Loss-of-function mutations in the CABLES1 gene are a novel cause of Cushing's disease.

The CABLES1 cell cycle regulator participates in the adrenal-pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing's disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene

A modified self‐controlled case series method for event‐dependent exposures and high event‐related mortality, with application to COVID‐19 vaccine safety

We propose a modified self‐controlled case series (SCCS) method to handle both event‐dependent exposures and high event‐related mortality. This development is motivated by an epidemiological study undertaken in France to quantify potential risks of cardiovascular events associated with COVID‐19 vaccines. Event‐dependence of vaccinations, and high event‐related mortality, are likely to arise in other SCCS studies of COVID‐19 vaccine safety. Using this case study and simulations to broaden its scope, we explore these features and the biases they may generate, implement the modified SCCS model, illustrate some of the properties of this model, and develop a new test for presence of a dose effect. The model we propose has wider application, notably when the event of interest is death

La méthode IIM pour une membrane immergée dans un fluide incompressible

La méthode IIM (Immersed Interface Method) permet d'étendre certaines méthodes numériques à des problèmes présentant des discontinuités. Elle est utilisée ici pour étudier un fluide incompressible régi par les équations de Navier-Stokes, dans lequel est immergée une membrane exerçant une force singulière. Nous utilisons une méthode de projection dans une grille de différences finies de type MAC. Une dérivation très complète des conditions de saut dans le cas où la viscosité est continue est présentée en annexe. Deux exemples numériques sont présentés : l'un sans membrane, et l'un où la membrane est immobile. Le cas général d'une membrane mobile est aussi étudié en profondeur.The Immersed Interface Method allows us to extend the scope of some numerical methods to discontinuous problems. Here we use it in the case of an incompressible fluid governed by the Navier-Stokes equations, in which a membrane is immersed, inducing a singular force. We use a projection method and staggered (MAC-type) finite difference approximations. A very complete derivation for the jump conditions is presented in the Appendix, for the case where the viscosity is continuous. Two numerical examples are shown : one without a membrane, and the other where the membrane is motionless. The general case of a moving membrane is also thoroughly studied

Des auristes aux otologistes (une histoire de l' otologie en France)

L histoire de l otologie française débute avec l apparition des auristes, défricheurs de la science de l oreille et pionniers du traitement de la surdité, au XVIIème siècle. Ils ont pu bénéficier du savoir anatomique et des traités médicaux imprimés issus du XVIème siècle pour développer leur connaissance de l oreille. L auristerie va atteindre son apogée au XVIIIème siècle grâce aux praticiens attachés aux instituts de sourd muets, tels Itard, Deleau ou Menière, qui vont pouvoir faire progresser la physiologie et la thérapeutique auriculaire.Les auristes vont laisser place aux otologistes, véritables spécialistes médico-chirurgicaux de l oreille, au cours du XIXème siècle, grâce à la reconnaissance de leur spécialité et aux progrès de la chirurgie. Les Annales des Maladies de l Oreille et du Larynx, publiées en 1875 marquent la fondation de l école française d ORL. Elle va progressivement se développer avec la création par Ladreit de Lacharrière, à l Institut des Jeunes Sourds, du premier service public d otologie en 1882, du premier enseignement officiel en 1996 par Castex puis du premier service hospitalier par Gouguenheim, à Lariboisière, en 1897. Cela aboutira à la création de la première chaire d ORL pour le Pr Moure à Bordeaux en 1913.La chirurgie prend son essor dans la seconde moitié du XIXème siècle avec l apparition de l anesthésie et de l asepsie. Les chirurgiens français, comme Duplay ou Malherbe, vont s intéresser à la chirurgie du rocher à la suite de l école allemande et vont initier le traitement chirurgical de l otite chronique avec l évidement petro-mastoïdien.Le XXème siècle sera celui de la chirurgie de la surdité avec le développement de la fenestration par Sourdille puis de la chirurgie stapedienne pour le traitement de l otospongiose. La chirurgie de l otite chronique continue sa progression avec le développement des techniques fermées et de la reconstruction tympano-ossiculaire. Les otologistes s aventurent alors dans l oreille interne, avec la chirurgie du neurinome et celle de l implant cochléaire initiée par Eyriès en 1957.PARIS-BIUM (751062103) / SudocPARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

Drug use for gastrointestinal symptoms during pregnancy: A French nationwide study 2010-2018.

PurposeTo describe drug prescription for gastrointestinal symptoms during pregnancy.MethodsUsing the French national health database, we identified pregnancies ending with a birth between April 2010 and December 2018, in France. We studied prescription of antacids, antispasmodics, antinauseants, laxatives and antidiarrheals during pregnancy, between two trimesters before and two trimesters after delivery. We also assessed hospitalization for gastrointestinal symptoms during pregnancy.ResultsAmong 6,365,471 pregnancies, 4,452,779 (74.0%) received at least one gastrointestinal drug during pregnancy; 2,228,275 (37.0%) received an antacid, 3,096,858 (51.5%) an antispasmodic, 1,861,731 (31.0%) an antinauseant, 919,116 (15.3%) a laxative and 617,808 (10.3%) an antidiarrheal. Prescription of proton pump inhibitors doubled from 12.2% in 2010 to 26.0% in 2018, while domperidone use decreased from 18.3% in 2010 to 2.2% in 2018. In addition, prescription of antacids increased from 7.0% during the trimester before pregnancy to 11.8% during the 1st trimester, 17.0% during the 2nd trimester and 23.4% during the 3rd trimester. Antispasmodic use was 10.6% during the trimester before pregnancy, 23.1% during the 1st trimester, 25.2% during the 2nd trimester and 24.0% during the 3rd trimester. Prescription of antinauseant drugs increased from 5.0% during the trimester before pregnancy to 25.7% during the 1st trimester, then decreased to 6.4% during the 2nd trimester and 3.2% during the 3rd trimester. Nausea/vomiting was the most common cause of hospitalization for gastrointestinal symptoms or diseases during pregnancy, although it accounted for only 1.0% of pregnancies.ConclusionsApproximately three-quarters of women use drugs for gastrointestinal symptoms during pregnancy in France. Prescription of gastrointestinal drugs during pregnancy should be the subject of more detailed risk-benefit assessment and recommendations

Pregnancy outcomes in women with rheumatoid arthritis: an 11-year French nationwide study

Background Rheumatoid arthritis (RA) can affect women of childbearing age. The management of patients with RA during pregnancy has evolved over the past decades, especially with the availability of new therapeutic molecules.Objectives To describe pregnancy in women with RA, to compare pregnancy outcomes with those of women in the general population and to compare pregnancy outcomes in women with active and inactive RA.Methods Using the French National Health Data System, we identified all pregnancies ending between 2010 and 2020 in patients with and without RA. Characteristics were described. Active RA was defined by conventional synthetic/biological/targeted synthetic disease-modifying antirheumatic drug initiation, systemic or intra-articular corticosteroid administration and/or RA-related hospitalisation. Pregnancy outcomes were compared computing multivariable logistic marginal regression model using generalised estimating equation (GEE).Results We included 11 792 RA and 10 413 681 non-RA pregnancies. Among RA pregnancies, 74.5% ended in live births and 0.4% in stillbirths. RA pregnancies resulted more frequently in preterm births (adjusted OR (ORa) 1.84; 95% CI 1.69 to 2.00) and very preterm births (ORa 1.43; 95% CI 1.20 to 1.71), low birth weight (ORa 1.65; 95% CI: 1.52 to 1.90), caesarean section (ORa 1.46; 95% CI 1.38 to 1.55) and pregnancy-related hospitalisation (ORa 1.30; 95% CI 1.22 to 1.39). Disease activity decreased during pregnancy. Active RA had higher rates of prematurity (ORa 2.02; 95% CI 1.71 to 2.38), small for gestational age (ORa 1.53; 95% CI 1.28 to 1.83) and caesarean section (ORa 1.25; 95% CI 1.11 to 1.40) than non-active RA.Conclusion Pregnancies in women with RA were associated with more adverse outcomes, especially if the disease was active. These findings should encourage physicians to closely monitor RA during this crucial period

Impact of Coronavirus disease 2019 (COVID-19) on contraception use in 2020 and up until the end of April 2021 in France

International audienceObjectives: To assess the impact of the COVID-19 pandemic on the use of reimbursed contraceptives in France after 15 months of the pandemic, according to age-group and updating previous data only pertaining to the first lockdown (2 months). Study design: We conducted a national register-based study by extracting all reimbursements of oral contraceptives (OC), emergency contraception (EC), intrauterine devices (IUD), and implants from the French National Health Insurance database (SNDS), which includes and covers 99.5% of the French population, in 2018, 2019, 2020 and from January 1, 2021 to April30, 2021. We calculated the expected use of contraceptives in 2020 and 2021 in the absence of the pandemic, based on 2018 and 2019 usage and taking annual trends into account. We assessed the difference between observed and expected dispensing rates by contraceptive type and by age-group (≤18 years old, 1835). Results: Dispensing of all contraceptives decreased compared to expect dispensing numbers: −2.0% for OC, −5.3% for EC, −9.5% for LNG-IUS, −8.6% for C-IUD, and −16.4% for implant. This decrease in the dispensing of contraceptives was observed in all age-groups, but mainly concerned women under the age of 18 years (−22% for OC, −10% for EC, −37.2% for LNG-IUS, −36.4% for C-IUD, −26.4% for implant) and those aged 18 to 25 (−5.1% for OC, −11.9% for EC, −18.1% for LNG-IUS, −15.9% for C-IUD, −17.6% for implants). Conclusions: Our study showed that the dispensing of contraceptives in France was markedly impacted by the COVID-19 pandemic. Prescriptions for long-acting contraceptive use and women under the age of 25 years were the most substantially impacted. Ensuring access to contraceptive methods during health emergencies must be a public health policy priority. Implications: The COVID-19 pandemic strongly impacted the dispensing of contraceptives in France with varying degrees of decreased dispensing according to the type of contraceptive, the age-group and the level of pandemic-related restrictions. The impact of these restrictions on unintended pregnancy at the population level remains undetermined

Impact of coronavirus disease 2019 on contraception use in France

International audienceTo limit the spread of the coronavirus disease 2019 (COVID 19), sanitary restrictions have been established since March 2020 in France. These restrictions and the waves of contamination may have had consequences on the use of health products in general, and on the use of contraceptives in particular. We aimed to assess the impact of COVID 19 pandemic from March 16th 2020 to April 30th 2021 in France on reimbursed contraceptives. We analyzed data from the French national health insurance database (SNDS) by extracting all oral contraception (OC), emergency contraception (EC), levonorgestrel-intrauterine system (LNG-IUS), copper-intrauterine device (C-IUD) and contraceptive implant dispensations in 2018, 2019, 2020 and to April 30th 2021. We computed the expected use of contraceptives in 2020 and 2021 without pandemic and its associated sanitary restrictions, by taking the annual trend into account. We assessed the evolution of dispensations by type of contraceptive and by age-groups (≤25 years old, between 25 and 35 and >35 years old) between observed and expected dispensations. After 15 months of pandemic, a decrease of all reimbursed contraceptives dispensations had been estimated, compared with what was expected: –2.0% for OC, –5.0% for EC, –9.5% for LNG-IUS, –8.6% for C-IUD, –16.4% for implant. Women under 25 years old were the most impacted by the decrease. This national study showed that the impact of the COVID 19 crisis was global on all reimbursed contraceptives, with different levels of impact depending on the type of contraceptive, the age-group and the severity of the restriction. OC dispensing decreased marginally compared with expectations. The decrease in long-acting contraceptives dispensing was more pronounced, especially for the implant. These results call for continued monitoring of contraceptive use over the long term and for prioritizing access to sexual health services during crises, especially among the youngest women who were most affected in this study

Reduced risk of severe COVID-19 in more than 1.4 million elderly people aged 75 years and older vaccinated with mRNA-based vaccines

International audienceRandomized clinical trials have shown mRNA-based vaccines to be 92–95% effective to prevent COVID-19 in adults. We aimed to estimate the impact of vaccination on the risk of severe COVID-19 (requiring hospitalization) in elderly people. Each 1,422,461 vaccinated subject aged 75 or older was matched to two unvaccinated subjects of same age, sex, administrative region, and type of residence. They were followed from date of first injection between 27 December 2020 and 24 February 2021 to 20 March 2021 for COVID-19 hospitalization. Mean age was 82.4 years (SD, 5.7) and median follow-up was 38 days [IQR, 17–54]. Adjusted Hazard Ratio for COVID-19 hospitalization from day 7 after the second dose was estimated at 0.14 (95% confidence interval, 0.11–0.17), i.e. an estimated 86% risk reduction in people aged 75 and older, highlighting the major impact of mRNA vaccination on reducing the risk of COVID-19 among elderly people