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Pleckstrin homology (PH) domains are structural motifs critical for cellular processes, such as signal transduction and cytoskeletal organization. Due to their involvement in various diseases, PH domains are promising therapeutic targets, yet their highly charged and hydrophobic binding sites are not ideal for traditional small drugs. In this study, we designed a DNA-encoded library (DEL) mimicking phospholipids to identify novel modulators targeting PH domains with uncharted chemical properties. Screening against several PH domains led to the discovery of 2DII, a small molecule that selectively binds to mSin1 PH . This compound can modulate mTORC2 activity by impairing mTORC2's membrane interactions, resulting in reduced AKT1 phosphorylation. A micromapping via Dexter energy transfer based on 2DII bearing an iridium catalyst (2DII-Ir), along with a biotin-diazirine small molecule was used for target identification by proteomics, which confirmed mSin1 as the primary intracellular target of 2DII, demonstrating its potential for selective mTORC2 pathway modulation. These findings introduce a novel strategy for targeting PH domains and provide a foundation for the development of therapeutic interventions that modulate PH-domain-dependent signaling pathways.

Purpose: This study by the EANM radiobiology working group aims to analyze the efficacy and toxicity of targeted radionuclide therapy (TRT) using radiopharmaceuticals approved by the EMA and FDA for neuroendocrine tumors and prostate cancer. It seeks to understand the correlation between physical parameters such as absorbed dose and TRT outcomes, alongside other biological factors., Methods: We reviewed clinical studies on TRT, focusing on the relationship between physical parameters and treatment outcomes, and applying basic radiobiological principles to radiopharmaceutical therapy to identify key factors affecting therapeutic success., Results: The analysis revealed that mean absorbed dose alone is insufficient to predict treatment response or toxicity. For absorbed doses below a certain threshold, outcomes are unpredictable, while doses above this threshold improve the likelihood of biological responses. However, even at higher absorbed doses, response plateaus indicate the need for additional parameters to explain outcome variability, including heterogeneity in target expression, anatomical disease location, (epi)genetics, DNA repair capacity, and the tumor microenvironment, aspects that will be discussed in Part II of this analysis., Conclusion: Understanding radiobiology is crucial for optimizing TRT. More dosimetric data is needed to refine treatment protocols. While absorbed dose is critical, it alone does not determine TRT outcomes. Future research should integrate biological parameters with physical dosimetry to enhance efficacy and minimize toxicity., Competing Interests: Declarations Ethics Not applicable. Competing interests JPP: founding member of AlphaKen, member of the Scientific Advisory board of PRECIRIX, research grants from PRECIRIX, ROCHE, ORANO and NH TherAguix; PMG: Immedica, advice on dosimetry procedures (personal fee); KH: consultant fees from: Advanced Accelerator Applications, a Novartis company, Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen, Merck, Molecular Partners, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, and Theragnostics, ymabs, research grants from: Advanced Accelerator Applications, a Novartis company, Boston Scientific, Janssen, stock or other ownership interests with: AdvanCell, Aktis Oncology, Convergent, NVision, Pharma 15, and Sofie Biosciences; DD: consultant fees Novartis, Telix, Immedica, Spectrum Dynamics; DT: Novartis Advisory Board (personal fees); FWBVL: nothing to disclose; JK: Novartis, Advisory Board (personal fee), GE Healthcare, Advisory Board (personal fee), Oncobeta (speaker's fee); UE: institutional grants from Novartis; ML: institutional grants from Ipsen, Nordic Nanovector, Novartis and PentixaPharm; KL: consultant fees from: Sofie Biosciences, Avidity Partners, research grants from: Mariana Oncology, Novartis, AMGEN, Debiopharm., (© 2024. The Author(s).)

Herein, we report the metal-free synthesis of polyfluoroalkyl aryl ethers via nucleophilic substitution of fluorosulfonates, obtained in one pot by bubbling of sulfuryl fluoride (SO 2 F 2 ). Polyfluoroalkyl aryl ethers are present in a variety of biologically active compounds, but previous methods for accessing them required metal catalysts or harsh conditions. With this method, their synthesis is possible under mild conditions and with a short reaction time (30 min) from commercially available starting materials and in yields of ≤97%. Various fluorinated alcohols could be used as electrophiles, and a diversity of electron-withdrawing groups on the aryl or heteroaryl group were tolerated.

Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence-a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21 Cip1 exclusively in the brains of male, but not female mice, and in a p16 Ink4a -independent manner. Conversely, exposure to chronic subordination stress (only males were tested) increased key senescent cell markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16 Ink4a -dependent manner. p16 Ink4a -positive cells in the brain of chronic subordination stress-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16 Ink4a cell clearance. Clearance of p16 Ink4a -positive cells was not sufficient to ameliorate the adverse effects of social stress on measured metrics of healthspan. Overall, our findings indicate that social stress induces an organ-specific and p16 Ink4a -dependent accumulation of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging., Competing Interests: Competing interests D.J.B. and J.M.v.D. have a potential financial interest related to this research. J.M.v.D. is a cofounder of Unity Biotechnology, D.J.B. and J.M.v.D. are co-inventors on patents held by Mayo Clinic and patent applications licensed to or filed by Unity Biotechnology, and D.J.B. and J.M.v.D. are Unity shareholders. Research in the Baker laboratory has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. The other authors declare no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host's immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428-e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, "rhinocerebral mucormycosis." A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds.

Introduction: Inclisiran, an siRNA targeting hepatic PCSK9 mRNA, administered twice-yearly (after initial and 3-month doses), substantially and sustainably reduced LDL-cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a reduced risk of major adverse cardiovascular events (MACE) is not yet established. In-silico trials applying a disease computational model to virtual patients receiving new treatments allow to emulate large scale long-term clinical trials. The SIRIUS in-silico trial programme aims to predict the efficacy of inclisiran on CV events in individuals with established atherosclerotic cardiovascular disease (ASCVD)., Methods and Results: A knowledge-based mechanistic model of ASCVD was built, calibrated, and validated to conduct the SIRIUS programme (NCT05974345) aiming to predict the effect of inclisiran on CV outcomes. The SIRIUS Virtual Population included patients with established ASCVD (previous myocardial infarction (MI), previous ischemic stroke (IS), previous symptomatic lower limb peripheral arterial disease (PAD) defined as either intermittent claudication with ankle-brachial index <0.85, prior peripheral arterial revascularization procedure, or vascular amputation) and fasting LDL-C ≥ 70 mg/dL, despite stable (≥4 weeks) well-tolerated lipid-lowering therapies.SIRIUS is an in-silico multi-arm trial programme. It follows an idealized crossover design where each virtual patient is its own control, comparing inclisiran to (i) placebo as adjunct to high-intensity statin therapy with or without ezetimibe, (ii) ezetimibe as adjunct to high-intensity statin therapy, (iii) evolocumab as adjunct to high-intensity statin therapy and ezetimibe.The co-primary efficacy outcomes are based on the time to the first occurrence of any component of 3P-MACE (composite of CV death, nonfatal MI, or nonfatal IS) and time to occurrence of CV death over 5 years., Perspectives/conclusion: The SIRIUS in-silico trial programme will provide early insights regarding potential effect of inclisiran on MACE in ASCVD patients, several years before the availability of the results from ongoing CV outcomes trials (ORION-4 and VICTORION-2-P)., Clinical Trial Registration: Clinicaltrials.gov identifier: NCT05974345., Competing Interests: Conflict of interest: Denis Angoulvant reports having received payment or honoraria for lectures, presentations, speakers bureaus or educational events from Amgen, Alnylam, Amarin, Astra Zeneca, Boehringer, BMS, Bouchara Recordati, Pfizer, Novartis, Novo Nordisk, Organon, Sanofi, Servier, Vifor. Gabriel Steg reports the following: research grants from Amarin and Sanofi. Consulting or speaking for Amarin, Amgen, BMS and Novo-Nordisk. Clinical Trials (Steering committee, CEC, DSMB) for Amarin, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Idorsia, Janssen, Novartis, Novo-Nordisk, Pfizer, Sanofi. Senior Associate Editor at Circulation and Chief Scientific Officer of Bioquantis Guillaume Mahé reports having received payments for consulting, speaking, or educational events from Amgen, Amarin, Bayer Healthcare, BMS, Leo Pharma, Novartis, Novo Nordisk, Pfizer and Sanofi. Bertrand Cariou reports having received payments for consulting, speaking, or educational events from Amgen, Astra Zeneca, BMS, Eli Lilly, Novartis, Novo Nordisk, Sanofi, Ultragenyx. Franck Boccara reports having received payments for consulting, speaking, or educational events from Amgen, Amarin, Novartis, Novo Nordisk, Boehringer, Servier, ViiV healthcare, Gilead and Sanofi. Pierre Amarenco reports the following: grants from the French government (PHRC: RIISC-THETIS, TST-40, SPICAF trials), Pfizer and AstraZeneca (TST trial). Speaker fee from Novartis, Viatris and Sanofi. Advisory board for Novartis and Neuraltide. Steering committee for Bayer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: Parents' perspectives on their child's obesity (BMI >IOTF-30) management are essential to ensure positive outcomes. This study explored parents' experiences in managing their children's obesity and investigated the sociocultural and environmental factors influencing such management on Reunion Island, a French overseas department in the Indian Ocean., Methods: This qualitative study used a general inductive analysis approach. Semi-structured telephone interviews were conducted from France, between January and April 2019, with nine parents of children treated in the Childhood Obesity Unit of the Children's Hospital on Reunion Island. The interviews were analysed by using thematic analysis until data saturation., Results: Four main themes emerged reflecting the stages of parents' experiences during treatment: a life history with feelings of justification and guilt, acceptance, involvement and activism. Cultural food traditions were a barrier to implementing healthier habits. Support and advice from the healthcare services alleviated feelings of isolation and motivated parents to be more proactive in their children's obesity management. Parents' involvement motivated their children and improved their relationships., Conclusions: Parent's involvement is essential in managing children's obesity. To maximise treatment outcomes, tailored interventions that address parents' unique family dynamics and sociocultural perspectives are key., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Water resources play a crucial role in the global water cycle and are affected by human activities and climate change. However, the impacts of hydropower infrastructures on the surface water extent and volume cycle are not well known. We used a multi-satellite approach to quantify the surface water storage variations over the 2000-2020 period and relate these variations to climate-induced and anthropogenic factors over the whole basin. Our results highlight that dam operations have strongly modified the water regime of the Mekong River, exhibiting a 55 % decrease in the seasonal cycle amplitude of inundation extent (from 3178 km 2 to 1414 km 2 ) and a 70 % decrease in surface water volume (from 1109 km 3 to 327 km 3 ) over 2000-2020. In the floodplains of the Lower Mekong Basin, where rice is cultivated, there has been a decline in water residence time by 30 to 50 days. The recent commissioning of big dams (2010 and 2014) has allowed us to choose 2015 as a turning point year. Results show a trend inversion in rice production, from a rise of 40 % between 2000 and 2014 to a decline of 10 % between 2015 and 2020, and a strong reduction in aquaculture growth, from +730 % between 2000 and 2014, to +53 % between 2015 and 2020. All these results show the negative impact of dams on the Mekong basin, causing a 70 % decline in surface water volumes, with major repercussions for agriculture and fisheries over the period 2000-2020. Therefore, new future projects such as the Funan Techo canal in Cambodia, scheduled to start construction at the end of 2024, will particularly affect 1300 km 2 of floodplains in the lower Mekong basin, with a reduction in the amount of water received, and other areas will be subjected to flooding. The human, material and economic damage could be catastrophic., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: A better understanding of the physiological response of silage maize to a mild reduction in nitrogen (N) fertilization and the identification of predictive biochemical markers of N utilization efficiency could contribute to limit the detrimental effect of the overuse of N inputs., Objectives: We integrated phenotypic and biochemical data to interpret the physiology of maize in response to a mild reduction in N fertilization under agronomic conditions and identify predictive leaf metabolic and proteic markers that could be used to pilot and rationalize N fertilization., Methods: Eco-physiological, developmental and yield-related traits were measured and complemented with metabolomic and proteomic approaches performed on young leaves of a core panel of 29 European genetically diverse dent hybrids cultivated in the field under non-limiting and reduced N fertilization conditions., Results: Metabolome and proteome data were analyzed either individually or in an integrated manner together with eco-physiological, developmental, phenotypic and yield-related traits. They allowed to identify (i) common N-responsive metabolites and proteins that could be used as predictive markers to monitor N fertilization, (ii) silage maize hybrids that exhibit improved agronomic performance when N fertilization is reduced., Conclusions: Among the N-responsive metabolites and proteins identified, a cytosolic NADP-dependent malic enzyme and four metabolite signatures stand out as promising markers that could be used for both breeding and agronomic purposes., (© 2024. The Author(s).)

In MRI studies, the aggregation of imaging data from multiple acquisition sites enhances sample size but may introduce site-related variabilities that hinder consistency in subsequent analyses. Deep learning methods for image translation have emerged as a solution for harmonizing MR images across sites. In this study, we introduce IGUANe (Image Generation with Unified Adversarial Networks), an original 3D model that leverages the strengths of domain translation and straightforward application of style transfer methods for multicenter brain MR image harmonization. IGUANe extends CycleGAN by integrating an arbitrary number of domains for training through a many-to-one architecture. The framework based on domain pairs enables the implementation of sampling strategies that prevent confusion between site-related and biological variabilities. During inference, the model can be applied to any image, even from an unknown acquisition site, making it a universal generator for harmonization. Trained on a dataset comprising T1-weighted images from 11 different scanners, IGUANe was evaluated on data from unseen sites. The assessments included the transformation of MR images with traveling subjects, the preservation of pairwise distances between MR images within domains, the evolution of volumetric patterns related to age and Alzheimer's disease (AD), and the performance in age regression and patient classification tasks. Comparisons with other harmonization and normalization methods suggest that IGUANe better preserves individual information in MR images and is more suitable for maintaining and reinforcing variabilities related to age and AD. Future studies may further assess IGUANe in other multicenter contexts, either using the same model or retraining it for applications to different image modalities. Codes and the trained IGUANe model are available at https://github.com/RocaVincent/iguane&#95;harmonization.git., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vincent Roca reports financial support was provided by Philips. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Influenza vaccine effectiveness (VE) varies seasonally due to host, virus and vaccine characteristics. To investigate how antigenic matching and dosage impact VE, we developed a mechanistic knowledge-based mathematical model. Immunization with a split vaccine is modeled for exposure to A/H1N1 or A/H3N2 virus strains. The model accounts for cross-reactivity of immune cells elicited during previous immunizations with new antigens. We simulated vaccine effectiveness (sVE) of high dose (HD) versus standard dose (SD) vaccines in the older population, from 2011 to 2022. We find that sVE is highly dependent on antigenic matching and that higher dosage improves immunogenicity, activation and memory formation of immune cells. In alignment with clinical observations, the HD vaccine performs better than the SD vaccine in all simulations, supporting the use of the HD vaccine in the older population. This model could be adapted to predict the impact of alternative virus strain selection on clinical outcomes in future influenza seasons., (© 2024. The Author(s).)

Jasmonates are important phytohormones that regulate plant tolerance to biotic and abiotic stresses, and developmental processes. Distinct jasmonates in different plant lineages activate a conserved signalling pathway that mediates these responses: dinor-12-oxo-phytodienoic acid (dn-OPDA) isomers in bryophytes and lycophytes, and JA-Ile in most vascular plants. In many cases, the final responses triggered by these phytohormones depend on the accumulation of specialized metabolites. To identify compounds regulated by the dn-OPDA pathway in the liverwort Marchantia polymorpha, untargeted metabolomic analyses were carried out in response to wounding, a stress that activates the dn-OPDA pathway. A previously unreported group of molecules was identified from these analyses: dn-OPDA-amino acid conjugates (dn-OPDA-aas). Their accumulation after wounding and herbivory was confirmed by targeted metabolic profiling in Marchantia and in all species in which we previously detected dn-iso-OPDA. Mutants in GRETCHEN-HAGEN 3A (MpGH3A) failed to accumulate dn-OPDA-aa conjugates and showed a constitutive activation of the OPDA pathway and increased resistance to herbivory. Our results show that dn-iso-OPDA bioactivity is reduced by amino acid conjugation. Therefore, jasmonate conjugation in land plants plays dichotomous roles: jasmonic acid (JA) conjugation with isoleucine (Ile) produces the bioactive JA-Ile in tracheophytes, whereas conjugation of dn-iso-OPDA with different amino acids deactivates the phytohormone in bryophytes and lycophytes., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Background: A key research priority for developing an HIV cure strategy is to define the viral dynamics and biomarkers associated with sustained post-treatment control. The ability to predict the likelihood of sustained post-treatment control or non-control could minimize the time off antiretroviral therapy (ART) for those destined to not control and anticipate longer periods off ART for those destined to control., Methods: Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either post-treatment control (plasma viremia ≤400 copies/mL at 2 of 3 time points for ≥24 weeks) or non-control., Results: Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be non-controllers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%)., Conclusions: Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through the early identification of people who are unlikely to become post-treatment controllers., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The ecological importance of great apes is widely recognised, yet few studies have highlighted the role of protecting great apes' habitats in mitigating climate change, particularly through carbon sequestration. This study used GIS tools to extract data from various sources, including the International Union for Conservation of Nature database, to examine carbon quantity and great ape abundance in African great ape habitats. Subsequently, we employed a generalised linear model to assess the relationship between locally measured great ape populations abundance and carbon storage across areas with different levels of protection. Our findings showed a positive relationship between the abundance of great apes in their habitats and carbon storage, likely since conservation efforts in great apes habitats may be strengthened with higher great ape populations. The results reveal that gorilla habitats exhibited higher carbon storage than chimpanzee habitats. Specifically, the areas inhabited by gorillas are associated with a mean increase of 27.47 t/ha in carbon storage. Additionally, we observed a positive association between highly protected areas and carbon storage within great ape habitats. Our model indicates that highly protected areas increase the mean carbon stored by 1.13 t/ha compared to medium protected areas, which show a reduction of 15.49 t/ha. This highlights the critical role that protected areas play in both species conservation and carbon sequestration, contributing significantly to climate mitigation efforts. Furthermore, our study underscores the significant contribution of great ape habitats, extending beyond protected areas, to carbon storage, highlighting the potential for synergistic conservation strategies targeting both great apes and carbon sequestration. Protecting great apes is vital for reducing carbon emissions from deforestation and boosting tropical forest carbon sinks. Since nearly 90% of great apes live outside protected areas, targeted conservation in these low-protected areas is also crucial., (© 2024. The Author(s).)

The spermosphere, a dynamic microenvironment surrounding germinating seeds, is shaped by the complex interactions between natural compounds exuded by seeds and seed-associated microbial communities. While peptides exuded by plants are known to influence microbiota diversity, little is known about those specifically exuded by seeds. In this study, we characterised the peptidome profile of the spermosphere for the first time using seeds from eight genotypes of common bean (Phaseolus vulgaris) grown in two contrasting production regions. An untargeted LC-MS/MS peptidomic analysis revealed 3,258 peptides derived from 414 precursor proteins of common bean in the spermosphere. This comprehensive peptidomic dataset provides valuable insights into the characteristics of peptides exuded by common bean seeds in the spermosphere. It can be used to identify peptides with potential antimicrobial or other biological activities, advancing our understanding of the functional roles of seed-exuded peptides in the spermosphere., (© 2024. The Author(s).)

Background and Aims: Prophylactic implantable cardioverter-defibrillators (ICDs) are not recommended until left ventricular ejection fraction (LVEF) has been reassessed 40 to 90 days after an acute myocardial infarction. In the current therapeutic era, the prognosis of sustained ventricular arrhythmias (VAs) occurring during this early post-infarction phase (i.e. within 3 months of hospital discharge) has not yet been specifically evaluated in post-myocardial infarction patients with impaired LVEF. Such was the aim of this retrospective study., Methods: Data analysis was based on a nationwide registry of 1032 consecutive patients with LVEF ≤ 35% after acute myocardial infarction who were implanted with an ICD after being prescribed a wearable cardioverter-defibrillator (WCD) for a period of 3 months upon discharge from hospital after the index infarction., Results: ICDs were implanted either because a sustained VA occurred while on WCD (VA+/WCD, n = 72) or because LVEF remained ≤35% at the end of the early post-infarction phase (VA-/WCD, n = 960). The median follow-up was 30.9 months. Sustained VAs occurred within 1 year after ICD implantation in 22.2% and 3.5% of VA+/WCD and VA-/WCD patients, respectively (P < .0001). The adjusted multivariable analysis showed that sustained VAs while on WCD independently predicted recurrence of sustained VAs at 1 year (adjusted hazard ratio [HR] 6.91; 95% confidence interval [CI] 3.73-12.81; P < .0001) and at the end of follow-up (adjusted HR 3.86; 95% CI 2.37-6.30; P < .0001) as well as 1-year mortality (adjusted HR 2.86; 95% CI 1.28-6.39; P = .012)., Conclusions: In patients with LVEF ≤ 35%, sustained VA during the early post-infarction phase is predictive of recurrent sustained VAs and 1-year mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Heliorhodopsins (HeRs) constitute a novel and distinct group of microbial rhodopsins, characterized by the inverted position of C- and N- termini relative to conventional Type I rhodopsins. The production of HeRs for structural and functional investigations has proven challenging, as evidenced by the structural elucidation of only two proteins and the functional characterization of a few others to date. Notably, no eukaryotic HeRs have been reported thus far. In this study, we report the first expression of three eukaryotic HeRs in the LEXSY expression system: from marine and freshwater algae and a free-living marine unicellular eukaryote. We spectroscopically characterized these HeRs, demonstrating that they were expressed in the functional states. Finally, we report their successful crystallization, thus paving the way for their further structural and functional studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Malaria is an acute, debilitating parasitic illness. There were 249 million cases of malaria in 2022, resulting in 608,000 deaths globally, 76% of which were children ≤5 years. The unique nature of this disease (recurrences leading to re-treatments and numerous organ systems affected), specific clinical treatment regimens, poor compliance, and diversity of affected populations (predominantly pediatrics, women of childbearing potential, pregnant and lactating women), often makes standard testing approaches inadequate, and tailor-made safety assessments are more appropriate. We provide best practice recommendations based on company experience for the non-clinical safety assessment of antimalarial drugs, with a focus on small molecules since they represent the majority of drug candidates for this illness. We focus on specific testing considerations for repeat dose toxicity studies, including combination toxicity assessments, since new drug treatment regimens typically foresee short treatment durations to improve compliance (i.e., 1 day) with combinations of compounds to improve efficacy and limit potential resistance. Due to the target population, the timing of reproductive, developmental, and juvenile toxicity studies may be earlier than general testing roadmaps for other small molecule drugs. In conclusion, key recommendations presented should enable a more effective and efficient development path whilst protecting clinical trial participants and patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The diagnostic conversion of major depressive disorder (MDD) to bipolar disorder (BD) is a topic that is currently the subject of several studies. However, there are few studies that clarify the interaction between conversion, substance use and biomarkers., Objectives: The aim of this study was to investigate serum biomarker levels and lifetime substance use as predictors for diagnostic conversion from major depressive disorder to bipolar disorder in an outpatient sample of adults., Methods: This was a prospective longitudinal study nested within a larger two-phase study. Male and female individuals, between the ages of 18 and 60, diagnosed with MDD by the Mini International Neuropsychiatric Interview Plus who participated in the two stages of the study were included. The instrument alcohol smoking and substance involvement screening test (ASSIST) was used to evaluate substance use. The enzyme linked immuno sorbent assay (ELISA) technique was used to measure the levels of the following biomarkers: brain derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α)., Results: The conversion rate from MDD to BD was 12.4%. The prevalence of female individuals, subjects with up to eight years of schooling, who had lifetime psychotic symptoms and reported lifetime use of cocaine was higher among individuals who converted their diagnosis to BD than among individuals who did not (P<0.05). In the crude analysis, there was no interaction between biomarkers and substance use except for NGF with cocaine. Based on the adjusted analysis model, it was observed that the interaction remains (OR: 1.476; 95% CI: 1.019-2.137)., Conclusions: Individuals with late diagnosis and treatment of bipolar disorder may have a worse prognosis. Therefore, results suggesting that NGF and cocaine use are potential predictors of conversion to bipolar disorder can help in clinical practice, contributing to the identification of conversion and to more specific therapeutic interventions., (Copyright © 2024 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.)

Background: Poverty is a key social determinant of mental health among forcibly displaced persons. This study aimed to design and pilot test a strategy to integrate existing mental health and economic inclusion interventions for displaced families in Ecuador., Methods: We conducted a series of qualitative interviews (n = 30), focus groups (n = 6), and workshops (n = 3) to develop a set of strategies for integrating cross-cutting and focused mental health and psychosocial support (MHPSS) strategies into an existing economic inclusion program for displaced families in Quito. We non-randomly assigned two field offices in Quito to (1) integrate cross-cutting strategies focused on improving economic outcomes or (2) integrate both those cross-cutting strategies plus focused MHPSS strategies into an economic inclusion program. We measured site-level implementation outcomes (adoption, appropriateness, acceptability, feasibility, fidelity, reach, retention, usability) and participant-level psychosocial (wellbeing, depressive symptoms, anxiety symptoms, functioning) and economic inclusion outcomes (financial resources, diet diversity, social capital/networks, self-reliance) over six months. We conducted a mixed-methods analysis to explore the acceptability and feasibility of the integration strategies and the ability to evaluate their effects in a future cluster randomized trial., Results: We developed a toolkit that included 10 strategies for integrating MHPSS into economic inclusion interventions. Fifty displaced persons participating in an existing economic inclusion program (25 per study condition) were enrolled and 88% remained in the study through the six-month follow-up. Participants and implementers reported that the integration strategy was appropriate, acceptable, feasible, and usable. Implementers, including people without prior experience in delivering mental health services, were able to deliver the intervention with high fidelity. Integration of focused MHPSS intervention components into an economic inclusion program appeared to improve MHPSS outcomes, the strength of social capital and networks, and engagement in economic and other programs., Conclusions: This study provides preliminary evidence of the acceptability and feasibility of integrating MHPSS into economic inclusion programs for displaced people. We found evidence supporting evaluation methods that can be employed in a future study to definitively test the added value of integrated approaches to mental health and economic wellbeing for displaced persons., (© 2024. The Author(s).)

Electroconvulsive therapy is an effective and well-tolerated antidepressant treatment for the elderly population. The place of electroconvulsive therapy in the treatment sequence for depression in the elderly is currently not well established. This review aims to identify the factors that contribute to a positive response and remission in elderly patients with depression undergoing electroconvulsive therapy treatment. We searched five bibliographic databases (Medline ALL Ovid, Embase.com, APA PsycInfo Ovid, Cochrane Library Wiley and Web of Science Core Collection) for articles published between 1995 and June 2023. Of the 2149 articles screened, 19 were included in the review. No significant associations were found between remission and/or response and salivary cortisol, baseline hippocampal and white matter hyperintensities, total amyloid load or global cortical atrophy. The reviewed articles did not show a significant difference in remission between unilateral and bilateral electroconvulsive therapy treatment. Other interesting findings are that moderately elevated levels of CRP and S100B levels, lower retardation scores, poorer performance on the word reading task at baseline and longer post-ictal reorientation time may be associated with higher remission and/or response rates. Medial temporal atrophy can be associated with lower Montgomery-Åsberg Depression Rating Scale (MADRS) decrease after electroconvulsive therapy. Finally, elderly patients had higher rates of electroconvulsive therapy response; retardation and psychotic features may mediate this association. Incorporation of this data into clinical practice may facilitate a personalised approach to electroconvulsive therapy. However, research on this topic is scarce and there are few studies that focus specifically on older people.

MYB fusions are recurrently found in select cancers, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared to other blood cancers, and in some patients are the only obvious somatic mutation detected. This suggests they may alone be sufficient to drive dendritic cell transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but mechanistically how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that in BPDCN leukemogenesis, MYB switches from being a regulator of dendritic cell lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in BPDCN patients increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired dendritic cell differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.

Rapid and precise diagnostic techniques are essential for identifying foodborne pathogens, including Bacillus cereus ( B. cereus ), which poses significant challenges to food safety. Traditional detection methods are limited by long incubation times and high costs. In this context, gold nanoparticle (AuNP)-based lateral flow assays (LFAs) are emerging as valuable tools for rapid screening. However, the use of antibodies in LFAs faces challenges, including complex production processes, ethical concerns, or variability. Here, we address these challenges by proposing an innovative approach using bacteriophage-derived proteins for pathogen detection on LFAs. We used the engineered endolysin cell-wall-binding domain (CBD) and distal tail proteins (Dit) from bacteriophages that specifically target B. cereus . The protein-binding properties, essential for the formation of efficient capture and detection biointerfaces in LFAs, were extensively characterized from the microstructural to the LFA device level. Machine-learning models leverage knowledge of the protein sequence to predict advantageous protein orientations on the nitrocellulose membrane and AuNPs. The study of the biointerface binding quantified the degree of attachment of AuNPs to bacteria, providing, for the first time, a microscopic model of the number of AuNPs binding to bacteria. It highlighted the binding of up to one hundred 40 nm AuNPs per bacterium in conditions mimicking LFAs. Eventually, phage proteins were demonstrated as efficient bioreceptors in a straightforward LFA prototype combining the two proteins, providing a rapid colorimetric response within 15 min upon the detection of 10 5 B. cereus cells. Recombinantly produced phage binding proteins present an opportunity to generate a customizable library of proteins with precise binding capabilities, offering a cost-effective and ethical alternative to antibodies. This study enhances our understanding of phage protein biointerfaces, laying the groundwork for their utilization as efficient bioreceptors in LFAs and rapid point-of-care diagnostic assays, thus potentially strengthening public health measures.

The reporting of adverse events (AEs) is fundamental to characterize safety profiles of novel therapeutic drug classes, however, conventional analysis strategies are suboptimal tools for this task. We therefore attempted to contribute to the modernization of AE analysis by encompassing the dimension of time, the duration and the recurrent nature of AEs induced by these extended treatment durations. This paper presents and highlights the benefits of alternative approaches to modernize AE analysis based on the MOTIVATE prospective study modeling immune-related AEs (irAEs) in patients with solid tumors (regardless of the primary site) treated with immune checkpoint inhibitor irrespective of disease stage. The probability of presenting an irAE over time was estimated using the prevalence function. The time-to-onset (TTO) and the mean number of recurrent irAEs were also assessed. Among the 147 patients analyzed, 39.7% had a melanoma, 37.7% a non-small cell lung cancer (NSCLC) and 74.8% were treated for metastatic disease. Despite a higher proportion of melanoma patients presenting at least one irAE, the prevalence of irAEs was lower in melanoma than in NSCLC patients over time. TTO analysis showed that irAEs occurred earlier in NSCLC patients whereas melanoma patients experienced more recurrent irAEs over the long-term. The prevalence function of non-metastatic and metastatic patients revealed different long-term toxicity profiles. These alternative methodologies capture different toxicity patterns (time-to-onset, recurrent, acute episodic or long-term moderate AEs) and provide a more consistent safety assessment for new therapeutics, thereby assisting clinicians and health authorities in their therapeutic decision-making processes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To describe Neisseria gonorrhoeae treatment failure to the recommended antimicrobial regimens (azithromycin, cefixime and ceftriaxone)., Methods: Our study was a longitudinal analysis of treatment failures from an observational open cohort of gonococcal infection cases collected in Québec, Canada (n = 2547) between September 2015 and December 2019. Epidemiological and clinical data were collected using a self-administered questionnaire, direct case interviews and chart reviews. Antimicrobial susceptibility testing was performed using the agar dilution method. To be retained as a treatment failure, cases must have had (i) a laboratory-confirmed gonococcal infection; (ii) a documented treatment; (iii) a positive test of cure (TOC) performed within a defined period and (iv) no sexual contact (vaginal, oral or anal), even protected with a condom, between the beginning of treatment and the positive TOC. A broader definition, including suspected cases, was also examined., Results: Among 1593 cases where a TOC was performed, 83 had a positive TOC: 11 were retained as treatment failure, and 6 were considered suspected cases (overall = 17/1593; 1.1%). Possible explanations for retained or suspected treatment failure included resistance to the antibiotics used for treatment (n = 1), pharyngeal infection (n = 9, of which 5 had been treated with ceftriaxone and 4 with other regimens); and azithromycin monotherapy (n = 1). Some cases had more than one potential explanation., Conclusions: Treatment failure occurred in 1.1% of cases of Neisseria gonorrhoeae infection for which a TOC was performed, including some cases of pharyngeal infection treated with ceftriaxone., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in individuals with obesity. Sexual dimorphism is present in MASLD. A noninvasive test to diagnose the severity of the disease, in particular the presence of Metabolic dysfunction-associated steatohepatitis (MASH), is lacking. This European multicenter prospective study uses a blood test based on mid-infrared (MIR) metabolic fingerprinting of individuals with severe or morbid obesity to diagnose MASH. Three hundred eighty-two individuals with severe or morbid obesity undergoing bariatric surgery were enrolled prospectively. Liver biopsies were obtained during surgery and assessed centrally. An algorithm was defined to calculate a score from the recorded MIR spectrum and to establish a diagnostic threshold to classify patients with MASH. Among the women (n = 217), MASH was diagnosed in 14.3% of cases. For women, the performance in terms of AUC were 0.83 and 0.82 in the calibration and validation groups, respectively. For a threshold of 0.1817, sensitivities were 86% and 70%, specificities were 81% and 75%, PPV were 43% and 32%, NPV were 97% and 94% and ACC were 82% and 74% for the calibration and validation groups, respectively. For men (n = 78; MASH: 33.3%), the performance of the spectral model was poor. The metabolic fingerprint obtained by MIR spectroscopy can rule out MASH in women with severe or morbid obesity. Its value in men needs new studies.Trial registration: ClinicalTrials.gov identifier: ClinicalTrials.gov identifier: NCT03978247 (04/06/2019)., (© 2024. The Author(s).)

Treating disruptive disorder with emotional dysregulation (DDED) is a challenge in terms of difficulties, objectives and results. In addition to a multi-disciplinary approach involving child psychiatrists, nurses, psychomotricists and educators, the use of animal mediation (dogs) appears relevant. Eight standardized group sessions with eight children aged 6 to 10, assessed by means of a semi-directive interview and several psychometric tools (MDI-C, Kidscreen, parent attachment inventory, child/family star, family/child star, alexithymia questionnaire) revealed improvements in listening skills, empathy, adaptability, socialization, anger and depression management, temper tantrum frequency, school complaints and depressive symptoms., (Copyright © 2024. Publié par Elsevier Masson SAS.)

Sugars, produced through photosynthesis, are at the core of all organic compounds synthesized and used for plant growth and their response to environmental changes. Their production, transport, and utilization are highly regulated and integrated throughout the plant life cycle. The maintenance of sugar partitioning between the different subcellular compartments and between cells is important in adjusting the photosynthesis performance and response to abiotic constraints. We investigated the consequences of the disruption of four genes coding for SWEET sugar transporters in Arabidopsis (SWEET11, SWEET12, SWEET16, and SWEET17) on plant photosynthesis and the response to drought. Our results show that mutations in both SWEET11 and SWEET12 genes lead to an increase of cytosolic sugars in mesophyll cells and phloem parenchyma cells, which impacts several photosynthesis-related parameters. Further, our results suggest that in the swt11swt12 double mutant, the sucrose-induced feedback mechanism on stomatal closure is poorly efficient. On the other hand, changes in fructose partitioning in mesophyll and vascular cells, measured in the swt16swt17 double mutant, positively impact gas exchanges, probably through an increased starch synthesis together with higher vacuolar sugar storage. Finally, we propose that the impaired sugar partitioning, rather than the total amount of sugars observed in the quadruple mutant, is responsible for the enhanced sensitivity upon drought. This work highlights the importance of considering SWEET-mediated sugar partitioning rather than global sugar content in photosynthesis performance and plant response to drought. Such knowledge will pave the way to design new strategies to maintain plant productivity in a challenging environment., (© 2024 Scandinavian Plant Physiology Society.)

Acousto-optic imaging (AOI) of absorbing objects embedded in highly scattering media remains challenging, since the detectable signal suitable for image reconstruction is weak. To increase the detected signals to a level required by live biological applications, we designed a high-peak-power quasi-continuous laser source based on the coherent combination of two pulsed amplifiers, delivering 100-µs-long pulses with a 9 W peak power at a 100 Hz repetition rate while maintaining an average power below 100 mW; jointly used with a digital holographic detection that maximizes the amount of collected signal, we demonstrate for the first time to our knowledge the optical imaging of 2-cm-thick highly scattering media (µ s ' ∼ 10 cm -1 ) at near-video frame rate (0.2 Hz) using the Fourier transform-AOI.

Conic sections are commonly used in reflective X-ray optics. Hyperbolic mirrors can focus a converging light source and are frequently paired with elliptical or parabolic mirrors in Wolter type configurations. This paper derives the closed-form expression for a mirror-centered hyperbolic shape, with zero-slope at the origin. Combined with the slope and curvature, such an expression facilitates metrology, manufacturing and mirror-bending calculations. Previous works consider ellipses, parabolas, magnifying hyperbolas or employ lengthy approximations. Here, the exact shape function is given in terms of the mirror incidence angle and the source and image distances., (open access.)

The Takagi-Taupin equations are solved in their simplest form (zero deformation) to obtain the Bragg-diffracted and transmitted complex amplitudes. The case of plane-parallel crystal plates is discussed using a matrix model. The equations are implemented in an open-source Python library crystalpy adapted for numerical applications such as crystal reflectivity calculations and ray tracing., (open access.)

Background: Appropriate prescription of Proton pump inhibitors (PPIs) remains an important concern amid the rising overuse. A gap exists in the literature regarding the benefit of PPI prophylaxis and the consequences of underprescription in patients at risk for upper gastrointestinal bleeding (UGIB)., Aims: This study aims to describe the characteristics of hemorrhage in relation to PPI use in patients experiencing UGIB, with a focus on high-risk individuals requiring gastroprotection., Methods: Data from a French multicentric cohort of patients experiencing UGIB were analyzed. Patients using PPI were compared to those without PPI considering bleeding etiologies and outcomes of peptic ulcer disease (PUD)-related hemorrhage. The rate of PPI use and its effect on bleeding characteristics in high-risk populations, defined based on international guidelines, were also assessed., Results: Among 2497 included patients, 31.1% were on PPI at bleeding onset. PPI users exhibited a significantly lower rate of PUD-related bleeding in comparison with those without PPI (24.7 vs 40.8%, respectively, p < 0.0001). Similar difference was observed in high-risk populations, of whom, only 40.3% had gastroprotection with PPI before bleeding onset. PPI prophylaxis, however, did not influence the severity of bleeding in the general study population or in high-risk groups. Multivariate analysis identified age, comorbidities, and having more than two anti-thrombotic agents as predictors of severe bleeding., Conclusions: PPI users appear to have a lower rate of bleeding ulcers compared to non-users. However, underprescription in high-risk groups raises the need for standardized care to ensure appropriate PPI use., Competing Interests: Declarations Conflict of interest Authors have no relevant financial or non-financial competing interests to disclose concerning this work., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Ageism in healthcare has received increased attention in recent years, but literature focusing on how it affects individuals living with rare diseases remains scant. The rare disease population already faces obstacles when navigating health systems, and ageism has the potential to exacerbate existing health inequities. We conducted a systematic review of peer-reviewed and gray literature on health inequities in rare disease populations, seeking to identify publications that reported primary or secondary data on the equitable or inequitable treatment of these populations, or that discussed related regulatory, moral, or philosophical issues. Our aims were to understand how health inequities in these populations arise, how they are justified from societal points of view, how they manifest themselves in laws and regulations, and what effects they have on health care access and health outcomes. We retrieved information from 63 publications, which we inductively synthesized into five categories: ethical discussions, societal preferences, regulations, access to care, and health outcomes. Integrating insights from these categories, we developed an Ethical Spectrum and Resource Allocation Framework, which explains the emergence of equity issues and how they are manifested in health systems. By providing a better understanding of the root causes of health inequities, particularly among older adults, the framework can inform health policymaking, improving access to care and health outcomes for rare disease patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: The diagnostic gaps for childhood tuberculosis (TB) remain considerable in settings with high TB incidence and resource constraints. We established and evaluated the performance of a scoring system based on a combination of serological tests and T-cell cytokine release assays, chosen for their ability to detect immune responses indicative of TB, in a context of high prevalence of pediatric HIV infection., Methods: We enrolled 628 consecutive children aged ≤15 years, admitted for TB suspicion. Multiple cytokine levels in QuantiFERON Gold In-Tube supernatants and antigen 85B (Ag85B) antibodies were assessed in children who tested positive with either Xpert TB or mycobacterial culture. The results were compared with those of control children., Results: Among the biomarkers most strongly associated with TB, random forest classification analysis selected Ag85B antibodies, interleukin-2/interferon-γ ratio, and monokine induced by interferon-γ for the scoring system. The receiver operating characteristic curve derived from our scoring system showed an area under the curve of 0.95 (0.91-0.99), yielding 91% sensitivity and 88% specificity. The internal bootstrap validation gave the following 95% confidence intervals for the score performance: sensitivity 71%-97% and specificity 79%-99%., Conclusions: This study suggests that supplementing the QuantiFERON assay with a combination of serological and T-cell markers could enhance childhood TB screening regardless of HIV status and age. Further validation among the target population is necessary to confirm the performance of this scoring system., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The combined impact of complete resection (oncological goal) and no functional loss (functional goal) in glioblastoma subgroups is currently unknown. This study aimed to develop a novel onco-functional outcome (OFO) to merge these two goals into one outcome, resulting in four classes: complete without deficits (OFO1), incomplete without deficits (OFO2), complete with deficits (OFO3), or incomplete with deficits (OFO4)., Methods: Between 2010-2020, 858 patients with tumor resection for eloquent glioblastoma were included. We analyzed the impact of OFO class on postoperative surgical outcomes using Cox proportional-hazards models with hazard ratios (HR) or logistic regression with odds ratios (OR), followed by specific subgroup analyses. We developed a risk model to predict OFO class preoperatively using logistic regression., Results: The OFO classification stratified the four OFO classes for overall survival (OS:19.0 versus 14.0 versus 12.0 versus 9.0 months), progression-free survival (PFS), and adjuvant therapy. OFO1 was associated with improved OS [HR= 0.67, (0.55-0.81); p < 0.001], and PFS [HR = 0.68, (0.57-0.81); p < 0.001] in the overall cohort and all clinical and molecular subgroups, except for MGMT-unmethylated tumors; and higher rate of adjuvant therapy [OR= 2.81, (1.71-4.84);p < 0.001]. In patients≥ 70 years, only OFO1 improved their survival outcomes. Safe surgery was especially important in patients with a preoperative KPS ≤ 80 to qualify for adjuvant treatment. Awake craniotomy more often led to OFO1 compared to asleep resection [OR = 1.93, (1.19-3.14); p = 0.008]., Conclusions: OFO1 was associated with improved OS, PFS, and receipt of adjuvant therapy in all glioblastoma patients with IDH-wildtype and MGMT-methylated tumors. Awake craniotomy was associated with achieving this optimal OFO status. Preventing deficits was more important than complete surgery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. MvdB has received honoraria for consultancy from Anheart Therapeutics, Boehringer Ingelheim, Fore Biotherapeutics, Genenta, Incyte, Mundipharm, Chimerix, Roche, and Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Coronary heart disease remains one of the leading causes of morbidity and mortality, and is responsible for significant social costs. Resumption of work is an essential objective when this pathology concerns working patients. French data remain patchy and relatively old. The French Society of Cardiology's Exercise, Rehabilitation, Sport and Prevention Group has proposed a multicentre study to update these data., Methods: Following an acute coronary syndrome (ACS), the cardiology team asked the patient, who was currently working, to complete a questionnaire on his or her pathology, occupation and plans to return to work. An interview after 6 months enabled the clinical and professional situation of the patient to be analyzed, in order to study the factors predictive of a return to work., Results: 364 patients were included in 6 interventional and 17 cardiac rehabilitation centres between 2018 and 2019. The resumption rate was 81% (n = 295), 93% of them in the same position, with a mean delay of 106 ± 56 days. The cardiologic independent factors for non-return were left ventricular ejection fraction, the presence of an anticoagulant, angina or heart failure, and occupational factors, shift work, exposure to cold, and imposed work rates. Factors that lengthened the time taken to return to work included delayed access to rehabilitation, the carrying of heavy loads, difficult postures and imposed work rates, as well as the patient's lack of a project, the absence of a cardiologist's opinion and the request for a modified workstation., Conclusion: The rate of return to work remains fairly stable despite the evolution of disease management, and the time to return to work relatively high. One way of improving the situation is to enhance access to cardiac rehabilitation programs, for example by offering alternatives such as tele-rehabilitation for a proportion of patients. This will free up more time for more severe patients, to better prepare them physically and psychologically for a return to work, which will also have a beneficial economic effect., Competing Interests: Déclaration de liens d'intérêt Les auteurs déclarent ne pas avoir de lien d'intérêt avec cet article, (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Hydathodes are small organs found on the leaf margins of vascular plants which release excess xylem sap through a process called guttation. While previous studies have hinted at additional functions of hydathode in metabolite transport or auxin metabolism, experimental support is limited. We conducted comprehensive transcriptomic, metabolomic and physiological analyses of mature Arabidopsis hydathodes. This study identified 1460 genes differentially expressed in hydathodes compared to leaf blades, indicating higher expression of most genes associated with auxin metabolism, metabolite transport, stress response, DNA, RNA or microRNA processes, plant cell wall dynamics and wax metabolism. Notably, we observed differential expression of genes encoding auxin-related transcriptional regulators, biosynthetic processes, transport and vacuolar storage supported by the measured accumulation of free and conjugated auxin in hydathodes. We also showed that 78% of the total content of 52 xylem metabolites was removed from guttation fluid at hydathodes. We demonstrate that NRT2.1 and PHT1;4 transporters capture nitrate and inorganic phosphate in guttation fluid, respectively, thus limiting the loss of nutrients during this process. Our transcriptomic and metabolomic analyses unveil an organ with its specific physiological and biological identity., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Aim: Renal dysfunction is a common complication of cirrhosis, occurring either as part of multiorgan involvement in acute illness or secondary to advanced liver disease. To date, no study has comprehensively assessed multiple renal function parameters in hospitalized patients with cirrhosis through a multiparametric analysis of renal biochemistry markers., Methods: We conducted a retrospective, observational study including all consecutive patients hospitalized with cirrhosis who underwent a 43-multiparametric renal function assessment between January 1, 2021, and June 30, 2023., Results: All patients showed at least one of the following renal abnormalities: Kidney Disease: Improving Global Outcomes stage G2 or higher, sodium and/or chloride excretion fraction <1%, electrolyte-free water clearance <0.4 mL/min, or tubular maximum phosphate reabsorption capacity <0.8 mmol/L. The estimated glomerular filtration rate equations significantly overestimated the measured creatinine clearance with median differences of +14 mL/min/1.73 m 2 (95% CI 6-29) and +9 mL/min/1.73 m 2 (95% CI 2-15) for European Kidney Function Consortium equations, respectively. Notably, 54% and 39% of patients demonstrated estimated glomerular filtration rates exceeding 30% of the measured creatinine clearance when the Chronic Kidney Disease - Epidemiology Collaboration and European Kidney Function Consortium formulas were employed, respectively. Substantial discrepancies in Kidney Disease: Improving Global Outcomes stage assignments were observed between the estimated glomerular filtration rate- and measured creatinine clearance-based assessments., Conclusions: This study underscores the value of a multiparametric renal function assessment as a routine tool for evaluating renal function in patients with cirrhosis. A high prevalence of medically actionable renal abnormalities spanning multiple renal function modules, including alterations in glomerular function, salt and solute-free water excretion, and proximal tubule phosphate reabsorption, has been demonstrated in hospitalized patients with cirrhosis., (© 2024 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Purpose: The purpose of this study was to identify potential association between transverse sinus stenosis (TSS) and temporal bone thinning downstream of TSS on computed tomography (CT)., Materials and Methods: Clinical and radiological data of patients with venous pulsatile tinnitus due to TSS (TSS group) and treated with stenting from 2019 to 2022 were retrospectively collected. An age-matched control group of patients with venous or neutral pulsatile tinnitus (control group) was built. CT measurements of temporal bone thickness were performed at the level of transverse-sigmoid sinus junction (E1) and the occipitomastoid suture (E2). E1; E2 and E1/E2 ratios obtained in TSS and control groups were compared., Results: A total of 122 patients with venous pulsatile tinnitus were included. There were 56 patients with TSS (TSS group; 56 women; mean age, 35.5 ± 11.3 [standard deviation] years) and 66 patients without TSS (control group; 54 women; mean age, 37.7 ± 10.5 [standard deviation] years). E1 measurements and E1/E2 ratios on the symptomatic and dominant sides were significantly lower in the TSS group by comparison with the contralateral side of the same group (P < 0.05) and the ipsilateral side of the control group (P < 0.05). There were no differences in median E2 values between the TSS group (6.8 mm; range: 3.5-10.8 mm) and the control group (7.1 mm; range: 2.9-11.2 mm) (P = 0.098). E1 = 0 mm was found only in the TSS group. At receiver operating characteristic (ROC) analysis, an E1/E2 ratio threshold of 0.562 maximized the ability to predict presence of TSS. An E1/E2 ratio < 0.562 was predictive of symptomatic TSS with an accuracy of 74% (95% confidence interval: 65-82%). The AUC for the diagnosis of TSS was 0.807 (95% CI: 0.729-0.885)., Conclusion: Temporal bone thickness is significantly reduced downstream of the stenosis on the pulsatile tinnitus side and may be a good indicator of symptomatic TSS., Competing Interests: Declaration of competing interest The authors have no competing interests to disclose in relation with this article., (Copyright © 2024 Société française de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Through their footprint throughout their life cycle, from production to use, medicines have a significant impact on the environment. Reducing this impact is rarely considered from the perspective of the choices that healthcare professionals might have to make when prescribing or dispensing medicines. Should we consider environmental impact, alongside effectiveness and tolerance, one of the dimensions of the proper use of medicines? To address this question, the 5th Forum of the Association for the Proper Use of Medicines highlighted the main sources of pharmaceutical pollution: the carbon footprint linked to production, greenhouse gas emissions, the impact of residues on water and waste from packaging. While the eco-design of medicines should make it possible to limit their environmental impact upstream, there are still few initiatives aimed at their use. The Swedish "Hazard Score" assessment tool, which classifies compounds according to their potential to pollute the aquatic environment, was presented as a tool for guiding prescription choices. Through the exchanges between the various stakeholders (public authorities, doctors, pharmacists, manufacturers, patients) during this forum, recommendations were drawn up both on scientific and ethical grounds., (Copyright © 2024 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.)

Purpose of Review: Technologies in healthcare incorporating artificial intelligence tools are experiencing rapid growth in static-image-based applications such as diagnostic imaging. Given the proliferation of artificial intelligence (AI)-technologies created for video-based imaging, ophthalmic microsurgery is likely to experience significant benefits from the application of emerging technologies to multiple facets of the care of the surgical patient., Recent Findings: Proof-of-concept research and early phase clinical trials are in progress for AI-based surgical technologies that aim to provide preoperative planning and decision support, intraoperative image enhancement, surgical guidance, surgical decision-making support, tactical assistive technologies, enhanced surgical training and assessment of trainee progress, and semi-autonomous tool control or autonomous elements of surgical procedures., Summary: The proliferation of AI-based technologies in static imaging in clinical ophthalmology, continued refinement of AI tools designed for video-based applications, and development of AI-based digital tools in allied surgical fields suggest that ophthalmic surgery is poised for the integration of AI into our microsurgical paradigm., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Hepatitis B Virus (HBV) infectivity data were reviewed and the 50% infectious dose (ID 50 ) was reassessed in different HBsAg-positive infection stages enabling modelling of transfusion-transmitted (TT)-HBV infection risk if HBsAg donor screening was replaced by individual donation nucleic acid amplification technology (ID-NAT). Quantitative HBsAg and HBV-DNA assays were performed against international standards to compare the ratio between potential infectious HBV virions and subviral HBsAg particles in Egyptian HBsAg-positive blood donors as well as in Japanese chimpanzee samples of known infectivity. HBV-DNA load below the quantification limit of detection was estimated against a reference standard by replicate NAT testing (n = 25). Infectivity of chimpanzee samples collected during ramp-up and declining viremic phase were tested in a human liver chimeric mice (HLCM) model and compared with published infectivity data from different HBsAg-positive infection stages. Lowest estimates of ID 50 in HBsAg-positive plasma were 3-6 HBV virions in chimpanzee studies. Infectivity decreased approximately 10-100-fold in the declining viremic phase using HLCM. In acute phase samples, HBV to HBsAg particle ratios varied between 1:10 2 -10 4 but in HBsAg-positive blood donors this particle ratio reached 1:10 6 -10 12 when viral load was below 100 HBV-DNA copies/mL. Modelled TT-HBV risk of an HBsAg-positive/ID-NAT nonreactive blood transfusion was estimated at 5.5%-27% for components containing 20-200 mL of plasma when assuming an ID 50 of 316 (point estimate between 100 and 1000) virions. It cannot be ensured that discontinuation of HBsAg donor screening and reliance on ID-NAT alone is safe., (© 2024 John Wiley & Sons Ltd.)

Background: DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has an essential role in the non-homologous end-joining pathway that repairs DNA double-strand breaks in V(D)J recombination involved in the expression of T- and B-cell receptors. Whereas homozygous mutations in Prkdc define the Scid mouse, a model that has been widely used in biology, human mutations in PRKDC are extremely rare and the disease spectrum has not been described so far., Objectives: To provide an update on the genetics, clinical spectrum, immunological profile, and therapy of DNA-PKcs deficiency in human., Methods: The clinical, biological, and treatment data from the 6 cases published to date and from 1 new patient were obtained and analyzed. Rubella PCR was performed on available granuloma material., Results: We report on 7 patients; 6 patients displayed the autosomal recessive p.L3062R mutation in PRKDC-encoding DNA-PKcs. Atypical severe combined immunodeficiency with inflammatory lesions, granulomas, and autoimmunity was the predominant clinical manifestation (n = 5 of 7). Rubella viral strain was detected in the granuloma of 1 patient over the 2 tested. T-cell counts, including naive CD4 + CD45RA + T cells and T-cell function were low at diagnosis for 6 patients. For most patients with available values, naive CD4 + CD45RA + T cells decreased over time (n = 5 of 6). Hematopoietic stem cell transplantation was performed in 5 patients, of whom 4 are still alive without transplant-related morbidity. Sustained T- and B-cell reconstitution was observed, respectively, for 4 and 3 patients, after a median follow-up of 8 years (range 3-16 years)., Conclusions: DNA-PKcs deficiency mainly manifests as an inflammatory disease with granuloma and autoimmune features, along with severe infections., Competing Interests: Disclosure statement Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. This research was funded by ANR (ANR-21-CE17-0064 [SOCSIMMUNITY]]), ANR-21-RHUS-08 [COVIFERON]) from the ANR–Recherche Hospitalo Universitaire Program; by the Horizon Europe (01057100 [UNDINE]) from the HORIZON-HLTH-2021-DISEASE-04; le Centre de référence des rhumatismes inflammatoires, des interféronopathies et des maladies autoimmunes (RAISE)., (Copyright © 2024. Published by Elsevier Inc.)

Background: Feline osteoarthritis (OA) leads to chronic pain and somatosensory sensitisation. In humans, sensory exposure can modulate chronic pain. Recently, electroencephalography (EEG) revealed a specific brain signature to human OA. However, EEG pain characterisation or its modulation does not exist in OA cats, and all EEG were conducted in sedated cats, using intradermal electrodes, which could alter sensory (pain) perception., New Method: Cats (n=11) affected by OA were assessed using ten gold-plated surface electrodes. Sensory stimuli were presented in random orders: response to mechanical temporal summation, grapefruit scent and mono-chromatic wavelengths (500 nm-blue, 525 nm-green and 627 nm-red light). The recorded EEG was processed to identify event-related potentials (ERP) and to perform spectral analysis (z-score)., Results: The procedure was well-tolerated. The ERPs were reported for both mechanical (F3, C3, Cz, P3, Pz) and olfactory stimuli (Cz, Pz). The main limitation was motion artifacts. Spectral analysis revealed a significant interaction between the power of EEG frequency bands and light wavelengths (p<0.001). All wavelengths considered, alpha band proportion was higher than that of delta and gamma bands (p<0.044), while the latter was lower than the beta band (p<0.016). Compared to green and red, exposure to blue light elicited distinct changes in EEG power over time (p<0.001)., Comparison With Existing Method: This is the first demonstration of EEG feasibility in conscious cats with surface electrodes recording brain activity while exposing them to sensory stimulations., Conclusion: The identification of ERPs and spectral patterns opens new avenues for investigating feline chronic pain and its potential modulation through sensory interventions., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Competing Interests The author declares no competing interests.

Phototoxicity and skin cancer are severe adverse effects of the anti-fungal drug voriconazole (VOR). These adverse effects resemble those seen in xeroderma pigmentosum, caused by defective DNA nucleotide excision repair (NER), and we show that VOR decreases NER capacity. We show that VOR treatment does not perturb the expression of NER, or other DNA damage-related genes, but that VOR localizes to heterochromatin, in complexes containing histone acetyltransferase general control of amino-acid synthesis 5-like 2. Impairment of general control of amino-acid synthesis 5-like 2 binding to histone H3 reduced acetylation of H3, restricting damage-dependent chromatin unfolding, thereby reducing NER initiation. Restoration of H3 histone acetylation using histone deacetylase inhibitors, rescued VOR-induced NER repression, thus offering a preventive therapeutic option. These findings underline the importance of DNA damage-dependent chromatin remodeling as an important prerequisite of functional DNA repair., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Avalanche resistive switching is the fundamental process that triggers the sudden change of the electrical properties in solid-state devices under the action of intense electric fields. Despite its relevance for information processing, ultrafast electronics, neuromorphic devices, resistive memories and brain-inspired computation, the nature of the local stochastic fluctuations that drive the formation of metallic regions within the insulating state has remained hidden. Here, using operando X-ray nano-imaging, we have captured the origin of resistive switching in a V 2 O 3 -based device under working conditions. V 2 O 3 is a paradigmatic Mott material, which undergoes a first-order metal-to-insulator phase transition together with a lattice transformation that breaks the threefold rotational symmetry of the rhombohedral metallic phase. We reveal a new class of volatile electronic switching triggered by nanoscale topological defects appearing in the shear-strain based order parameter that describes the insulating phase. Our results pave the way to the use of strain engineering approaches to manipulate such topological defects and achieve the full dynamical control of the electronic Mott switching. Topology-driven, reversible electronic transitions are relevant across a broad range of quantum materials, comprising transition metal oxides, chalcogenides and kagome metals., (© 2024. The Author(s).)

Importance: Age-related macular degeneration (AMD) is a highly prevalent and debilitating retinal condition that affects more than 200 million people globally, with the severe late-stage forms-neovascular AMD (nAMD) and geographic atrophy (GA)-affecting more than 11 million people globally. However, much is unknown about the economic burden of the disease., Objective: To estimate the economic burden associated with late-stage AMD in Bulgaria, Germany, and the US at the societal level., Design, Setting, and Participants: This study used the prevalence approach cost-of-illness economic modeling to estimate costs attributable to late-stage AMD. Data on health care resource utilization, well-being, and productivity were obtained via primary data collection. Additional data required for the model were sourced from available published literature. Data were collected from January 2021 to March 2022, and analyzed from April to July 2022. Participants older than 50 years residing in Bulgaria, Germany, and the US who were diagnosed with late-stage AMD (nAMD or any form of GA) in 1 or both eyes and caregivers who care for people diagnosed with late-stage AMD were recruited through ophthalmological clinics in Bulgaria and Germany and via online newsletters and social media in the US., Main Outcomes and Measures: The main outcomes were direct medical costs (disease-related health care expenditures), indirect medical costs (care support and assistive technology), well-being cost (loss of well-being), and productivity cost (loss in productivity due to the diseases for both patient and caregivers)., Results: Of the 128 individuals with late-stage AMD in this study, 80 (62%) were female, and 120 (94%) were aged 60 years or older. Of the 61 caregivers, 43 (70%) were female and 55 (91%) were aged 45 years or older. Estimated per-annum total costs attributable to late-stage AMD were €449.5 million ($512.5 million) in Bulgaria, €7.6 billion ($8.6 billion) in Germany, and €43.2 billion ($49.4 billion) in the US. Across all countries, 10% to 13% of the total cost incurred was attributed to direct medical costs. In Germany and Bulgaria, the biggest contributor to the total economic burden was reduced well-being (67% and 76%, respectively), whereas in the US, loss of productivity (42%) was the biggest contributor., Conclusions and Relevance: The findings of this study indicate a substantial burden of late-stage AMD on patients and caregivers in the US, Germany, and Bulgaria. Across the 3 countries, reduced well-being and loss of productivity were relatively large contributors to the total economic burden. Implementing measures to reduce AMD incidence, delay disease progression, and alleviate humanistic burden may help reduce the economic burden of late-stage AMD.