Search

We show that elastic scattering pp→pp differential cross sections as function of the four-momentum transfer square |t| have a universal property, such that the ratio of bump-to-dip positions is constant from the energies of the ISR to the LHC, from tens of GeV and up to the TeV scale. We explore this property to compare the geometrical scaling observed at the ISR with the recently proposed scaling law at the LHC. We argue that, at the LHC, within present experimental uncertainties, there is in fact a family of scaling laws. We discuss the constraints that the scaling laws impose on the parametrization of the elastic pp→pp scattering amplitude.

Social support from family and friends, albeit associated with beneficial health effects, does not always help to cope with pain. This may be because humans elicit mixed expectations of social support and evaluative judgment. The present studies aimed to test whether pet dogs are a more beneficial source of support in a painful situation than human companions because they are not evaluative. For this, 74 (Study 1) and 50 (Study 2) women completed a cold-pressor task in the presence of either their own (S1) or an unfamiliar (S2) dog, a friend (S1), or an unknown human companion (S2), or alone. In both studies, participants reported less pain and exhibited less pain behavior in the presence of dogs compared to human companions. Reactions to pain were moderated by attitudes towards dogs in S2. This suggests that pet dogs may help individuals to cope with painful situations, especially if the individual in pain generally feels affectionate towards dogs.

Background & Aims: The goal of treatment in autoimmune hepatitis (AIH) is induction of remission to prevent the development of liver fibrosis, cirrhosis, and its related complications. Various definitions of treatment response and remission have been used. The International Autoimmune Hepatitis Group (IAIHG) recently defined consensus criteria for treatment response. We aimed to validate the IAIHG response criteria in our cohort and establish correlations with survival endpoints. Methods: We performed a retrospective, multicentric cohort study in one tertiary and seven secondary care centres in Belgium. Eligible patients were at least 18 years of age at data collection and were diagnosed with AIH by a simplified IAIHG score of ≥6. Complete biochemical response (CBR) was defined according to the IAIHG consensus criteria as normalisation of transaminases and serum IgG within the first 6 months of treatment. The primary endpoint was liver-related survival – defined as freedom from liver-related death or liver transplantation. Secondary endpoints were overall mortality and transplant-free survival. Outcomes were compared between patients attaining CBR and those with insufficient response. Results: Biochemical response status could be determined in 200 patients with AIH: CBR was achieved in 128 (64.0%) individuals. Patients not achieving CBR more frequently presented with cirrhosis on initial histology (22.2% vs. 10.9%, p = 0.036). Liver-related mortality or liver transplantation as a primary outcome occurred in 26 patients (13.0%). Patients achieving CBR exhibited superior liver-related (hazard ratio 0.118; 95% CI 0.052-0.267; p

Addressing global change requires standardised observations across all ecosystem spheres. To that end, the distributed Integrated European Long-Term Ecosystem, critical zone and socio-ecological Research Infrastructure (eLTER RI) strives for an optimal observational design of its over 200 in-situ facilities. Their spatial distribution should be unbiased to scale local data to its continental target region.Therefore, we assessed biases in the emerging eLTER RI in-situ facility network. We (i) conducted a survey describing the emerging eLTER RI, (ii) detected critical gaps in its coverage of Reference Parameters by identifying biases in a six-dimensional thematic space and determined regions, where these biases cluster spatially, and (iii) derived recommendations to further develop the eLTER RI network.Three distinct gaps were identified: the Iberian, Eastern and Nordic Gap. They resulted mainly from underrepresentation of agricultural lands, mesic and dry regions with low economic density and the Mediterranean, Continental and Boreal biogeoregions. The patterns of underrepresentation are driven by various factors including the thematic context of site establishment over the past decades, operations logistics and funding constraints. We consider closing these gaps of highest priority for spatial network development.Mitigating the biases in the eLTER RI network is crucial to enable confident scaling of local data to the European scale. This will allow the eLTER RI to provide a comprehensive foundation for scientists, policy and decision makers to face global change. Next, a comprehensive dataset of possible additional research sites over Europe must be analysed to derive site- and country-specific recommendations for cost-efficient gap mitigation.

The storage mechanisms of solid-solid supercapacitors based on graphene oxide (rGO/GO/rGO) were explored by Zhang Q et al. (Zhang et al., 2014) [1], using Density Functional Theory (DFT) and Impedance Spectroscopy (EIS) to elucidate the unusual capacitive behavior of GO sandwich films. Their study revealed alternating charged layers without diffusion zones. Analysis of complex impedance (Z*) data, ranging from 10−3 to 3.106 Hz, was conducted using an equivalent circuit, though this was limited to Nyquist plot data.To further investigate charge storage mechanisms, the current study delved deeper into complex impedance (Z*) and conductivity (σ*). A theoretical approach identified relaxation processes in the imaginary parts of (Z″) and (σ'') across frequencies. Extrapolation up to 3.10^9 Hz and deconvolution confirmed three distinct relaxation processes in Z* and σ*, similar to Cole-Cole relaxation, which describes Maxwell-Wagner-Sillars (MWS) relaxation. This reflects local electrical interactions between active sites on molecular chains and counterions, creating induced dipolar moments or diffusion processes.The identified relaxations at low, medium, and high frequencies correspond well with DFT results, attributed to specific regions: graphene oxide (GO), the (rGO/GO) interface, and reduced graphene (rGO). Key parameters extracted from each relaxation, such as relaxation time, ionic strength, and conductivity values at different frequencies, showed good correlation. This approach, based on deep conductivity (σ*) analysis, effectively highlighted the charge conduction and storage mechanisms in rGO/GO/rGO supercapacitor films.

Summary: Background: The metabolic environment plays a crucial role in the development of heart failure (HF). Our prior research demonstrated that myo-inositol, a metabolite transported by the sodium-myo-inositol co-transporter 1 (SMIT-1), can induce oxidative stress and may be detrimental to heart function. However, plasmatic myo-inositol concentration has not been comprehensively assessed in large cohorts of patients with heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Methods: Plasmatic myo-inositol levels were measured using mass spectrometry and correlated with clinical characteristics in no HF subjects and patients with HFrEF and HFpEF from Belgian (male, no HF, 53%; HFrEF, 84% and HFpEF, 40%) and Canadian cohorts (male, no HF, 51%; HFrEF, 92% and HFpEF, 62%). Findings: Myo-inositol levels were significantly elevated in patients with HF, with a more pronounced increase observed in the HFpEF population of both cohorts. After adjusting for age, sex, body mass index, hypertension, diabetes, and atrial fibrillation, we observed that both HFpEF status and impaired kidney function were associated with elevated plasma myo-inositol. Unlike HFrEF, abnormally high myo-inositol (≥69.8 μM) was linked to unfavourable clinical outcomes (hazard ratio, 1.62; 95% confidence interval, [1.05–2.5]) in patients with HFpEF. These elevated levels were correlated with NTproBNP, troponin, and cardiac fibrosis in this subset of patients. Interpretation: Myo-inositol is a metabolite elevated in patients with HF and strongly correlated to kidney failure. In patients with HFpEF, high myo-inositol levels predict poor clinical outcomes and are linked to markers of cardiac adverse remodelling. This suggests that myo-inositol and its transporter SMIT1 may have a role in the pathophysiology of HFpEF. Funding: BECAME-HF was supported by Collaborative Bilateral Research Program Québec – Wallonie-Brussels Federation.

Objectives: The 2022 mpox epidemic reached a peak in Belgium and the rest of Europe in July 2022, after which it unexpectedly subsided. This study investigates epidemiological, behavioral, and immunological factors behind the waning of the epidemic in Belgium. Methods: We investigated temporal evolutions in the characteristics and behavior of mpox patients using national surveillance data and data from a prospective registry of mpox patients in the Institute of Tropical Medicine (Antwerp). We studied behavioral changes in the population at risk using a survey among HIV-preexposure prophylaxis (PrEP) users. We determined the seroprevalence of anti-orthopoxvirus antibodies among HIV-PrEP users across four-time points in 2022. Results: Mpox patients diagnosed at the end of the epidemic had less sexual risk behavior compared to those diagnosed earlier: they engaged less in sex at mass events, had fewer sexual partners, and were less likely to belong to the sexual network's central group. Among HIV-PrEP users there were no notable changes in sexual behavior. Anti-orthopoxvirus seroprevalence did not notably increase before the start of national vaccination campaigns. Conclusion: The observed changes in group immunity and behavior in the population at greater risk of exposure to mpox seem unable to explain the waning of the mpox epidemic. A change in the profile of mpox patients might have contributed to the decline in cases.

In this work, we propose a new protocol for producing model microplastics from an industrial polymer and compare it to a conventional method, cryomilling. Polypropylene industrial pellets were chosen due to their widespread production and frequent presence in the environment, making them a notable source of microplastics. Both protocols start with aging under Ultra-Violet light of the pellets but differ in the subsequent mechanical stress applied—strong vs. soft—to break down the photodegraded pellets into microplastics. All generated particles were fully characterized in terms of size, shape, oxidation rate, and stability in aqueous media.Microplastics produced via cryomilling exhibited significant size and oxidation heterogeneity and tended to aggregate in water. Although the new protocol involving soft mechanical stress required a longer preparation time, it simulated more accurately the environmental degradation of raw plastic. This method successfully produced oxidized microplastics with a controlled size distribution centered around 50 µm which remained stable in water without stabilizers.

Abstract As an important immune stimulator and modulator, IFNγ is crucial for gut homeostasis and its dysregulation links to diverse colon pathologies, such as colitis and colorectal cancer (CRC). Here, we demonstrated that the epigenetic regulator, CBX3 (also known as HP1γ) antagonizes IFNγ signaling in the colon epithelium by transcriptionally repressing two critical IFNγ-responsive genes: STAT1 and CD274 (encoding Programmed death-ligand 1, PD-L1). Accordingly, CBX3 deletion resulted in chronic mouse colon inflammation, accompanied by upregulated STAT1 and CD274 expressions. Chromatin immunoprecipitation indicated that CBX3 tethers to STAT1 and CD274 promoters to inhibit their expression. Reversely, IFNγ significantly reduces CBX3 binding to these promoters and primes gene expression. This antagonist effect between CBX3 and IFNγ on STAT1/PD-L1 expression was also observed in CRC. Strikingly, CBX3 deletion heightened CRC cells sensitivity to IFNγ, which ultimately enhanced their chemosensitivity under IFNγ stimulation in vitro with CRC cells and in vivo with a syngeneic mouse tumor model. Overall, this work reveals that by negatively tuning IFNγ-stimulated immune genes’ transcription, CBX3 participates in modulating colon inflammatory response and CRC chemo-resistance.

Abstract The International Network on Esophageal Atresia (INoEA) stands as a beacon of collaboration in addressing the complexities of this congenital condition on a global scale. The eleven board members, from various countries (USA, Canada, France, Australia, Italy, Sweden, Germany, and The Netherlands) and backgrounds (pediatric gastroenterology, pediatric surgery, pediatric pulmonology, nursing, and parents) met in a face-to-face symposium in Lille in November 2023, to identify challenges and solutions for improving global collaboration of the network.

Mathematical modeling is widely used for describing infection transmission and evaluating interventions. The lack of reliable social parameters in the literature has been mentioned by many modeling studies, leading to limitations in the validity and interpretation of the results. Using data from the European MSM Internet survey 2017, we developed a network model to describe sex acts among MSM in Belgium. The model simulates daily sex acts among steady, persistent casual and one-off partners in a population of 10,000 MSM, grouped as low- or high-activity by using three different definitions. Model calibration was used to estimate partnership duration and homophily rates to match the distribution of cumulative sex partners over 12 months. We estimated an average duration between 1065 and 1409 days for steady partnerships, 4–6 and 251–299 days for assortative high- and low-activity individuals and 8–13 days for disassortative persistent casual partnerships, respectively, varying across the three definitions. High-quality data on social network and behavioral parameters are scarce in the literature. Our study addresses this lack of information by providing a method to estimate crucial parameters for network specification.

Abstract The effect of high-dose pyridoxine (PN) on activity of 5-fluorouracil (FUra) and folinic acid (FA)-containing regimens was studied in 50 patients including 14 with digestive tract, and 36 with breast carcinomas (BC) in advanced stages with poor prognostic characteristics. Patients with colorectal, and pancreas adenocarcinoma received oxaliplatin, irinotecan, FUra, FA (Folfirinox), and patients with squamous cell carcinoma of the esophagus had paclitaxel, carboplatin, FUra, FA (TCbF). Patients with BC received AVCF (doxorubicin, vinorelbine, cyclophosphamide, FUra, FA) followed by TCbF or TCbF only, and patients who overexpressed HER2 received TCbF plus trastuzumab and pertuzumab. PN (1000–3000 mg/day iv) preceded each administration of FUra and FA. 47 patients (94%) responded, including 16 (32%) with CR. Median tumor reduction was 93%. Median event-free survival (EFS) was 37.7 months. The 25 patients with tumor shrinkage ≥ 91% had EFS of 52% from 42 months onwards. Unexpected toxicity did not occur. PN enhances potency of chemotherapy regimens comprising FUra and FA.

Abstract The discovery of upstream regulatory genes of a gene of interest still remains challenging. Here we applied a scalable computational method to unbiasedly predict candidate regulatory genes of critical transcription factors by searching the whole genome. We illustrated our approach with a case study on the master regulator FOXP3 of human primary regulatory T cells (Tregs). While target genes of FOXP3 have been identified, its upstream regulatory machinery still remains elusive. Our methodology selected five top-ranked candidates that were tested via proof-of-concept experiments. Following knockdown, three out of five candidates showed significant effects on the mRNA expression of FOXP3 across multiple donors. This provides insights into the regulatory mechanisms modulating FOXP3 transcriptional expression in Tregs. Overall, at the genome level this represents a high level of accuracy in predicting upstream regulatory genes of key genes of interest.

Abstract Stress in early life can affect the progeny and increase the risk to develop psychiatric and cardiometabolic diseases across generations. The cross-generational effects of early life stress have been modeled in mice and demonstrated to be associated with epigenetic factors in the germline. While stress is known to affect gut microbial features, whether its effects can persist across life and be passed to the progeny is not well defined. Here we show that early postnatal stress in mice shifts the fecal microbial composition (binary Jaccard index) throughout life, including abundance of eight amplicon sequencing variants (ASVs). Further effects on fecal microbial composition, structure (weighted Jaccard index), and abundance of 16 ASVs are detected in the progeny across two generations. These effects are not accompanied by changes in bacterial metabolites in any generation. These results suggest that changes in the fecal microbial community induced by early life traumatic stress can be perpetuated from exposed parent to the offspring.

Abstract Background This study aimed to assess the spatial distribution of Anopheles mosquito larval habitats and the environmental factors associated with them, as a prerequisite for the implementation of larviciding. Methods The study was conducted in December 2021, during the transition period between the end of the short rainy season (September–November) and the short dry season (December-February). Physical, biological, and land cover data were integrated with entomological observations to collect Anopheles larvae in three major towns: Mitzic, Oyem, and Bitam, using the "dipping" method during the transition from rainy to dry season. The collected larvae were then reared in a field laboratory established for the study period. After the Anopheles mosquitoes had emerged, their species were identified using appropriate morphological taxonomic keys. To determine the influence of environmental factors on the breeding of Anopheles mosquitoes, multiple-factor analysis (MFA) and a binomial generalized linear model were used. Results According to the study, only 33.1% out of the 284 larval habitats examined were found to be positive for Anopheles larvae, which were primarily identified as belonging to the Anopheles gambiae complex. The findings of the research suggested that the presence of An. gambiae complex larvae in larval habitats was associated with various significant factors such as higher urbanization, the size and type of the larval habitats (pools and puddles), co-occurrence with Culex and Aedes larvae, hot spots in ambient temperature, moderate rainfall, and land use patterns. Conclusions The results of this research mark the initiation of a focused vector control plan that aims to eradicate or lessen the larval habitats of An. gambiae mosquitoes in Gabon's Woleu Ntem province. This approach deals with the root causes of malaria transmission through larvae and is consistent with the World Health Organization's (WHO) worldwide objective to decrease malaria prevalence in regions where it is endemic.

Abstract Background Tick-borne encephalitis (TBE) is a severe human neuroinfection caused by TBE virus (TBEV). TBEV is transmitted by tick bites and by the consumption of unpasteurized dairy products from infected asymptomatic ruminants. In France, several food-borne transmission events have been reported since 2020, raising the question of the level of exposure of domestic ungulates to TBEV. In this study, our objectives were (i) to estimate TBEV seroprevalence and quantify antibodies titres in cattle in the historical endemic area of TBEV in France using the micro virus neutralisation test (MNT) and (ii) to compare the performance of two veterinary cELISA kits with MNT for detecting anti-TBEV antibodies in cattle in various epidemiological contexts. A total of 344 cattle sera from four grid cells of 100 km² in Alsace-Lorraine (endemic region) and 84 from western France, assumed to be TBEV-free, were investigated. Results In Alsace-Lorraine, cattle were exposed to the virus with an overall estimated seroprevalence of 57.6% (95% CI: 52.1–62.8%, n = 344), varying locally from 29.9% (95% CI: 21.0–40.0%) to 92.1% (95% CI: 84.5–96.8%). Seroprevalence did not increase with age, with one- to three-year-old cattle being as highly exposed as older ones, suggesting a short-life duration of antibodies. The proportion of sera with MNT titres lower than 1:40 per grid cell decreased with increased seroprevalence. Both cELISA kits showed high specificity (> 90%) and low sensitivity (less than 78.1%) compared with MNT. Sensitivity was lower for sera with neutralising antibodies titres below 1:40, suggesting that sensitivity of these tests varied with local virus circulation intensity. Conclusions Our results highlight that cattle were highly exposed to TBEV. Screening strategy and serological tests should be carefully chosen according to the purpose of the serological study and with regard to the limitations of each method.

Abstract Background Gastrointestinal nematodes (GINs) have a major impact on sheep production, health, and welfare worldwide. Norway is no exception, but there are only a few studies on the prevalence of GINs in Norwegian sheep. The aim of this study was to investigate the current occurrence of the most important nematodes in sheep flocks in Norway. Faecal samples were collected from flocks in 2021/2022, mainly from three geographical regions in Norway, i.e., northern, eastern, and western. In each of 134 flocks included, individual samples from 10 lambs (autumn) were pooled. Third stage larvae (L3) were cultivated and harvested (Baermann method) from the pooled samples. The DNA was then extracted and further analysed using droplet digital PCR (ddPCR). This enables assessment of the proportions of the three most important nematode species/genera, i.e., H. contortus, T. circumcincta, and Trichostrongylus. The fractional abundance/relative proportion of each species/genus was assessed by performing duplex assays with universal strongyle and species/genus-specific primers and probe sets. In addition, the occurrence of Nematodirus eggs was assessed by standard faecal egg counts (i.e., McMaster method). Results Of the 134 flocks sampled, 24 were from the northern region, 31 from eastern, and 71 from western Norway. In addition, some flocks from central (n = 7), and southern (n = 1) Norway were included. Among the sampled flocks, T. circumcincta occurred most commonly (94%), followed by H. contortus (60%) and Trichostrongylus (55%), and Nematodirus (51%). In general, mixed infections were observed, with 38% and 18% of flocks infected with three or all four genera, respectively. Conclusions The results of this study indicate that GINs are widespread in Norway. Teladorsagia circumcincta seems to be present in most flocks based on this screening. Moreover, the results show that Nematodirus spp. infect lambs throughout the country, predominantly N. battus, and indicate that this nematode has become more abundant, which could lead to an increase in nematodirosis.

Abstract Background Information is scarce on unplanned transfers from geriatric rehabilitation back to acute care despite their potential impact on patients’ functional recovery. This study aimed 1) to determine the incidence rate and causes of unplanned transfers; 2) to compare the characteristics and outcomes of patients with and without unplanned transfer. Methods Consecutive stays (n = 2375) in a tertiary geriatric rehabilitation unit were included. Unplanned transfers to acute care and their causes were analyzed from discharge summaries. Data on patients’ socio-demographics, health, functional, and mental status; length of stay; discharge destination; and death, were extracted from the hospital database. Bi- and multi-variable analyses investigated the association between patients’ characteristics and unplanned transfers. Results One in six (16.7%) rehabilitation stays was interrupted by a transfer, most often secondary to infections (19.3%), cardiac (16.8%), abdominal (12.7%), trauma (12.2%), and neurological problems (9.4%). Older patients (AdjORage≥85: 0.70; 95%CI: 0. 53–0.94, P = .016), and those admitted for gait disorders (AdjOR: 0.73; 95%CI: 0.53–0.99, P = .046) had lower odds of transfer to acute care. In contrast, men (AdjOR: 1.71; 95%CI: 1.29–2.26, P

Abstract We study how the coupling between axion-like particles (ALPs) and matter can be obtained at the level of on-shell scattering amplitudes. We identify three conditions that allow us to compute amplitudes that correspond to shift-symmetric Lagrangians, at the level of operators with dimension 5 or higher, and we discuss how they relate and extend the Adler’s zero condition. These conditions are necessary to reduce the number of coefficients consistent with the little-group scaling to the one expected from the Lagrangian approach. We also show how our formalism easily explains that the dimension-5 interaction involving one ALP and two massless spin-1 bosons receive corrections from higher order operators only when the ALP has a non-vanishing mass. As a direct application of our results, we perform a phenomenological study of the inelastic scattering ℓ + ℓ − → ϕh (with ℓ ± two charged leptons, ϕ the ALP and h the Higgs boson) for which, as a result of the structure of the 3-point and 4-point amplitudes, dimension-7 operators can dominate over the dimension-5 ones well before the energy reaches the cutoff of the theory.

Abstract Background Extracorporeal blood purification has been widely used in intensive care medicine, nephrology, toxicology, and other fields. During the last decade, with the emergence of new adsorptive blood purification devices, hemoadsorption has been increasingly applied during CPB in cardiac surgery, for patients at different inflammatory risks, or for postoperative complications. Clinical evidence so far has not provided definite answers concerning this adjunctive treatment. The current systematic review aimed to critically assess the role of perioperative hemoadsorption in cardiac surgery, by summarizing the current knowledge in this clinical setting. Methods A literature search of PubMed, Cochrane library, and the database provided by CytoSorbents was conducted on June 1st, 2023. The search terms were chosen by applying neutral search keywords to perform a non-biased systematic search, including language variations of terms “cardiac surgery” and “hemoadsorption”. The screening and selection process followed scientific principles (PRISMA statement). Abstracts were considered for inclusion if they were written in English and published within the last ten years. Publications were eligible for assessment if reporting on original data from any type of study (excluding case reports) in which a hemoadsorption device was investigated during or after cardiac surgery. Results were summarized according to sub-fields and presented in a tabular view. Results The search resulted in 29 publications with a total of 1,057 patients who were treated with hemoadsorption and 988 control patients. Articles were grouped and descriptively analyzed due to the remarkable variability in study designs, however, all reported exclusively on CytoSorb® therapy. A total of 62% (18/29) of the included articles reported on safety and no unanticipated adverse events have been observed. The most frequently reported clinical outcome associated with hemoadsorption was reduced vasopressor demand resulting in better hemodynamic stability. Conclusions The role of hemoadsorption in cardiac surgery seems to be justified in selected high-risk cases in infective endocarditis, aortic surgery, heart transplantation, and emergency surgery in patients under antithrombotic therapy, as well as in those who develop a dysregulated inflammatory response, vasoplegia, or septic shock postoperatively. Future large randomized controlled trials are needed to better define proper patient selection, dosing, and timing of the therapy.

Abstract Drug-recalcitrant infections are a leading global-health concern. Bacterial cells benefit from phenotypic variation, which can suggest effective antimicrobial strategies. However, probing phenotypic variation entails spatiotemporal analysis of individual cells that is technically challenging, and hard to integrate into drug discovery. In this work, we develop a multi-condition microfluidic platform suitable for imaging two-dimensional growth of bacterial cells during transitions between separate environmental conditions. With this platform, we implement a dynamic single-cell screening for pheno-tuning compounds, which induce a phenotypic change and decrease cell-to-cell variation, aiming to undermine the entire bacterial population and make it more vulnerable to other drugs. We apply this strategy to mycobacteria, as tuberculosis poses a major public-health threat. Our lead compound impairs Mycobacterium tuberculosis via a peculiar mode of action and enhances other anti-tubercular drugs. This work proves that harnessing phenotypic variation represents a successful approach to tackle pathogens that are increasingly difficult to treat.

Abstract Background Tight diabetes control is often applied in older persons with neurocognitive disorder resulting in increased hypoglycemic episodes but little is known about the pattern of brain injury in these overtreated patients. This study aims to: (a) quantify the prevalence of diabetes overtreatment in cognitively impaired older adults in a clinical population followed in an academic memory clinic (b) identify risk factors contributing to overtreatment; and (c) explore the association between diabetes overtreatment and specific brain region volume changes. Methods Retrospective study of older patients with type 2 diabetes and cognitive impairment who were diagnosed in a memory clinic from 2013 to 2020. Patients were classified into vulnerable and dependent according to their health profile. Overtreatment was defined when glycated hemoglobin was under 7% for vulnerable and 7.6% for dependent patients. Characteristics associated to overtreatment were examined in multivariable analysis. Grey matter volume in defined brain regions was measured from MRI using voxel-based morphometry and compared in patients over- vs. adequately treated. Results Among 161 patients included (median age 76.8 years, range 60.8–93.3 years, 32.9% women), 29.8% were considered as adequately treated, 54.0% as overtreated, and 16.2% as undertreated. In multivariable analyses, no association was observed between diabetes overtreatment and age or the severity of cognitive impairment. Among patients with neuroimaging data (N = 71), associations between overtreatment and grey matter loss were observed in several brain regions. Specifically, significant reductions in grey matter were found in the caudate (adj β coeff: -0.217, 95%CI: [-0.416 to -0.018], p = .033), the precentral gyri (adj βcoeff:-0.277, 95%CI: [-0.482 to -0.073], p = .009), the superior frontal gyri (adj βcoeff: -0.244, 95%CI: [-0.458 to -0.030], p = .026), the calcarine cortex (adj βcoeff:-0.193, 95%CI: [-0.386 to -0.001], p = .049), the superior occipital gyri (adj βcoeff: -0.291, 95%CI: [-0.521 to -0.061], p = .014) and the inferior occipital gyri (adj βcoeff: -0.236, 95%CI: [-0.456 to – 0.015], p = .036). Conclusion A significant proportion of older patients with diabetes and neurocognitive disorder were subjected to excessively intensive treatment. The association identified with volume loss in several specific brain regions highlights the need to further investigate the potential cerebral damages associated with overtreatment and related hypoglycemia in larger sample.

Abstract Plant biostimulants are widely applied in agriculture for their ability to improve plant fitness. In the present work, the impact of Graminaceae-derived protein hydrolysate (P) and its lighter molecular fraction F3 (

Abstract Due to the complexity of the biomedical domain, the ability to capture semantically meaningful representations of terms in context is a long-standing challenge. Despite important progress in the past years, no evaluation benchmark has been developed to evaluate how well language models represent biomedical concepts according to their corresponding context. Inspired by the Word-in-Context (WiC) benchmark, in which word sense disambiguation is reformulated as a binary classification task, we propose a novel dataset, BioWiC, to evaluate the ability of language models to encode biomedical terms in context. BioWiC comprises 20’156 instances, covering over 7’400 unique biomedical terms, making it the largest WiC dataset in the biomedical domain. We evaluate BioWiC both intrinsically and extrinsically and show that it could be used as a reliable benchmark for evaluating context-dependent embeddings in biomedical corpora. In addition, we conduct several experiments using a variety of discriminative and generative large language models to establish robust baselines that can serve as a foundation for future research.

We offer readers one of the very first books to appear on Nietzsche, and certainly the first to attempt to show that Nietzsche is a genuine “philosopher”. Why was Nietzsche not considered a philosopher by many of his contemporaries? And in what sense can he nonetheless be declared a philosopher? These are the questions addressed in this essay by Hans Vaihinger, one of the very few Neo-Kantians to take an interest in Nietzsche’s work.

The emergence of electric vehicles has brought new issues such as the problem of rolling element bearings (REBs) operating at high speeds. Losses due to these components in mechanical transmissions are a key issue and must therefore be taken into account right from the design stage of these systems. Among these losses, the one induced by the motion of rolling elements, known as drag loss, becomes predominant in high-speed REBs. Although an experimental approach is still possible, it is difficult to isolate this loss in order to study it properly. A numerical approach based on CFD is therefore a possible way forward, even if other issues arise. The aim of this article is to study the ability of such an approach to correctly estimate the drag coefficient associated with the motion of rolling elements. The influence of the numerical domain extension, the mesh refinement, the simplification of the ring shape, and the presence of the cage on the values of the drag coefficient is presented. While it seems possible to compromise on the calculation domain and mesh size, it appears that the other parameters must be taken into account as much as possible to obtain realistic results.

Commonly used to decode the human brain's structural complexity, ex vivo dissection focuses on a given structure or region but cannot depict the whole brain organization (for example, its arterial distribution territories). Where dissection reaches its limit, the combination of tissue sectioning and 3D reconstruction may provide a volume for the assessment of structures from any view angle, following them dynamically to understand their spatial relationships. However, to produce sections, standard histological tissue processing protocols for paraffin embedding cannot be applied to a cerebral hemisphere as the latter is extensively larger than the conventional specimens. This paper presents a protocol for paraffin embedding of the whole human cerebral hemisphere and a method to reconstruct 3D volumes from serially sectioned and photographed paraffin blocks containing embedded hemispheres. Seven ex vivo whole human cerebral hemispheres were included, two were serially sectioned. Main cerebral arteries were injected with colored media to label arterial territories. A detailed description of every step, from tissue processing to image acquisition of cut blockfaces and volume reconstruction, is provided. Tissue processing and section cutting were reproducible, and the former provided complete and homogeneous paraffin wax impregnation. 3D visualization of the reconstructed whole human cerebral hemisphere successfully showed the distribution territories of the main cerebral arteries. In addition, we discuss the challenges we faced and overcame while developing the presented method and highlight its originality.

Abstract Introduction Even though the local tolerance of prostaglandin (PG) analogues has improved drastically since the introduction of preservative-free (PF) eye drops, prescription patterns still vary widely among practitioners and between countries and could have an impact on the ocular surface of treated patients and, in consequence, their adherence. The aim of this study is to explore the prescribing patterns of PG analogues monotherapy in France and to evaluate their impact on ocular surface status. Methods This was a national multicenter cross-sectional observational study that was conducted by 18 glaucoma experts in France. Patients over 18 years of age and receiving monotherapy with topical PG analogues for the treatment of ocular hypertension and/or glaucoma, with no history of prior glaucoma surgery, were consecutively selected from the glaucoma outpatient clinics of participating physicians and underwent an ocular surface examination. Results A total of 344 eyes of 344 patients were enrolled between November 2022 and November 2023. Prescribed PG monotherapy was PF in 271 (78.7%) patients. Clinical history and ocular surface evaluation indicated that 79.4% of the study population (n = 273) presented with at least one symptom or clinical sign of dry eye and that three patients out of four had an unstable tear film. Subgroup analysis comparing preserved and PF PG analogues showed a higher prevalence of conjunctival hyperemia and corneal staining in the preserved group. Multivariate analysis identified conjunctival hyperemia as consistently associated with preservative use (odds ratio = 7.654; p = 0.003 for moderate conjunctival hyperemia). Conclusions This study highlights the growing trend toward PF PG analogue prescriptions by specialists in France. However, ocular surface issues remain prevalent, impacting patient adherence and treatment efficacy. Comprehensive ocular surface examinations are crucial in glaucoma management to enhance long-term tolerance, compliance, and overall treatment success.

Overload of fluoride ions in water is observed in several regions of southern Tunisia, mainly the regions close to the mining basin of Gafsa: Metlaoui, Omlarayes and Redayef. This study concerns fluoride removal from Metlaoui's tap water by electrocoagulation (EC) using aluminum electrodes in a batch reactor. This water contains 3.5 mg·L−1 of fluoride, the highest concentration observed in these basins. The effect of the operating conditions of EC treatment on tap water defluoridation was analyzed, namely, current density, temperature and interelectrode distance. Hydroxide aluminum flocs, formed with different durations of EC, were used as sorbents in fluorinated deionized water ([F−] = 3.5 mg·L−1) and Metlaoui's tap water. Flocs formed after 30 min of EC, produced by dissolving (79 ± 1) mg·L−1 of aluminum and adjusted at pH = 6.5, allowed the adsorption of (98 ± 1)% of fluoride ions from deionized fluorinated water. Flocs adjusted at different pH, from 5 to 9, were used as sorbents in fluorinated deionized water and Metlaoui's tap water. Acidic and neutral flocs allowed the best yields of fluoride adsorption. Contrary to the literature, this work highlighted the absence of ion exchange of hydroxide anion by fluoride anion in water, highlighting a mechanism of physical adsorption on aluminum hydroxide flocs. HIGHLIGHTS Electrocoagulation (EC) was studied for the defluoridation of Tunisian groundwater.; Defluoridation was also evaluated through adsorption onto Al(OH)3 flocs generated by EC.; Fluorides in synthetic water were predominantly removed through physical adsorption.; In Tunisian groundwater, the adsorption of F− competed with the adsorption of other anions.; The EC defluoridation process could be scaled up at a constant current/volume ratio.;

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is estimated to affect 30% of the world’s population, and its prevalence is increasing in line with obesity. Liver fibrosis is closely related to mortality, making it the most important clinical parameter for MASLD. It is currently assessed by liver biopsy – an invasive procedure that has some limitations. There is thus an urgent need for a reliable non-invasive means to diagnose earlier MASLD stages. Methods A discovery study was performed on 158 plasma samples from histologically-characterised MASLD patients using mass spectrometry (MS)-based quantitative proteomics. Differentially abundant proteins were selected for verification by ELISA in the same cohort. They were subsequently validated in an independent MASLD cohort (n = 200). Results From the 72 proteins differentially abundant between patients with early (F0-2) and advanced fibrosis (F3-4), we selected Insulin-like growth factor-binding protein complex acid labile subunit (ALS) and Galectin-3-binding protein (Gal-3BP) for further study. In our validation cohort, AUROCs with 95% CIs of 0.744 [0.673 – 0.816] and 0.735 [0.661 – 0.81] were obtained for ALS and Gal-3BP, respectively. Combining ALS and Gal-3BP improved the assessment of advanced liver fibrosis, giving an AUROC of 0.796 [0.731. 0.862]. The {ALS; Gal-3BP} model surpassed classic fibrosis panels in predicting advanced liver fibrosis. Conclusions Further investigations with complementary cohorts will be needed to confirm the usefulness of ALS and Gal-3BP individually and in combination with other biomarkers for diagnosis of liver fibrosis. With the availability of ELISA assays, these findings could be rapidly clinically translated, providing direct benefits for patients. Graphical Abstract

Abstract NRAS and KRAS activating point mutations are present in 10–30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting.

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies whose production is promoted by autoreactive T follicular helper (TFH) cells. During SLE pathogenesis, basophils accumulate in secondary lymphoid organs (SLO), amplify autoantibody production and disease progression through mechanisms that remain to be defined. Here, we provide evidence for a direct functional relationship between TFH cells and basophils during lupus pathogenesis, both in humans and mice. PD-L1 upregulation on basophils and IL-4 production are associated with TFH and TFH2 cell expansions and with disease activity. Pathogenic TFH cell accumulation, maintenance, and function in SLO were dependent on PD-L1 and IL-4 in basophils, which induced a transcriptional program allowing TFH2 cell differentiation and function. Our study establishes a direct mechanistic link between basophils and TFH cells in SLE that promotes autoantibody production and lupus nephritis.

Abstract Background During the first COVID-19 pandemic wave, COVID-19-associated pulmonary aspergillosis (CAPA) has been reported in up to 11–28% of critically ill COVID-19 patients and associated with increased mortality. As new SARS-CoV-2 variants emerged, the characteristics of critically ill COVID-19 patients have evolved, particularly in the era of Omicron. The purpose of this study is to investigate the characteristics of CAPA in the era of new variants. Methods This is a prospective multicenter observational cohort study conducted in France in 36 participating intensive care units (ICU), between December 7th, 2021 and April 26th 2023. Diagnosis criteria of CAPA relied on European Confederation of Medical Mycology (ECMM)/International Society for Human & Animal Mycology (ISHAM) consensus criteria. Results 566 patients were included over the study period. The prevalence of CAPA was 5.1% [95% CI 3.4–7.3], and rose to 9.1% among patients who required invasive mechanical ventilation (IMV). Univariable analysis showed that CAPA patients were more frequently immunosuppressed and required more frequently IMV support, vasopressors and renal replacement therapy during ICU stay than non-CAPA patients. SAPS II score at ICU admission, immunosuppression, and a SARS-CoV-2 Delta variant were independently associated with CAPA in multivariable logistic regression analysis. Although CAPA was not significantly associated with day-28 mortality, patients with CAPA experienced a longer duration of mechanical ventilation and ICU stay. Conclusion This study contributes valuable insights into the prevalence, characteristics, and outcomes of CAPA in the era of Delta and Omicron variants. We report a lower prevalence of CAPA (5.1%) among critically-ill COVID-19 patients than previously reported, mainly affecting intubated-patients. Duration of mechanical ventilation and ICU stay were significantly longer in CAPA patients.

Background: Electronic health can help improve perioperative outcomes and overcome organizational constraints related to human resources and health care-related costs. In this initial report, we assess patient compliance with a digital platform including pre- and rehabilitation programs, checklists, electronic patient-reported outcomes (ePROs), and remote monitoring after surgery. Materials and Methods: Twenty-four patients undergoing major uro-oncological surgery were prospectively included and followed from the surgical decision time point to the 3-month follow-up visit by Betty.care app. The primary end-point was patient compliance with the digital tool materials, grouped into four domains: safety, education, ePRO collection, and remote monitoring. Results and Limitations: The mean age was 62 years. The mean hospital stay was 1.8 days (50% of outpatient surgeries). Four complications occurred (16.7%), including one emergency readmission. The compliance of patients for fulfilling or reading all safety, education, and ePRO questionnaires was 79.2%, 76.5%, and 86.2%, respectively. The activation of real-time notifications as predefined by Betty.care detected half of the complications. All the generated alerts were related to a confirmed postoperative grade 2 or 3 complication. The mean duration of daily remote monitoring was 18.5 days after discharge. Satisfaction with their perioperative pathway was scored 8.4 out of 10 by patients. Conclusions: In conclusion, the implementation of a mobile app that provides a holistic approach to the perioperative period, integrating prehabilitation, rehabilitation, ePRO collection, checklists, and remote monitoring is feasible in clinical practice with good patient compliance. These preliminary findings suggest that the Betty.care digital platform could improve outcomes, facilitate recovery, and secure at-home discharge.

Background and Aim: Keratitis is a serious ocular infection often caused by pathogenic micro-organisms such as Acanthamoeba spp. Among other harmful microbes, Acanthamoeba keratitis presents a particular challenge due to its resistance to conventional antimicrobial agents. Piper betle Linn., commonly known as betel leaf, has been traditionally used for its medicinal properties. This study aimed to assess the potential of the leaf ethanol extract of P. betle Linn. in the treatment of Acanthamoeba triangularis in monoculture and co-culture with two prevalent pathogenic bacteria, Staphylococcus aureus and Pseudomonas aeruginosa, associated with keratitis. Materials and Methods: Minimum inhibitory concentrations (MICs) of A. triangularis, S. aureus, and P. aeruginosa extracts in monoculture and coinfected conditions were examined. In addition, this study explored the potential of the extract in preventing Acanthamoeba adherence in both monoculture and co-culture environments. Scanning electron microscopy (SEM) analysis confirmed the impact of the extract on Acanthamoeba cell membranes, including acanthopodia. Furthermore, a time-kill kinetic assay was used to validate the amoebicidal activity of the extract against A. triangularis and the tested bacteria. Results: MICs for trophozoites, cysts, P. aeruginosa, and S. aureus in the monoculture were 0.25, 0.25, 0.51, and 0.128 mg/mL, respectively, whereas the MICs for Acanthamoeba coinfected with bacteria were higher than those in the monoculture. This extract inhibited the growth of A. triangularis trophozoites and cysts for up to 72 h. Moreover, P. betle extract effectively prevented the adherence of Acanthamoeba to contact lenses under monoculture conditions. SEM analysis confirmed that P. betle extract affects the cell membrane of Acanthamoeba, including Acanthopodia. In addition, the time-kill kinetic assay confirmed that the extract contained amoebicidal activity against A. triangularis, including the tested bacteria. Notably, S. aureus was more susceptible than A. triangularis and P. aeruginosa to P. betle extract treatment. Unexpectedly, our study revealed that S. aureus negatively affected A. triangularis in the co-culture after 3 days of incubation, whereas P. aeruginosa facilitated the growth of A. triangularis in the presence of the extract. Conclusion: This study provides compelling evidence of the anti-adhesive and anti-Acanthamoeba properties of P. betle leaf extract against A. triangularis under monoculture and co-culture conditions. The observed impact on Acanthamoeba cell membranes, coupled with the time-kill kinetic assay results, underscores the potential of P. betle leaf extract as a promising agent for combating Acanthamoeba-related infections in humans and animals.

Abstract Background African giant pouched rats, trained by Anti-Persoonsmijnen Ontmijnende Product Ontwikkeling (APOPO), have demonstrated their ability to detect tuberculosis (TB) from sputum. We assessed rat-based case detection and compared the mycobacterium bacillary load (MTB-load) in children versus adults. Methods From January–December 2022, samples were collected prospectively from 69 Directly Observed Therapy (DOT) facilities’ presumed TB patients. Using an average of five rats, APOPO re-evaluated patients with bacteriologically negative (sputum-smear microscopy or Xpert MTB/RIF) results. Rat-positive samples were tested using concentrated smear light-emitting diode microscopy to confirm TB detection before treatment initiation. The rats’ identification of pulmonary TB is based on smelling TB-specific volatile organic compounds (VOCs) in sputum. Using STATA, Chi-square for odds ratio and confidence interval was calculated and evaluated: (1) the yield of rat-based TB detection compared to that of the health facilities; (2) rat-based TB detection in children versus adults; and (3) rats’ ability to detect TB across MTB-loads and between children and adults. Results From 35,766 patients, 5.3% (1900/35,766) were smear-positive and 94.7% (33,866/35,766) were smear or Xpert-negatives at DOTS facility. Of those with negative results, 2029 TB cases were detected using rats, contributing to 52% (2029/3929 of total TB identified), which otherwise would have been missed. Compared to DOT facilities, rats were six-fold more likely to detect TB among Acid Fast Bacilli (AFB) 1+/scanty [90% (1829/2029) versus 60% (1139/1900), odds ratio, OR = 6.11, 95% confidence interval, CI: 5.14–7.26]; twice more likely to identify TB cases among children [71% (91/129) versus 51% (1795/3542), OR = 2.3, 95% CI: 1.59–3.42]; and twice more likely to identify TB cases among children with AFB 1+/scanty than adults with the same MTB-load [5% (86/1703) versus 3% (28/1067), OR = 2.0, 95% CI: 1.28–3.03]. Conclusions Rats contributed over half of the TB cases identified in program settings, and children, especially those with a lower MTB-load, were more likely to be diagnosed with TB by rats. The chemical signatures, VOCs, were only available for adults, and further research describing the characteristics of VOCs in children versus adults may pave the way to enhance TB diagnosis in children.

Abstract Deciphering past climate variability in the Western Pacific Warm Pool (WPWP), the Earth’s largest heat and moisture centre, is vital for understanding the global climate system. Nevertheless, its long-term evolution remains controversial, largely due to ambiguities in existing proxy interpretations and discrepancies between records. Here, we present a weathering and erosion reconstruction from the WPWP spanning the last 140,000 years, based on the mineralogy and geochemistry of a sediment core from offshore of northern New Guinea. The paleo-weathering reconstruction is consistent with the simulated precipitation evolution on nearby islands, thereby suggesting a close coupling between climate variability and island weathering in a tropical setting. In addition, our combined data-model interpretation of WPWP climate history shows many similarities to the East Asian Summer Monsoon (EASM) variability over orbital timescales. Overall, our study highlights the critical role of precession-paced interhemispheric energy redistribution, via the West Pacific meridional sea-surface pressure gradient, in linking orbital-scale WPWP climate and EASM variability.

Abstract This research explores different methodologies to modulate the effects of drowsiness on functional connectivity (FC) during resting-state functional magnetic resonance imaging (RS-fMRI). The study utilized a cohort of students (MRi-Share) and classified individuals into drowsy, alert, and mixed/undetermined states based on observed respiratory oscillations. We analyzed the FC group difference between drowsy and alert individuals after five different processing methods: the reference method, two based on physiological and a global signal regression of the BOLD time series signal, and two based on Gaussian standardizations of the FC distribution. According to the reference method, drowsy individuals exhibit higher cortico-cortical FC than alert individuals. First, we demonstrated that each method reduced the differences between drowsy and alert states. The second result is that the global signal regression was quantitively the most effective, minimizing significant FC differences to only 3.3% of the total FCs. However, one should consider the risks of overcorrection often associated with this methodology. Therefore, choosing a less aggressive form of regression, such as the physiological method or Gaussian-based approaches, might be a more cautious approach. Third and last, using the Gaussian-based methods, cortico-subcortical and intra-default mode network (DMN) FCs were significantly greater in alert than drowsy subjects. These findings bear resemblance to the anticipated patterns during the onset of sleep, where the cortex isolates itself to assist in transitioning into deeper slow wave sleep phases, simultaneously disconnecting the DMN.

Abstract Background The association of physical activity (PA) and lung function (LF) varies from no measurable effect to delayed LF decline. We assessed the association between accelerometery-assessed PA and LF in a sample of apparently healthy, community-dwelling subjects. Methods We included two cross-sectional studies using data from the PneumoLaus study (2014–17 and 2018–21), conducted in Lausanne, Switzerland. PA was assessed by accelerometry and categorised as inactivity, light, moderate or vigorous. Forced expiratory volume in 1 second (FEV1), forced volume capacity (FVC) and maximal mid-expiratory flow (MMEF) were measured by spirometry and expressed in percentage of predicted value (PV). Results Overall, 1′910 (54.7% women, 62.0 ± 9.7 years) and 1′174 (53.4% women, 65.8 ± 9.5 years) participants were included in the first and the second surveys, respectively. In both surveys, moderate and vigorous PA showed a weak but significant correlation with FEV1 in percentage (PV) (R = 0.106 and 0.132 for the first and 0.111 and 0.125 for the second surveys, p

Abstract Hepatoblastomas (HB) display heterogeneous cellular phenotypes that influence the clinical outcome, but the underlying mechanisms are poorly understood. Here, we use a single-cell multiomic strategy to unravel the molecular determinants of this plasticity. We identify a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP) and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population bordering scLP and scH areas in spatial transcriptomics. Chromatin accessibility landscapes reveal the gene regulatory networks of each differentiation pole, and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy.

Abstract Background Arthroplasty registries are rarely used to inform encounters between clinician and patient. This study is part of a larger one which aimed to develop an information tool allowing both to benefit from previous patients’ experience after total hip arthroplasty (THA). This study focuses on generating the information tool specifically for pain outcomes. Methods Data from the Geneva Arthroplasty Registry (GAR) about patients receiving a primary elective THA between 1996 and 2019 was used. Selected outcomes were identified from patient and surgeon surveys: pain walking, climbing stairs, night pain, pain interference, and pain medication. Clusters of patients with homogeneous outcomes at 1, 5, and 10 years postoperatively were generated based on selected predictors evaluated preoperatively using conditional inference trees (CITs). Results Data from 6,836 THAs were analysed and 14 CITs generated with 17 predictors found significant (p

Abstract Background Lung cancers represent the main cause of cancer related-death worldwide. Recently, immunotherapy alone or in combination with chemotherapy has deeply impacted the therapeutic care leading to an improved overall survival. However, relapse will finally occur, with no efficient second line treatment so far. New therapies development based on the comprehension of resistance mechanisms is necessary. However, the difficulties to obtain tumor samples before and after first line treatment hamper to clearly understand the consequence of these molecules on tumor cells and also to identify adapted second line therapies. Methods To overcome this difficulty, we developed multicellular tumor spheroids (MCTS) using characterized Non-Small Cell Lung Cancer (NSCLC) cell lines, monocytes from healthy donors and fibroblasts. MCTS were treated with carboplatin-paclitaxel or -gemcitabine combinations according to clinical administration schedules. The treatments impact was studied using cell viability assay, histological analyses, 3’RNA sequencing, real-time PCR, flow cytometry and confocal microscopy. Results We showed that treatments induced a decrease in cell viability and strong modifications in the transcriptomic profile notably at the level of pathways involved in DNA damage repair and cell cycle. Interestingly, we also observed a modification of genes expression considered as hallmarks of response to immune check point inhibitors and immunogenicity, particularly an increase in CD274 gene expression, coding for PD-L1. This result was validated at the protein level and shown to be restricted to tumor cells on MCTS containing fibroblasts and macrophages. This increase was also observed in an additional cell line, expressing low basal CD274 level. Conclusions This study shows that MCTS are interesting models to study the impact of first line therapies using conditions close to clinical practice and also to identify more adapted second line or concomitant therapies for lung cancer treatment.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient‐derived ones, using various approaches including RNA‐sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172‐phosphorylated CDK4. This was associated with high p16INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild‐type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re‐induction of cell cycle genes upon drug washout. A senescence‐associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumours from short‐survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy.

In 2018, J. M. Gómez et al. showed that the problem of finding the packing number $ \rho(F_2(P_n)) $ of the 2-token graph $ F_2(P_n) $ of the path $ P_n $ of length $ n\ge 2 $ is equivalent to determining the maximum size of a binary code $ S' $ of constant weight $ w = 2 $ that can correct a single adjacent transposition. By determining the exact value of $ \rho(F_2(P_n)) $, they proved a conjecture of Rob Pratt. In this paper, we study a related problem, which consists of determining the packing number $ \rho(F_3(P_n)) $ of the graph $ F_3(P_n) $. This problem corresponds to the Sloane's problem of finding the maximum size of $ S' $ of constant weight $ w = 3 $ that can correct a single adjacent transposition. Since the maximum packing set problem is computationally equivalent to the maximum independent set problem, which is an NP-hard problem, then no polynomial time algorithms are expected to be found. Nevertheless, we compute the exact value of $ \rho(F_3(P_n)) $ for $ n\leq 12 $, and we also present some algorithms that produce a lower bound for $ \rho(F_3(P_n)) $ with $ 13\leq n\leq 44 $. Finally, we establish an upper bound for $ \rho(F_3(P_n)) $ with $ n\geq 13 $.

Abstract The perception and appreciation of food flavor depends on many interacting chemical compounds and external factors, and therefore proves challenging to understand and predict. Here, we combine extensive chemical and sensory analyses of 250 different beers to train machine learning models that allow predicting flavor and consumer appreciation. For each beer, we measure over 200 chemical properties, perform quantitative descriptive sensory analysis with a trained tasting panel and map data from over 180,000 consumer reviews to train 10 different machine learning models. The best-performing algorithm, Gradient Boosting, yields models that significantly outperform predictions based on conventional statistics and accurately predict complex food features and consumer appreciation from chemical profiles. Model dissection allows identifying specific and unexpected compounds as drivers of beer flavor and appreciation. Adding these compounds results in variants of commercial alcoholic and non-alcoholic beers with improved consumer appreciation. Together, our study reveals how big data and machine learning uncover complex links between food chemistry, flavor and consumer perception, and lays the foundation to develop novel, tailored foods with superior flavors.

The early and precise identification of the different phenological stages of the bean (Phaseolus vulgaris L.) allows for the determination of critical and timely moments for the implementation of certain agricultural activities that contribute in a significant manner to the output and quality of the harvest, as well as the necessary actions to prevent and control possible damage caused by plagues and diseases. Overall, the standard procedure for phenological identification is conducted by the farmer. This can lead to the possibility of overlooking important findings during the phenological development of the plant, which could result in the appearance of plagues and diseases. In recent years, deep learning (DL) methods have been used to analyze crop behavior and minimize risk in agricultural decision making. One of the most used DL methods in image processing is the convolutional neural network (CNN) due to its high capacity for learning relevant features and recognizing objects in images. In this article, a transfer learning approach and a data augmentation method were applied. A station equipped with RGB cameras was used to gather data from images during the complete phenological cycle of the bean. The information gathered was used to create a set of data to evaluate the performance of each of the four proposed network models: AlexNet, VGG19, SqueezeNet, and GoogleNet. The metrics used were accuracy, precision, sensitivity, specificity, and F1-Score. The results of the best architecture obtained in the validation were those of GoogleNet, which obtained 96.71% accuracy, 96.81% precision, 95.77% sensitivity, 98.73% specificity, and 96.25% F1-Score.

Heat shock proteins are intracellular proteins expressed in prokaryotes and eukaryotes that help protect the cell from stress. They play an important role in regulating cell cycle and cell death, work as molecular chaperons during the folding of newly synthesized proteins, and also in the degradation of misfolded proteins. They are not only produced under stress conditions like acidosis, energy depletion, and oxidative stress but are also continuously synthesized as a result of their housekeeping functions. There are different heat shock protein families based on their molecular weight, like HSP70, HSP90, HSP60, HSP27, HSP40, etc. Heat shock proteins are involved in many cancers, particularly hepatocellular carcinoma, the main primary tumor of the liver in adults. Their deregulations in hepatocellular carcinoma are associated with metastasis, angiogenesis, cell invasion, and cell proliferation and upregulated heat shock proteins can be used as either diagnostic or prognostic markers. Targeting heat shock proteins is a relevant strategy for the treatment of patients with liver cancer. In this review, we provide insights into heat shock proteins and heat shock protein-like proteins (clusterin) in the progression of hepatocellular carcinoma and their use as therapeutic targets.

A new osmiine bee species, Hoplitis (Hoplitis) onosmaevae sp. nov. (Megachilidae), is described. So far, this species is exclusively known from the Mercantour National Park in the southwestern French Alps and from mountainous ranges in Turkey and northern Iraq, two areas separated by at least 2000 km. Phylogenetic analyses based on mitochondrial and nuclear genes revealed that H. onosmaevae is closely related to H. adunca (Panzer, 1798), H. benoisti (Alfken, 1935) and H. manicata (Morice, 1901). Hoplitis onosmaevae is presumably narrowly oligolectic and harvests pollen only on flowers of Onosma L. (Boraginaceae). It has a particularly long proboscis, which is probably an adaptation to collect nectar from the long-tubed flowers of this plant genus. The females collect pollen by buzzing the Onosma flowers, a rare behavior in megachilid bees. The species nests in insect burrows in dead wood, similar to H. adunca and H. manicata but unlike other closely related representatives of the subgenus Hoplitis, suggesting a single origin of nesting in dead wood and hollow stems in this lineage. In France, H. onosmaevae inhabits alpine steppe-like habitats close to forests and appears to be extremely local, since only two populations are currently known. The conservation status of this extremely rare bee species in Europe is discussed.

Abstract Background Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients. Methods Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling. Results Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20–81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9–11.6] and 1.4 months [95%CI:1.2–2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses. Conclusions This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy. Trial registration EudraCT N°: 2015–005464-42; Clinicaltrial.gov number: NCT02992912.