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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.

Abstract Epilepsy is defined by the abrupt emergence of harmful seizures, but the nature of these regime shifts remains enigmatic. From the perspective of dynamical systems theory, such critical transitions occur upon inconspicuous perturbations in highly interconnected systems and can be modeled as mathematical bifurcations between alternative regimes. The predictability of critical transitions represents a major challenge, but the theory predicts the appearance of subtle dynamical signatures on the verge of instability. Whether such dynamical signatures can be measured before impending seizures remains uncertain. Here, we verified that predictions on bifurcations applied to the onset of hippocampal seizures, providing concordant results from in silico modeling, optogenetics experiments in male mice and intracranial EEG recordings in human patients with epilepsy. Leveraging pharmacological control over neural excitability, we showed that the boundary between physiological excitability and seizures can be inferred from dynamical signatures passively recorded or actively probed in hippocampal circuits. Of importance for the design of future neurotechnologies, active probing surpassed passive recording to decode underlying levels of neural excitability, notably when assessed from a network of propagating neural responses. Our findings provide a promising approach for predicting and preventing seizures, based on a sound understanding of their dynamics.

BACKGROUND: Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively. RESULTS: We systematically investigate both dominance-here representing any non-additive within-locus interaction-and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance. CONCLUSIONS: Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5 untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

Abstract Cerebral white matter damage (WMD) is the most frequent brain lesion observed in infants surviving premature birth. Qualitative B-mode cranial ultrasound (cUS) is widely used to assess brain integrity at bedside. Its limitations include lower discriminatory power to predict long-term outcomes compared to magnetic resonance imaging (MRI). Shear wave elastography (SWE), a promising ultrasound imaging modality, might improve this limitation by detecting quantitative differences in tissue stiffness. The study enrolled 90 neonates (52% female, mean gestational age = 30.1 $$\pm \hspace{0.17em}$$ ± 4.5 weeks), including 78 preterm and 12 term controls. Preterm neonates underwent B-mode and SWE assessments in frontal white matter (WM), parietal WM, and thalami on day of life (DOL) 3, DOL8, DOL21, 40 weeks, and MRI at term equivalent age (TEA). Term infants were assessed on DOL3 only. Our data revealed that brain stiffness increased with gestational age in preterm infants but remained lower at TEA compared to the control group. In the frontal WM, elasticity values were lower in preterm infants with WMD detected on B-mode or MRI at TEA and show a good predictive value at DOL3. Thus, brain stiffness measurement using SWE could be a useful screening method for early identification of preterm infants at high WMD risk. Registration numbers: EudraCT number ID-RCB: 2012-A01530-43, ClinicalTrial.gov number NCT02042716.

Beyond a threshold applied compressive stress, porous rocks typically undergo either dilatant or compactant inelastic deformation and the response of their physical properties to deformation mode is key to mass transport, heat transport and pressure evolution in crustal systems. Transitions in failure modes—involving switches between dilatancy and compaction—have also been observed, but to date have received little attention. Here, we perform a series of targeted mechanical deformation experiments on porous andesites, designed to elucidate complex post-failure deformation behaviour. By investigating a sample suite and effective pressure range that straddles the transition between positive and negative volumetric responses to compression, we show two post-failure critical stress states: a transition from compaction to dilation ([Formula: see text]), and a transition from dilation to compaction, which we term [Formula: see text]. We demonstrate that multiple switches in deformation mode can be driven by stress application under conditions relevant to the shallow crust. While the effect on fluid flow properties of compaction-to-dilation switching may be masked by a net reduction in sample porosity, samples that underwent dilatant-to-compactant failure mode switching exhibited an increase in permeability of approximately two orders of magnitude, despite only slight net volumetric change. Such a substantial permeability enhancement underscores the importance of post-failure deformation in influencing solute and heat transfer in the crust, and the generation of supra-hydrostatic fluid pressures in volcanic environments.

The development of new antimalarials is required because of the threat of resistance to current antimalarial therapies. To discover new antimalarial chemotypes, we screened the Janssen Jumpstarter library against the P. falciparum asexual parasite and identified the 7-N-substituted-3-oxadiazole quinolone hit class. We established the structure-activity relationship and optimized the antimalarial potency. The optimized analog WJM228 (17) showed robust metabolic stability in vitro, although the aqueous solubility was limited. Forward genetic resistance studies uncovered that WJM228 targets the Qo site of cytochrome b (cyt b), an important component of the mitochondrial electron transport chain (ETC) that is essential for pyrimidine biosynthesis and an established antimalarial target. Profiling against drug-resistant parasites confirmed that WJM228 confers resistance to the Qo site but not Qi site mutations, and in a biosensor assay, it was shown to impact the ETC via inhibition of cyt b. Consistent with other cyt b targeted antimalarials, WJM228 prevented pre-erythrocytic parasite and male gamete development and reduced asexual parasitemia in a P. berghei mouse model of malaria. Correcting the limited aqueous solubility and the high susceptibility to cyt b Qo site resistant parasites found in the clinic will be major obstacles in the future development of the 3-oxadiazole quinolone antimalarial class.

This scientific commentary refers to Chronic intracranial EEG recordings and interictal spike rate reveal multiscale temporal modulations in seizure states by Schroeder et al. (https://doi.org/10.1093/braincomms/fcad205).

Introduction: PRP is gaining increasing interest for pain relief and improvement of joint function in patients with knee osteoarthritis (KOA) but practices and results remain heterogeneous limiting its adoption as standard of care. Current international recommendations are to collect real-life evidence of efficacy with a systematic monitoring of PRP quality and patients' outcomes. We aimed to analyze the response of patients presenting KOA and treated with standardized PRP injection in routine care. We also investigated the potential contributing factors including patient's phenotype and PRP characteristics. Methods: Patients with symptomatic KOA and that failed first-line therapy received a single injection of a qualified PRP prepared using medical devices allowing to recover a high/very high volume of very pure PRP. Visual analogue scale (VAS) and Western Ontario and McMaster Osteoarthritis Index (WOMAC) score were recorded at baseline and during 18 months follow-up. Results: 431 patients had available follow-up data at 3 months, 291 at 6 months, 137 at 12 months and 44 at 18 months. PRP induced a significant decrease of WOMAC score at all follow up endpoints (29.2 ± 19.2 at 3 months, p

Introduction. The study presents an approach for detecting and identifying the causes of damage to individual key elements of metal structures of the hydroelectric power plant’s trash-rack structure under anthropogenic dynamic impacts. Strength and hydraulic calculations were performed, as well as modal analysis of the structure. The approach is determined and instrumental measurements of actual dynamic characteristics of the trash-rack structure at different pressures are carried out.Materials and methods. A methodology consisting of two blocks was developed to perform measurements of dynamic anthropogenic impacts. The first block is an instrumental and visual inspection to determine the compliance of structures with design solutions, as well as to identify characteristic defects of the trash-rack structure. The measurement of natural frequencies of vibrations and vibration accelerations of structures at different pressures was carried out using piezoelectric vibration transducers AR90, the measurement of vibration accelerations by seismic receivers A16 and the receiving station MIC-200. The second block is mathematical modelling. The hydraulic regime and the stress-strain state were specified, frequencies and forms of natural vibrations of the structure were determined. Computational studies were carried out in the universal industrial software complex ANSYS Mechanical and ANSYS CFX.Results. The survey revealed the presence of systematically occurring cracks in the load-bearing frame, the mismatch of the position of the struts to the design. Hydrodynamic loads are specified, diameter and frequency of vortex formation are determined. The stresses in the metal struts do not exceed the standard values for the steel used. The performed direct measurement of vibration of structural elements demonstrated that the most dangerous frequency range is 40.30–41.75 Hz.Conclusions. It is revealed that the main cause of damage to the trash-rack structure is the displacement of forced frequencies and the shape of natural oscillations to the zone of operation of hydraulic units, which led to the concentration of stresses at the ends of the struts in the zone adjacent to the gussets. The junction of struts to the gusset had insufficient length, which led to the transfer of stresses to the edge of the gusset and, as a result, to the concentration of stresses and the formation of cracks in the direction of the main stresses in the node.

Abstract Background Lack of Cytomegalovirus (CMV) knowledge among healthcare professionals has been proven to be the main threat to pregnant women's awareness, preventing them from reducing the risk of infection. The aims of this study were to assess the knowledge and practices of French-speaking Swiss perinatal professionals in terms of CMV prevention, as well as the sociodemographic-professional factors that influence them. Methods This observational study used a cross-sectional design to collect data-via an anonymous electronic questionnaire in French distributed to gynecologists-obstetricians, general practitioners and midwives via various channels: e-mails and social networks of partner centers, professional associations, and conferences. The 41-item questionnaire collected data on sociodemographic and professional characteristics, general CMV knowledge, national recommendation knowledge and prevention practices. Univariable and multivariable analyses were performed. Results A total of 110 gynecologist-obstetricians, 5 general practitioners and 226 midwives participated in the study. While more than 80% of practitioners were familiar with protective hygiene measures, significant gaps were highlighted concerning the transmission routes, as well as the signs of short- and long-term congenital CMV infection. Regarding practice, 63.3% of participants provided information on CMV to their patients, mainly during the first antenatal visit. Among those who did not, lack of knowledge and forgetfulness were the two main reasons cited. Concerning systematic screening, 45.7% of participants offered it to their patients, and 37.3% only offered it to “at risk” groups. The existence of national guidelines on CMV was known by 62.0% of participants. Multivariable analysis revealed that working as a gynecologist-obstetrician was independently associated with higher score of preventive practices, while performing ultrasound or preconception consultations was independently associated with a higher score of general CMV knowledge, and working in a university hospital was independently associated with a higher score of Swiss recommendation knowledge. A level of training higher than the basic medical or midwifery diploma and participation in fetal medicine symposia both promote a higher score of CMV knowledge and prevention practices in line with current recommendations. Conclusion This study confirms the significant gaps in CMV knowledge among French-speaking Swiss caregivers along with the heterogeneity of their prevention practices. To raise awareness among pregnant women and reduce the burden of congenital CMV infections, improving professional knowledge through access to specific training and standardizing practices should be a national priority.

Abstract Background and purpose The only validated treatment to prevent brain damage associated with hypoxia–ischemia (HI) encephalopathy of the newborn is controlled hypothermia with limited benefits. Additional putative neuroprotective drug candidates include sildenafil citrate, a phosphodiesterase-type 5 inhibitor. The main objective of this preclinical study is to assess its ability to reduce HI-induced neuroinflammation, in particular through its potential effect on microglial activation. Methods HI was induced in P10 Sprague–Dawley rats by unilateral carotid permanent artery occlusion and hypoxia (HI) and treated by either hypothermia (HT) alone, Sildenafil (Sild) alone or combined treatment (SildHT). Lesion size and glial activation were analyzed by immunohistochemistry, qRT-PCR, and proteomic analyses performed at P13. Results None of the treatments was associated with a significant early reduction in lesion size 72h after HI, despite significant changes in tissue loss distribution. Significant reductions in both Iba1 + (within the ipsilateral hemisphere) and GFAP + cells (within the ipsilateral hippocampus) were observed in SildHT group, but not in the other treatment groups. In microglia-sorted cells, pro-inflammatory markers, i.e. Il1b, Il6, Nos2, and CD86 were significantly downregulated in SildHT treatment group only. These changes were restricted to the ipsilateral hemisphere, were not evidenced in sorted astrocytes, and were not sex dependent. Proteomic analyses in sorted microglia refined the pro-inflammatory effect of HI and confirmed a biologically relevant impact of SildHT on specific molecular pathways including genes related to neutrophilic functions. Conclusions Our findings suggest that Sildenafil combined with controlled hypothermia produces maximum effect in mitigating microglial activation induced by HI through complex proteomic regulation. The reduction of neuroinflammation induced by Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection.

The 2022 monkeypox outbreak, caused by the zoonotic monkeypox virus, has spread across 6 World Health Organization regions (the Americas, Africa, Europe, Eastern Mediterranean, Western Pacific, and South-East Asia) and was declared a public health emergency of international concern on July 23, 2022. The global situation is especially concerning given the atypically high rate of person-to-person transmission, which suggests viral evolution to an established human pathogen. Pregnant women are at heightened risk of vertical transmission of the monkeypox virus because of immune vulnerability and natural depletion of population immunity to smallpox among reproductive-age women, and because orthopoxviral cell entry mechanisms can overcome the typically viral-resistant syncytiotrophoblast barrier within the placenta. Data on pregnancy outcomes following monkeypox infection are scarce but include reports of miscarriage, intrauterine demise, preterm birth, and congenital infection. This article forecasts the issues that maternity units might face and proposes guidelines to protect the health of pregnant women and fetuses exposed to the monkeypox virus. We review the pathophysiology and clinical features of monkeypox infection and discuss the obstetrical implications of the unusually high prevalence of anogenital lesions. We describe the use of real-time polymerase chain reaction tests from mucocutaneous and oropharyngeal sites to confirm infection, and share an algorithm for the antenatal management of pregnant women with monkeypox virus exposure. On the basis of the best available knowledge from prenatal orthopoxvirus infections, we discuss the sonographic features of congenital monkeypox and the role of invasive testing in establishing fetal infection. We suggest a protocol for cesarean delivery to avoid the horizontal transmission of the monkeypox virus at birth and address the controversy of mother-infant separation in the postpartum period. Obstetrical concerns related to antiviral therapy with tecovirimat and vaccinia immune globulin are highlighted, including the risks of heart rate-corrected QT-interval prolongation, inaccuracies in blood glucose monitoring, and the predisposition to iatrogenic venous thromboembolism. The possibility of monkeypox vaccine hesitancy during pregnancy is discussed, and strategies are offered to mitigate these risks. Finally, we conclude with a research proposal to address knowledge gaps related to the impact of monkeypox infection on maternal, fetal, and neonatal health.

BACKGROUND AND AIM: In Switzerland, a cantonal authorisation is required to introduce opioid agonist treatments (OAT). We investigated and compared the terms of these cantonal OAT authorisations throughout Switzerland. The primary objective was to determine how the overseeing cantonal officials implemented and perceived the legal requirements. METHOD: We started with a cross-sectional analysis of legal texts and cantonal OAT guidelines. Based on the document analysis, we conducted 26 semi-structured interviews with the cantonal officials who grant OAT authorisations. FINDINGS: In most cantons (21 of 25), the OAT authorisation is specific to the person treated and must be renewed every year. Today, 21 cantons either have implemented or are implementing the same web-based software to process and manage OAT authorisation requests. Cantons have implemented diverging requirements regarding, amongst others, the involvement of third parties in OAT and the training required of prescribing physicians. Lastly, the OAT process does not seem to be a high priority for the overseeing officials. CONCLUSIONS: From a legal standpoint, OAT authorisations should be straightforward, yet we found significant divergences among cantonal systems. We could not find scientific evidence that supports a given framework. We recommend harmonizing the 26 cantonal systems while reviewing the need for OAT authorisation.

To assess the genetic characteristics of the early emerging SARS-CoV-2 Omicron variant strains, we retrospectively analyzed a collection of 150 nasopharyngeal samples taken from a series of outpatient cases tested positive by a referenced qRT-PCR assay during the reported period of Omicron variant emergence in December 2021, in northeastern region of France. Next Generation Sequencing (NGS) analysis of SARS-CoV-2 spike sequences revealed that only 3 (2 %) of these detected strains were Omicron variants, while 147 (98 %) were identified as previously described delta variants. Our phylogenetic analyzes of SARS-CoV-2 RNA genomes showed that these French early emerging Omicron variants may have originated from South Africa or India. In addition, whole viral genome sequences NGS comparison analyzes allowed us to identify an original and uncharacterized Y170W spike mutation that was weakly and transiently detected during the period of SARS-CoV-2 Omicron variant emergence in human populations. Molecular modeling and docking experiments indicated that this original mutated residue Y170W was neither directly involved in binding to the SARS-CoV-2 receptor ACE2 nor in interacting with known neutralizing antibody sites. However, this new mutation may be responsible for preventing the transition from the closed to the open Spike conformation, thus promoting the early emergence of the Omicron variant. Overall, these results underscore the epidemiological utility of a routine whole-genome viral NGS strategy that enables genotypic characterization of emerging or mutant SARS-CoV-2 variants, which could have significant implications for public health policy.

Objectives Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy.Design This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022.Setting Data were collected from the databases of six Teratology Information Services.Participants This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women.Results Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses.Conclusions This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings.

Sediment geochemistry is one lens through which lake sediments are studied to reconstruct local and regional environmental processes. The measurement of sediment elemental composition has historically relied on expensive and destructive methods that limit the spatial and temporal scale of study. Micro-X-ray fluorescence (µXRF) core scanning offers a non-destructive, high-resolution alternative, but its results (i.e., intensity expressed as counts per second) are considered semi-quantitative and comparison among sites requires calibration. Calibration methods are emerging, although they are not yet widely employed and require further assessment of their efficacy. Using 135 sediment samples from 48 lakes across Canada, we assessed the congruence between µXRF and conventionally measured element compositions with various normalization and calibration techniques. Normalization of µXRF data to common proxies (e.g., Ca, Si, Ti, coherence:incoherence ratio, and total counts per second) often improved correlations between µXRF and conventional data, but increases were modest and not consistent for all elements. Our results suggest that µXRF normalization techniques should be applied cautiously, as no proxy represents a “one-size-fits-all” solution. The performance of multivariate log-ratio calibration (MLC) was more consistent, yielding moderate to strong improvement of the correlations between reference and predicted element concentrations. Random forest regression models outperformed partial least squares regression models for almost all elements. MLC may be applied where knowledge of elemental concentration is of great importance, or when comparing across multiple sites with diverse sediment geochemistries. Overall, our results reinforce uncalibrated µXRF core scanning as a strong investigative tool for measuring sediment geochemistry. Although calibrated µXRF data shows promise, conventional methods for measuring sediment geochemistry are still necessary for comparing element concentrations with sediment quality guidelines.

Abstract Background Strain-level diversity is widespread among bacterial species and can expand the functional potential of natural microbial communities. However, to what extent communities undergo consistent shifts in strain composition in response to environmental/host changes is less well understood. Results Here, we used shotgun metagenomics to compare the gut microbiota of two behavioral states of the Western honeybee (Apis mellifera), namely nurse and forager bees. While their gut microbiota is composed of the same bacterial species, we detect consistent changes in strain-level composition between nurses and foragers. Single nucleotide variant profiles of predominant bacterial species cluster by behavioral state. Moreover, we identify strain-specific gene content related to nutrient utilization, vitamin biosynthesis, and cell–cell interactions specifically associated with the two behavioral states. Conclusions Our findings show that strain-level diversity in host-associated communities can undergo consistent changes in response to host behavioral changes modulating the functional potential of the community.

Abstract Background Complications requiring medical interventions during childbirth are far from rare, even after uncomplicated pregnancies. It is often a challenge for maternity healthcare professionals to know how to prepare future parents for these eventualities without causing unnecessary anxiety. Studies on traumatic birth experiences have shown that feelings of loss of control, insufficient information, and lack of participation in medical decisions during childbirth are factors of difficult experiences. However, little is known about the information and communication needs of expectant parents about childbirth during the prenatal period. To gain a deeper understanding of the information and communication needs of first-time pregnant women and partners, we explored their perceptions and expectations for their upcoming childbirth, and the actions they initiated to prepare for it. Methods Semi-structured interviews were conducted individually with first-time pregnant women and partners of pregnant women aged 18 years or older, with an uncomplicated pregnancy. Thematic analysis was used to identify themes and sub-themes. Results Twenty expectant parents (15 pregnant women and five partners of pregnant women) were interviewed. Six themes were identified: Childbirth event; Childbirth experience; Childbirth environment; Organisation of care; Participation in decision making; Roles within the couple and transition to parenthood. Conclusions This study contributes to a better understanding of the information needs of future parents expecting their first child. Results highlighted that the notion of “childbirth risks” went beyond the prospect of complications during birth, but also encompassed concerns related to a feeling of loss of control over the event. Expectant parents showed an ambivalent attitude towards consulting risk information, believing it important to prepare for the unpredictability of childbirth, while avoiding information they considered too worrying. They expressed a desire to receive concrete, practical information, and needed to familiarise themselves in advance with the birth environment. Establishing a respectful relationship with the healthcare teams was also considered important. The findings suggest that information on childbirth should not be limited to the transmission of knowledge, but should primarily be based on the establishment of a relationship of trust with healthcare professionals, taking into account each person’s individual values and expectations.

Abstract Hydraulic stimulation of enhanced deep geothermal reservoirs commonly targets pre-existing joint networks with the goal of increasing reservoir permeability. Here, we study the permeability and strength of joint-free and jointed Buntsandstein sandstones from the EPS-1 exploratory borehole at the Soultz-sous-Forêts geothermal site (France). The studied jointed samples contain naturally formed fractures that are variably filled with secondary mineralisation. We find that the permeability of these rocks is more sensitive to the presence and orientation of bedding than to the presence of joints at the scale of the samples: permeability is lowest in samples where bedding is oriented perpendicular to the direction of fluid flow. While well-sealed joints can act as barriers to fluid flow, partially filled joints neither inhibit nor promote fluid flow with respect to their joint-free counterparts. These samples were then deformed under triaxial conditions to assess (1) whether deformation reactivates pre-existing joints, and (2) how permeability changes as a result of deformation. We find that the mechanical response of the rocks depends on the extent to which joints are sealed. Well-sealed joints locally increase rock strength and experimentally induced fractures do not exploit pre-existing joint surfaces; partially sealed joints, by contrast, act as planes of weakness that localise strain. Although the permeability of all samples increased during deformation, permeability increase was largest in samples with poorly filled joints. We conclude that hydraulic stimulation operations must carefully consider the extent to which targeted joint networks are filled. Partially sealed joints are ideal targets for stimulation: these features act as planes of weakness within the rock mass and their reactivation can result in significant increases in permeability. By contrast, well-sealed joints may increase rock strength locally and may never reactivate during stimulation, making them poor targets for permeability enhancement.

Abstract Problem Research so far has evaluated the effect of antenatal classes, but few studies have investigated its usefulness from the perspective of mothers after birth. Background Antenatal classes evolved from pain management to a mother-centred approach, including birth plans and parenting education. Evaluating the perception of the usefulness of these classes is important to meet mother’s needs. However, so far, research on the mothers’ perception of the usefulness of these classes is sparse, particularly when measured after childbirth. Given that antenatal classes are considered as adult education, it is necessary to carry out this evaluation after mothers have had an opportunity to apply some of the competences they acquired during the antenatal classes during their childbirth. Aim This study investigated mothers’ satisfaction and perceived usefulness of antenatal classes provided within a university hospital in Switzerland, as assessed in the postpartum period. Methods Primiparous mothers who gave birth at a Swiss university hospital from January 2018 to September 2020 were contacted. Those who had attended the hospital’s antenatal classes were invited to complete a questionnaire consisting of a quantitative and qualitative part about usefulness and satisfaction about antenatal classes. Quantitative data were analysed using both descriptive and inferential statistics. Qualitative data were analysed using thematic analysis. Findings Among the 259 mothers who answered, 61% (n = 158) were globally satisfied with the antenatal classes and 56.2% (n = 145) found the sessions useful in general. However, looking at the utility score of each theme, none of them achieved a score of usefulness above 44%. The timing of some of these sessions was questioned. Some mothers regretted the lack of accurate information, especially on labour complications and postnatal care. Discussion Antenatal classes were valued for their peer support. However, in their salutogenic vision of empowerment, they did not address the complications of childbirth, even though this was what some mothers needed. Furthermore, these classes could also be more oriented towards the postpartum period, as requested by some mothers. Conclusion Revising antenatal classes to fit mothers’ needs could lead to greater satisfaction and thus a better impact on the well-being of mothers and their families.

The vast majority of gastric cancer (GC) cases are adenocarcinomas including intestinal and diffuse GC. The incidence of diffuse GC, often associated with poor overall survival, has constantly increased in Western countries. Epidemiological studies have reported increased mortality from GC after occupational exposure to pro-carcinogens that are metabolically activated by cytochrome P450 enzymes through aryl hydrocarbon receptor (AhR). However, little is known about the role of AhR and environmental AhR ligands in diffuse GC as compared to intestinal GC in Western patients. In a cohort of 29, we demonstrated a significant increase in AhR protein and mRNA expression levels in GCs independently of their subtypes and clinical parameters. AhR and RHOA mRNA expression were correlated in diffuse GC. Further, our study aimed to characterize in GC how AhR and the AhR-related genes cytochrome P450 1A1 (CYP1A1) and P450 1B1 (CYP1B1) affect the mRNA expression of a panel of genes involved in cancer development and progression. In diffuse GC, CYP1A1 expression correlated with genes involved in IGF signaling, epithelial–mesenchymal transition (Vimentin), and migration (MMP2). Using the poorly differentiated KATO III epithelial cell line, two well-known AhR pollutant ligands, namely 2-3-7-8 tetrachlorodibenzo-p-dioxin (TCDD) and benzo[a]pyrene (BaP), strongly increased the expression of CYP1A1 and Interleukin1β (IL1B), and to a lesser extend UGT1, NQO1, and AhR Repressor (AhRR). Moreover, the increased expression of CYP1B1 was seen in diffuse GC, and IHC staining indicated that CYP1B1 is mainly expressed in stromal cells. TCDD treatment increased CYP1B1 expression in KATO III cells, although at lower levels as compared to CYP1A1. In intestinal GC, CYP1B1 expression is inversely correlated with several cancer-related genes such as IDO1, a gene involved in the early steps of tryptophan metabolism that contributes to the endogenous AhR ligand kynurenine expression. Altogether, our data provide evidence for a major role of AhR in GC, as an environmental xenobiotic receptor, through different mechanisms and pathways in diffuse and intestinal GC. Our results support the continued efforts to clarify the identity of exogenous AhR ligands in diffuse GC in order to define new therapeutic strategies.

ABSTRACTSeveral studies have found associations between specific bacterial genera and semen parameters. Bacteria are known to influence the composition of their niche and, consequently, could affect the composition of the seminal plasma. This study integrated microbiota profiling and metabolomics to explore the influence of seminal bacteria on semen metabolite composition in infertile couples, revealing associations between specific bacterial genera and metabolite profiles. Amino acids and acylcarnitines were the predominant metabolite groups identified in seminal plasma. Different microbiota profiles did not result in globally diverse metabolite compositions in seminal plasma. Nevertheless, levels of specific metabolites increased in the presence of a dysbiotic microbiota. Urocanate was significantly increased in abnormal semen samples (adjusted P-value < 0.001) and enriched in samples dominated by Prevotella spp. (P-value < 0.05), which was previously linked to a negative impact on semen. Therefore, varying microbiota profiles can influence the abundance of certain metabolites, potentially having an immunomodulatory effect, as seen with urocanate.IMPORTANCEMale infertility is often considered idiopathic since the specific cause of infertility often remains unidentified. Recently, variations in the seminal microbiota composition have been associated with normal and abnormal semen parameters and may, therefore, influence male infertility. Bacteria are known to alter the metabolite composition of their ecological niches, and thus, seminal bacteria might affect the composition of the seminal fluid, crucial in the fertilization process. Our research indicates that distinct seminal microbiota profiles are not associated with widespread changes in the metabolite composition of the seminal fluid. Instead, the presence of particular metabolites with immunomodulatory functions, such as urocanate, could shed light on the interplay between seminal microbiota and variations in semen parameters.

CD8+ T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-κB transcription factors have crucial functions in the regulation of immune responses, the CD8+ T cell-autonomous roles of the different NF-κB subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8+ T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8+ T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8+ T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8+ T cells, RelA is dispensable for their protective activity in pathological contexts.

Abstract Background Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively. Results We systematically investigate both dominance—here representing any non-additive within-locus interaction—and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance. Conclusions Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality.