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The seven members of the A3 family of cytidine deaminases (A3A to A3H) share a conserved catalytic activity that converts cytidines in single-stranded (ss) DNA into uridines, thereby inducing mutations. After their initial identification as cell-intrinsic defenses against HIV and other retroviruses, A3s were also found to impair many additional viruses. Moreover, some of the A3 proteins (A3A, A3B and A3H haplotype I) are dysregulated in cancer cells, thereby causing chromosomal mutations that can be selected to fuel progression of malignancy. Viral mechanisms that increase transcription of A3 genes or induce proteasomal degradation of A3 proteins have been characterized. However, only a few underlying biological mechanisms regulating levels of A3s in uninfected cells have been described. Here, we characterize that the von Hippel–Lindau tumor suppressor (pVHL), via its CRL(pVHL), induces degradation of all 7 A3 proteins. Two independent lines of evidence supported the conclusion that the multi-protein CRL(pVHL) complex is necessary for A3 degradation. CRL(pVHL) more effectively induced degradation of nuclear, pro-cancer A3 (A3B) than the cytoplasmic, anti-retroviral A3 (A3G). These results identify specific cellular factors that regulate A3s post-translationally.

Summary Background Few studies of mental health or substance abuse have focused on rural life. This study aimed to evaluate the association between socio-demographic and clinical characteristics and the probability of rural alcoholic women seeking help on their own at a specialty treatment service. Methods This exploratory study used a cross-sectional design to collect data from alcoholic women upon admission to a French outpatient department. Multiple logistic regression models tested whether the socio-demographic and clinical characteristics of these women predicted the likelihood that they would seek treatment at a specialty service on their own. Results Among 50 rural alcoholic women, the probability of seeking help on their own at a specialty treatment service was 5.6 times greater (95% CI 1.2–25.7, P = 0.03) for participants with a history of physical and/or sexual trauma and 5.1 times greater (95% CI 1.1–24, P = 0.03) among women with no complementary health insurance. Conclusion Increased knowledge of the specific characteristics of rural alcoholic women is needed to develop programs that will increase awareness of and access to specialty treatment services among these women.

International audience; Background: Subjects with heart failure (HF) are at higher risk of developing thrombosis. We investigated whether endothelium activation and inflammation induce a prothrombotic biological profile in patients with acute decompensated HF (ADHF) and sinus rhythm.Methods: Our prospective study included 34 ADHF patients, 30 patients with stable chronic HF (CHF) and 30 control inpatients without HF. In vitro thrombin generation and its downregulation by activated protein C (APC) was monitored by calibrated automated thrombography at hospital admission, at the day of discharge and after discharge, following at least six weeks of clinical stability. Circulating endothelium-derived extracellular vesicles (eEVs) were quantified by flow cytometry and nucleosomes by ELISA.Results: Thrombin generation is increased and APC sensitivity is decreased independently of platelets in ADHF at admission compared to controls (p < 0.01). Thrombin generation was also increased in CHF but only in the presence of platelets. Plasma markers of endothelium activation (von Willebrand factor, factor VIII, procoagulant eEVs and circulating nucleosomes) and the ability of plasmas to induce neutrophil extracellular trap formation in control neutrophils are elevated in ADHF at admission compared to controls (p < 0.001). In-hospital prothrombotic changes in ADHF improved significantly at the post-discharge time-point. Circulating nucleosomes were positively correlated with APC sensitivity (p = 0.013) and annexin-V-positive eEVs (p = 0.004).Conclusions: This proof-of-concept study identified an endothelial-driven hypercoagulable phenotype at the acute phase of decompensated HF contrasting with the platelet-dependent prothrombotic state in CHF. These results highlighted a cross-talk between circulating eEVs and nucleosomes, procoagulant factors and impairment of the APC anticoagulant activity in ADHF.

BACKGROUND: COVID-19 can induce pulmonary and systemic inflammation and subsequent multi-organ dysfunction In patients with severe COVID-19, no data are availa

We aimed to assess the effectiveness of recommended drug prescriptions at hospital discharge on 1-year mortality in patients with heart failure (HF) and reduced ejection fraction (HFREF).We used data from the EPICAL2 cohort study. HF patients ≥18years old with left ventricular ejection fraction (LVEF)40% and alive at discharge were included and followed up for mortality. Socio-demographic, clinical and therapeutic data were collected at admission. Therapeutic data were collected at discharge and at 6month. Prescription of an angiotensin-converting enzyme (ACE) inhibitor (or an angiotensin II receptor blocker [ARB] in case of ACE inhibitor intolerance) and a β-blocker at discharge were considered "guideline-consistent discharge prescription" (GCDP). A frailty Cox model after propensity score (PS) matching was used to assess the association of GCDP with survival.Among 624 patients included, the mean (SD) age was 73.6 (12.8) years; 65% were male. A total of 412 (65.6%) patients received GCDP, and 82.8% still had guideline consistent prescription at 6months. A total of 166 patients died during the follow-up, 78 in the GCDP group and 88 in the other group. Before PS matching, patients with GCDP were younger (|StDiff|=48.32%) and had higher body mass index (BMI) (|StDiff|=11.71%), lower LVEF (|StDiff|=23.13%) and lower Charlson index (|StDiff|=55.27%) than patients without GCDP. After PS matching, all characteristics were balanced between the two treatment groups, and GCDP was associated with reduced mortality (pooled HR=0.51, 95% CI [0.35-0.73]).Prescription of ACE (or ARB) inhibitors and β-blockers for patients with HFREF may be low despite the evidence for morbidity and mortality improvement with these medications but remains associated with reduced 1-year mortality in unselected HFREF patients.

Background & Aims Ulcerative colitis (UC) is increasingly recognized as a progressive disease and patients with long-standing disease can develop colorectal stricture. Few data about its incidence in UC are available, while risk factors for colorectal strictures in UC remain to be determined. We assessed the incidence of and risk factors for developing colorectal strictures in a large UC population. Methods All adult patients followed at Nancy University hospital and at the centre hospitalier de Luxembourg for UC, between January 2004 and July 2019, were eligible for inclusion in this multicenter retrospective cohort study. Results A total of 439 patients with UC were included. Median follow-up duration was 9.6 years. Incidence of colorectal stricture was 3.6%. The cumulative probability of developing this complication was 1% at 5 years and 2.3% at 10 years. Median age at stricture diagnosis was 47.9 years (41.0; 63.0), and median time from UC diagnosis to onset of stricture was 11.5 years (5; 15.3). Montreal A3 classification (age > 40 years) (P = .008) and steroids use (HR = 4.1; 95% CI, 1.1-16.1) were independent risk factors for stricture, whereas mesalamine-treated patients carried a lower risk (HR = 0.3; 95% CI, 0.1-0.9). Dysplasia was found in 6 patients with strictures (42.9%) and among them 5 developed a colorectal cancer (33.3%). Conclusions Patients with Montreal A3 classification and those exposed to steroids have a higher risk for strictures, while use of mesalamine lowers this risk. These factors should be assessed in daily clinical practice to prevent stricture occurrence in these patients.

Background There are currently no guidelines on the need to assess disease activity before stoma reversal in Crohn’s disease (CD). We sought to determine the value of cross-sectional imaging for detecting active CD before stoma reversal. Methods 38 CD patients underwent cross-sectional imaging before stoma reversal. CD activity was blindly evaluated by an independent radiologist. Postoperative outcomes were recorded. Results Before stoma reversal, cross-sectional imaging identified active CD in 20 of the 38 study participants (52.6%). In 9 out of 10 tested patients, radiologic and endoscopic assessments gave concordant findings with regard to CD recurrence before stoma reversal. Stoma reversal was delayed in half of the patients with active CD and in none of the patients without active CD. Before stoma reversal, tumor necrosis factor alpha antagonists or immunosuppressants were initiated in 45% of the patients with active CD and 5.6% of the patients without active CD. In the year following stoma reversal, the recurrence rate (in a radiologic assessment) was higher in patients with active CD than in patients without active CD (75.0% vs. 30.8%, respectively; p = 0.04). Conclusion Cross-sectional imaging revealed postoperative recurrence in about a quarter of patients before stoma reversal; this finding may influence the postoperative treatment strategy and outcomes.

Etat de la question L’objectif de cette etude etait d’evaluer l’efficacite d’une prescription medicamenteuse conforme (PMC) aux recommandations europeennes a la sortie de l’hopital sur la mortalite a un an chez les patients en insuffisance cardiaque a fraction d’ejection ventriculaire gauche (FEVG) reduite (ICFER) en conditions de pratique courante. Materiel et methodes Les donnees de la cohorte « Epidemiologie de l’insuffisance cardiaque aigue en Lorraine » (EPICAL2) ont ete utilisees. Les individus presentant une FEVG Resultats Sur 632 patients ICFER, l’âge moyen (± ET) etait de 73,8 (± 12,9) ans, et 65 % etaient des hommes. La PMC etait prescrite a 65,5 % des ICFER, et maintenue a 6 mois chez 81,8 % d’entre eux. Les patients sous PMC etaient plus jeunes (Difference standardisee, |StDiff| = 48,91 %), avaient un indice de masse corporelle plus eleve (|StDiff| = 12,54 %), une FEVG (|StDiff| = 21,96 %) et un indice de Charlson (|StDiff| = 55,78 %) plus faibles que les patients sans PMC. Au total, 165 deces sont survenus, dont 78 dans le groupe sous PMC. Apres appariement sur le SP et ajustement sur les caracteristiques non equilibrees residuelles, c’est-a-dire IMC (|StDiff| = 11,68 %) et antecedent d’hypertension (|StDiff| = 11,07 %), la PMC etait associee a une mortalite reduite (HR combine = 0,54, 95 % CI [0,35–0,83]). Conclusion La PMC est suboptimale malgre les preuves disponibles dans l’ICFER mais semble rester efficace pour reduire la mortalite a un an en conditions de pratique courante.

In low-income countries, health system deficiencies may undermine treatment continuity and adherence to antiretroviral therapy (ART) that are crucial for the success of large-scale public ART programs. In addition to examining the effects of individual characteristics, on non-adherence to ART and treatment interruption behaviors – i.e. treatment interruption for more than 2 consecutive days during the previous 4 weeks, this study aims to extend our knowledge on the role played by healthcare supply-related characteristics in shaping these two treatment outcomes. These effects are examined using multilevel logistic models applied to a sub-sample of 2381 ART-treated patients followed-up in 27 treatment centers in Cameroon (ANRS-EVAL survey, 2006–2007). Multivariate models show that factors common to both non-adherence and treatment interruption include binge drinking (at the individual-level) and large hospital size (at the healthcare supply-level). Among the individual factors, financial difficulties of paying for HIV-care are the major correlates of treatment interruption [Adjusted Odds Ratio (AOR) 95% confidence interval (CI) = 11.73(7.24–19.00)]. By contrast, individual factors associated with an increased risk of non-adherence include: having a main partner but not living in a couple compared to patients living in a couple [AOR(95%CI) = 1.51(1.14–2.01)]; experience of discrimination in the family environment [AOR(95%CI) = 1.74(1.14–2.65)]; a lack of regular meals [AOR(95%CI) = 1.93(1.44–2.57)], and switching antiretroviral drugs (ARV) regimen [AOR(95%CI) = 1.36(1.08–1.70)]. At healthcare facility-level, the main correlate of ART interruption was antiretroviral stock-outs [AOR(95%CI) = 1.76(1.01–3.32)] whereas the lack of psychosocial support from specialized staff and lack of task-shifting to nurses in medical follow-up were both associated with a higher-risk of non-adherence [respective AOR (95%CI) = 2.81(1.13–6.95) and 1.51(1.00–3.40)]. Results reveal different patterns of factors for non-adherence and treatment interruption behaviors. They also suggest that psychosocial support interventions targeted at the individual patient-level will not be sufficient to achieve favorable treatment outcomes if not combined with interventions focused on strengthening health systems, including appropriate drug supplies and human resources policies, as well as sustainable and equitable financing mechanisms.

International audience; HTLV-I bZIP factor (HBZ) contains a C-terminal zipper domain involved in its interaction with c-Jun. This interaction leads to a reduction of c-Jun DNA-binding activity and prevents the protein from activating transcription of AP-1-dependent promoters. However, it remained unclear whether the negative effect of HBZ-SP1 was due to its weak DNA-binding activity or to its capacity to target cellular factors to transcriptionally-inactive nuclear bodies. To answer this question, we produced a mutant in which specific residues present in the modulatory and DNA-binding domain of HBZ-SP1 were substituted for the corresponding c-Fos amino acids to improve the DNA-binding activity of the c-Jun/HBZ-SP1 heterodimer. The stability of the mutant, its interaction with c-Jun, DNA-binding activity of the resulting heterodimer, and its effect on the c-Jun activity were tested. In conclusion, we demonstrate that the repression of c-Jun activity in vivo is mainly due to the HBZ-SP1-mediated sequestration of c-Jun to the HBZ-NBs.

Calpains are a family of calcium-dependent cysteine proteases involved in major cellular processes including cell death. Their intracellular localization is essential to the understanding of their biological functions. In a previous confocal microscopy study, we observed the presence of a calpain 3-like protein in the mammalian brain. We thus first identified and confirmed the presence of a calpain 3-like protease in a neuronal cell model (NGF-differentiated PC12 cells). The goal of this study was to determine, for the first time in non-muscular cells, the relation between the subcellular localization, activation and function of this protease. We thus investigated its ability to regulate nuclear IkappaBalpha and therefore NF-kappaB activation after cell death stimulation. The IkappaBalpha/NF-kappaB signalling pathway indeed influences the neurodegenerative process by directly affecting gene expression in neurons. In the present study, we found that calpain 3 is present in the cytoplasm and nucleus of neuron-like PC12 cells and could be activated through autolysis in the nuclei of cells undergoing apoptosis after ionomycin treatment. Moreover, in these conditions, we demonstrated formation of the IkappaBalpha/calpain 3 complex and an increase in calpain-dependent IkappaBalpha cleavage products in cell nuclei. Stimulation of calpain-dependent cell death in neuron activated nuclear calpain 3-like protease and IkappaBalpha proteolysis resulted in the regulation of NF-kappaB activation. These data suggest a new mechanism by which calpain 3 activation is able to regulate the IkappaBalpha/NF-kappaB pathway and thus neurodegenerative processes.

Objectif Decrire la mortalite des egoutiers de la ville de Paris (France). Methodes La cohorte des 1898 egoutiers, hommes, presents a la ville de Paris depuis 1970, a ete constituee en 2011 et a ete suivie en mortalite de 1970 a 2011. Le statut vital et les causes de deces ont ete determines par appariement avec des bases de donnees nationales. Des ratio standardises de mortalite (SMR) et des taux de mortalite en exces (TME, estimes par la methode de Pohar-Perme) ont ete calcules en utilisant les taux de mortalite de la population du departement de Seine-Saint-Denis comme reference externe. Resultats Un exces de mortalite, statistiquement significatif, est observe pour toutes causes (908 cas ; SMR = 1,40) et cancers toutes localisations confondues (396 cas ; SMR = 1,57). Les exces de deces, statistiquement significatifs, s’observent pour les maladies malignes (24 cas ; SMR = 1,69 ; TME significatifs a partir de 20 ans apres embauche) et non malignes (49 cas ; SMR = 1,81 ; TME significatifs a partir de 15 ans apres embauche) du foie, le cancer « trachee, bronches, poumon » (TBP) (117 cas ; SMR = 1,71 ; TME significatifs entre 30 et 50 ans apres embauche), le cancer de l’œsophage (33 cas ; SMR = 2,50 ; TME significatifs a partir de 20 ans apres embauche), les maladies infectieuses toutes localisations confondues (41 cas, SMR = 1,40 ; TME significatifs a partir de 20 ans apres embauche), les maladies explicitement liees a l’alcool (33 cas, SMR = 1,54 ; TME significatifs a partir de 20 ans apres embauche) et le suicide (25 cas ; SMR = 3,52 ; TME significatifs et constants apres embauche). L’exces de deces pour toutes causes, tous cancers, cancer TBP, ensemble maladies du foie augmente legerement avec la duree d’emploi. Un exces de deces est observe apres 20 ans d’emploi pour cancer de l’œsophage, maladies explicitement liees a l’alcool, maladies infectieuses. A l’inverse de ce qui est observe pour le cancer TBP, un SMR proche de 1 est observee pour des causes dont le tabac est un facteur etiologique possible (cancer vessie, estomac et maladies cardiovasculaires). Conclusion Les exces de deces observes par maladies malignes et non malignes du foie, par cancer TBP et maladies infectieuses suggerent un effet possible des expositions professionnelles sur la sante des egoutiers. L’absence d’informations individuelles sur la consommation de tabac, d’alcool et sur les expositions professionnelles demande la plus grande prudence quant a l’interpretation des resultats.

Objectifs L’analyse de la mortalite de cohortes professionnelles historiques est principalement realisee sur la base de calculs de ratios standardises de mortalite (standardized mortality ratio [SMR]). Dans les etudes de population sur le cancer, les methodes de survie relative ont ete developpees afin d’evaluer, chez les patients atteints de cancer, la mortalite due au cancer par rapport aux autres causes de deces. L’objectif de la presentation est de montrer comment ces methodes d’analyse peuvent etre utilisees en epidemiologie en sante au travail. Methodes Comme le calcul du SMR, ces analyses comparent la mortalite observee dans la cohorte a celle de la population prise pour reference externe. Elles s’appuient sur l’estimation de la survie nette (calculee selon la methode de Pohar-Perme), de laquelle sont deduits le taux de mortalite relatif (TMR) et le taux de mortalite en exces (TME). Applique a l’epidemiologie en sante au travail, ce dernier peut etre interprete en termes de taux de mortalite du a l’exposition professionnelle de la cohorte etudiee. Le TME et le TMR peuvent etre calcules en fonction du delai depuis la premiere exposition permettant ainsi de mettre en evidence les periodes au cours desquelles l’exces (ou le deficit) de mortalite apparait. Le modele du SMR suppose un TME constant au cours du temps. Resultats L’utilisation de cette methodologie sera illustree au travers d’exemples issus d’une etude de la mortalite dans une cohorte de 1898 egoutiers suivis en mortalite de 1970 a 2010. Le TMR par maladie de l’appareil digestif est sensiblement constant en fonction du temps ecoule depuis l’embauche, proche de la valeur du SMR. En revanche le TMR par cancer « trachee, bronches, poumon » est plus eleve que le SMR entre 35 et 45 ans apres l’embauche et le TME met en evidence une surmortalite superieure a 2 pour mille et par an apres 35 ans apres l’embauche. Pour les deces par maladies de l’appareil cardiovasculaire des egoutiers en activite, le SMR (19 cas, SMR = 1,13) est statistiquement non significatif mais le TME met en evidence un exces de mortalite statistiquement significatif apres une vingtaine d’annee d’activite. Conclusions A la difference du SMR, coefficient unique caracterisant l’ensemble de la periode de suivi, le TMR ou le TME permettent une lecture dynamique de la mortalite d’une cohorte. Les exces de mortalite observes doivent etre interpretes en relation avec les caracteristiques de l’exposition.

Introduction Le score de propension (SP) et la variable instrumentale (VI) sont des methodes d’analyse utilisees en recherche observationnelle pour prendre en compte les biais de confusion et particulierement le biais d’indication. Il est apparu que ces deux methodes etaient de plus en plus employees conjointement dans des etudes evaluant l’efficacite et/ou le risque des interventions de sante. Afin de decrire et d’analyser l’agrement entre le SP et la VI dans ce contexte, une revue de la litterature a ete realisee. Methodes Revue des etudes observationnelles evaluant l’effet d’une intervention de sante sur un critere de jugement de type morbi- et/ou mortalite, et ayant eu recours a une analyse avec SP et une analyse avec VI. Les bases de donnees Medline et Web of Science ont ete interrogees. Resultats Trente-sept etudes, la plupart publiees au cours des cinq dernieres annees, ont ete incluses et ont permis la comparaison de 55 paires de resultats issus d’analyses avec SP et VI. Il est apparu que l’agrement etait faible entre les deux methodes (coefficient Kappa de Cohen = 0,21 [IC95 % : 0,00–0,41]). Dans 23 cas (42 %), les resultats etaient non significatifs pour une methode et significatifs pour l’autre. Le plus souvent, l’analyse avec VI produisait des resultats non significatifs (87 %). Conclusion Dans les etudes publiees a ce jour, l’analyse avec SP et la methode des VI conduisent souvent a des resultats non concordants. Si ce resultat peut refleter une difference dans le controle des biais de confusion, d’autres interpretations sont a envisager. Ce constat invite d’un cote les chercheurs a considerer attentivement leur choix des methodes d’analyse, et de l’autre les lecteurs a faire preuve de prudence en interpretant les resultats des etudes. L’effort de recherche methodologique et appliquee sur l’analyse des donnees observationnelles pour l’evaluation des interventions de sante doit etre poursuivi.