenty-five Rwandan Extension Specialists participated in the Dairy Dynamic Management education, research, and outreach program. Once trained, the extension specialists supported 30 small holder dairy farmers in performing proper husbandry and animal health practices for mastitis control and reduction of bacterial counts in the udder. Over the 16-week program, 30 small holder dairy farmers and 100 dairy cows were surveyed weekly for animal husbandry, animal health, and mastitis indicators. Outcomes were evaluated by monitoring animal health, foodborne pathogens in milk, and compliance to animal husbandry protocols. Quarter milk samples were collected weekly and evaluated for the presence of bacteria that are common causes of mastitis. We found a statistically significant reduction of mean total bacterial counts and prevalence of bacterial species in quarters over the 16-week training (P≤.01). Smallholders were monitored through observing farmers performing hygienic milking protocols. Farmers conducted the protocol correctly greater than 90% of the time by the end of the 16-week program for 5 of 7 steps for proper hygienic milking procedures, indicating farmers were eager to learn and adopt the procedures. However, follow-up and retraining with Extension Specialists is vital to continued success. We demonstrate that an integrative One Health education, research, and outreach program can be successful in improving animal health, food safety, and food security and this framework can be applied to other agricultural sectors and geographic regions.

The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for Weakly Interacting Massive Particles (WIMPs), while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector., 77 pages, 40 figures, 1262 references

A novel online distillation technique was developed for the XENON1T dark matter experiment to reduce intrinsic background components more volatile than xenon, such as krypton or argon, while the detector was operating. The method is based on a continuous purification of the gaseous volume of the detector system using the XENON1T cryogenic distillation column. A krypton-in-xenon concentration of (360±60)ppq was achieved. It is the lowest concentration measured in the fiducial volume of an operating dark matter detector to date. A model was developed and fit to the data to describe the krypton evolution in the liquid and gas volumes of the detector system for several operation modes over the time span of 550 days, including the commissioning and science runs of XENON1T. The online distillation was also successfully applied to remove 37Ar after its injection for a low energy calibration in XENON1T. This makes the usage of 37Ar as a regular calibration source possible in the future. The online distillation can be applied to next-generation LXe TPC experiments to remove krypton prior to, or during, any science run. The model developed here allows further optimization of the distillation strategy for future large scale detectors.

The XENON collaboration has published stringent limits on specific dark matter -nucleon recoil spectra from dark matter recoiling on the liquid xenon detector target. In this paper, we present an approximate likelihood for the XENON1T 1 tonne-year nuclear recoil search applicable to any nuclear recoil spectrum. Alongside this paper, we publish data and code to compute upper limits using the method we present. The approximate likelihood is constructed in bins of reconstructed energy, profiled along the signal expectation in each bin. This approach can be used to compute an approximate likelihood and therefore most statistical results for any nuclear recoil spectrum. Computing approximate results with this method is approximately three orders of magnitude faster than the likelihood used in the original publications of XENON1T, where limits were set for specific families of recoil spectra. Using this same method, we include toy Monte Carlo simulation-derived binwise likelihoods for the upcoming XENONnT experiment that can similarly be used to assess the sensitivity to arbitrary nuclear recoil signatures in its eventual 20 tonne-year exposure., Comment: Accepted by European Physical Journal C

Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (gBRCA)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel. Patients and Methods: Eligible patients (N = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300–400 mg twice daily continuous). Antitumor activity and adverse events were assessed during crossover veliparib treatment. BRCA reversion mutations at crossover were analyzed retrospectively using next-generation sequencing on plasma circulating tumor DNA (ctDNA). Results: Seventy-five patients in the placebo plus carboplatin/paclitaxel arm received ≥1 dose of crossover veliparib postprogression (mean treatment duration: 154 days). Eight of 50 (16%) patients with measurable disease had a RECIST v1.1 response. Activity was greater in patients with PFI ≥180 days compared with Conclusions: Crossover veliparib monotherapy demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel. PFI appeared to affect veliparib activity. BRCA reversion mutations may promote cross-resistance and limit veliparib activity following progression on platinum.

The selection of low-radioactive construction materials is of the utmost importance for rare-event searches and thus critical to the XENONnT experiment. Results of an extensive radioassay program are reported, in which material samples have been screened with gamma-ray spectroscopy, mass spectrometry, and $$^{222}$$ 222 Rn emanation measurements. Furthermore, the cleanliness procedures applied to remove or mitigate surface contamination of detector materials are described. Screening results, used as inputs for a XENONnT Monte Carlo simulation, predict a reduction of materials background ($$\sim $$ ∼ 17%) with respect to its predecessor XENON1T. Through radon emanation measurements, the expected $$^{222}$$ 222 Rn activity concentration in XENONnT is determined to be 4.2 ($$^{+0.5}_{-0.7}$$ - 0.7 + 0.5 ) $$\upmu $$ μ Bq/kg, a factor three lower with respect to XENON1T. This radon concentration will be further suppressed by means of the novel radon distillation system.

As of 2019, the United States (US) was not on track to achieve targets for elimination, due to increasing incidence and treatment barriers. In 2020, the COVID-19 pandemic disrupted HCV services globally and in the US. As healthcare services normalize, there is an urgent need to reassess progress and evaluate scenarios that restore a pathway toward HCV elimination.We updated a validated Markov model to estimate HCV-related morbidity and mortality in the US. Five scenarios were developed to bookend possible HCV outcomes in the wake of the pandemic. These included 1) return to pre-COVID-19 treatment forecasts; 2) achieve elimination targets through treatment and harm reduction; 3) long-term treatment disruptions; 4/5) achieve elimination targets through increased treatment without increased harm reduction, starting in either 2022 or 2025.From 2014-2019, more than 1.2 million patients were treated for HCV in the US. Elimination targets in 2030 could be achieved in the US by treating an additional 3.2-3.3 million patients from 2020 to 2030, or by preventing new infections through expanded harm reduction programs and treating up to 2.7 million patients. Intervention scenarios could prevent over 30,000 HCC cases and over 29,000 liver-related deaths.The US has made strides toward HCV elimination, but gains could be lost in the wake of the pandemic. However, it is still possible to avert nearly 30,000 deaths through increased harm reduction and increased treatment rates. This requires a coordinated effort from the entire HCV community.

This article presents a novel software tool for the interactive visualization of spatial triangles. These triangles serve as the geometric foundation for spatial mechanism design; both synthesis and analysis. Moreover, the conceptualization and visualization of triangles facilitate the mastery of the synthesis and analysis of spatial mechanisms. This interactive visualization tool has been developed to facilitate the teaching and learning of spatial mechanisms at the graduate and undergraduate levels. The trigonometry employed and the interactive MATLAB implementation are presented. It is hoped that the dissemination of this software tool will facilitate the learning and advancement of spatial mechanism design techniques.

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare systemic necrotizing vasculitis. The national incidence and prevalence of GPA/MPA and patient mortality remain unknown in France. A real-life study using retrospective data from the French National Health Data System was set up to describe the epidemiology and demographic characteristics of hospitalized GPA and MPA patients, overall and by disease.All adult patients (≥18 years of age) hospitalized for GPA (ICD-10 M31.3) or MPA (ICD-10 M31.7) between 01 and 01-2010 and 31-12-2017 and affiliated to the General health insurance Scheme (covering 76% of the French population) were included in this national retrospective observational study. Descriptive analyses, univariate and multivariable logistic models, Kaplan-Meier survival analysis, and Cox models were performed.The study involved 4445 prevalent GPA patients (including 1578 incident patients) and 1833 prevalent MPA patients (878 incident patients). Distinction between GPA and MPA diagnosis could not be made for 303 patients (149 incident patients). In people aged over 20 years, the age-standardized incidence rates of GPA and MPA were 0.5 and 0.3/100,000 person-years, respectively and the age-standardized prevalence rates were 10 and 4/100,000 person-years, respectively. The standardized mortality ratios in GPA and MPA patients aged over 20 years were 2.0 and 2.7, respectively, and remained constant. Renal failure, pulmonary and urinary tract infections, as well as coronary disease were more frequent among MPA than GPA patients. One-year survival rates among GPA and MPA patients were 96% (95%CI 94%-97%) and 94% (92%-95%), respectively. Five-year survival rates among GPA and MPA patients were 81% (95% CI 79%-83%) and 72% (68%-75%), respectively. After adjusting for comorbidities, the risk of death was still higher in MPA (hazard ratio 1.26 [95%CI 1.06-1.50]) than in GPA patients.Despite advances in the therapeutic management of patients, mortality rates are still high and stable over time, highlighting the need for improved management.

Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual’s ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. Plasma proteomic profiles from 650 adult humans are measured before and after a 20-week exercise regimen to determine proteins associated with baseline cardiorespiratory fitness and improvements in response to exercise.

Surgery is the only potential curative option of CRLM if resectable. The curative approach in patients over 70 years old is challenging mainly because of comorbidities and other geriatric syndromes. Herein, we report outcomes of older patients with resectable CRLM in our center. We retrospectively analyzed characteristics and outcomes of older patients with CRLM operated at “Centre Hospitalier de l’Université de Montréal” (CHUM) between 2010 and 2019. We identified 210 patients aged ≥70 years with a median age of 76 (range: 70–85). CRLM were synchronous in 56% of patients. Median disease-free survival (DFS) was 41.3 months. Median overall survival (OS) was 62.2 months and estimated 5-year survival rate was 51.5% similar to those of younger counterparts. Patients with metachronous CRLM had a trend to a higher OS compared to those with synchronous disease (67.2 vs. 58.7 months, p = 0.42). Factors associated with lower survival in the multivariate analysis were right-sided tumors and increased Charlson Comorbidity index (CCI). Survival outcomes of patients aged ≥70 years were comparable to those of younger patients and those reported in the literature. Age should not be a limiting factor in the curative management of older patients with resectable CRLM.

This paper discusses the effect of conformism on the demand for products that differ in quality and studies its implications for firm selection, entry, average quality, and trade patterns. Demand for each variety is shown to fall when consumers have a lower degree of conformism or when the distribution of conformism becomes more concentrated. This induces firms facing lower demand and of lower quality to exit the market, which raises average quality and diminishes product diversity. In an international trade context, home consumption bias is amplified when there is a lower degree of conformism. Home consumption bias is mitigated by the presence of global conformism, in which individuals tend to conform to people across the world rather than within their own country.

International audience; Covalent Organic Frameworks RIO-13, RIO-12, RIO-11, and RIO-11m were investigated towards their CO2 capture properties by thermogravimetric analysis at 1 atm and 40 °C. These microporous COFs bear in common the azine backbone composed of hydroxy-benzene moieties but differ in the relative number of hydroxyl groups present in each material. Thus, their sorption capacities were studied as a function of their textural and chemical properties. Their maximum CO2 uptake values showed a strong correlation with an increasing specific surface area, but that property alone could not fully explain the CO2 uptake data. Hence, the specific CO2 uptake, combined with DFT calculations, indicated that the relative number of hydroxyl groups in the COF backbone acts as an adsorption threshold, as the hydroxyl groups were indeed identified as relevant adsorption sites in all the studied COFs. Additionally, the best performing COF was thoroughly investigated, experimentally and theoretically, for its CO2 capture properties in a variety of CO2 concentrations and temperatures, and showed excellent isothermal recyclability up to 3 cycles.

This article studies the provision of urban green areas in cities where residents have preferences for the size of and access to those areas. At the optimum, the number of urban green spaces is a nonmonotone function of distance to the city center, while the sizes and distances to other urban green areas increase as one moves to the urban fringe. This article empirically investigates those properties for the 300 largest European cities by using the Global Monitoring Environment Services Urban Atlas database (European Environmental Agency). The empirical analysis confirms the nonmonotone relationship between the number of urban green spaces and the distance to the city center. The distance between two parks also increases as one moves toward the urban fringe.

The Western Cape province was the early epicentre of the coronavirus disease 2019 pandemic in South Africa and on the African continent. In this short article we report on an initiative set up within the provincial Department of Health early in the pandemic to facilitate collective learning and support for health workers and managers across the health system, emphasising the importance of leadership, systems resilience, nonhierarchical learning and connectedness. These strategies included regular and systematic engagement with organised labour, different ways of gauging and responding to staff morale, and daily ‘huddles’ for raid learning and responsive action. We propose three transformational actions that could deliver health systems that protect staff during good times and in times of system shocks. (a) Continuously invest in building the foundations of system resilience in good times, to draw on in an acute crisis situation. (b) Provide consistent leadership for an explicit commitment to supporting health workers through decisive action across the system. (c) Optimise available resources and partners, act on improvement ideas and obstacles. Build trusting relationships amongst and across actors.

OBJECTIVE To review the outcome of dogs that underwent Zurich cementless total hip arthroplasty (Z-THA) for the repair of acute and chronic capital physeal fractures (CPF) and document the CPF-related hip remodeling. STUDY DESIGN Retrospective study. SAMPLE POPULATION Fifty-three Z-THA in 53 dogs. METHODS Medical records of dogs (2006-2019) that underwent Z-THA for CPF management were reviewed. Dogs were divided into two groups on the basis of the days elapsed between CPF diagnosis and Z-THA, acute (≤30 days) and chronic (>30 days). Hip remodeling variables were determined from preoperative radiographs or intraoperatively. Descriptive statistics were performed, and the complication rates, outcome, and coxofemoral remodeling were recorded. Comparisons of remodeling variables and rates between groups were performed by using Fisher's exact test. RESULTS In total, 23 of 53 (43.4%) cases were acute, and 30 of 53 (56.6%) cases were chronic. There was no difference in the femoral remodeling rates between the acute and chronic groups (P = .184), whereas acetabular remodeling was more prevalent in the chronic group (P

Contains fulltext : 235681.pdf (Publisher’s version ) (Open Access) AIMS: Uterine fibroids are benign tumours that cause various complaints. These complaints may significantly compromise quality of life, necessitating a clinical intervention in 25-50% of the affected women. Hysterectomy, myomectomy or embolization may offer symptomatic relief, but are costly, include a recovery period, can cause serious side-effects, sometimes fail to treat symptoms completely and are not always desired by patients. Ulipristal is a conservative long-term treatment that has a fibroid-volume decreasing effect, acceptable side-effects while preserving fertility and may be an alternative to surgical alternatives. Currently, ulipristal is investigated by the European Medicine Agency and suspended from marketing authorization because it may cause drug-induced liver injury (DILI). However, many drugs can cause severe DILI and prospective studies estimate 14-19 DILI cases/100 000 people. METHODS: This overview will discuss the risk-benefit balance between ulipristal and DILI, describe the safety-efficacy balance of ulipristal and its alternative treatments and the arguments that led to the suspension of its marketing authorization. RESULTS: Ulipristal may be associated with DILI resulting in a risk of severe liver injury in 1.5:100 000 patients and fatal liver injury in 0.1:100 000 patients. This risk needs to be weighed against the higher mortality risk of >1:1000 and higher incidence of severe complications after surgery. CONCLUSION: The DILI risk of ulipristal is considerably lower than that of other medicines that are not suspended, nor need additional safety measures. When evaluating drugs and drug safety, risks that apply to the alternative nonpharmacological treatment options should be taken into consideration.

Background Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. Methods We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. Results During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. Conclusion Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. Implications for Practice Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.

A thermally stable carbocationic covalent organic network (CON), named RIO-70 was prepared from pararosaniline hydrochloride, an inexpensive dye, and triformylphloroglucinol in solvothermal conditions. This nanoporous organic material has shown a specific surface area of 990 m2 g-1 and pore size of 10.3 A. The material has CO2 uptake of 2.14 mmol g-1 (0.5 bar), 2.7 mmol g-1 (1 bar), and 6.8 mmol g-1 (20 bar), the latter corresponding to 3 CO2 molecules adsorbed per pore per sheet. It is shown to be a semiconductor, with electrical conductivity (σ) of 3.17×10-7 S cm-1 , which increases to 5.26×10-4 S cm-1 upon exposure to I2 vapor. DFT calculations using periodic conditions support the findings.