University of Caen Normandy

Background This feasibility study evaluated adherence and effectiveness to a digital multimodal intervention (cognitive and physical training) for cancer-related cognitive impairment (CRCI) in patients with breast cancer. Methods Breast cancer patients undergoing radiotherapy and with significant cognitive complaints impacting quality of life participated in a 12-week intervention, combining non-simultaneous 20-min cognitive and 30-min physical sessions, twice weekly. Assessments included perceived cognitive impairment (PCI), objective cognition, fatigue, anxiety/depression, sleep and satisfaction. High level of adherence was defined as completing 9/12 weeks of the program. A week was complete when at least 70% of each of the planned sessions was completed. Physical activity intensity was defined by max age-related heart rate. Results Among 419 radiotherapy-treated patients with breast cancer, 170 had cognitive complaints (41%), 83 were eligible (49%), 29 were not included (35%) due to organizational issue and 20 among eligible contacted patients agreed to participate (37%). The majority of participants (48.3 ± 8 years of age) received chemotherapy (18/20) and 17 had I-II cancer stage. Eleven of twenty participants were highly adherent (higher adherence in physical (95%) than cognitive training (55%)). All expressed satisfaction. Post-intervention, overall objective cognition (p = 0.016), PCI (p = 0.004), fatigue (p = 0.011), and depression (p = 0.049) significantly improved. Post-intervention, high adherence was associated with significant improvements in PCI (p = 0.01) and fatigue (p = 0.03). High-intensity physical training was associated with significant improvements in PCI (p < 0.05), fatigue (p = 0.011) and depression (p = 0.037). Conclusions This intervention showed to be feasible and potentially efficient for the management of CRCI in patients with breast cancer. Trial registration NCT04213365, 27/12/2019.

Intraspecific trait variation, whether phenotypic or due to genotypic differences, can influence ecosystem functioning, especially in the case of ecosystem engineering species. Here, we investigated a coastal ecosystem dominated by 2 distinct genetic lineages of the native brown mussel Perna perna in 2 biogeographical regions along the South African coastline. Both euendolithic corrosion and genetically based behavioural differences have been shown to improve the microclimate of mussel beds and thus reduce abiotic stress for associated macrofauna. We therefore hypothesized that euendolithic corrosion of mussel shells, and its interactions with known genotypic variation, would affect the bioengineering capabilities of mussels on the rocky shores. Two manipulative field experiments revealed that macrofaunal communities differed significantly between experimental sites, reflecting the effects of biogeography and regional patterns in species distribution. Unexpectedly, neither euendolithic corrosion nor its interaction with P. perna genetic lineages influenced macrofaunal community structure. In marine bioengineered habitats, the associated macrofauna respond differently to intraspecific trait variations in the engineer depending on their own sensitivity to environmental stressors. In addition, this influence is limited to the spatio-temporal context in which trait variations have an effect. Although intraspecific trait variation was previously demonstrated to influence ecosystem processes in mussel beds, regional/biogeographic effects were more important in determining the composition of the associated macrofauna. Identifying the relative influence of genotypic and phenotypic intraspecific trait variation versus biogeography and large-scale processes on both ecosystem engineers and their associated communities is required to predict their ecosystem-level consequences for coastal communities under the effects of global climate change.

This study evaluated the in vitro and in silico probiotic potential and technological characteristics of Lacticaseibacillus rhamnosus MW019593 isolated from Algerian cow’s milk. Safety was verified by the absence of hemolytic activity, biogenic amine production, and antibiotic sensitivity. Functional probiotic properties of L. rhamnosus MW019593 included moderate inhibition of gastrointestinal pathogens such as Salmonella, Listeria, Clostridioides, and Escherichia coli, tolerance to pH 2–3 and up to 1% bile salts, 46.4% hydrophobicity, 42.4% autoaggregation, and 12.9% adhesion to Caco-2/TC7 cells without cytotoxicity. The ability to form biofilms with a thickness of 23.7 µm, comparable to L. rhamnosus ATCC 53103, was observed using confocal microscopy. Technologically, L. rhamnosus MW019593 and ATCC 53103 showed similar growth profiles and biomass yields, reaching approximately 5 × 10⁹ CFU/mL with a 63% yield after lyophilization. No significant difference in strain viability was noted at 4 °C and − 20 °C, which are suitable temperatures to maintain their viability for 3 months. Whole genome sequencing (WGS) was conducted on L. rhamnosus MW019593, followed by comprehensive in silico genomic analysis. Taxonomic validation using average nucleotide identity (ANI) and genome-to-genome distance hybridization (GGDH) confirmed the strain’s affiliation to this species. Gene screening revealed the absence of virulence and antibiotic resistance genes, while beneficial genes, including those for bacteriocin production, were identified. These findings, supported by the demonstrated safety, functional, and technological properties of the strain, highlight its promising potential for food and therapeutic applications, pending in vivo validation.

Herein, we describe an economic, straightforward and selective synthesis for trigonal heteroleptic silver(I) complexes bearing N‐Heterocyclic Carbenes (NHC) and bidentate ligands. The procedure allows to synthesize the targeted compounds in mild conditions and short reaction time with various NHC associated with bis‐pyridylamine or diphosphine as second ligands. Silver(I) complexes have been fully structurally and photophysically characterized, unveiling the different role and impact of the ligands in the photophysical behavior of this family of silver(I) complexes.

Background Type 2 diabetes (T2D) is a phenotypically heterogeneous disease. The use of insulin is required in a significant portion of people with T2D, despite recent developments in antidiabetic medications. This study analyzes glycemic outcomes in automated insulin delivery (AID) users with T2D with different insulin requirements. Methods This is a retrospective, real-world analysis including MiniMed 780G (MM780G) data uploaded to CareLink Personal (January 2020 to April 2024). Four cohorts were identified based on phenotypes of T2D: (A) users with total daily dose of insulin (TDD) ≥ 100 IU, (B) users with self-reported T2D, (C) users with self-reported T2D and TDD ≥ 100 IU, and (D) users with self-reported T2D and TDD <100 IU. Glycemic outcomes and insulin use were assessed post-AID, pre-AID versus post-AID, and six-month longitudinal post-AID. Results A total of 26 427 users were included in this study, of which 18 466 in cohort A, 10 795 in cohort B, 2 834 in cohort C, and 7 961 in cohort D. Mean time in range (TIR) was 71.1% ± 12.2 for cohort A, 75.1% ±14.1 for cohort B, 72.2% ± 15.0 for cohort C, and 76.1% ± 13.6 for cohort D. Mean time below range (TBR) <70 mg/dL was ≤1% in all cohorts. The users in cohort C using the recommended optimal settings (glucose target [GT] of 100 mg/dL and active insulin time [AIT] of two hours) had a greater TIR with 78.7% ± 10.8. All cohorts increased ≥10% post-AID compared with pre-AID. Conclusions The use of this AID is associated with effective therapy outcomes, as indicated by over 70% TIR, and appears to be safe, as demonstrated by a low TBR in a large cohort of real-life users with self-reported T2D and high or low TDD.

Background and Importance (⁶⁸Ga)Ga-DOTATOC is a radiopharmaceutical preparation (composed of gallium-68 and a radiopharmaceutical kit, SOMAKIT TOC) used in positron emission tomography (PET) for imaging somatostatin receptor overexpression in patients with gastroenteropancreatic neuroendocrine tumours, in order to localise primary tumours and their metastases. Data on adverse drug reactions (ADRs) associated with this preparation are scarce in the literature.1 2 We report a case following administration of (⁶⁸Ga)Ga-DOTATOC that has not been previously described in the literature. Aim and Objectives This study explores the case of a patient who presented to the nuclear medicine department for this examination. The patient reported a metallic taste in the mouth immediately after the administration of (⁶⁸Ga)Ga-DOTATOC with no prior history of this symptom. Material and Methods Our pharmacovigilance centre was notified and we searched the European pharmacovigilance database, EudraVigilance to investigate a possible link between this symptom and (⁶⁸Ga)Ga-DOTATOC. Results The patient’s general condition remained stable and this symptom did not recur. An investigation into other possible causes, including excipients and radiolabelled impurities (with a free gallium content of 0.52%, within the ≤ 2% recommended threshold), was conducted. Based on the chronology of the event, our pharmacovigilance centre deemed the reaction probably imputable to (⁶⁸Ga)Ga-DOTATOC. However, the radiopharmaceutical preparation was not contraindicated for this patient. EudraVigilance, the European database for adverse drug reaction (ADR) reports, has identified 60 individual cases of SOMAKIT TOC up to 29 September 2024. Two of these cases reported dysgeusia with this drug. Conclusion and Relevance This symptom, a metallic taste in the mouth, is probably an ADR associated with (⁶⁸Ga)Ga-DOTATOC. Pharmacovigilance plays a crucial role in identifying and documenting rare ADRs that have not yet been described in the literature. The use of the European database, EudraVigilance, and the World Health Organization’s global database, VigiBase, can provide valuable insights into the safety profiles of diagnostic or even therapeutic radiopharmaceuticals. References and/or Acknowledgements • Somakit Toc - European public assessment report - Product information. https://www.ema.europa.eu/en/documents/product-information/somakit-toc-epar-product-information_en.pdf • Summary of product characteristics for GalliAd, 0.74 −1.85 GBq, radionuclide generator. https://www.ire.eu/medias/296/UK.pdf Conflict of Interest No conflict of interest

Background and Importance Radioligand therapy, a therapeutic application of the radiotheranostic concept, is based on the use of a therapeutic radiopharmaceutical that targets a biomarker of interest in a given pathology. One example is (¹⁷⁷Lu)Lu-DOTATATE, used in the treatment of metastatic or inoperable, well-differentiated gastroenteropancreatic neuroendocrine tumours expressing somatostatin receptors. Clinical trials used to determine the safety of the drug do not represent a ‘real-life’ population. In order to provide a comprehensive safety analysis, we have used the World Health Organization’s pharmacovigilance database, VigiBase. Aim and Objectives This study aims to elucidate a comprehensive safety profile with real-life data of a therapeutic radiopharmaceutical such as (¹⁷⁷Lu)Lu-DOTATATE using VigiBase. Material and Methods An extraction of individual safety reports (ICSRs) reported and associated with (¹⁷⁷Lu)Lu-DOTATATE was performed. The general characteristics of the ICSRs were recorded. Adverse drug reactions (ADR) reporter in the ICSRs were sorted to create an ADR dictionary divided into classes and subclasses. A retrospective disproportionality analysis of ICSRs was then performed using the information component (IC, at alpha risk 0.05: IC025). The different classes of ADR were described, including the identification of overlaps between classes and the time taken for ADR to appear after initiation of the radiopharmaceutical. Results A total of 3,984 ICSRs related to (¹⁷⁷Lu)Lu-DOTATATE were analysed, with the majority of reports originating from the Americas (65%) and reported by physicians (45%). The most commonly co-reported drugs were octreotide (6%), amino acids (6%), ondansetron (6%), and lanreotide (5%). Disproportionality analysis identified significant associations between (¹⁷⁷Lu)Lu-DOTATATE and several ADR classes, including haematologic malignancies (IC025=2.48), haematologic disorders (IC025=2.15), liver disorders (IC025=1.43), renal failure (IC025=1.16), infections (IC025=0.91), alopecia (IC025=0.74), and metabolic disorders (IC025=0.17). The overlaps between classes were identified, including an overlap between haematological disorders and infections. The median time to onset of ADRs was also calculated and the longest delay was observed for haematologic malignancies. Conclusion and Relevance The VigiBase pharmacovigilance database, offers essential insights into the safety profile of (¹⁷⁷Lu)Lu-DOTATATE and can be leveraged for the evaluation of the safety of other therapeutic radiopharmaceuticals. Conflict of Interest No conflict of interest

Heterocycle synthesis is an intense research area due to their significant importance in pharmaceutical, material chemistry and fine synthesis. Key innovations include transition metal‐based‐catalyzed heterocyclic derivatives synthesis, which facilitates diverse structural modifications, enhances selectivities and efficiency. The necessity to develop more greener technologies for the construction of new C−C and C−N bonds has strived chemists to re‐design their synthetic strategy plan and to introduce abundant starting materials. Among these new transformations, acceptorless dehydrogenative coupling (ADC) reactions have received increased attention thanks to their atom‐economy, the use of alcohols as pro‐electrophiles and the formation of water and hydrogen gas as only by‐products. These methods exemplify the interplay between traditional and cutting‐edge techniques, providing a robust synthetic toolkit to address the growing demand for biologically relevant compounds with tailored functionalities. This review will focus on the acceptorless dehydrogenative coupling methodologies for the synthesis of nitrogen‐containing 5‐ and 6‐membered heterocyclic derivatives (such as pyrroles, pyrimidines, quinazolines, and quinoxalines) in the presence of 3d‐metal complexes. The state of the art of the ADC process underscores the continuous evolution of synthetic strategies and emphases its importance in creating valuable and structurally diverse compounds, ensuring their centrality in both academic and pharmaceutical research.

Calciprotein particles (CPPs) are calcium‐ and phosphate‐containing nanoparticles numbers of which are increased in patients with chronic kidney disease (CKD). CPPs have been associated with the development of vascular disease, although the underlying mechanisms are unknown. We previously showed that CPPs induce endothelial cell (EC) dysfunction by reducing nitric oxide (NO) bioavailability and generating superoxide (O2.−). Here, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca²⁺) overload, which may trigger mitochondrial dysfunction and, consequently, EC activation. Exposure of human umbilical vein ECs to CPPs resulted in significantly increased cytosolic and mitochondrial Ca²⁺ levels compared to vehicle‐treated ECs. Proteome analysis demonstrated impaired endoplasmic reticulum calcium signalling, and decreased enrichment of proteins in the mitochondrial OXPHOS complexes I–III in CPP‐exposed ECs. Respirometry data confirmed these findings and demonstrated decreased basal and maximal respiration in CPP‐exposed ECs. This was accompanied by reduced mitochondrial membrane potential, reduced antioxidant capacity and loss of mitochondria. In the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor, CPP‐induced EC activation and cell death were attenuated. Taken together, our data indicate that CPP‐induced Ca²⁺ overload is an important trigger of mitochondrial dysfunction, and EC activation and cell loss, which eventually may contribute to the development of vascular diseases in CKD. Interventions that target CPP‐induced mitochondrial dysfunction might preserve EC function and possibly alleviate the development of vascular diseases in CKD. image Key points Calciprotein particles (CPPs) are calcium‐ and phosphate‐containing nanoparticles numbers of which are increased in patients with chronic kidney disease and which have been associated with the development of vascular disease. In this study, we tested the hypothesis that CPPs induce mitochondrial calcium (Ca²⁺) overload in endothelial cells, thereby triggering mitochondrial dysfunction and endothelial activation. We show that exposure of HUVECs (human umbilical vein endothelial cells) to CPPs results in increased cytosolic and mitochondrial Ca²⁺ levels, which is associated with alterations in mitochondrial processes (proteome analysis), cellular respiration, mitochondrial integrity and number. CPP‐induced EC activation and cell death were attenuated in the presence of cyclosporin A, a potent mitochondrial permeability transition pore inhibitor. Our data indicate that CPP‐induced Ca²⁺ overload triggers mitochondrial dysfunction, endothelial activation and cell loss. Interventions that target CPP‐induced mitochondrial dysfunction might preserve EC function in chronic kidney disease.

Like bacteria and plants, fungi produce a remarkable diversity of small molecules with potent activities for human health known as natural products or secondary metabolites. One such example is mycophenolic acid (MPA), a powerful immunosuppressant drug that is administered daily to millions of transplant recipients worldwide. Production of MPA is restricted to a very limited number of filamentous fungi, and little is known about its biosynthetic modalities. It is therefore a particular challenge to improve our knowledge of the biosynthesis of this valuable natural compound, as this would contribute to a better understanding of the specialized metabolism of fungi and could also lead to the identification of new fungal producers for the supply of immunosuppressants. Here, we were interested in deciphering the origin and evolution of the fungal MPA biosynthetic pathway. Large-scale analyses of fungal genomic resources led us to identify several new species that harbour a gene cluster for MPA biosynthesis. Phylogenomic analysis suggests that the MPA biosynthetic gene cluster originated early in a common ancestor of the fungal family Aspergillaceae but was repeatedly lost and it is now present in a narrow but diverse set of filamentous fungi. Moreover, comparison of the IMPDH protein sequences that are the target of the MPA drug as well as analysis of MPA production and susceptibility suggest that all MPA fungal producers are resistant to this toxic compound, but that this resistance is likely to be based on different molecular mechanisms. Our study provides new insight into the evolution of the biosynthesis of the important secondary metabolite MPA in fungi.

Introduction Recent literature has reported instances of drug associated with hypertension with serotonin reuptake inhibitors (SRIs). Nonetheless, the association between SRIs and hypertension development is the subject of ongoing debate. It remains uncertain whether this is indicative of a class effect, and if dose-effect exist. To investigate the potential class effect associating SRIs with hypertension reporting, we utilized real-world data from VigiBase®, the World Health Organization (WHO) pharmacovigilance database. Methods We conducted an updated disproportionality analysis within VigiBase® to identify a signal of hypertension reporting with individual SRIs by calculating adjusted reporting odds ratios (aRORs) within a multivariate case/non-case study design. Additionally, we explored the presence of a dose-effect relationship. Results The database contained 13,682 reports of SRI associated with hypertension (2.2%), predominantly in women (70.0%). Hypertension was most reported in the 45-64 years old age group (44.8%). A total of 3,879 cases were associated with sertraline, 2,862 with fluoxetine, 2,516 with citalopram, 2,586 with escitalopram, 2,441 with paroxetine, 201 with fluvoxamine and 8 with zimeldine. A significant ROR was observed for all SRIs in both univariate (RORs ranging from 1.39 to 1.54) and multivariable analyses (aRORs ranging from 1.16 to 1.40) after adjustments for age group, sex, concurrent antihypertensive medication and drugs knowns to induce hypertension, except for fluvoxamine and zimeldine. No dose-response relationship was identified. Conclusion This investigation, conducted under real life conditions, unveils a notable pharmacovigilance safety signal associating SRI usage with hypertension reporting. No dose-response effect was detectable. Further longitudinal studies are warranted.

This study explores using transformer models to analyze data from the KM3NeT/ORCA neutrino telescope. Due to the increasing detector’s size, reconstructing neutrino events is challenging. By training models on simulations for the full detector (115 detection units) and fine-tuning them on smaller configurations, significant performance improvements can be achieved compared to models trained from scratch on limited data samples. This approach also helps estimate the detector’s sensitivity as it grows.

The TempWeb workshop (series) is an established co-located event at The Web Conference that aims at bringing together researchers and practitioners across various domains, taking the constantly evolving Web as a primary object of research. In this context, research questions aim at the investigation of infrastructures, scalable methods, and innovative software for aggregating, querying, and analyzing heterogeneous data at Web scale. To this end, submissions commonly address core fields of studies in computer science and aspects such as temporal IE/IR, Web mining, Web archiving and large scale data analysis to just name a few. However, TempWeb does not only address computer science related research, but also attracts not necessarily technical innovations from application domains such as the social sciences, marketing, economics, etc. As a consequence, TempWeb has developed as a forum for a community from science and industry across various disciplines. For its 2024 edition, topics of TempWeb covered again a wide spectrum of Web related research ranging from studies of control mechanisms, via terminological studies, up to community analysis and content recommendation. Date : 14 May 2024. Website : http://temporalweb.net/.

The Web Science conference series (WebSci) is an established venue for Web related research across disciplines. The co-located PhD symposium is an endeavor in fostering interdisciplinary thinking and collaboration at an early stage. Bringing PhD students from various disciplines together is, according to our understanding, an important step towards a more comprehensive investigation of the Web. As such, the PhD symposium is intended to establish a forum for the next generation of Web Scientists. Following the spirit of "unity in diversity" the many facets of Web related research ranging from computer science, the social sciences, via marketing and economics up to application domains such as, e.g., geography are addressed in this unique event. By doing so, a joint understanding beyond the limits of one's own discipline can emerge that might allow a more interdisciplinary and inclusive future of the Web. Date : 21 May 2024. Website : https://websci24.webscience.org/program/phd-symposium/.

We report on the generation of sub-30 fs pulses from a diode-pumped Yb,Gd:YAP laser. Using soft-aperture Kerr-lens mode-locking, soliton pulses as short as 23 fs were achieved at 1082.3 nm, with an average output power of 45 mW at a repetition rate of 67.25 MHz. The mode-locked laser also produced a maximum average output power of 101 mW at 1056.5 nm with a slightly longer pulse duration of 34 fs, corresponding to a peak power of 38.9 kW. To the best of our knowledge, this is the first demonstration of Kerr-lens mode-locked operation in a diode-pumped Yb,Gd:YAP laser, with the shortest pulses ever reported from any Yb³⁺-doped perovskite-type crystal.

Rare genetic variants in ARID2 are responsible for a recently described neurodevelopmental condition called ARID2-related disorder (ARID2-RD). ARID2 belongs to PBAF, a unit of the SWI/SNF complex, which is a chromatin remodeling complex. This work aims to further delineate the phenotypic spectrum of ARID2-RD, providing clinicians with additional data for better care and aid in the future diagnosis of this condition. We obtained the genotypes and phenotypes of 27 previously unreported individuals with ARID2-RD and compared this series with findings in the literature. We also assessed peripheral blood DNA methylation profiles in individuals with ARID2-RD compared to episignatures of controls, unresolved cases, and other neurodevelopmental disorders. The main clinical features of ARID2-RD are developmental delay, speech disorders, intellectual disability (ID), behavior problems, short stature, and various dysmorphic and ectodermal features. Genome-wide differential methylation analysis revealed a global hypermethylated profile in ARID2-RD that could aid in reclassifying variants of uncertain significance. Our study doubles the number of reported individuals with ARID2 pathogenic variants to 53. It confirms loss-of-function as a pathomechanism and shows the absence of a clear genotype-phenotype correlation. We provide evidence for a unique DNA methylation episignature for ARID2-RD and further delineate the ARID2-associated phenotype.