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Purpose This study was performed to assess the risk factors for artificial urinary sphincter (AUS) explantation in a large multicenter cohort. Methods We retrospectively reviewed the medical records for all 1,233 implantations of the AMS-800 AUS device in male nonneurological patients from 2005 to 2020 across 13 French centers. Patients with neurological conditions were excluded from the study. To identify factors associated with explantation-free survival, survival analysis was performed. Explantation was defined as the complete removal of the device, whereas revision referred to the replacement of the device or its components. Results The study included 1,107 patients, of whom 281 underwent AUS explantation. The median survival without explantation was 83 months. The leading causes of explantation were infection and erosion. Univariate analysis revealed several significant risk factors for explantation: age above 75 years (34.6% in the explanted group vs. 25.8% in the nonexplanted group, P=0.007), history of radiotherapy (43.5% vs. 31.3%, P=0.001), and anticoagulant use (15% vs. 8.6%, P

Abstract Image‐based machine learning tools are an ascendant ‘big data’ research avenue. Citizen science platforms, like iNaturalist, and museum‐led initiatives provide researchers with an abundance of data and knowledge to extract. These include extraction of metadata, species identification, and phenomic data. Ecological and evolutionary biologists are increasingly using complex, multi‐step processes on data. These processes often include machine learning techniques, often built by others, that are difficult to reuse by other members in a collaboration. We present a conceptual workflow model for machine learning applications using image data to extract biological knowledge in the emerging field of imageomics. We derive an implementation of this conceptual workflow for a specific imageomics application that adheres to FAIR principles as a formal workflow definition that allows fully automated and reproducible execution, and consists of reusable workflow components. We outline technologies and best practices for creating an automated, reusable and modular workflow, and we show how they promote the reuse of machine learning models and their adaptation for new research questions. This conceptual workflow can be adapted: it can be semi‐automated, contain different components than those presented here, or have parallel components for comparative studies. We encourage researchers—both computer scientists and biologists—to build upon this conceptual workflow that combines machine learning tools on image data to answer novel scientific questions in their respective fields.

IntroductionLaparoscopy has become a fundamental aspect of surgery, presenting new challenges such as fatigue, encompassing both muscular and cognitive components. Given its potential to affect surgical precision and create difficulties for the surgeon, it is crucial to study the mechanisms of fatigue for patient safety and the well-being of surgeons. This study aims to demonstrate the influence of general fatigue on surgeons’ performance, incorporating assessments of movement quality through balance, kinematics, and muscle activation, as well as perceived workload. Additionally, the study seeks to evaluate how surgeons’ experience may affect fatigue outcomes.Methods and analysisA controlled cross-over laboratory trial involving 29 residents and surgeons from the obstetrics and gynecology department of Nantes University Hospital is underway. Recruitment started in March 2023 and ended in September 2023. Participants with varying levels of experience perform two one-hour sessions of training box exercises, one in the morning (control condition) and the other at the end of a workday. The primary outcome is a composite score derived from the time to complete the Suturing and Knot Tying Training and Testing (SUTT) exercise, along with the number and quality of stitches. Secondary outcomes include perceived fatigue, discomfort, physical strain, muscle tension, mental workload, muscle activation (measured by surface electromyography), balance (measured using a force platform), and kinematics (measured using motion capture).Ethics and disseminationThe study received ethical approval from the local ethics committee CERNI in December 2022 (n°13,122,022). Results will be presented in international conferences, submitted to peer-reviewed journals, and serve as a feasibility study for subsequent publications.

Abstract Objectives To assess the efficacy and safety of preoperative neoadjuvant everolimus in renal angiomyolipomas (AML) patients with or without Tuberous Sclerosis Complex (TSC). Materials and Methods This multi‐institutional retrospective study enrolled renal AML patients who underwent partial nephrectomy (PN) or total nephrectomy after receiving at least 1 month of pre‐operative everolimus. Imaging evaluations were collected before and after treatment, along with demographic, surgical, and follow‐up information. The primary outcome was tumor volume reduction of ≥25%, with additional outcomes including recurrence, perioperative outcomes, renal function, and safety. Results From January 2015 to July 2022, 68 renal AML patients were studied—41 with TSC and 27 without. During everolimus treatment, 61.0% (25/41) of TSC patients and 44.4% (12/27) of non‐TSC patients achieved tumor reduction of ≥25%. Additionally, 41.5% (17/41) of TSC patients and 18.5% (5/27) of non‐TSC patients achieved a ≥ 50% reduction. Three TSC patients and 1 non‐TSC patient discontinued treatment due to side‐effects. Most patients (92.7% TSC, 85.2% non‐TSC) underwent PN. After everolimus treatment, the necessary total nephrectomy decreased to 41.2% (7/17) from baseline. Postoperatively, 1 grade 3 and 3 grade 2 complications occurred, with no grade 4 or 5 complications. After a median follow‐up of 24 months, only 1 TSC patient recurred with a diameter >3 cm. Retrospective nature is the major limitation of this study. Conclusion Everolimus was effective and well‐tolerated in neoadjuvant treatment for renal AML, especially in TSC patients. This neoadjuvant combination strategy of everolimus and PN could effectively controls recurrence and preserves renal function.

Background: There is no definitive evidence of the prognosis impact of histological variants (HVs) in patients who undergo surgical resection of a nonmetastatic renal cell carcinoma (nm-RCC) with venous tumor thrombus (TT). Objective: To investigate the impact of HVs on the prognosis of patients with nm-RCC with TT after radical surgery. Design, setting, and participants: Patients who underwent radical nephrectomy with the removal of the venous TT for an nm-RCC were included in a retrospective study. Outcome measurements and statistical analysis: Three groups were identified: clear cell (ccRCC), papillary (pRCC), and chromophobe (chRCC) RCC. The primary outcome measures (disease-free and overall survival [OS]) were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional hazard models were used to study the impact of HVs on survival. Results and limitations: A total of 873 patients were included. The histological subtypes were distributed as follows: ccRCC in 780 cases, pRCC in 58 cases, and chRCC in 35 cases. At the time of data analysis, 612 patients were recurrence free and 228 had died. A survival analysis revealed significant differences in both OS and recurrence-free survival across histological subtypes, with the poorest outcomes observed in pRCC patients (p

Background A combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy, and biomarkers of neoadjuvant toripalimab plus axitinib in non-metastatic clear cell RCC.Methods This is a single-institution, single-arm phase II clinical trial. Patients with non-metastatic biopsy-proven clear cell RCC (T2-T3N0-1M0) are enrolled. Patients will receive axitinib 5 mg twice daily combined with toripalimab 240 mg every 3 weeks (three cycles) for up to 12 weeks. Patients then will receive partial (PN) or radical nephrectomy (RN) after neoadjuvant therapy. The primary endpoint is objective response rate (ORR). Secondary endpoints include disease-free survival, safety, and perioperative complication rate. Predictive biomarkers are involved in exploratory analysis.Results A total of 20 patients were enrolled in the study, with 19 of them undergoing surgery. One patient declined surgery. The primary endpoint ORR was 45%. The posterior distribution of πORR had a mean of 0.44 (95% credible intervals: 0.24–0.64), meeting the predefined primary endpoint with an ORR of 32%. Tumor shrinkage was observed in 95% of patients prior to nephrectomy. Furthermore, four patients achieved a pathological complete response. Grade ≥3 adverse events occurred in 25% of patients, including hypertension, hyperglycemia, glutamic pyruvic transaminase/glutamic oxaloacetic transaminase (ALT/AST) increase, and proteinuria. Postoperatively, one grade 4a and eight grade 1–2 complications were noted. In comparison to patients with stable disease, responders exhibited significant differences in immune factors such as Arginase 1(ARG1), Melanoma antigen (MAGEs), Dendritic Cell (DC), TNF Superfamily Member 13 (TNFSF13), Apelin Receptor (APLNR), and C-C Motif Chemokine Ligand 3 Like 1 (CCL3-L1). The limitation of this trial was the small sample size.Conclusion Neoadjuvant toripalimab combined with axitinib shows encouraging activity and acceptable toxicity in locally advanced clear cell RCC and warrants further study.Trial registration number clinicaltrials.gov, NCT04118855.

The authors wish to make the following correction to their paper [...]

Background: Artificial urinary sphincter (AUS) is a gold standard treatment in male stress urinary incontinence but remains poorly used in elderly patients. Objective: To assess the efficacy, safety, and reoperation-free survival of AUS implantation in male patients over 75 yr of age. Design, setting, and participants: We retrospectively reviewed the charts of all 1233 non-neurological male AUS implantations between 2005 and 2020 at 13 French centers. We compared 330 patients ≥75 yr old (GROUP75+) with 903 patients

Abstract Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.

Active felsic magmatism has been rarely probed in situ by drilling but one recent exception is quenched rhyolite sampled during the 2009 Iceland Deep Drilling Project (IDDP). We report finding of rare zircons of up to ∼100 µm in size in rhyolite glasses from the IDDP-1 well products and the host 1724 AD Viti granophyres. The applied SHRIMP U-Th dating for both the IDDP and the Viti granophyre zircons gives zero-age (±2 kyr), and therefore suggests that the IDDP-1 zircons have crystallized from an active magma intrusion rather than due to the 20–80 ka post-caldera magmatic episodes recorded by nearby domes and ridges. Ti-in-zircon geothermometer for Viti granophyre reveals zircon crystallization temperatures ∼800°C–900°C, whereas IDDP-1 rhyolite zircon cores show Ti content higher than 100 ppm, corresponding to temperatures up to ∼1,100°C according to the Ti-in-zircon thermometer. According to our thermochemical model at such elevated temperatures as 1,100°C, rhyolitic magma cannot be saturated with zircon and zircon crystallization is not possible. We explain this controversy by either kinetic effects or non-ideal Ti incorporation into growing zircons at low pressures that start to grow from nucleus at temperatures ∼930°C. High temperatures recorded by IDDP-1 zircon together with an occurrence of baddeleyite require that the rhyolite magma formed by partial melting of the host granophyre due to basaltic magma intrusion. Zr concentration profiles in glass around zircons are flat, suggesting residence in rhyolitic melt for >4 years. In our thermochemical modeling, three scenarios are considered. The host felsite rocks are intruded by: 1) a basaltic sill, 2) rhyolite magma 3) rhyolite sill connected to a deeper magmatic system. Based on the solution of the heat conduction equation accounting for the release of latent heat and effective thermal conductivity, these data confirm that the rhyolite magma could be produced by felsic crust melting as a result of injection of a basaltic or rhyolite sill during the Krafla Fires eruption (1975 AD).

Previous computational and experimental studies showed that charges located at the surroundings of hydrogen bonds can exert two opposite effects on them: rupture or strengthening of the hydrogen bond. This work aims to generalize the effect of charges in different hydrogen-bonded systems and to propose a coherent explanation of this effect. For these purposes, 19 systems with intra- and intermolecular hydrogen bonds were studied computationally with DFT. The FT-IR spectra of the systems were simulated, and two energy components of the hydrogen bond were studied separately to determine their variation upon the presence of a charge: charge transfer and molecular overlap. It was determined that either the breaking or strengthening of the hydrogen bond can be favored one over the other, for instance, depending on the heteroatom involved in the hydrogen bond. In addition, it is showed that the strengthening of the hydrogen bond by the presence of a charge is directly related to the decrease in charge transfer between the monomers, which is explained by an increase in molecular overlapping, suggesting a more covalent character of the interaction. The understanding of how hydrogen bonds are affected by charges is important, as it is a key towards a strategy to manipulate hydrogen bonds at convenience.

Here, the authors studied how cerebellar stimulation alleviates levodopa-induced dyskinesia (LID). They demonstrated that Purkinje cell opto-stimulation is sufficient to prevent LID development and can normalize brain activity in a wide motor network in mice.

Abstract Introduction Cisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for patients with non-metastatic muscle invasive bladder cancer (MIBC). Unfortunately, many patients are not candidates to receive cisplatin due to renal impairment. Additionally, no predictive biomarkers for pathological complete response (pCR) are currently validated in clinical practice. Studies evaluating immune checkpoint inhibitors in the peri-operative setting are emerging with promising results. Clinical trials are clearly required in the neoadjuvant setting in order to improve therapeutic strategies. Methods and analysis Oncodistinct 004 – AURA is an ongoing multicenter phase II randomized trial assessing the efficacy and safety of avelumab single-agent or combined to different NAC regimens in patients with non-metastatic MIBC. Patients are enrolled in two distinct cohorts according to their eligibility to receive cisplatin-based NAC. In the cisplatin eligible cohort, patients are randomized in a 1:1 fashion to receive avelumab combined with cisplatin-gemcitabine or with dose-dense methotrexate-vinblastine-doxorubicin-cisplatin. In the cisplatin ineligible cohort, patients are randomized at a 1:1 ratio to paclitaxel-gemcitabine associated to avelumab or avelumab alone. Primary endpoint is pCR. Secondary endpoints are pathological response and safety. Ethics and dissemination The study is approved by ethics committee from all participating centers. All participants provide informed consent prior inclusion to the study. Once completed, results will be published in peer-reviewed journals. Trial registration number ClinicalTrials.gov (NCT03674424).

Peripheral membrane proteins (PMPs) include a wide variety of proteins that have in common to bind transiently to the chemically complex interfacial region of membranes through their interfacial binding site (IBS). In contrast to protein-protein or protein-DNA/RNA interfaces, peripheral protein-membrane interfaces are poorly characterized. We collected a dataset of PMP domains representative of the variety of PMP functions: membrane-targeting domains (Annexin, C1, C2, discoidin C2, PH, PX), enzymes (PLA, PLC/D) and lipid-transfer proteins (START). The dataset contains 1328 experimental structures and 1194 AphaFold models. We mapped the amino acid composition and structural patterns of the IBS of each protein in this dataset, and evaluated which were more likely to be found at the IBS compared to the rest of the domains' accessible surface. In agreement with earlier work we find that about two thirds of the PMPs in the dataset have protruding hydrophobes (Leu, Ile, Phe, Tyr, Trp and Met) at their IBS. The three aromatic amino acids Trp, Tyr and Phe are a hallmark of PMPs IBS regardless of whether they protrude on loops or not. This is also the case for lysines but not arginines suggesting that, unlike for Arg-rich membrane-active peptides, the less membrane-disruptive lysine is preferred in PMPs. Another striking observation was the over-representation of glycines at the IBS of PMPs compared to the rest of their surface, possibly procuring IBS loops a much-needed flexibility to insert in-between membrane lipids. The analysis of the 9 superfamilies revealed amino acid distribution patterns in agreement with their known functions and membrane-binding mechanisms. Besides revealing novel amino acids patterns at protein-membrane interfaces, our work contributes a new PMP dataset and an analysis pipeline that can be further built upon for future studies of PMPs properties, or for developing PMPs prediction tools using for example, machine learning approaches.

We present here the synthesis, chemical, and photophysical study of a series of three new copper halide derivatives, namely 2a–c. They are all tetranuclear copper-iodide clusters of general formula [Cu(μ3-I)P]4 consisting of a cubane-like {Cu4I4} motif and P = phosphine. They differ in the type of the phosphines used as ligands: a monophosphine with a single pendant ester unit (complex 2a), two pendant ester units (2b), and a diphosphine containing two esters in the linker (2c). The molecular structure of the complexes was determined by single-crystal X-ray diffraction analysis. All the investigated derivatives were found to be photo- and thermally-stable luminescent species. In the solid state, the complexes display intense and long-lived photoluminescence in the orange region with PLQY values of 0.43–0.84 at room temperature associated mainly with a 3CC excited state with mixed 3XMCT character.

Objectives We aimed to apply natural language processing algorithms in routine healthcare records to identify reported somatic passivity (external control of sensations, actions and impulses) and thought interference symptoms (thought broadcasting, insertion, withdrawal), first-rank symptoms traditionally central to diagnosing schizophrenia, and determine associations with prognosis by analysing routine outcomes.Design Four algorithms were developed on deidentified mental healthcare data and applied to ascertain recorded symptoms over the 3 months following first presentation to a mental healthcare provider in a cohort of patients with a primary schizophreniform disorder (ICD-10 F20-F29) diagnosis.Setting and participants From the electronic health records of a large secondary mental healthcare provider in south London, 9323 patients were ascertained from 2007 to the data extraction date (25 February 2020).Outcomes The primary binary dependent variable for logistic regression analyses was any negative outcome (Mental Health Act section, >2 antipsychotics prescribed, >22 days spent in crisis care) over the subsequent 2 years.Results Final adjusted models indicated significant associations of this composite outcome with baseline somatic passivity (prevalence 4.9%; adjusted OR 1.61, 95% CI 1.37 to 1.88), thought insertion (10.7%; 1.24, 95% CI 1.15 to 1.55) and thought withdrawal (4.9%; 1.36, 95% CI 1.10 to 1.69), but not independently with thought broadcast (10.3%; 1.05, 95% CI 0.91 to 1.22).Conclusions Symptoms traditionally central to the diagnosis of schizophrenia, but under-represented in current diagnostic frameworks, were thus identified as important predictors of short-term to medium-term prognosis in schizophreniform disorders.

Description of the subject. Given the current low price of milk, a lot of producers have decided to process their milk into products with a higher added-value, including butter. However, all milks are not suitable to be transformed into butter. It would thus be useful to be able to predict milk processing properties. Objectives. The aim of this paper was to study the ability of milk to be processed into butter using infrared spectrophotometry. Method. A normalized protocol for the production of butter was developed. Milk samples (n = 110) collected between 2013 and 2016 were analyzed by near and medium infrared spectrometry (315 spectra). Butter samples were also analyzed by visible-near infrared spectrometry (220 spectra). Composition of the products was subsequently assessed using validated prediction equations. Principal components analyses were performed to discriminate samples. Results. Butter properties seemed to be influenced by seasons and feedings. Water content and color parameters could be predicted on the basis of butter infrared spectra. Conclusions. It was possible to correlate butter characteristics with milk properties. However, it was not possible to predict butter characteristics on the basis of milk near infrared spectra. It could be interesting to try predictions from milk medium infrared spectra.

Non-invasive assessment of axon radii via MRI bears great potential for clinical and neuroscience research as it is a main determinant of the neuronal conduction velocity. However, there is a lack of representative histological reference data at the scale of the cross-section of MRI voxels for validating the MRI-visible, effective radius (reff). Because the current gold standard stems from neuroanatomical studies designed to estimate the bulk-determined arithmetic mean radius (rarith) on small ensembles of axons, it is unsuited to estimate the tail-weighted reff. We propose CNN-based segmentation on high-resolution, large-scale light microscopy (lsLM) data to generate a representative reference for reff. In a human corpus callosum, we assessed estimation accuracy and bias of rarith and reff. Furthermore, we investigated whether mapping anatomy-related variation of rarith and reff is confounded by low-frequency variation of the image intensity, e.g., due to staining heterogeneity. Finally, we analyzed the error due to outstandingly large axons in reff. Compared to rarith, reff was estimated with higher accuracy (maximum normalized-root-mean-square-error of reff: 8.5 %; rarith: 19.5 %) and lower bias (maximum absolute normalized-mean-bias-error of reff: 4.8 %; rarith: 13.4 %). While rarith was confounded by variation of the image intensity, variation of reff seemed anatomy-related. The largest axons contributed between 0.8 % and 2.9 % to reff. In conclusion, the proposed method is a step towards representatively estimating reff at MRI voxel resolution. Further investigations are required to assess generalization to other brains and brain areas with different axon radii distributions.

Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells. Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age. Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.

The selective ring-opening reaction of fluoroalkylidene-oxetanes was directed by the presence of the fluorine atom, enabling a two-step access to tetrasubstituted fluoroalkenes with excellent geometry control. Despite its small van der Waals radii electronic, rather than steric influences of the fluorine atom governed the ring-opening reaction with bromide ions, even in the presence of bulky substituents.

Abstract Background Threatened preterm delivery (TPD) is the leading cause of inpatient admissions during pregnancy. The ability to predict the risk of imminent preterm delivery is thus a major priority in obstetrics. The aim of our study is to assess the diagnostic performance of the test to detect the placental alpha microglobulin 1 (PAMG-1) for the prediction of delivery within 7 days in women with TPD. Methods This is a prospective multicenter diagnostic study. Inclusion criteria are singleton pregnancy, gestational age between 24 + 0 and 33 + 6 weeks inclusive, cervical measurement 25 mm or less assessed by transvaginal ultrasound (with or without uterine contractions), clinically intact membranes and cervical dilatation

Abstract Background Central nervous system damage in multiple sclerosis (MS) is responsible for serious deficiencies. Current therapies are focused on the treatment of inflammation; however, there is an urgent need for innovative therapies promoting neuroregeneration, particularly myelin repair. It is demonstrated that testosterone can act through neural androgen receptors and several clinical observations stimulated an interest in the potential protective effects of testosterone treatment for MS. Here, we sought to demonstrate the effects of a testosterone supplementation in testosterone-deficient men with relapsing-remitting MS. Methods/design This report presents the rationale and methodology of TOTEM RRMS, a French, phase 2, multicenter, randomized, placebo-controlled, and double-blind trial, which aims to prevent the progression of MS in men with low testosterone levels by administration of testosterone undecanoate, who were kept under natalizumab (Tysabri®) to overcome the anti-inflammatory effect of testosterone. Forty patients will be randomized into two groups receiving either a testosterone treatment (Nebido®) or a matching placebo. The intervention period for each group will last 66 weeks (treatment will be injected at baseline, week 6, and then every 12 weeks). The main objective is to determine the neuroprotective and remyelinating effects of testosterone using tensor diffusion imaging techniques and thalamic atrophy analyses. As secondary objectives, impacts of the testosterone supplementation will be studied using other conventional and unconventional MRI parameters and with clinical outcomes. Discussion The action of testosterone is observed in different experimental autoimmune encephalomyelitis models and epidemiological studies in humans. However, despite several preclinical data and some small clinical trials in MS, clear evidence for a therapeutic effect of hormone therapy is still missing. Therefore, our goal is to demonstrate the effects of testosterone therapies in MS. As there is no effective treatment currently available on fatigue in MS, careful attention should also be paid to secondary endpoints: fatigue, cognitive functions, and other symptoms that may improve life quality. Assuming a positive outcome of the trial, this treatment could be considered as a new neuroprotective and remyelinating therapy in relapsing-remitting MS and could be applicable to other demyelinating diseases. Trial registration ClinicalTrials.gov NCT03910738. Registered on 10 April 2019.

Summary: Septins are GTP-binding proteins involved in several membrane remodeling mechanisms. They associate with membranes, presumably using a polybasic domain (PB1) that interacts with phosphoinositides (PIs). Membrane-bound septins assemble into microscopic structures that regulate membrane shape. How septins interact with PIs and then assemble and shape membranes is poorly understood. Here, we found that septin 9 has a second polybasic domain (PB2) conserved in the human septin family. Similar to PB1, PB2 binds specifically to PIs, and both domains are critical for septin filament formation. However, septin 9 membrane association is not dependent on these PB domains, but on putative PB-adjacent amphipathic helices. The presence of PB domains guarantees protein enrichment in PI-contained membranes, which is critical for PI-enriched organelles. In particular, we found that septin 9 PB domains control the assembly and functionality of the Golgi apparatus. Our findings offer further insight into the role of septins in organelle morphology. : Membrane Architecture; Molecular Interaction; Cell Biology; Functional Aspects of Cell Biology Subject Areas: Membrane Architecture, Molecular Interaction, Cell Biology, Functional Aspects of Cell Biology

Phenomena related to asymmetric amplification are considered to be key to understanding the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been studied to understand such chiral amplification, in particular based on non-linear effects. Three decades after the theoretical demonstration that a chiral catalyst, when not enantiopure, could be more enantioselective than its enantiopure counterpart, we show here a new experimental example of nonlinear hyperpositive effect. We report here our investigations in the enantioselective zinc-catalyzed alkylation of benzaldehyde with N-pyrrolidinyl norephedrine as partially resolved chiral ligand, which shows a significant hyperpositive non-linear effect. A study of the underlying mechanism was conducted, which allows us to confirm a mechanism that implies a monomeric and a dimeric complex both catalyzing the reaction at a steady state and giving different enantioselectivities.

Peripheral membrane proteins (PMPs) bind temporarily to the surface of biological membranes. They also exist in a soluble form and their tertiary structure is often known. Yet, their membrane-bound form and their interfacial-binding site with membrane lipids remain difficult to observe directly. Their binding and unbinding mechanism, the conformational changes of the PMPs and their influence on the membrane structure are notoriously challenging to study experimentally. Molecular dynamics simulations are particularly useful to fill some knowledge-gaps and provide hypothesis that can be experimentally challenged to further our understanding of PMP-membrane recognition. Because of the time-scales of PMP-membrane binding events and the computational costs associated with molecular dynamics simulations, membrane models at different levels of resolution are used and often combined in multiscale simulation strategies. We here review membrane models belonging to three classes: atomistic, coarse-grained and implicit. Differences between models are rooted in the underlying theories and the reference data they are parameterized against. The choice of membrane model should therefore not only be guided by its computational efficiency. The range of applications of each model is discussed and illustrated using examples from the literature.

A pandemic linked to the new coronavirus strain (SARS-CoV-2) has been raging for several months. Pediatric populations are less impacted than adults, and critical respiratory diseases seem rare (1, 2). We report the case of an infant, who presented with life-threatening apneas at home requiring basic life support. SARS-CoV-2 was subsequently identified in the patient's nasopharyngeal aspirate. He did not present with bronchiolitis or hypoxic failure as described in severe forms of COVID−19. The outcome was favorable in a few hours. The occurrence of apneas is not uncommon during viral respiratory infections in early infancy; however, there are very few descriptions related to a documented SARS-CoV-2 respiratory tract infection. In light of this clinical case, it seems necessary to quickly bring up a potential COVID-19 contamination in infants admitted for life-threatening apnea, in order to properly report and isolate these patients to avoid further nosocomial dissemination of SARS-CoV-2.

Bio-nanotechnology has emerged as an efficient and competitive methodology for the production of added-value nanomaterials (NMs). This review article gathers knowledge gleaned from the literature regarding the biosynthesis of sulfur-based chalcogenide nanoparticles (S-NPs), such as CdS, ZnS and PbS NPs, using various biological resources, namely bacteria, fungi including yeast, algae, plant extracts, single biomolecules, and viruses. In addition, this work sheds light onto the hypothetical mechanistic aspects, and discusses the impact of varying the experimental parameters, such as the employed bio-entity, time, pH, and biomass concentration, on the obtained S-NPs and, consequently, on their properties. Furthermore, various bio-applications of these NMs are described. Finally, key elements regarding the whole process are summed up and some hints are provided to overcome encountered bottlenecks towards the improved and scalable production of biogenic S-NPs.

Acute inflammation is a physiological response to injury or infection, with a cascade of steps that ultimately lead to the recruitment of immune cells to clear invading pathogens and heal wounds. However, chronic inflammation arising from the continued presence of the initial trigger, or the dysfunction of signalling and/or effector pathways, is harmful to health. While successful ageing in older adults, including centenarians, is associated with low levels of inflammation, elevated inflammation increases the risk of poor health and death. Hence inflammation has been described as one of seven pillars of ageing. Age-associated sterile, chronic, and low-grade inflammation is commonly termed inflammageing—it is not simply a consequence of increasing chronological age, but is also a marker of biological ageing, multimorbidity, and mortality risk. While inflammageing was initially thought to be caused by “continuous antigenic load and stress”, reports from the last two decades describe a much more complex phenomenon also involving cellular senescence and the ageing of the immune system. In this review, we explore some of the main sources and consequences of inflammageing in the context of immunosenescence and highlight potential interventions. In particular, we assess the contribution of cellular senescence to age-associated inflammation, identify patterns of pro- and anti-inflammatory markers characteristic of inflammageing, describe alterations in the ageing immune system that lead to elevated inflammation, and finally assess the ways that diet, exercise, and pharmacological interventions can reduce inflammageing and thus, improve later life health.

Background: Endometrial cancer is the most common pelvic gynecological cancer in France. The most frequent symptom is post-menopausal bleeding and is one of the primary reasons for consultation in gynecological emergencies. The treatment is very codified and consists of a surgical intervention for anatomopathological analysis. The latter is frequently reassuring. These interventions are often performed in mild situations and there is currently no element to be sufficiently reassuring to avoid surgery. This study aims to explore the sensitivity of an innovative marker: Human Epididymis 4 (HE4) in the diagnosis approach of endometrial cancer in case of postmenopausal bleedings. Methods: This is a prospective multicenter diagnostic study with three centers involved. Inclusion criteria are any patient with post-menopausal bleeding who is to undergo hysteroscopy, endometrial biopsy, or endometrial resection. In accordance with the recommendations for the management of post-menopausal bleedings, the medical conduct consists of performing a clinical examination, an ultrasound and, in general, even in case of paraclinical examination reassuring, an anatomopathological analysis. This pathological analysis can be obtained in several ways: biopsy, hysteroscopy-curettage (which is the most frequently performed surgery), and hysterectomy. Our protocol consists of taking a blood sample from each woman who will undergo one of the interventions mentioned above. The dosage of HE4 and CA125 requires the withdrawal of an additional heparinized tube during the preoperative assessment usually performed. This research is therefore classified as non-interventional. The primary outcome is to evaluate the sensitivity of the HE4 marker in patients with postmenopausal bleeding in the diagnosis of endometrial cancer. The secondary outcomes are other parameters (specificity, VPP, VPN) of HE4, Evaluating the diagnostic capabilities of the CA125 marker alone and associated with HE4, as well as those of the REM and REM-B algorithms. We aim to include 100 patients over a period of one year in three centers. Discussion: As of now, there is no biological marker used in routine practice in the diagnosis of endometrial cancer. The ultimate goal of HE4 in endometrial cancer is to avoid surgery for those who are identified as non-sick. This study is the precursor of others for use in routine practice, HE4 would represent a great help to diagnosis if our study demonstrates it as reliable in the management of these patients and avoid many unnecessary and risky surgeries.

Background: The aim of this study was to report the outcomes of artificial urinary sphincter (AUS) in women with stress urinary incontinence (SUI) resulting from intrinsic sphincter deficiency after a follow up of 10 years. Methods: The charts of female patients with moderate-to-severe SUI who underwent open AUS implantation between November 1994 and April 2007 were reviewed retrospectively. All patients were operated on by a single experienced surgeon through an open retropubic approach with systematic bladder incision. Primary endpoint was postoperative continence categorized as complete continence (no pads used), improved incontinence, or unchanged incontinence. Results: A total of 63 women (mean age: 58 years, range: 17–82) underwent open AUS implantation. There were seven (11.1%) intraoperative complications. At the last follow up, 26 (41.3%) initial AUSs remained in situ and 21 (33.3%) patients had at least one revision or reimplantation. Of these 47 patients (74.6%), 35 (74.5%) were fully continent, 3 (6.4%) had improved incontinence, and 9 (19.1%) had unchanged incontinence. A total of 20 patients (31.7%) experienced postoperative complications, but only 2 (3.2%) were Clavien ⩾3. After a median follow up of 14 ± 6 years, 20 (31.7%) explantations and 29 (46%) revisions occurred. The average time without explantation or revision was 11.6 and 9 years, respectively. Conclusions: In our experience, AUS is a good option for women with moderate to severe SUI, with good long-term outcomes.

Recently, several studies have demonstrated that diaminodicyanoquinone derivatives (DADQs) could present interesting fluorescence properties. Furthermore, some DADQs under the solid state are capable of showing quantum yields that can reach values of 90%. Besides, the diaminodiacyanoquinone core represents a versatile building block propense either to modification or integration into different systems to obtain and provide them unique photophysical features. Herein, we carried out a theoretical study on the fluorescence properties of three different diaminodicyanoquinodimethane systems. Therefore, time-dependent density functional theory (TD-DFT) was used to obtain the values associated with the dipole moments, oscillator strengths, and the conformational energies between the ground and the first excited states of each molecule. The results suggest that only two of the three studied systems possess significant luminescent properties. In a further stage, the theoretical insights were confirmed by means of experimental measurements, which not only retrieved the photoluminescence of the DADQs, but also suggest a preliminary and promising antibacterial activity of these systems.

Silver selenide (Ag2Se) is a promising nanomaterial due to its outstanding optoelectronic properties and countless bio-applications. To the best of our knowledge, we report, for the first time, a simple and easy method for the ultrasound-assisted synthesis of Ag2Se nanoparticles (NPs) by mixing aqueous solutions of silver nitrate (AgNO3) and selenous acid (H2SeO3) that act as Ag and Se sources, respectively, in the presence of dissolved fructose and starch that act as reducing and stabilizing agents, respectively. The concentrations of mono- and polysaccharides were screened to determine their effect on the size, shape and colloidal stability of the as-synthesized Ag2Se NPs which, in turn, impact the optical properties of these NPs. The morphology of the as-synthesized Ag2Se NPs was characterized by transmission electron microscopy (TEM) and both α- and β-phases of Ag2Se were determined by X-ray diffraction (XRD). The optical properties of Ag2Se were studied using UV–Vis spectroscopy and its elemental composition was determined non-destructively using scanning electron microscopy–energy-dispersive spectroscopy (SEM–EDS). The biological activity of the Ag2Se NPs was assessed using cytotoxic and bactericidal approaches. Our findings pave the way to the cost-effective, fast and scalable production of valuable Ag2Se NPs that may be utilized in numerous fields.

Change detection (CD) in SAR (Synthethic Aperture Radar) images has been widely studied in recent years and has become increasingly attractive due to the growth of available datasets. The potential of CD has been shown in different fields, including disaster monitoring and military applications. Access to multi-temporal SAR images of the same scene is now possible, and therefore we can improve the performance and the interpretation of CD. Apart from specific SAR campaign measurements, the ground truth of the scene is usually unknown or only partially known when dealing with open data. This is a critical issue when the purpose is to detect targets, such as vehicles or ships. Indeed, typical change detection methods can only provide relative changes; the actual number of targets on each day cannot be determined. Ideally, this change detection should occur between a target-free image and one with the objects of interest. To do so, we propose to benefit from pixels’ intrinsic temporal behavior to compute a frozen background reference (FBR) image and perform change detection from this reference image. We will then consider that the scene consists only of immobile objects (e.g., buildings and trees) and removable objects that can appear and disappear from acquisition to another (e.g., cars and ships). Our FBR images will, therefore, aim to estimate the immobile background of the scene to obtain, after change detection, the exact amount of targets present on each day. This study was conducted first with simulated SAR data for different number of acquisition dates and Signal-to-Noise Ratio (SNR). We presented an application in the region of Singapore to estimate the number of ships in the study area for each acquisition.

Christian networks played a major role in the city expertise during the "Glorious Thirty". Along with the public authorities, they contributed to the definition of what could be a social life specific to the large housing estates. There was also, in these networks, a special attention to the issue of the inhabitants' involvement. The purpose of that text is therefore to examine, in a context of crisis of many of these housing estates from the 1970s onwards, the contribution of the Christian proficiency in the invention of a new procedure in the public action, later recognised as an official branch of the public intervention : urban policy.

Human noroviruses (huNoV) are the most frequent cause of non-bacterial acute gastroenteritis worldwide, particularly genogroup II genotype 4 (GII.4) variants. The viral nonstructural (NS) proteins encoded by the ORF1 polyprotein induce vesical clusters harboring the viral replication sites. Little is known so far about the ultrastructure of these replication organelles or the contribution of individual NS proteins to their biogenesis. We compared the ultrastructural changes induced by expression of norovirus ORF1 polyproteins with those induced upon infection with murine norovirus (MNV). Characteristic membrane alterations induced by ORF1 expression resembled those found in MNV infected cells, consisting of vesicle accumulations likely built from the endoplasmic reticulum (ER) which included single membrane vesicles (SMVs), double membrane vesicles (DMVs) and multi membrane vesicles (MMVs). In-depth analysis using electron tomography suggested that MMVs originate through the enwrapping of SMVs with tubular structures similar to mechanisms reported for picornaviruses. Expression of GII.4 NS1-2, NS3 and NS4 fused to GFP revealed distinct membrane alterations when analyzed by correlative light and electron microscopy. Expression of NS1-2 induced proliferation of smooth ER membranes forming long tubular structures that were affected by mutations in the active center of the putative NS1-2 hydrolase domain. NS3 was associated with ER membranes around lipid droplets (LDs) and induced the formation of convoluted membranes, which were even more pronounced in case of NS4. Interestingly, NS4 was the only GII.4 protein capable of inducing SMV and DMV formation when expressed individually. Our work provides the first ultrastructural analysis of norovirus GII.4 induced vesicle clusters and suggests that their morphology and biogenesis is most similar to picornaviruses. We further identified NS4 as a key factor in the formation of membrane alterations of huNoV and provide models of the putative membrane topologies of NS1-2, NS3 and NS4 to guide future studies.

The aim of this study was to assess the impact of body-mass index on robot-assisted laparoscopic sacrocolpopexy (RALSCP). A retrospective study was conducted on women who underwent a RALSCP. Data were collected prospectively from 17 obese and 78 non-obese patients treated between January 2008 and January 2013. Obesity was defined as a body-mass index (BMI) of ≥30 kg/m2. Relationships with outcome analysed using Mann– Whitney U-test and Fisher’s exact test. The operating time was the same in both groups: 220 vs 200 min in the obese and non-obese groups, respectively (P=0.232). The median follow-up was 12 months in both non-obese and obese patients. Overall anatomic repair rate was 94.1% and 97.4% for obese and non-obese patients, respectively (P=0.95). The overall reoperation rate (including surgery for de novo urinary-stress incontinence) was 5.9% for obese vs 11.5% for non-obese patients (P=0.8). These findings suggest that RALSCP is a viable option for obese women. The complication rates and outcomes for obese women were similar to those for non-obese women.

Noroviruses are the major cause of non-bacterial acute gastroenteritis in humans and livestock worldwide, despite being physically among the simplest animal viruses. The icosahedral capsid encasing the norovirus RNA genome is made of 90 dimers of a single ca 60-kDa polypeptide chain, VP1, arranged with T = 3 icosahedral symmetry. Here we study the conformational dynamics of this main building block of the norovirus capsid. We use molecular modeling and all-atom molecular dynamics simulations of the VP1 dimer for two genogroups with 50% sequence identity. We focus on the two points of flexibility in VP1 known from the crystal structure of the genogroup I (GI, human) capsid and from subsequent cryo-electron microscopy work on the GII capsid (also human). First, with a homology model of the GIII (bovine) VP1 dimer subjected to simulated annealing then classical molecular dynamics simulations, we show that the N-terminal arm conformation seen in the GI crystal structure is also favored in GIII VP1 but depends on the protonation state of critical residues. Second, simulations of the GI dimer show that the VP1 spike domain will not keep the position found in the GII electron microscopy work. Our main finding is a consistent propensity of the VP1 dimer to assume prominently asymmetric conformations. In order to probe this result, we obtain new SAXS data on GI VP1 dimers. These data are not interpretable as a population of symmetric dimers, but readily modeled by a highly asymmetric dimer. We go on to discuss possible implications of spontaneously asymmetric conformations in the successive steps of norovirus capsid assembly. Our work brings new lights on the surprising conformational range encoded in the norovirus major capsid protein.

Cells sense and respond to nanoscale variations in the distribution of ligands to adhesion receptors. This makes single molecule localization microscopy (SMLM) an attractive tool to map the distribution of ligands on nanopatterned surfaces. We explore the use of SMLM spatial cluster analysis to detect nanodomains of the cell adhesion-stimulating tripeptide arginine-glycine-aspartic acid (RGD). These domains were formed by the phase separation of block copolymers with controllable spacing on the scale of tens of nanometers. We first determined the topology of the block copolymer with atomic force microscopy (AFM) and then imaged the localization of individual RGD peptides with direct stochastic optical reconstruction microscopy (dSTORM). To compare the data, we analyzed the dSTORM data with DBSCAN (density-based spatial clustering application with noise). The ligand distribution and polymer topology are not necessary identical since peptides may attach to the polymer outside the nanodomains and/or coupling and detection of peptides within the nanodomains is incomplete. We therefore performed simulations to explore the extent to which nanodomains could be mapped with dSTORM. We found that successful detection of nanodomains by dSTORM was influenced by the inter-domain spacing and the localization precision of individual fluorophores, and less by non-specific absorption of ligands to the substratum. For example, under our imaging conditions, DBSCAN identification of nanodomains spaced further than 50 nm apart was largely independent of background localisations, while nanodomains spaced closer than 50 nm required a localization precision of ~11 nm to correctly estimate the modal nearest neighbor distance (NDD) between nanodomains. We therefore conclude that SMLM is a promising technique to directly map the distribution and nanoscale organization of ligands and would benefit from an improved localization precision.

Intraperitoneal rupture of cystic ovarian teratoma is a rare complication. We report a case in a 29-year-old female, with increased abdominal circumference 2 months after vaginal delivery. MRI/CT raised this diagnosis associated to chemical peritonitis. A malignant ovarian mass with peritoneal carcinomatosis was excluded. Laparoscopic oophorectomy was performed and histologic analysis confirmed imaging findings. This case demonstrates the interest of imaging before surgery in pelvic masses to avoid misdiagnosing and to provide adequate treatment.

Background and Purpose: Chlormadinone acetate (CMA) is a synthetic progestin for which cases of intracranial meningioma have been reported following prolonged exposure., Method: An observational cohort study was conducted based on the French national health data system. Women aged 10-70 years and who started CMA between 2007 and 2017 were included. Participants were considered to be exposed if they had received a cumulative dose >360 mg of CMA during the first 6 months and very slightly exposed (control group) when they had received a cumulative dose ≤360 mg. The outcome was surgery or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma., Results: In total, 828,499 women were included: 469,976 in the exposed group (mean age 39.1 years, SD 10.1) and 358,523 in the control group (38.3 years, SD 11.0). Surgery or radiotherapy for intracranial meningioma between 2007 and 2017 was recorded for 164 and 104 women in the exposed and control groups, respectively. The incidence of meningioma was 18.5 and 6.8 per 100,000 person-years for the exposed and control groups respectively (crude RR = 2.7, 95% confidence interval [CI] 2.1-3.5; age-adjusted RR = 3.1, 95% CI 2.4-4.0). Meningioma incidence reached almost 47 cases/100,000 person-years in the most exposed group (>8.64 g), giving an age-adjusted RR of 6.9, 95% CI 5.1-9.2, relative to the control group., Conclusions: A strong dose-effect relationship was observed between prolonged use of CMA and risk of meningiomas. As with other progestogens, meningiomas associated with CMA are more likely to be found at the base of the skull., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The brain helps us survive by forming internal representations of the external world 1,2 . Excitatory cortical neurons are often precisely tuned to specific external stimuli 3,4 . However, inhibitory neurons, such as parvalbumin-positive (PV) interneurons, are generally less selective 5 . PV interneurons differ from excitatory neurons in their neurotransmitter receptor subtypes, including AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) 6,7 . Excitatory neurons express calcium-impermeable AMPARs that contain the GluA2 subunit (encoded by GRIA2), whereas PV interneurons express receptors that lack the GluA2 subunit and are calcium-permeable (CP-AMPARs). Here we demonstrate a causal relationship between CP-AMPAR expression and the low feature selectivity of PV interneurons. We find low expression stoichiometry of GRIA2 mRNA relative to other subunits in PV interneurons that is conserved across ferrets, rodents, marmosets and humans, and causes abundant CP-AMPAR expression. Replacing CP-AMPARs in PV interneurons with calcium-impermeable AMPARs increased their orientation selectivity in the visual cortex. Manipulations to induce sparse CP-AMPAR expression demonstrated that this increase was cell-autonomous and could occur with changes beyond development. Notably, excitatory-PV interneuron connectivity rates and unitary synaptic strength were unaltered by CP-AMPAR removal, which suggested that the selectivity of PV interneurons can be altered without markedly changing connectivity. In Gria2-knockout mice, in which all AMPARs are calcium-permeable, excitatory neurons showed significantly degraded orientation selectivity, which suggested that CP-AMPARs are sufficient to drive lower selectivity regardless of cell type. Moreover, hippocampal PV interneurons, which usually exhibit low spatial tuning, became more spatially selective after removing CP-AMPARs, which indicated that CP-AMPARs suppress the feature selectivity of PV interneurons independent of modality. These results reveal a new role of CP-AMPARs in maintaining low-selectivity sensory representation in PV interneurons and implicate a conserved molecular mechanism that distinguishes this cell type in the neocortex., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: The French Health Authority (Haute Autorité de santé) and French scientific societies (Collège national des gynécologues et obstétriciens français) recommend the use of midurethral slings as the surgical treatment of choice for stress incontinence due to urethral hypermobility and failure of hygienic diet and pelvic rehabilitation. Within a year of implantation, almost 90% of patients no longer experience stress urinary incontinence. Despite their recognized efficacy, retropubic and/or trans-obturator midurethral sling can expose patients to potentially severe infectious complications., Methods: A comprehensive literature review using Pubmed, Medline, Embase and Cochrane: "stress urinary incontinence", and/or the following keywords "complications", "infections", "abscess", "prosthetic exposures", "fistula", "erosion", "cellulitis", "fasciitis" in association with the keywords "midurethral slings", "suburethral sling", "tension free vaginal tape" and "trans-obturator tape. In the 330 articles, 61 really dealt with infectious complications following the implantation of synthetic midurethral slings in women., Results: Preoperative urinalysis and intraoperative antibiotic prophylaxis were rarely reported (n=1 and n=11, respectively). We recorded thirty-six cases of abscess, twenty-one cases of cellulitis, sixteen cases of fistula and forty-one cases of prosthetic exposure. In 95.5% of cases, patients were treated with broad-spectrum antibiotics. Total explantation of the prosthesis was performed in 56% of patients at the initial management, with two-stage explantation performed in 23% of cases, partial explantation was carried out in 12% of cases, and the prosthesis was left in place in 9% of cases. No deaths were recorded., Conclusion: To limit the risk of urinary tract infections and potential prosthetic infections, a prophylactic approach should be adopted by performing a preoperative urinalysis and administering intraoperative antibiotic prophylaxis should be discussed. In the event of prosthetic and/or surgical site infection, broad-spectrum probabilistic antibiotic therapy should be initiated as early as possible until targeted antibiotic therapy. Total explantation of the prosthesis appears to be the most appropriate surgical strategy., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Erb-b2 receptor tyrosine kinase 2 (ERBB2)-activating mutations are therapeutically actionable alterations found in various cancers, including metastatic breast cancer (MBC). We developed multiplex digital PCR assays to detect and quantify ERBB2 mutations in circulating tumor DNA from liquid biopsies. We studied the plasma from 272 patients with hormone-receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) MBC to detect 17 ERBB2 mutations using a screening assay. The assay was developed on the three-color Crystal dPCR™ naica® platform with a two-step strategy for precise mutation identification. We found that nine patients (3.3%) harbored at least one ERBB2 mutation. The mutation rate was higher in patients with lobular histology (5.9%) compared to invasive breast carcinoma of no special type (2.6%). A total of 12 mutations were found with the following frequencies: L755S (25.00%), V777L (25.00%), S310Y (16.67%), L869R (16.67%), S310F (8.33%), and D769H (8.33%). Matched tumor samples from six patients identified the same mutations with an 83% concordance rate. In summary, our highly sensitive multiplex digital PCR assays are well suited for plasma-based monitoring of ERBB2 mutational status in patients with MBC., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)