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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.

The BIO-MAÏDO (Bio-physicochemistry of tropical clouds at Maïdo: processes and impacts on secondary organic aerosols formation) campaign was conducted from 13 March to 4 April 2019 on the tropical island of Réunion. The main objective of the project was to improve understanding of cloud impacts on the formation of secondary organic aerosols (SOA) from biogenic volatile organic compound (BVOC) precursors in a tropical environment. Instruments were deployed at five sites: a receptor site, Maïdo Observatory (MO) at 2165 m a.s.l. and four sites along the slope of the Maïdo mountain. Observations include measurements of volatile organic compounds (VOCs) and characterization of the physical, chemical and biological (bacterial diversity and culture-based approaches) properties of aerosols and cloud water. Turbulent parameters of the boundary layer, radiative fluxes and emissions fluxes of BVOCs from the surrounding vegetation were measured to help interpret observed chemical concentrations in the different phases. Dynamical analyses showed two preferred trajectory routes for air masses arriving at MO during the daytime. Both trajectories correspond to return branches of the trade winds associated with upslope thermal breezes, where air masses likely encountered cloud processing. The highest mixing ratios of oxygenated VOCs (OVOCs) were measured above the site located in the endemic forest and the highest contribution of OVOCs to total VOCs at MO. Chemical compositions of particles during daytime showed higher concentrations of oxalic acid, a tracer of cloud processing and photochemical aging, and a more oxidized organic aerosol at MO than at other sites. Approximately 20 % of the dissolved organic compounds were analyzed. Additional analyses by ultra-high-resolution mass spectrometry will explore the complexity of the missing cloud organic matter.

Abstract Fractional charges are one of the wonders of the fractional quantum Hall effect. Such objects are also anticipated in two-dimensional hexagonal lattices under time reversal symmetry—emerging as bound states of a rotating bond texture called a Kekulé vortex. However, the physical mechanisms inducing such topological defects remain elusive, preventing experimental realization. Here, we report the observation of Kekulé vortices in the local density of states of graphene under time reversal symmetry. The vortices result from intervalley scattering on chemisorbed hydrogen adatoms. We uncover that their 2π winding is reminiscent of the Berry phase π of the massless Dirac electrons. We can also induce a Kekulé pattern without vortices by creating point scatterers such as divacancies, which break different point symmetries. Our local-probe study thus confirms point defects as versatile building blocks for Kekulé engineering of graphene’s electronic structure.

Abstract Much evidence supports the ecological and agronomic benefits of diversity, of both crops and environments, for building resilience and sustainability in agroecosystems. Farmers' knowledge about crop diversity is well‐documented, but aside from studies on how farmers exchange seeds and knowledge through networks, the interactions of social factors and the diversity of crops and cultivated environments have been mainly overlooked. One factor receiving attention is farmers' access to land, but in only one of its dimensions, the security of access. Here we address the different strategies by which farmers gain access to land. How does the plurality of modes of access to land influence crop choices, and thereby crop diversity? How does this plurality influence the range of environments available to individual farmers for cultivating crop diversity? Analysing data from 51 interviews with farmers and 312 plots in agrosilvopastoral systems in northwestern Morocco, we described eight different modes of access. Each mode offers different opportunities and constraints concerning the kind of crops that can be grown on the plot. We found that an increase in the number of modes of access to land increases the crop diversity of farmers' holdings, regardless of the total area each farmer cultivates. Accessing additional plots contributed to both environmental heterogeneity and to crop diversity of farms. In striving to gain access to land and to grow diverse crops, farmers are motivated by their notion of what it means to be a ‘real farmer’, that is, the relation to their identity. Farmers mobilize not only their economic power but also their social relationships to gain access to plots of land. Their choices are also based on their relationships to tree crops such as olive, which are economic and cultural keystone species, as well as markers of land ownership and control. Multiple modes of access to land characterize many smallholder farming systems, which support a large fraction of the world's population. Recognizing diverse social practices of access to land that allow farmers to continue to mobilize multiple modes of access can increase resilience against unpredictable events and help maintain sustainable agroecosystems. Read the free Plain Language Summary for this article on the Journal blog.

The study is devoted to the cognitive analysis of the current state of the Eurasian Economic Commission, which is the main institution of integration of the economies of the Western Eurasia. Deconstruction of the European principle of the “four freedoms” that was laid down in the basis of the EAEU allows authors to conclude that further implementation of the latter will lead to the reproduction of the EU’s weaknesses that have become obvious today. Moreover, it will lead to internal conflicts, primarily between corporations, which will be mainly Russian, and the member states. The predictable result will be a decrease in the functionality of the Eurasian Union, which has already taken noticeable forms. It produces the obvious risks of turning of this important negotiating platform into an artifact that does not meet the challenges that arose with the beginning of Russia’s Special military operation. The authors see a way out in «balancing» the principle of «four freedoms», which de facto leads to redistribution of resources in favor of corporations, with the principle of security. The extrapolation of latter to the economic sphere can allow not only to strengthen the regulatory role of states, but also to move to the creation of a production circuit within the Eurasian Economic Union based on the common system of division of labor. In their theoretical constructions, the authors appeal to the successful experience of China, which managed to introduce a system of moral and ethical restrictions for business, and thereby managed to make profitable a «long» investment focused not on the consumption of an individual, but on the prosperity of society as a whole.

Abstract In medicine, abnormalities in quantitative metrics such as the volume reduction of one brain region of an individual versus a control group are often provided as deviations from so-called normal values. These normative reference values are traditionally calculated based on the quantitative values from a control group, which can be adjusted for relevant clinical co-variables, such as age or sex. However, these average normative values do not take into account the globality of the available quantitative information. For example, quantitative analysis of T1-weighted magnetic resonance images based on anatomical structure segmentation frequently includes over 100 cerebral structures in the quantitative reports, and these tend to be analyzed separately. In this study, we propose a global approach to personalized normative values for each brain structure using an unsupervised Artificial Intelligence technique known as generative manifold learning. We test the potential benefit of these personalized normative values in comparison with the more traditional average normative values on a population of patients with drug-resistant epilepsy operated for focal cortical dysplasia, as well as on a supplementary healthy group and on patients with Alzheimer’s disease.

Powering aircraft by sustainable aviation fuels (SAFs) is a pathway to reduce the climate impact of aviation by lowering aviation lifecycle CO2 emissions and by reducing ice crystal numbers and radiative forcing from contrails. While the effect of SAF blends on contrails has been measured previously, here we present novel measurements on particle emission and contrails from 100 % SAF combustion. During the ECLIF3 (Emission and CLimate Impact of alternative Fuels) campaign, a collaboration between the Deutsches Zentrum für Luft- und Raumfahrt (DLR), Airbus, Rolls-Royce, and Neste, the DLR Falcon 20 research aircraft performed in situ measurements following an Airbus A350-941 source aircraft powered by Rolls-Royce Trent XWB-84 engines in 1 to 2 min old contrails at cruise altitudes. Apparent ice emission indices of 100 % HEFA-SPK (hydro-processed esters and fatty acids–synthetic paraffinic kerosene) were measured and compared to Jet A-1 fuel contrails at similar engine and ambient ice-supersaturated conditions within a single flight. A 56 % reduction in ice particle numbers per mass of burned fuel was measured for 100 % HEFA-SPK compared to Jet A-1 under engine cruise conditions. The measured 35 % reduction in soot particle numbers suggests reduced ice activation by the low-sulfur HEFA fuel. Contrail properties are consistently modeled with a contrail plume model. Global climate model simulations for the 2018 fleet conservatively estimate a 26 % decrease in contrail radiative forcing and stronger decreases for larger particle reductions. Our results indicate that higher hydrogen content fuels as well as clean engines with low particle emissions may lead to reduced climate forcing from contrails.

Introduction: The chronic use of psychostimulants increases the risk of addiction and, there is no specific pharmacologic treatment for psychostimulant addiction. The vasopressin (AVP) system is a possible pharmacological target in drug addiction. Previous results obtained in our laboratory showed that amphetamine (AMPH) treatment decreases lateral septum (LS) AVP levels in male rats, and AVP microinjection in LS decreases addictive-like behavior. The aim of the present work was to investigate the effect of AMPH treatment on LS AVP levels and the effect of LS AVP administration on the expression of AMPH-conditioned place preference (CPP) in female rats. The secondary objectives were to study the effect of LS AVP administration on LS GABA and glutamate release in male and female rats and on nucleus accumbens (NAc) dopamine (DA) release in female rats.Methods: Female rats were conditioned with AMPH (1.5 mg/kg i.p.) or saline for 4 days.Results: Conditioning with AMPH did not change LS AVP content in females. However, AVP microinjection into the LS decreased the expression of conditioned place preference (CPP) to AMPH. Glutamate and GABA extracellular levels in the LS induced by AVP were studied in males and females. NAc GABA and DA extracellular levels induced by LS AVP microinjection in female rats were measured by microdialysis. In males, AVP perfusion produced a significant increase in LS GABA extracellular levels; however, a decrease in GABA extracellular levels was observed in females. Both in males and females, LS AVP perfusion did not produce changes in LS glutamate extracellular levels. Microinjection of AVP into the LS did not change GABA or DA extracellular levels in the NAc of females.Discussion: Therefore, AVP administration into the LS produces different LS-NAc neurochemical responses in females than males but decreases CPP to AMPH in both sexes. The behavioral response in males is due to a decrease in NAc DA levels, but in females, it could be due to a preventive increase in NAc DA levels. It is reasonable to postulate that, in females, the decrease in conditioning produced by AVP microinjection is influenced by other factors inherent to sex, and an effect on anxiety cannot be discarded.

Abstract For most patients with childhood myelodysplastic syndrome (cMDS), allogeneic hematopoietic stem cell transplantation (allo‐HSCT) remains the only curative option. In the case of increased blasts (cMDS‐IB), the benefit of pretransplant cytoreductive therapy remains controversial. In this multicenter retrospective study, the outcomes of all French children who underwent allo‐HSCT for cMDS reported in the SFGM‐TC registry between 2000 and 2020 were analyzed (n = 84). The median age at transplantation was 10.2 years. HSCT was performed from matched sibling donors (MSD) in 29% of the cases, matched unrelated donors (MUD) in 44%, haploidentical in 6%, and cord blood in 21%. Myeloablative conditioning was used in 91% of cases. Forty‐eight percent of patients presented with cMDS‐IB at diagnosis (median BM blasts: 8%). Among them, 50% received pretransplant cytoreductive therapy. Five‐year overall survival (OS), cumulative incidence of nonrelapse mortality (NRM), and relapse were 67%, 26%, and 12%, respectively. Six‐month cumulative incidence of grade II–IV acute graft‐versus‐host disease was 46%. Considering the whole cohort, age under 12, busulfan/cyclophosphamide/melphalan conditioning or MUD were associated with poorer 5‐year OS. In the cMDS‐IB subgroup, pretransplant cytoreductive therapy was associated with a better OS in univariate analysis. This seems to be mainly due to a decreased NRM since no impact on the incidence of relapse was observed. Overall, those data may argue in favor of cytoreduction for cMDS‐IB. They need to be confirmed on a larger scale and prospectively.

IntroductionLinks have been established between SARS-CoV-2 and endoplasmic reticulum stress (ERS). However, the relationships between inflammation, ERS, and the volume of organ damage are not well known in humans. The aim of this study was to explore whether ERS explains lung damage volume (LDV) among COVID-19 patients admitted to the intensive care unit (ICU).Materials and methodsWe conducted a single-center retrospective study (ancillary analysis of a prospective cohort) including severe COVID-19 ICU patients who had a chest computed tomography (CT) scan 24 h before/after admission to assess LDV. We performed two multivariate linear regression models to identify factors associated with plasma levels of 78 kDa-Glucose-Regulated Protein (GRP78; ERS marker) and Interleukin-6 (IL-6; inflammation marker) at admission.ResultsAmong 63 patients analyzed, GRP78 plasma level was associated with LDV in both multivariate models (β = 22.23 [4.08;40.38]; p = 0.0179, β = 20.47 [0.74;40.20]; p = 0.0423) but not with organ failure (Sequential Organ Failure Assessment (SOFA) score) at admission (r = 0.03 [−0.22;0.28]; p = 0.2559). GRP78 plasma level was lower among ICU survivors (1539.4 [1139.2;1941.1] vs. 1714.2 [1555.2;2579.1] pg./mL. respectively; p = 0.0297). IL-6 plasma level was associated with SOFA score at admission in both multivariate models (β = 136.60 [65.50;207.70]; p = 0.0003, β = 193.70 [116.60;270.90]; p

Summary: Background: Maternal pertussis vaccination with Tdap vaccine is recommended to protect newborns from severe postnatal infection. HIV-exposed uninfected (HEU) infants have a higher incidence of pertussis infection and may particularly benefit from maternal immunization. The impact of HIV infection on the quality of IgG and memory B cell (MBC) responses to Tdap vaccination in pregnant women (PW) living with HIV (PWH) is unknown. Methods: In this observational study, humoral immune responses to Tdap vaccination, including IgG levels, Fc-dependent effector functions, and MBC frequencies, were measured before and after vaccination in 40 PWH and 42 HIV-uninfected PW. Placental transfer of IgG and avidity were assessed in cord blood (CB). Soluble and cellular immune activation markers were quantified at baseline. Findings: One month after vaccination, PWH had lower frequencies of MBC compared with HIV-uninfected PW. At delivery, PWH had attenuated pertussis-specific IgG levels and Fc-dependent effector functions. Reduced levels of maternal vaccine polyfunctional IgG and IgG avidity were transferred to HEU as compared to HIV-unexposed newborns. After adjustment with ethnicity, maternal antibody levels and gestational age at vaccination, HIV infection was independently associated with decreased levels of PT specific-IgG in CB. Both maternal and neonatal pertussis-specific IgG responses as well as PT-specific IgG avidity were inversely correlated with maternal sCD14 levels before vaccination among PWH. Interpretation: Maternal HIV infection is associated with attenuated humoral immune responses to Tdap vaccination that correlate with sCD14. Suboptimal transfer of maternal immunity may further increase the risk of severe pertussis infection in HEU infants. Funding: This work was supported by IRIS Fund managed by the Foundation Roi Baudouin [2017J1820690206902], Association Vésale pour la Recherche Médicale and the Medical Council of CHU Saint-Pierre and has been funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, US Department of Health and Human Services, under Award No. U19AI145825. N.D. is a clinical researcher and A.M. is Research Director at the Fonds de la Recherche Scientifique (F.R.S.-FNRS), Belgium. M.E.A. was partially supported by NIH NIAID 1U19AI14825. This article is published with the support of the Fondation Universitaire of Belgium.

Summary: Background: The increasing volume and intricacy of sequencing data, along with other clinical and diagnostic data, like drug responses and measurable residual disease, creates challenges for efficient clinical comprehension and interpretation. Using paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) as a use case, we present an artificial intelligence (AI)-assisted clinical framework clinALL that integrates genomic and clinical data into a user-friendly interface to support routine diagnostics and reveal translational insights for hematologic neoplasia. Methods: We performed targeted RNA sequencing in 1365 cases with haematological neoplasms, primarily paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) from the AIEOP-BFM ALL study. We carried out fluorescence in situ hybridization (FISH), karyotyping and arrayCGH as part of the routine diagnostics. The analysis results of these assays as well as additional clinical information were integrated into an interactive web interface using Bokeh, where the main graph is based on Uniform Manifold Approximation and Projection (UMAP) analysis of the gene expression data. At the backend of the clinALL, we built both shallow machine learning models and a deep neural network using Scikit-learn and PyTorch respectively. Findings: By applying clinALL, 78% of undetermined patients under the current diagnostic protocol were stratified, and ambiguous cases were investigated. Translational insights were discovered, including IKZF1plus status dependent subpopulations of BCR::ABL1 positive patients, and a subpopulation within ETV6::RUNX1 positive patients that has a high relapse frequency. Our best machine learning models, LDA and PASNET-like neural network models, achieve F1 scores above 97% in predicting patients’ subgroups. Interpretation: An AI-assisted clinical framework that integrates both genomic and clinical data can take full advantage of the available data, improve point-of-care decision-making and reveal clinically relevant insights promptly. Such a lightweight and easily transferable framework works for both whole transcriptome data as well as the cost-effective targeted RNA-seq, enabling efficient and equitable delivery of personalized medicine in small clinics in developing countries. Funding: German Ministry of Education and Research (BMBF), German Research Foundation (DFG) and Foundation for Polish Science.

The aim of this work is to present a methodology for the reconstruction of missing fracture density within highly fractured intervals, which can represent preferential fluid flow pathways. The lack of record can be very common due to the intense presence of fractures, dissolution processes, or data acquisition issues. The superposition of numerous fractures makes the definition of fracture surfaces impossible, as a consequence, modeling such zones is challenging. In order to address this issue, the usage of direct sampling multiple-point statistics to perform gap filling in well logs is demonstrated as an alternative to other techniques. It reproduces data patterns and provides several models representing uncertainty. The method was tested in intervals from a highly fractured well, by removing previously known fracture density data, and simulating different scenarios with direct sampling. Simulation results are compared to the observed data using cross-validation and continuous rank probability score. The reference scenario training data set consists in one well and two variables: fracture density and fracture occurrence. A sensitivity analysis is carried out considering additional variables, additional wells, different intervals, resampling with extremes, and other gap filling techniques. The auxiliary variable plays an important role in pattern matching, but adding wells and logs increases the complexity of the method without improving pattern retrieval. Best results are obtained applying extreme values theory for stochastic process with the enrichment of the fracture density data at the tail region, followed by resampling of the new values. The enriched data is used for the gap filling resulting in lower continuous rank probability score, and the achievement of extreme fracture density values.

Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2 . More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.

Abstract The identification of gene fusions has become an integral part of soft tissue and bone tumour diagnosis. We investigated the added value of targeted RNA‐based sequencing (targeted RNA‐seq, Archer FusionPlex) to our current molecular diagnostic workflow of these tumours, which is based on fluorescence in situ hybridisation (FISH) for the detection of gene fusions using 25 probes. In a series of 131 diagnostic samples targeted RNA‐seq identified a gene fusion, BCOR internal tandem duplication or ALK deletion in 47 cases (35.9%). For 74 cases, encompassing 137 FISH analyses, concordance between FISH and targeted RNA‐seq was evaluated. A positive or negative FISH result was confirmed by targeted RNA‐seq in 27 out of 49 (55.1%) and 81 out of 88 (92.0%) analyses, respectively. While negative concordance was high, targeted RNA‐seq identified a canonical gene fusion in seven cases despite a negative FISH result. The 22 discordant FISH‐positive analyses showed a lower percentage of rearrangement‐positive nuclei (range 15–41%) compared to the concordant FISH‐positive analyses (>41% of nuclei in 88.9% of cases). Six FISH analyses (in four cases) were finally considered false positive based on histological and targeted RNA‐seq findings. For the EWSR1 FISH probe, we observed a gene‐dependent disparity (p = 0.0020), with 8 out of 35 cases showing a discordance between FISH and targeted RNA‐seq (22.9%). This study demonstrates an added value of targeted RNA‐seq to our current diagnostic workflow of soft tissue and bone tumours in 19 out of 131 cases (14.5%), which we categorised as altered diagnosis (3 cases), added precision (6 cases), or augmented spectrum (10 cases). In the latter subgroup, four novel fusion transcripts were found for which the clinical relevance remains unclear: NAB2::NCOA2, YAP1::NUTM2B, HSPA8::BRAF, and PDE2A::PLAG1. Overall, targeted RNA‐seq has proven extremely valuable in the diagnostic workflow of soft tissue and bone tumours.