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The effect of high density (apoE-depleted HDL3) on cell growth of a human tumor cell line (A549) was studied and related to its binding on the plasma membrane. HDL3 were shown to stimulate the incorporation of [3H]thymidine into DNA and cell proliferation; these effects were dose-dependent. As HDL3, apoA-I and apoA-I-liposomes complexes (but not apoA-II) were able to stimulate DNA synthesis in serum-free conditions. This effect was maximum for 15-30 micrograms HDL3 protein/ml concentration. Binding of HDL3 on whole cells occurred by two mechanisms: the first was specific for HDL3; the second, of lower affinity, was phospholipid-dependent and was inhibited by low density lipoprotein or by phospholipid particles. Internalization and degradation of bound HDL3 were not observed. The specific sites (27.9 +/- 2.2 ng HDL3 protein/ng cell protein) accounted for only 2.5% of total (specific+phospholipid) binding sites and they bound HDL3 with a dissociation constant (KD) of 2.47 +/- 0.46 microgram HDL3 protein/ml (2.6 +/- 0.5 x 10(-8) M). The apparent KD value of total binding sites (specific+phospholipid) was eightfold higher (20.4 +/- 6.1 micrograms HDL3 protein/ml). Analysis of the membrane specific binding sites by ligand blotting with 125I-labeled HDL3 showed a single protein with an apparent molecular mass of 110 kDa. When HDL3 binding on phospholipid sites was inhibited by rigid phospholipid particles, the stimulation of [3H]thymidine incorporation related to HDL3 concentration did not show a maximum peak as previously observed but reached a plateau at a concentration as low as 5 micrograms HDL3 protein/ml. This low concentration also nearly saturated the specific binding sites with HDL3. When binding on specific protein sites was suppressed by tetranitromethane, DNA synthesis was not stimulated but, in contrast, inhibited. The stimulating effect of HDL3 on DNA biosynthesis is therefore likely dependent on HDL3 occupying specific binding sites.

The Nuclear Energy Division of the French Atomic Energy commission is carrying out research in the transmutation field in order to access the possibility of eliminating long-lived nuclear waste. Within this frame, many selected targets of highly enriched actinides or fission products are irradiated in the Phénix French Nuclear Reactor, and analysed before and after irradiation for their elemental and isotopic composition. Among them, the 153Eu presents a major analytical challenge because neutronic calculation codes predict the formation of isobaric interferences of samarium and gadolinium isotopes after irradiation. An analytical method was developed by using a Multiple Collector-Inductively Coupled Plasma Mass Spectrometer (MC-ICP-MS, Isoprobe) equipped with a collision/reaction cell in order to circumvent these interferences. In this article, it is shown that direct Europium isotopic ratios measurements are possible in the presence of O2used as reactant gas in the cell due to the opposite behaviour of Eu and Sm/Gd towards this gas. SmO+and GdO+oxide ions are fully formed whereas Eu is mainly present as Eu+. The separation efficiency of the Isoprobe's collision reaction-cell was studied on both natural Eu and certified 153Eu enriched solutions. Accuracy of the measurement was found to be within the reference value uncertainty. Reproducibility of 151Eu/153Eu isotopic ratio measurement were found to be lower than 0.3‰, in the case of natural solution, and lower than 4‰ with the153Eu enriched solution, respectively. This study presents an original measurement method for a triple Eu/Gd/Sm isobaric interference resolution in order to measure the Eu isotopic composition with high precision and accuracy. [ABSTRACT FROM AUTHOR]

In the research field concerning the nuclear transmutation of long-lived radionuclides, numerous isotopically enriched elements have been irradiated in the Phénix French reactor in order to determine basic neutronic data. The precise and accurate measurement of isotopic composition of these elements after irradiation is of prime interest. Among these elements, the 95Mo target presents an interesting analytical challenge as the irradiation generates, among others, the interfering isotopes 92Mo and 92Zr. A method using multiple collector inductively coupled plasma mass spectrometry (MC-ICPMS) has been developed for the precise measurement of Mo isotope composition in natural Mo and 95Mo enriched samples solutions in the presence of Zr isobaric interferences. The Mo/Zr separation was performed in situ by injecting N2O as a reaction gas in the collision–reaction cell of the instrument. The reason why a selective chemical reaction of Zr+ with N2O forms mainly ZrO2+ product whereas Mo is not reactive, is explained. This technique leads to an efficient separation of Mo and Zr, reflected by the similar accuracy and uncertainty obtained for natural and isotopically enriched Mo isotope composition with and without Zr addition. This study demonstrates the capability of the collision–reaction cell of the MC-ICPMS to separate efficiently Mo and Zr, instead of using chemical separation techniques, and to produce precise and reproducible Mo isotopic data. [ABSTRACT FROM AUTHOR]

Superconducting rf (SRF) cavities are traditionally fabricated from superconducting material sheets or made of copper coated with superconducting material, followed by trim machining and electron-beam welding. An alternative technique to traditional shaping methods, such as deep-drawing and spinning, is electrohydraulic forming (EHF). In EHF, half-cells are obtained through ultrahigh-speed deformation of blank sheets, using shockwaves induced in water by a pulsed electrical discharge. With respect to traditional methods, such a highly dynamic process can yield interesting results in terms of effectiveness, repeatability, final shape precision, higher formability, and reduced springback. In this paper, the first results of EHF on high purity niobium are presented and discussed. The simulations performed in order to master the multiphysics phenomena of EHF and to adjust its process parameters are presented. The microstructures of niobium half-cells produced by EHF and by spinning have been compared in terms of damage created in the material during the forming operation. The damage was assessed through hardness measurements, residual resistivity ratio (RRR) measurements, and electron backscattered diffraction analyses. It was found that EHF does not worsen the damage of the material during forming and instead, some areas of the half-cell have shown lower damage compared to spinning. Moreover, EHF is particularly advantageous to reduce the forming time, preserve roughness, and to meet the final required shape accuracy.

Switzerland was the first European country to approve the use of unmanned aerial vehicles (UAVs) for the purpose of plant protection treatments. The regulatory framework that has been established requires UAV sprayers to undergo a series of technical assessments that have generated a substantial amount of data. Here, we first describe the regulatory framework and the underlying rationales, followed by analyzing data from the technical assessments. The results show that the UAV sprayers being used in Switzerland achieve homogeneous transversal spray liquid distributions with coefficients of variation below 15 % at effective swath widths that are typically lower than those indicated by UAV manufacturers. Moreover, the lateral wind generated by the UAV sprayers as measured at distances of 10 m and 20 m, respectively, is not substantially affected by UAV size or weight. A survey we conducted to gain insight into agricultural practices under the current regulatory framework suggests that up to 11.5 % of the total of Swiss vineyards were treated with UAV sprayers in 2023. Other uses, such as spreading slug pellets, seem to gain importance as well. Finally, efficacy trials performed in Swiss vineyards suggest that UAV sprayers achieve limited control efficacy of powdery and downy mildew at high disease pressure, which is likely to be due to the relatively low amount of deposit around and on the bunches. We conclude this paper by outlining future regulatory challenges and directions for further development. © 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry., (© 2025 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.)

Objectives: To evaluate ChatGPT's accuracy as information source for women and maternity-care workers on "nutrition" and "red flags" in pregnancy., Methods: Accuracy of ChatGPT-generated recommendations was assessed by a 5-point Likert scale by eight raters for ten indicators per topic in four languages (French, English, German and Dutch). Accuracy and interrater agreement were calculated per topic and language., Results: For both topics, median accuracy scores of ChatGPT-generated recommendations were excellent (5.0; IQR 4-5) independently of language. Median accuracy scores varied with a maximum of 1 on a 5-point Likert-scare according to question's framing. Overall accuracy scores were 83-89 % for 'nutrition in pregnancy' versus 96-98 % for 'red flags in pregnancy'. Inter-rater agreement was good to excellent for both topics., Conclusion: Although ChatGPT generated accurate recommendations regarding the tested indicators for nutrition and red flags during pregnancy, women should be aware of ChatGPT's limitations such as inconsistencies according to formulation, language and the woman's personal context., Innovation: Despite a growing interest in the potential use of artificial intelligence in healthcare, this is, to the best of our knowledge, the first study assessing potential limitations that may impact accuracy of ChatGPT-generated recommendations such as language and question-framing in key domains of perinatal health., Competing Interests: 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., (© 2025 The Authors. Published by Elsevier B.V.)

Background and Objective: Standardised procedures for performing and reporting safety monitoring studies investigating medications use in pregnancy may help improve data quality and the speed of data generation. The objective of this study was to provide recommendations on the statistical analysis and reporting of single-arm pregnancy medication safety studies using primary source datasets., Methods: A Delphi consensus-setting protocol was used to acquire agreement on recommendations from experts with extensive knowledge and experience in conducting studies investigating medication safety in pregnancy. A series of recommendations, along with their scientific justifications and examples of how to calculate and describe exposure and outcome incidences, were critiqued and improved through a series of online Delphi review rounds. Agreement to inclusion scoring was assessed using a five-point Likert scale. Recommendations with a median Likert-scale score of at least 4, where ≥ 80% of the expert panel scored the recommendation at level 4 or higher, was used as the threshold for inclusion., Results: The Delphi consensus methodology produced a set of 30 recommendations spread over five themes. These included descriptions of (1) study sample, (2) medication exposure, (3) maternal outcomes, (4) pregnancy and birth outcomes, and (5) fetal and neonatal outcomes. Of the 30 recommendations, 19 were strongly advised while 11 were included for consideration where their implementation may be beneficial for supplementing data communication., Conclusion: Use of the finalised set of recommendations should be encouraged to help standardise published evidence around medication use in pregnancy., Competing Interests: Declarations. Funding: The ConcePTION project is jointly funded by the Innovative Medicines Initiative (call 13, topic 9, grant agreement number 821520) and through benefit in kind contributions from European Federation of Pharmaceutical Industries (EFPIA) companies. The contribution of EFPIA partners to this manuscript has involved the provision of personnel time and expertise only. No academic/clinical partners have received financial incentives from EFPIA partners during the performance of this task. All of the recommendations provided required consensual agreement. The research leading to the results communicated in this manuscript was conducted as part of the ConcePTION consortium. This paper only reflects the personal views of the stated authors. The research activities of Michael Ceulemans are supported by a Senior Postdoctoral Fellowship fundamental research of the Research Foundation Flanders (FWO, 1246425N). Conflict of interest: JLR, MC, AO, UW, GF, KKH declare no conflicts of interest; no other financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no previous or ongoing relationships or activities that could appear to have influenced the submitted work. AM and DJL were Novartis associates whist working on this manuscript and other aspects of the ConcePTION project, and both hold shares in Novartis Pharma AG. DJL also owns shares in Alcon, Novartis, Sandoz, and GlaxoSmithKline, and is an Honorary Senior Lecturer (Clinical), School of Life and Medical Sciences, University of Hertfordshire. AA is a current Novartis associate and holds shares in Novartis Pharma and Incyte. YG is an employee of Novartis Pharma AG. DS is a current AbbVie employee and current shareholder in AbbVie stocks. MS is an employee of Novo Nordisk A/S and holds shares in Novo Nordisk. LMY provided consultancy for Sanofi Genzyme South Africa on two occasions in 2021 relating to genetic testing in Gaucher’s Disease (April 2021) and a conference lecture on genetic testing in cardiac clinics (Sept 2021). KD, MO and EB are staff members of the Berlin Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy which is financially supported by the German Federal Institute for Drugs and Medical Devices (BfArM). TC receives research funding from the following industry sponsors and a foundation: Amgen, AstraZeneca; GlaxoSmithKline; Janssen Pharmaceuticals; Pfizer, Inc.; Regeneron; Hoffman La-Roche-Genentech; Genzyme Sanofi-Aventis; Takeda Pharmaceutical Company Limited; Sanofi; UCB Pharma, USA; Leo Pharma, Sun Pharma Global FZE; Gilead; Novartis; and the Gerber Foundation. EvP is an Editorial Board member of Drug Safety but was not involved in the original selection of the target journal, selecting the peer reviewers for the manuscript, nor any of the subsequent editorial decisions. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Availability of data and materials: May be made available on request, please contact the corresponding author. Code availability: Not applicable. Author contributions: JLR, DJL and LMY conceptualised the study; JLR, LMY and AO developed the study protocol and the Delphi consensus collection materials; JLR and AO acted as co-ordinators of the Delphi process with guidance from LMY; AM, MS, UW, JLR and YG drafted the statistical analysis plan and the preliminary recommendations; all authors participated in the Delphi process; JLR and AO finalised the documentation of the final recommendations; JLR wrote the first draft of the manuscript; all authors provided critical comments to finalise the manuscript. All authors have read and approved the final version., (© 2025. Crown.)

Objectives: Data are lacking regarding the long-term consequences of SARS-CoV-2 and COVID-19 mRNA vaccine on infants exposed in utero. We aimed to evaluate the neurodevelopment of infants exposed prenatally to SARS-CoV-2 or mRNA-COVID-19 vaccine during pregnancy at 12 months after birth., Methods: Infants born to mothers exposed to SARS-CoV-2 or mRNA-COVID-19 vaccine during pregnancy, or unexposed to either the virus or the vaccine were enrolled from 2021 to 2023. Infants with prenatal exposure to the virus or vaccine were compared with infants without prenatal exposure to the virus and/or vaccine. Parents received a neurodevelopmental questionnaire (ages and stages questionnaire third edition) at 12 months after birth assessing five subdomains: communication, gross motor, fine motor, problem-solving, and personal social development. A low score was defined as <2 standard deviations below the normative mean in at least one of the subdomains., Results: A total of 330 infants were included (76 in the SARS-CoV-2 group, 153 in the mRNA-COVID-19 vaccine group, and 101 in the reference group). In utero exposure to the SARS-CoV-2 or mRNA-COVID-19 vaccine was not associated with an increased risk of a low score for at least one subdomain compared with the reference group. The crude ORs were 1.16 (95% CI, 0.59-2.28) and 1.04 (95% CI, 0.58-1.86), respectively. Results remained consistent in the multivariate analysis, showing no increased risk of a low score for at least one subdomain for infants exposed to the SARS-CoV-2 or mRNA-COVID-19 vaccine, compared with the reference group. The adjusted ORs were 1.74 (95% CI, 0.76-3.99) and 0.76 (95% CI, 0.39-1.49), respectively., Discussion: In utero exposure to SARS-CoV-2 or mRNA-COVID-19 vaccine was not associated with an increased risk of a low score for at least one ages and stages questionnaire third edition subdomain at 12 months after birth. Additional studies are needed to confirm our results, especially longer-term evaluation of infant development., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lung cancer is the leading cause of cancer death worldwide, with poor survival despite recent therapeutic advances. A better understanding of the complexity of the tumor microenvironment is needed to improve patients' outcome., Methods: We applied a computational immunology approach (involving immune cell proportion estimation by deconvolution, transcription factor activity inference, pathways and immune scores estimations) in order to characterize bulk transcriptomics of 62 primary lung adenocarcinoma (LUAD) samples from patients across disease stages. Focusing specifically on early stage samples, we validated our findings using an independent LUAD cohort with 70 bulk RNAseq and 15 scRNAseq datasets and on TCGA datasets., Results: Through our methodology and feature integration pipeline, we identified groups of immune cells related to disease stage as well as potential immune response or evasion and survival. More specifically, we reported a duality in the behavior of immune cells, notably natural killer (NK) cells, which was shown to be associated with survival and could be relevant for immune response or evasion. These distinct NK cell populations were further characterized using scRNAseq data, showing potential differences in their cytotoxic activity., Conclusion: The dual profile of several immune cells, most notably T-cell populations, have been discussed in the context of diseases such as cancer. Here, we report the duality of NK cells which should be taken into account in conjunction with other immune cell populations and behaviors in predicting prognosis, immune response or evasion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Hurtado, Khajavi, Essabbar, Kammer, Xie, Coullomb, Pradines, Casanova, Kruczynski, Gouin, Clermont, Boutillet, Senosain, Zou, Zhao, Burq, Mahfoudi, Besse, Launay, Passioukov, Chetaille, Favre, Maldonado, Cruzalegui, Delfour, Mazières and Pancaldi.)

The French National Metrology Institute (LNE) initiated a series of events to identify priorities for test methods and their harmonisation that directly address regulatory needs in Nanomedicine. One of these workshops entitled "The International Standardisation Roadmap for Nanomedicine" held in October 2023 (Paris, France) brought together key experts in the characterisation of nanomedicines and medical products containing nanomaterials, including the Joint Research Centre of the European Commission, SINTEF Industry and the metrology institutes of France, the UK, the USA and Canada, two flagship initiatives of the European Commission (PHOENIX and SAFE-n-MEDTECH Open Innovation Test Beds), representatives of a working party on mRNA vaccines at the European Directorate for the Quality of Medicines (EDQM) and members of international standardisation and pre-normative organisations (including CEN, ISO, ASTM, VAMAS). Two take-home message came out from the discussion. First, developing standard test methods and Reference Materials (RMs) for nanomedicines is a key priority for the European Commission and various stakeholders. Furthermore, there was a unanimous recognition of the need for a unified approach between standardisation committees, regulators and the nanomedicine community. At the USA, Canadian and European level, examples of success stories and of future initiative have been discussed. Future perspectives include the creation of a dedicated Working Group under CEN/TC 352 to consolidate efforts and develop a nanomedicine standardisation roadmap., (© 2024. The Author(s).)

Drug-tolerance has emerged as one of the major non-genetic adaptive processes driving resistance to targeted therapy (TT) in non-small cell lung cancer (NSCLC). However, the kinetics and sequence of molecular events governing this adaptive response remain poorly understood. Here, we combine real-time monitoring of the cell-cycle dynamics and single-cell RNA sequencing in a broad panel of oncogenic addiction such as EGFR-, ALK-, BRAF- and KRAS-mutant NSCLC, treated with their corresponding TT. We identify a common path of drug adaptation, which invariably involves alveolar type 1 (AT1) differentiation and Rho-associated protein kinase (ROCK)-mediated cytoskeletal remodeling. We also isolate and characterize a rare population of early escapers, which represent the earliest resistance-initiating cells that emerge in the first hours of treatment from the AT1-like population. A phenotypic drug screen identify farnesyltransferase inhibitors (FTI) such as tipifarnib as the most effective drugs in preventing relapse to TT in vitro and in vivo in several models of oncogenic addiction, which is confirmed by genetic depletion of the farnesyltransferase. These findings pave the way for the development of treatments combining TT and FTI to effectively prevent tumor relapse in oncogene-addicted NSCLC patients., (© 2024. The Author(s).)

TDP1 removes transcription-blocking topoisomerase I cleavage complexes (TOP1ccs), and its inactivating H493R mutation causes the neurodegenerative syndrome SCAN1. However, the molecular mechanism underlying the SCAN1 phenotype is unclear. Here, we generate human SCAN1 cell models using CRISPR-Cas9 and show that they accumulate TOP1ccs along with changes in gene expression and genomic distribution of R-loops. SCAN1 cells also accumulate transcriptional DNA double-strand breaks (DSBs) specifically in the G1 cell population due to increased DSB formation and lack of repair, both resulting from abortive removal of transcription-blocking TOP1ccs. Deficient TDP1 activity causes increased DSB production, and the presence of mutated TDP1 protein hampers DSB repair by a TDP2-dependent backup pathway. This study provides powerful models to study TDP1 functions under physiological and pathological conditions and unravels that a gain of function of the mutated TDP1 protein, which prevents DSB repair, rather than a loss of TDP1 activity itself, could contribute to SCAN1 pathogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Alice Panchaud has received financial support from the Swiss Federal Office of Public Health to research COVID-19 during pregnancy and from the CHUV foundation for the COVI-PREG registry. Alice Panchaud has received two grants for research on COVID-19 vaccines and medications: i) Safety monitoring of COVID-19 vaccines in the EU—Reopening of competition no. 20 under a framework contract following procurement procedure EMA/2017/09/PE (Lot 3); ii) Efficacy and safety studies on Medicines EMA/2017/09/PE/11, Lot 4, WP 2 lead “Study on impact of COVID-19 infection and medicines in pregnancy”. Isabelle Boucoiran has received a grant from Ferring for a study on COVID-19 in pregnancy and consultant fees from Pfizer and Moderna for immunization in pregnancy unrelated to SARS-CoV-2. All other authors declare no conflicts of interest.

Introduction and Objective: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework., Methods: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available., Results: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs)., Conclusions: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible., (© 2023. The Author(s).)

Small GTPases are highly regulated proteins that control essential signaling pathways through the activity of their effector proteins. Among the RHOA subfamily, RHOB regulates peculiar functions that could be associated with the control of the endocytic trafficking of signaling proteins. Here, we used an optimized assay based on tripartite split-GFP complementation to localize GTPase-effector complexes with high-resolution. The detection of RHOB interaction with the Rhotekin Rho binding domain (RBD) that specifically recognizes the active GTP-bound GTPase, is performed in vitro by the concomitant addition of recombinant GFP1-9 and a GFP nanobody. Analysis of RHOB-RBD complexes localization profiles combined with immunostaining and live cell imaging indicated a serum-dependent reorganization of the endosomal and membrane pool of active RHOB. We further applied this technology to the detection of RHO-effector complexes that highlighted their subcellular localization with high resolution among the different cellular compartments., 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 © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objectives: This study aimed to evaluate the risk of congenital malformation among pregnant women exposed to the mRNA COVID-19 vaccines during the first trimester of pregnancy, which is a developmental period where the foetus is at risk of teratogenicity., Methods: Pregnant women were prospectively enrolled from March 2021 to March 2022, at the time of COVID-19 vaccination. Pregnant women exposed to at least one dose of mRNA COVID-19 vaccine from conception to 11 weeks of gestations and 6 days were compared with pregnant women exposed to the vaccine from 12 weeks to the end of pregnancy. The primary outcome was a confirmed congenital malformation at birth., Results: A total of 1450 pregnant women were enrolled including 124 in the first trimester and 1326 in the second and third trimester. The overall proportion of congenital malformation was 0.81% (n = 1/124; 95% CI: 0.02-4.41) and 0.83% (n = 11/1326; 95% CI: 0.41-1.48) among pregnant exposed to the COVID-19 vaccine during the first and second/third trimester, respectively. First trimester exposure was not associated with a higher risk of congenital malformation with a relative risk of 0.89 (95% CI: 0.12-6.80) with no significant changes after adjustment through exploratory analysis., Conclusions: Pregnant women exposed to mRNA COVID-19 vaccine before 12 weeks of gestation did not have an increased risk of congenital malformation compared with women exposed outside the teratogenic window. Because vaccination is safe and effective, emphasis must be placed on promoting vaccination during pregnancy., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Thrombopoietin receptor agonists (TPO-RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first-line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end-points included the sustained remission off-treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)-4, IL-9 and IL-17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor-β levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: With the rise in the number of women giving birth at an advanced age, the association between advanced maternal age and adverse obstetrical outcomes is a growing concern in developed countries. Despite the well-established link between advanced maternal age and pregnancy-related complications, there has been limited research examining the specific risks related to unscheduled cesarean delivery in nulliparas at term., Objective: This study aimed to evaluate the risks associated with unscheduled cesarean delivery in nulliparas at ≥37 weeks of gestation, comparing the outcomes of younger patients with those aged ≥40 years., Study Design: This retrospective cohort study was conducted in a tertiary maternity hospital in Switzerland (high-income country). The study included nulliparas who delivered a live-born infant at ≥37 weeks between January 2015 and December 2019. We excluded pregnant women who had a planned cesarean delivery, were aged <18 years, multiparous, delivered before 37 weeks of gestation, or had pregnancies that ended in stillbirth. Participants were divided into 2 age groups: (1) ≥40 years and (2) <40 years. The primary outcome was the incidence of unscheduled cesarean delivery. Its association with advanced maternal age was evaluated after adjusting for confounding factors by multivariate logistic regression, expressed as an adjusted odds ratio. Secondary outcomes included pregnancy outcomes and neonatal outcomes., Results: A total of 5211 patients were included: 173 in the ≥40-years (advanced maternal age) group and 5038 in the <40-years (non-advanced maternal age) group; 26.01% (95% confidence interval, 19.65-33.22; n=45) of women in the advanced maternal age group had an unscheduled cesarean delivery, whereas 15.26% (95% confidence interval, 14.28-16.29; n=769) of women in the non-advanced maternal age group underwent the procedure. Advanced maternal age was associated with unscheduled cesarean delivery, with an adjusted odds ratio of 1.51 (95% confidence interval, 1.06-2.17; P=.024). Among vaginal deliveries, assisted procedures were performed on 29.7% (95% confidence interval, 21.9-38.4; n=38) of advanced maternal age patients vs 20.1% (95% confidence interval, 18.9-21.3; n=856) of non-advanced maternal age patients. Postpartum blood loss >1000 mL occurred in 5.8% (95% confidence interval, 2.8-10.4; n=10) of advanced maternal age patients and 3.1% (95% confidence interval, 2.6-3.6; n=156) of non-advanced maternal age patients., Conclusion: Advanced maternal age is associated with increased risk of unscheduled cesarean delivery among nulliparas. This provides healthcare professionals with confirmation that advanced age may represent an individual risk factor, suggesting that nulliparous patients aged over 40 years may benefit from improved information regarding the factors contributing to this pregnancy outcome., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Edible gold (Au) is commonly used as a food additive (E175 in EU) for confectionery and cake decorations, coatings and in beverages. Food-grade gold is most often composed of thin Au sheets or flakes exhibiting micro- and nanometric dimensions in their thickness. Concerns about the impact of mineral particles used as food additives on human health are increasing with respect to the particular physico-chemical properties of nanosized particles, which enable them to cross biological barriers and interact with various body cell compartments. In this study, male and female mice were exposed daily to E175 or an Au nanomaterial (Ref-Au) incorporated into food at relevant human dose for 90 days in order to determine the potential toxicity of edible gold., Results: E175 or Ref-Au exposure in mice did not induce any histomorphological damage of the liver, spleen or intestine, nor any genotoxic effects in the colon and liver despite an apparent higher intestinal absorption level of Au particles in mice exposed to Ref-Au compared to the E175 food additive. No changes in the intestinal microbiota were reported after treatment with Ref-Au, regardless of sex. In contrast, after E175 exposure, an increase in the Firmicutes/Bacteroidetes ratio and in the abundance of Proteobacteria were observed in females, while a decrease in the production of short-chain fatty acids occurred in both sexes. Moreover, increased production of IL-6, TNFα and IL-1β was observed in the colon of female mice at the end of the 90-day exposure to E175, whereas, decreased IL-6, IL-1β, IL-17 and TGFβ levels were found in the male colon., Conclusions: These results revealed that a 90-day exposure to E175 added to the diet alters the gut microbiota and intestinal immune response in a sex-dependent manner in mice. Within the dose range of human exposure to E175, these alterations remained low in both sexes and mostly appeared to be nontoxic. However, at the higher dose, the observed gut dysbiosis and the intestinal low-grade inflammation in female mice could favour the occurrence of metabolic disorders supporting the establishment of toxic reference values for the safe use of gold as food additive., (© 2023. The Author(s).)

The lack of inclusion of pregnant women in clinical trials evaluating the effectiveness of medicines to treat COVID-19 has made it difficult to establish evidence-based treatment guidelines for pregnant women. Our aim was to provide a review of the evolution and updates of the national guidelines on medicines used in pregnant women with COVID-19 published by the obstetrician and gynecologists' societies in thirteen countries in 2020-2022. Based on the results of the RECOVERY (Randomized Evaluation of COVID-19 Therapy) trial, the national societies successively recommended against prescribing hydroxychloroquine, lopinavir-ritonavir and azithromycin. Guidelines for remdesivir differed completely between countries, from compassionate or conditional use to recommendation against. Nirmatrelvir-ritonavir was authorized in Australia and the UK only in research settings and was no longer recommended in the UK at the end of 2022. After initial reluctance to use corticosteroids, the results of the RECOVERY trial have enabled the recommendation of dexamethasone in case of severe COVID-19 since mid-2020. Some societies recommended prescribing tocilizumab to pregnant patients with hypoxia and systemic inflammation from June 2021. Anti-SARS-CoV-2 monoclonal antibodies were authorized at the end of 2021 with conditional use in some countries, and then no longer recommended in Belgium and the USA at the end of 2022. The gradual convergence of the recommendations, although delayed compared to the general population, highlights the importance of the inclusion of pregnant women in clinical trials and of international collaboration to improve the pharmacological treatment of pregnant women with COVID-19.

Cell-free DNA in human blood plasma (cfDNA) is now widely used and studied as a biomarker for several physiological and pathological situations. In addition to genetic and epigenetic alterations that provide information about the presence and the nature of non-constitutive DNA in the body, cfDNA concentration and size distribution may potentially be independent biomarkers suitable for monitoring at-risk patients and therapy efficacy. Here, we describe a simple, in-line, method, which measures cfDNA concentration and size distribution from only a few microliters of plasma without the need to extract and/or concentrate the DNA prior to the analysis. This method is based on a dual hydrodynamic and electrokinetic actuation, adapted for samples containing salts and proteins such as biological fluids. The method provides analytical performances equivalent to those obtained after purification and concentration of cfDNA, with a precision of ∼1% for size features and of 10-20% for the concentrations of the different size fractions. We show that concentration and size distribution of cfDNA analyzed from plasma can differentiate advanced lung cancer patients from healthy controls. This simple and cost-effective method should facilitate further investigations into the potential clinical usefulness of cfDNA size profiling.

Background: The incidence of diabetes mellitus (both pregestational and gestational) is increasing worldwide, and hyperglycemia during pregnancy is associated with adverse pregnancy outcomes. Evidence on the safety and efficacy of metformin during pregnancy has accumulated resulting in an increase in its prescription in many reports., Aims: We aimed to determine the prevalence of antidiabetic drug use (insulins and blood glucose-lowering drugs) before and during pregnancy in Switzerland and the changes therein during pregnancy and over time., Methods: We conducted a descriptive study using Swiss health insurance claims (2012-2019). We established the MAMA cohort by identifying deliveries and estimating the last menstrual period. We identified claims for any antidiabetic medication (ADM), insulins, blood glucose-lowering drugs, and individual substances within each class. We defined three groups of pattern use based on timing of dispensation: (1) dispensation of at least one ADM in the prepregnancy period and in or after trimester 2 (T2) (pregestational diabetes); (2) dispensation for the first time in or after T2 (GDM); and (3) dispensation in the prepregnancy period and no dispensation in or after T2 (discontinuers). Within the pregestational diabetes group, we further defined continuers (dispensation for the same group of ADM) and switchers (different ADM group dispensed in the prepregnancy period and in or after T2)., Results: MAMA included 104,098 deliveries with a mean maternal age at delivery of 31.7. Antidiabetic dispensations among pregnancies with pregestational and gestational diabetes increased over time. Insulin was the most dispensed medication for both diseases. Between 2017 and 2019, less than 10% of pregnancies treated for pregestational diabetes continued metformin rather than switching to insulin. Metformin was offered to less than 2% of pregnancies to treat gestational diabetes (2017-2019)., Conclusion: Despite its position in the guidelines and the attractive alternative that metformin represents to patients who may encounter barriers with insulin therapy, there was reluctance to prescribe it., Competing Interests: The authors declare no conflict of interest which could have biased this work., (Copyright © 2023 Eva Gerbier et al.)

Aim: The objective of this study was to describe the use of COVID-19-related medicines during pregnancy and their evolution between the early/late periods of the pandemic., Methods: Pregnant women who tested positive for SARS-CoV-2 from March 2020 to July 2021 were included using the COVI-PREG registry. Exposure to the following COVID-19-related medicines was recorded: antibiotics, antivirals, hydroxychloroquine, corticosteroids, anti-interleukin-6 and immunoglobulins. We described the prevalence of medicines used, by trimester of pregnancy, maternal COVID-19 severity level and early/late period of the pandemic (before and after 1 July 2020)., Findings: We included 1964 pregnant patients who tested positive for SARS-CoV-2. Overall, 10.4% (205/1964) received at least one COVID-19-related medicine including antibiotics (8.6%; 169/1694), corticosteroids (3.2%; 62/1964), antivirals (2.0%; 39/1964), hydroxychloroquine (1.4%; 27/1964) and anti-interleukin-6 (0.3%; 5/1964). The use of at least one COVID-19-related medicine was 3.1% (12/381) in asymptomatic individuals, 4.2% (52/1233) in outpatients, 19.7% (46/233) in inpatients without oxygen, 72.1% (44/61) in those requiring standard oxygen, 95.7% (22/23) in those requiring high flow oxygen, 96.2% (25/26) in patients who required intubation and 57.1% (4/7) among patients who died. The proportion who received medicines to treat COVID-19 was higher before than after July 2020 (16.7% vs. 7.7%). Antibiotics, antivirals and hydroxychloroquine had lower rates of use during the late period., Conclusion: Medicine use in pregnancy increased with disease severity. The trend towards increased use of corticosteroids seems to be aligned with changing guidelines. Evidence is still needed regarding the effectiveness and safety of COVID-19-related medicines in pregnancy., (© 2022 British Pharmacological Society.)

Introduction and Objective: The risks and benefits of medication use in pregnancy are typically established through post-marketing observational studies. As there is currently no standardised or systematic approach to the post-marketing assessment of medication safety in pregnancy, data generated through pregnancy pharmacovigilance (PregPV) research can be heterogenous and difficult to interpret. The aim of this article is to describe the development of a reference framework of core data elements (CDEs) for collection in primary source PregPV studies that can be used to standardise data collection procedures and, thereby, improve data harmonisation and evidence synthesis capabilities., Methods: This CDE reference framework was developed within the Innovative Medicines Initiative (IMI) ConcePTION project by experts in pharmacovigilance, pharmacoepidemiology, medical statistics, risk-benefit communication, clinical teratology, reproductive toxicology, genetics, obstetrics, paediatrics, and child psychology. The framework was produced through a scoping review of data collection systems used by established PregPV datasets, followed by extensive discussion and debate around the value, definition, and derivation of each data item identified from these systems., Results: The finalised listing of CDEs comprises 98 individual data elements, arranged into 14 tables of related fields. These data elements are openly available on the European Network of Teratology Information Services (ENTIS) website ( http://www.entis-org.eu/cde )., Discussion: With this set of recommendations, we aim to standardise PregPV primary source data collection processes to improve the speed at which high-quality evidence-based statements can be provided about the safety of medication use in pregnancy., (© 2023. The Author(s).)

Macrophages are essential for HIV-1 pathogenesis and represent major viral reservoirs. Therefore, it is critical to understand macrophage infection, especially in tissue macrophages, which are widely infected in vivo, but poorly permissive to cell-free infection. Although cell-to-cell transmission of HIV-1 is a determinant mode of macrophage infection in vivo, how HIV-1 transfers toward macrophages remains elusive. Here, we demonstrate that fusion of infected CD4+ T lymphocytes with human macrophages leads to their efficient and productive infection. Importantly, several tissue macrophage populations undergo this heterotypic cell fusion, including synovial, placental, lung alveolar, and tonsil macrophages. We also find that this mode of infection is modulated by the macrophage polarization state. This fusion process engages a specific short-lived adhesion structure and is controlled by the CD81 tetraspanin, which activates RhoA/ROCK-dependent actomyosin contractility in macrophages. Our study provides important insights into the mechanisms underlying infection of tissue-resident macrophages, and establishment of persistent cellular reservoirs in patients., (© 2023 Mascarau et al.)

With COVID-19 vaccination hesitancy at around 50% in the obstetric population, it is critical to identify which women should be addressed and how. Our study aimed to assess COVID-19 vaccination willingness among pregnant and postpartum women in Europe and to investigate associated determinants. This study was a cross-sectional, web-based survey conducted in Belgium, Norway, Switzerland, The Netherlands, and United Kingdom (UK) in June-August 2021. Among 3194 pregnant women, the proportions of women vaccinated or willing to be vaccinated ranged from 80.5% in Belgium to 21.5% in Norway. The associated characteristics were country of residence, chronic illness, history of flu vaccine, trimester of pregnancy, belief that COVID-19 is more severe during pregnancy, and belief that the COVID-19 vaccine is effective and safe during pregnancy. Among 1659 postpartum women, the proportions of women vaccinated or willing to be vaccinated ranged from 86.0% in the UK to 58.6% in Switzerland. The associated determinants were country of residence, chronic illness, history of flu vaccine, breastfeeding, and belief that the COVID-19 vaccine is safe during breastfeeding. Vaccine hesitancy in the obstetric population depends on medical history and especially on the opinion that the vaccine is safe and on the country of residence.

Objective: This sequential, prospective meta-analysis sought to identify risk factors among pregnant and postpartum women with COVID-19 for adverse outcomes related to disease severity, maternal morbidities, neonatal mortality and morbidity, and adverse birth outcomes., Data Sources: We prospectively invited study investigators to join the sequential, prospective meta-analysis via professional research networks beginning in March 2020., Study Eligibility Criteria: Eligible studies included those recruiting at least 25 consecutive cases of COVID-19 in pregnancy within a defined catchment area., Methods: We included individual patient data from 21 participating studies. Data quality was assessed, and harmonized variables for risk factors and outcomes were constructed. Duplicate cases were removed. Pooled estimates for the absolute and relative risk of adverse outcomes comparing those with and without each risk factor were generated using a 2-stage meta-analysis., Results: We collected data from 33 countries and territories, including 21,977 cases of SARS-CoV-2 infection in pregnancy or postpartum. We found that women with comorbidities (preexisting diabetes mellitus, hypertension, cardiovascular disease) vs those without were at higher risk for COVID-19 severity and adverse pregnancy outcomes (fetal death, preterm birth, low birthweight). Participants with COVID-19 and HIV were 1.74 times (95% confidence interval, 1.12-2.71) more likely to be admitted to the intensive care unit. Pregnant women who were underweight before pregnancy were at higher risk of intensive care unit admission (relative risk, 5.53; 95% confidence interval, 2.27-13.44), ventilation (relative risk, 9.36; 95% confidence interval, 3.87-22.63), and pregnancy-related death (relative risk, 14.10; 95% confidence interval, 2.83-70.36). Prepregnancy obesity was also a risk factor for severe COVID-19 outcomes including intensive care unit admission (relative risk, 1.81; 95% confidence interval, 1.26-2.60), ventilation (relative risk, 2.05; 95% confidence interval, 1.20-3.51), any critical care (relative risk, 1.89; 95% confidence interval, 1.28-2.77), and pneumonia (relative risk, 1.66; 95% confidence interval, 1.18-2.33). Anemic pregnant women with COVID-19 also had increased risk of intensive care unit admission (relative risk, 1.63; 95% confidence interval, 1.25-2.11) and death (relative risk, 2.36; 95% confidence interval, 1.15-4.81)., Conclusion: We found that pregnant women with comorbidities including diabetes mellitus, hypertension, and cardiovascular disease were at increased risk for severe COVID-19-related outcomes, maternal morbidities, and adverse birth outcomes. We also identified several less commonly known risk factors, including HIV infection, prepregnancy underweight, and anemia. Although pregnant women are already considered a high-risk population, special priority for prevention and treatment should be given to pregnant women with these additional risk factors., (Copyright © 2022. Published by Elsevier Inc.)

Nocturia is the complaint that an individual has to wake up at night one or more times to urinate. It is a frequent condition among older adults and entails detrimental effects with regard to sleeping, sexual activity, comfort, depression, mental function and vitality. It is clinically important to distinguish it from global polyuria, defined as a urinary rate ≥ 125 ml/h (3000 ml/day), as well as from nocturnal polyuria, which is an abnormally large volume of urine during sleep associated with a decreased daytime urine production. A Frequency Volume Chart (FVC), overnight water deprivation test with renal concentrating capacity test, and the nocturnal bladder capacity index are some of the methods that help establish the underlying pathology of this condition and hence define an adequate treatment plan., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Despite a growing body of research on the risks of SARS-CoV-2 infection during pregnancy, there is continued controversy given heterogeneity in the quality and design of published studies., Methods: We screened ongoing studies in our sequential, prospective meta-analysis. We pooled individual participant data to estimate the absolute and relative risk (RR) of adverse outcomes among pregnant women with SARS-CoV-2 infection, compared with confirmed negative pregnancies. We evaluated the risk of bias using a modified Newcastle-Ottawa Scale., Results: We screened 137 studies and included 12 studies in 12 countries involving 13 136 pregnant women.Pregnant women with SARS-CoV-2 infection-as compared with uninfected pregnant women-were at significantly increased risk of maternal mortality (10 studies; n=1490; RR 7.68, 95% CI 1.70 to 34.61); admission to intensive care unit (8 studies; n=6660; RR 3.81, 95% CI 2.03 to 7.17); receiving mechanical ventilation (7 studies; n=4887; RR 15.23, 95% CI 4.32 to 53.71); receiving any critical care (7 studies; n=4735; RR 5.48, 95% CI 2.57 to 11.72); and being diagnosed with pneumonia (6 studies; n=4573; RR 23.46, 95% CI 3.03 to 181.39) and thromboembolic disease (8 studies; n=5146; RR 5.50, 95% CI 1.12 to 27.12).Neonates born to women with SARS-CoV-2 infection were more likely to be admitted to a neonatal care unit after birth (7 studies; n=7637; RR 1.86, 95% CI 1.12 to 3.08); be born preterm (7 studies; n=6233; RR 1.71, 95% CI 1.28 to 2.29) or moderately preterm (7 studies; n=6071; RR 2.92, 95% CI 1.88 to 4.54); and to be born low birth weight (12 studies; n=11 930; RR 1.19, 95% CI 1.02 to 1.40). Infection was not linked to stillbirth. Studies were generally at low or moderate risk of bias., Conclusions: This analysis indicates that SARS-CoV-2 infection at any time during pregnancy increases the risk of maternal death, severe maternal morbidities and neonatal morbidity, but not stillbirth or intrauterine growth restriction. As more data become available, we will update these findings per the published protocol., Competing Interests: Competing interests: CW declares a relationship with Ferring Pharmaceuticals COVID-19 Investigational Grant and NHMRC Fellowship (salary support). AP declares the following research grants to her institution: ‘H2020-Grant—Consortium member of Innovative medicine initiative call 13 topic 9 «ConcePTION», Efficacy and safety studies on Medicines EMA/2017/09/PE/11, Lot 4, WP 2 lead, Safety monitoring of COVID-19 vaccines in the EU—Reopening of competition no. 20 under a framework contract following procurement procedure EMA/2017/09/PE (Lot 3) (Euro 110,000), Federal Office of Public Health (207,000 CHF)’. EM declares a relationship with the National Institute for Health Research (project grant for PAN COVID study). DM declares a relationship with the Canadian Institutes of Health Research (payments to institution only), Public Health Agency of Canada (payments to institution only), BC Women’s Foundation (payments to institution only) and is a member of the COVID-19 Immunity Task Force sponsored by the Canadian government. TDM declares a relationship with Pfizer (site principal investigator for SARS-CoV-2 vaccination in pregnancy study, money paid to institution and member of Medical Advisory Board for SARS-CoV-2 vaccination in pregnancy study, money paid to TDM), NICHD (subcommittee chair for the NICHD Maternal-Fetal Medicine Units Network Gestational Research Assessments of COVID-19 (GRAVID) study) and Society for Maternal-Fetal Medicine (board member). EL declares a relationship with the US NIH (paid institution) and is an employee of AbbVie, but was employed at the University of Washington at the time of the study. KK declares a relationship with the Bill & Melinda Gates Foundation. VJF declares a relationship with the Bill & Melinda Gates Foundation (payments to institution), Yellow Chair Foundation (payments to institution), Robert Woods Johnson Foundation (payments to institution), CDC Foundation, California Health Care Foundation (payments to institution), Tara Health Foundation (payments to institution), UCSF Women’s Health Center of Excellence (payments to institution) and California Department of Health Care Services (payments made to institution). JS-B declares a relationship with the Ferring Pharmaceuticals, which gave a grant ($10 000) for the expenses of RECOGEST trial and is a part of the Columbian Federation of Perinatology. YA declares a relationship with the Bill & Melinda Gates Foundation (payments made to institution), CDC Foundation (payments made to institution), Robert Woods Johnson Foundation (payments made to institution) and UCLA Dean’s Office COVID-19 research (payments made to institution). RC declares a relationship with the NIH HD36801 (MFMU Network DCC). MCN declares a relationship with the BMGF (project grant made to institution), EDCTP, Sanofi, AstraZeneca, Pfizer (research grants made to institution), Sanofi Pasteur (payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events) and Sanofi Pasteur and Pfizer (payment for expert testimony). ESM declares a relationship with Pfizer (site principal investigator for phase 2/3 RCT of COVID vaccine during pregnancy). OS declares a relationship with the NordForsk Funding (Nordic research funding grant number: 105545), the Swedish Medical Products Agency (funding for reports on COVID-19 vaccines and pregnancy) and Karolinska Institutet (funding for COVID research and pregnancy: 2020-01567). EG declares a relationship with the Stavros Niarchos Foundation, Santander Foundation and ‘La Caixa’ Foundation (payments made to institution). SAM declares a relationship with BMGF (funded study in South Africa)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

The protocadherin proteins are cell adhesion molecules at the crossroad of signaling pathways playing a major role in neuronal development. It is now understood that their role as signaling hubs is not only important for the normal physiology of cells but also for the regulation of hallmarks of cancerogenesis. Importantly, protocadherins form a cluster of genes that are regulated by DNA methylation. We have identified for the first time that PCDHB15 gene is DNA-hypermethylated on its unique exon in the metastatic melanoma-derived cell lines and patients' metastases compared to primary tumors. This DNA hypermethylation silences the gene, and treatment with the DNA demethylating agent 5-aza-2'-deoxycytidine reinduces its expression. We explored the role of PCDHB15 in melanoma aggressiveness and showed that overexpression impairs invasiveness and aggregation of metastatic melanoma cells in vitro and formation of lung metastasis in vivo. These findings highlight important modifications of the methylation of the PCDHβ genes in melanoma and support a functional role of PCDHB15 silencing in melanoma aggressiveness., (© 2022. The Author(s).)