Compliance with the pregnancy prevention program among women initiating isotretinoin treatment between 2014 and 2021: A nationwide cohort study on the French Health Data System (SNDS).

BACKGROUND: Despite the French pregnancy prevention program (PPP), a considerable number of pregnancies are potentially exposed to oral isotretinoin. New measures were taken by the French Medicines Agency, including the restriction of initial isotretinoin prescriptions to dermatology specialists in May 2015 and a new information campaign on teratogenicity in January 2019. OBJECTIVES: The aims were to: describe, between 2014 and 2021, compliance with PPP recommendations: isotretinoin use as a second-line treatment, first prescription by a dermatology specialist, monthly prescription renewal and pregnancy testing (PT); assess the effect of the 2015 and 2019 measures on PT compliance; and identify the determinants of PT noncompliance. METHODS: A retrospective cohort study was conducted among women aged 11-50 years initiating isotretinoin between 2014 and 2021 using the French Health Data System. PT compliance corresponded to pregnancy test completion and specific delays between prescription and dispensation. Time series analyses were performed to evaluate the effect of the 2015 and 2019 measures on PT compliance, and log-binomial and Poisson multivariate regression models were used to identify the determinants of PT noncompliance. RESULTS: Isotretinoin was prescribed as a second-line treatment in 64% of initiations, mainly by dermatology specialists (92%). A new monthly prescription was observed in 98% of dispensations. PT compliance reached 61%, 72% and 25% at initiation, renewals and end of treatment, respectively. The 2015 measure was associated with better PT compliance at initiation and renewals. The 2019 measure had no significant effect on PT compliance at the initiation or end of treatment but was associated with a decrease in PT compliance at renewals. Age, low socioeconomic level, initiation by a nondermatology specialist and during summer were associated with PT noncompliance. CONCLUSIONS: Understanding factors associated with PT noncompliance could help to target specific subpopulations of women treated with isotretinoin.

REALMS: Resilient exploration and lunar mapping system.

Space resource utilisation is opening a new space era. The scientific proof of the presence of water ice on the south pole of the Moon, the recent advances in oxygen extraction from lunar regolith, and its use as a material to build shelters are positioning the Moon, again, at the centre of important space programs. These worldwide programs, led by ARTEMIS, expect robotics to be the disrupting technology enabling humankind's next giant leap. However, Moon robots require a high level of autonomy to perform lunar exploration tasks more efficiently without being constantly controlled from Earth. Furthermore, having more than one robotic system will increase the resilience and robustness of the global system, improving its success rate, as well as providing additional redundancy. This paper introduces the Resilient Exploration and Lunar Mapping System, developed with a scalable architecture for semi-autonomous lunar mapping. It leverages Visual Simultaneous Localization and Mapping techniques on multiple rovers to map large lunar environments. Several resilience mechanisms are implemented, such as two-agent redundancy, delay invariant communications, a multi-master architecture different control modes. This study presents the experimental results of REALMS with two robots and its potential to be scaled to a larger number of robots, increasing the map coverage and system redundancy. The system's performance is verified and validated in a lunar analogue facility, and a larger lunar environment during the European Space Agency (ESA)-European Space Resources Innovation Centre Space Resources Challenge. The results of the different experiments show the efficiency of REALMS and the benefits of using semi-autonomous systems.

Unexpected catalytic activity of nanorippled graphene.

Graphite is one of the most chemically inert materials. Its elementary constituent, monolayer graphene, is generally expected to inherit most of the parent material's properties including chemical inertness. Here, we show that, unlike graphite, defect-free monolayer graphene exhibits a strong activity with respect to splitting molecular hydrogen, which is comparable to that of metallic and other known catalysts for this reaction. We attribute the unexpected catalytic activity to surface corrugations (nanoscale ripples), a conclusion supported by theory. Nanoripples are likely to play a role in other chemical reactions involving graphene and, because nanorippling is inherent to atomically thin crystals, can be important for two-dimensional (2D) materials in general.

Hallucinating symmetric protein assemblies.

Deep learning generative approaches provide an opportunity to broadly explore protein structure space beyond the sequences and structures of natural proteins. Here, we use deep network hallucination to generate a wide range of symmetric protein homo-oligomers given only a specification of the number of protomers and the protomer length. Crystal structures of seven designs are very similar to the computational models (median root mean square deviation: 0.6 angstroms), as are three cryo-electron microscopy structures of giant 10-nanometer rings with up to 1550 residues and C33 symmetry; all differ considerably from previously solved structures. Our results highlight the rich diversity of new protein structures that can be generated using deep learning and pave the way for the design of increasingly complex components for nanomachines and biomaterials.

Robust deep learning-based protein sequence design using ProteinMPNN.

Although deep learning has revolutionized protein structure prediction, almost all experimentally characterized de novo protein designs have been generated using physically based approaches such as Rosetta. Here, we describe a deep learning-based protein sequence design method, ProteinMPNN, that has outstanding performance in both in silico and experimental tests. On native protein backbones, ProteinMPNN has a sequence recovery of 52.4% compared with 32.9% for Rosetta. The amino acid sequence at different positions can be coupled between single or multiple chains, enabling application to a wide range of current protein design challenges. We demonstrate the broad utility and high accuracy of ProteinMPNN using x-ray crystallography, cryo-electron microscopy, and functional studies by rescuing previously failed designs, which were made using Rosetta or AlphaFold, of protein monomers, cyclic homo-oligomers, tetrahedral nanoparticles, and target-binding proteins.

Outbreak of Ichthyophthirius multifiliis associated with Aeromonas hydrophila in Pangasianodon hypophthalmus: The role of turmeric oil in enhancing immunity and inducing resistance against co-infection.

Ichthyophthirius multifiliis, a ciliated parasite causing ichthyophthiriasis (white spot disease) in freshwater fishes, results in significant economic loss to the aquaculture sector. One of the important predisposing factors for ichthyophthiriasis is low water temperature (i.e., below 20°C), which affects the health and makes freshwater fishes more susceptible to parasitic infections. During ichthyophthiriasis, fishes are stressed and acute immune reactions are compromised, which enables the aquatic bacterial pathogens to simultaneously infect the host and increase the severity of disease. In the present work, we aimed to understand the parasite-bacteria co-infection mechanism in fish. Later, Curcuma longa (turmeric) essential oil was used as a promising management strategy to improve immunity and control co-infections in fish. A natural outbreak of I. multifiliis was reported (validated by 16S rRNA PCR and sequencing method) in Pangasianodon hypophthalmus from a culture facility of ICAR-CIFRI, India. The fish showed clinical signs including hemorrhage, ulcer, discoloration, and redness in the body surface. Further microbiological analysis revealed that Aeromonas hydrophila was associated (validated by 16S rRNA PCR and sequencing method) with the infection and mortality of P. hypophthalmus, confirmed by hemolysin and survival assay. This created a scenario of co-infections, where both infectious agents are active together, causing ichthyophthiriasis and motile Aeromonas septicemia (MAS) in P. hypophthalmus. Interestingly, turmeric oil supplementation induced protective immunity in P. hypophthalmus against the co-infection condition. The study showed that P. hypophthalmus fingerlings supplemented with turmeric oil, at an optimum concentration (10 ppm), exhibited significantly increased survival against co-infection. The optimum concentration induced anti-stress and antioxidative response in fingerlings, marked by a significant decrease in cortisol and elevated levels of superoxide dismutase (SOD) and catalase (CAT) in treated animals as compared with the controls. Furthermore, the study indicated that supplementation of turmeric oil increases both non-specific and specific immune response, and significantly higher values of immune genes (interleukin-1ß, transferrin, and C3), HSP70, HSP90, and IgM were observed in P. hypophthalmus treatment groups. Our findings suggest that C. longa (turmeric) oil modulates stress, antioxidant, and immunological responses, probably contributing to enhanced protection in P. hypophthalmus. Hence, the application of turmeric oil treatment in aquaculture might become a management strategy to control co-infections in fishes. However, this hypothesis needs further validation.

High cubicity of D2O ice inside spherical nanopores of MIL-101(Cr) framework: a neutron diffraction study.

Although cubic ice (ice Ic) is considered to be an important phase of water that impacts ice cloud formation in the Earth's upper atmosphere, its properties have not been studied to the same extent as those of hexagonal ice (ice Ih). This is because pristine ice Ic is not formed in simple laboratory conditions. Ice Ic formed in ambient conditions has a stacking disordered array of both hexagonal and cubic-structured hydrogen-bonded water molecules. It is therefore an active area of research to find ways of developing stacking disorder-free pure ice Ic. We demonstrate the evolution of almost pure ice Ic structure within the spherical nanopores of a hydrostable Cr-based metal-organic framework MIL-101(Cr) with an average pore size of 1 nm by low-temperature neutron diffraction study on D2O. It is observed that at temperatures below 230 K a fraction of liquid D2O transforms into ice and more than 94% of ice crystals evolved inside the pore are cubic in shape. This is a significantly high fraction of ice Ic formed under simple conditions inside the spherical pores of a Cr-based MOF. It is also observed that upon increasing the temperature, ice Ic remains stable until its melting point, without being transformed into ice Ih. This observation is in contrast to our previous observation of ice structure in the 2D cylindrical nanopores of MCM-41, where H2O ice after creeping out from the cylindrical channel was seen to be dominated by hexagonal shape. In the present study, the D2O molecules were confined into well-defined spherical nanopores, which hindered the growth of crystals above a certain size, thus minimizing the stacking disordered array. Nanoconfinement of water inside uniform spherical pores is therefore a promising method for the evolution of a significantly large fraction of cubic ice by minimizing the stacking disorder. This finding may open up the possibility of forming ice Ic with 100% cubicity under simple laboratory conditions, which will help in exploring the microphysics of ice cloud formation in the upper atmosphere.

Specific features of amoxicillin-associated Drug Reaction with Eosinophilia and Systemic Symptoms syndrome: a nationwide study.

BACKGROUND: Growing evidence indicates that amoxicillin induces herpesvirus replication in vitro. As these play a central pathophysiological role in Drug Reaction with Eosinophilia and Systemic Symptoms syndrome (DRESS), amoxicillin could present with specific DRESS features. OBJECTIVE: To characterize the onset patterns of amoxicillin-associated DRESS. METHODS: All cases of DRESS (Kardaun score ≥4) involving amoxicillin and reported in the French Pharmacovigilance Database between January 1, 2004 and November 30, 2019 were included. Onset circumstances for these cases were categorized considering the onset delay from amoxicillin initiation, and the presence of concomitant medications with a compatible time to onset. RESULTS: A total of 146 probable cases or definite cases of DRESS were included. Three onset circumstances were identified: (i) 'amoxicillin clear culprit' where amoxicillin was the sole suspect drug or when concomitant drugs of compatible time to onset were not reported to cause DRESS (n = 62); (ii) 'amoxicillin possible culprit' in the presence of other potentially culprit drugs in addition to amoxicillin (n = 44) and (iii) 'flare' where amoxicillin, used after DRESS onset, induced flare-up reactions (n = 40). The median time to onset was 5 days (IQR 2-11) in 'clear culprit', and 18 days (IQR 7-26) in 'possible culprit' cases. In 'flare' cases, the median latency between amoxicillin initiation and flare-up reactions was 3 days (IQR 2-5). CONCLUSIONS: Amoxicillin can induce DRESS with a specific early onset and exacerbate DRESS from another drug.

The cardiovascular safety of oral alitretinoin: a population-based cohort study involving 19 513 patients exposed to oral alitretinoin.

BACKGROUND: Oral alitretinoin is a retinoid used for severe chronic hand eczema. Although caution is recommended for patients with uncontrolled dyslipidaemia or cardiovascular risk factors, the actual atherothrombotic risk has not been investigated thus far. OBJECTIVES: To detect any excess of atherothrombotic events among patients exposed to alitretinoin, during treatment or in the 2 years following initiation. METHODS: Using the French Health Insurance database, we compared the number of patients who had an atherothrombotic event (coronary artery disease, ischaemic stroke or peripheral artery disease requiring revascularization) in the population exposed to oral alitretinoin vs. the general population of the same age, sex and baseline cardiovascular risk, using standardized morbidity ratios (SMRs). RESULTS: Between 2009 and 2017, 19 513 patients were exposed to oral alitretinoin in France. Sixty-four (0·3%) patients had an atherothrombotic event while on alitretinoin. Patients receiving alitretinoin experienced no more atherothrombotic events than the general population: patients without cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·65 [95% confidence interval (CI) 0·26-1·34] during alitretinoin treatment, and 1·21 (95% CI 0·90-1·59) in the 2 years following initiation; patients with cardiovascular risk factors or previous atherothrombotic events had a SMR of 0·82 (95% CI 0·60-1·08) during alitretinoin treatment and 0·95 (95% CI 0·82-1·09) in the 2 years following initiation. Taken separately, SMRs for each outcome did not increase either. CONCLUSIONS: These data from an exhaustive nationwide population-based study do not support an increase in the incidence of atherothrombotic events with alitretinoin use, regardless of the baseline cardiovascular risk of the patient.

Evolution of confined ice nano structures at different levels of pore filling: a synchrotron based X-ray diffraction study.

We have thoroughly investigated the crystal structure of ice evolved from super cooled water confined in MCM-41 cylindrical nano pores through a synchrotron-based X-ray diffraction (XRD) technique for two different levels of pore filling. A rigorous analysis of XRD data shows that the nucleation dynamics and the structure of nucleated ice highly depend on the level of pore filling. In the nearly fully hydrated pores, ice crystallites start nucleating inside the pores below 240 K and creep out of the pores to form bulk crystals having crystalline structure of a mixed phase of hexagonal and cubic forms. In the partially hydrated pores, on the other hand, ice crystals cannot creep out of the pore crossing the energy barrier. The crystalline ice particles remaining inside the cylindrical pore show a short range "cubic rich" structure. The "pure cubic" phase has not been identified at either of the pore fillings in these 2.5 nm average size pores. A large fraction of water inside the pores remains in the super cooled liquid phase even at 180 K. This observation is relevant for understanding the ice nucleation through the pore condensation and freezing mechanism, which is a major pathway for the formation of cirrus clouds in the upper atmosphere.

Correlated paramagnetism and interplay of magnetic and phononic degrees of freedom in 3d-5d coupled La2CuIrO6.

Conventional paramagnetism-a state with finite magnetic moment per ion sans long range magnetic ordering, but with lowering temperature the moment each ion picks up a particular direction, breaking spin rotational symmetry, and results into long-range magnetic ordering. However, in systems with competing multiple degrees of freedom this conventional notion may easily break and results into short range correlation much above the global magnetic transition temperature. La2CuIrO6 with complex interplay of spins (s = 1/2) on Cu site and pseudo-spin (j  = 1/2) on Ir site owing to strong spin-orbit coupling provides fertile ground to observe such correlated phenomena. By a comprehensive temperature dependent Raman study, we have shown the presence of such a correlated paramagnetic state in La2CuIrO6 much above the long-range magnetic ordering temperature (T N ). Our observation of strong interactions of phonons, associated with Cu/Ir octahedra, with underlying magnetic degrees of freedom mirrored in the observed Fano asymmetry, which remarkably persists as high as ~3.5T N clearly signals the existence of correlated paramagnetism hence broken spin rotational symmetry. Our detailed analysis also reveals anomalous changes in the self-energy parameters of the phonon modes, i.e. mode frequencies and linewidth, below T N , providing a useful gauge for monitoring the strong coupling between phonons and magnetic degrees of freedom.

Transient major hypothermia associated with acetaminophen: A pediatric case report and literature review.

We report the case of a 4-month-old baby boy who presented hypothermia (rectal temperature 36°C) after acetaminophen intake for post-vaccination fever. A recurrence of the hypothermia was observed after acetaminophen rechallenge for fever. We reviewed 14 other pediatric cases of hypothermia secondary to therapeutic doses of acetaminophen. Hypothermia after a therapeutic dose is a very rare side effect of acetaminophen. Several hypotheses have been made but the exact mechanism remains unknown.

Variability of the EG95 antigen-coding gene of Echinococcus granulosus in animal and human origin: implications for vaccine development.

In the present study, the genetic variability of the EG95 protein-coding gene in several animal and human isolates of Echinococcus granulosus was investigated. A total of 24 isolates collected from cattle, buffalo, sheep, goat, dog and man were amplified by Eg95-coding gene-specific primers. From the generated sequence information, a conceptual amino acid sequence was deduced. Phylogenetically, the Eg95 coding gene belongs to the Eg95-1/Eg95-2/Eg95-3/Eg95-4 cluster. Further confirmation on the maximum composite likelihood analysis revealed that the overall transition/transversion bias was 2.913. This finding indicated thatthere is bias towards transitional and transversional substitution. Using artificial neural networks, a B-cell epitope was predicted on primary sequence information. Stretches of amino acid residues varied between animal and human isolates when hydrophobicity was considered. Flexibility also varied between larval and adult stages of the organism. This observation is important to develop vaccines. However, cytotoxic T-lymphocyte epitopes on primary sequence data remained constant in all isolates. In this study, agretope identification started with hydrophobic amino acids. Amino acids with the same physico-chemical properties were present in the middle. The conformational propensity of the Eg95-coding gene of 156 amino acid residues had α-turns and ß-turns, and α-amphipathic regions up to 129, 138-156 and 151-155 residues, respectively. The results indicated potential T-cell antigenic sites. The overall Tajima's D value was negative (-2.404165), indicative of negative selection pressure.

[Drug and food interactions with contraceptives: CNGOF Contraception Guidelines]. / Interactions avec les contraceptifs. RPC Contraception CNGOF.

INTRODUCTION: The risk of drug interaction with hormonal contraceptives should be anticipated as it may lead to unplanned pregnancies. These are frequently reported with some drugs, such as antiepileptics, and with some contraceptive methods, such as the implant, not always understood by patients as hormonal contraception. OBJECTIVES: The aim of this work was to review all drugs and foods at risk of interaction with contraceptives. METHODS: The official recommendations established by the French Agency for the safety of medicinal products have been taken into account, supported by a review of the literature. RESULTS: There is a risk of drug-drug interaction with all hormonal contraceptives regardless of their route of administration. Most interactions lead to a decrease in the effectiveness of hormonal contraceptives. If an enzyme inducer drug is started in a woman with an hormonal contraception, it is recommended, if the treatment is short, to use an additional mechanical contraception (barrier method) for the duration of the treatment and the cycle following its arrest and if the treatment is long, it is recommended to choose a non-hormonal contraceptive method. On the contrary, some drugs may increase ethinylestradiol levels and potentially the risk of complications. Exceptionally, it is the hormonal contraceptive that will alter the pharmacokinetics of another drug, for example, lamotrigine. CONCLUSIONS: The risk of drug interaction leading to a decrease in the contraceptive effectiveness needs to be known to prescribers in order to be taken into account when prescribing any new drug in a woman with hormonal contraception (and whatever its route of administration).

[Contraception: CNGOF Guidelines for Clinical Practice (Short Version)]. / Contraception : Recommandations pour la Pratique Clinique du CNGOF (texte court).

The French College of Obstetrics and Gynecology (CNGOF) releases its first global recommendations for clinical practice in contraception, to provide physicians with an updated synthesis of available data as a basis for their practice. The French Health Authority (HAS) methodology was used. Twelve practical issues were selected by the organizing committee and the task force members. The available literature was screened until December 2017, and allowed the release of evidence-based, graded recommendations. This synthesis is issued from 12 developed texts, previously reviewed by experts and physicians from public and private practices, with an experience in the contraceptive field. Male and female sterilization, as well as the use of hormonal treatments without contraceptive label were excluded from the field of this analysis. Specific practical recommendations on the management of contraception prescription, patient information including efficacy, risks, and benefits of the different contraception methods, follow up, intrauterine contraception, emergency contraception, local and natural methods, contraception in teenagers and after 40, contraception in vascular high-risk situations, and in case of cancer risk are provided. The short/mid-term future of contraception mostly relies on improving the use of currently available methods. This includes reinforced information for users and increased access to contraception for women, whatever the social and clinical context. That is the goal of these recommendations.

Cyclin E and FGF8 are downstream cell growth regulators in distinct tumor suppressor effects of ANXA7 in hormone-resistant cancer cells of breast versus prostate origin.

Tumor suppressor function of Annexin-A7 (ANXA7) was demonstrated by cancer-prone phenotype in Anxa7(+/-) mice and ANXA7 profiling in human cancers including prostate and breast. Consistent with its more evident in vivo tumor suppressor role in prostate cancer, wild-type(wt)-ANXA7 in vitro induced similar G2-arrests, but reduced survival more drastically in prostate cancer cells compared to breast cancer cells (DU145 versus MDA-MB-231 and -435). In all three hormone-resistant cancer cell lines, wt-ANXA7 abolished the expression of the oncogenic low-molecular weight (LMW) cyclin E which was for the first time encountered in prostate cancer cells. Dominant-negative nMMM-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) failed to abrogate LMW-cyclin E and simultaneously induced fibroblast growth factor 8 (FGF8) in DU145 that was consistent with the continuing cell cycle progression and reduced cell death. Adenoviral vector alone induced FGF8 in MDA-MB-231/435 cell lines, but not in DU145 cells. Our data indicated that the LMW-Cyclin E expressions in breast cancer and prostate cancer cell-lines were differentially regulated by wild-type and dominant-negative ANXA7 isoforms, demonstrating a different survival mechanism utilized by breast cancer cells. Conventional tumor suppressor p53 failed to completely abolish FGF8 and LMW-cyclin E in breast cancer cells, which were eventually translated into their survival. Thus, ANXA7 tumor suppression could modulate FGF8 and cyclin E expression, and control implying more specific associations with the annexin properties of ANXA7 in prostate tumorigenesis.