[Role of cellular metabolism in the control of chronic viral hepatitis]. / Rôle du métabolisme cellulaire dans le contrôle des hépatites virales chroniques.

Hepatitis viruses modify the cellular metabolism of hepatocytes by interacting with specific enzymes such as glucokinase. The metabolic changes induced by viruses can have a direct impact on the innate antiviral response. The complex interactions between viral components, innate immunity, and hepatocyte metabolism explain why chronic hepatitis infections lead to liver inflammation, progressing to cirrhosis, fibrosis, and hepatocellular carcinoma. Metabolic regulators could be used in innovative therapies to deprive viruses of key metabolites and induce an antiviral defense.

Title: Rôle du métabolisme cellulaire dans le contrôle des hépatites virales chroniques. Abstract: Les virus des hépatites modifient le métabolisme cellulaire des hépatocytes en interagissant avec des enzymes spécifiques, telles que la glucokinase. Les changements métaboliques induits par les virus peuvent avoir un impact direct sur la réponse antivirale innée. Les interactions complexes entre les composants viraux, l'immunité innée et le métabolisme des hépatocytes expliquent pourquoi les infections hépatiques chroniques conduisent à l'inflammation du foie, évoluant vers la cirrhose, la fibrose et le carcinome hépatocellulaire. Des régulateurs du métabolisme pourraient être utilisés dans des thérapies innovantes pour priver les virus de métabolites clés et induire une défense antivirale.

[Evolution of the obstetrical Shock Index in postpartum haemorrhage according to the use of sulprostone]. / Évolution du Shock Index obstétrical lors d'une hémorragie du post-partum selon le recours à la sulprostone.

OBJECTIVES: The Shock Index (SI) is used in emergency medicine to assess the severity of active bleeding and in the postpartum context for postpartum haemorrhage (PPH). We investigated the diagnostic value of haemodynamic parameters (SI, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP)) in predicting subsequent use of uterotonic sulprostone treatment. METHODS: This was a retrospective study including parturients with PPH ≥ 500mL between January 2017 and December 2018. Hemodynamic parameters at the diagnosis of PPH were compared according to whether the patient required subsequent sulprostone treatment (sulprostone(+) group) or not (sulprostone(-) group). RESULTS: We included in the analysis 147 patients. The SI was significantly higher in the sulprostone(+) group (0.92±0.28 vs. 0.83±0.22; p=0.04). The SBP (107.2±17.5 vs. 113.8±17.7mmHg; p=0.03), DBP (56.8±12,2 vs. 61.5±13,2mmHg; p=0.04), MAP (73.6±12.6 vs. 78.5±13.4mmHg; p=0.03) were significantly lower in the same group. No difference between AUC of these parameters to predict the use of sulprostone was found (AUC between 0.59 and 0.61). No significant difference was found for the HR between the two groups. CONCLUSION: The diagnostic value of SI appeared to be low and similar to other haemodynamic parameters in predicting the use of sulprostone.

Clinical practice recommendations for nurse-administered intramuscular injections in mental health: A modified Delphi study.

AIM: To develop clinical practice recommendations for nurse-administered intramuscular injections in mental health. BACKGROUND: Intramuscular injection is the main route of long-acting injectable antipsychotics' administration that appear to improve the long-term prognosis of mental illness. Specific guidelines related to the nurse administration of intramuscular injections need to be updated and to explore not only the technical aspects of this procedure. DESIGN: A modified RAND/University of California Los Angeles (UCLA) appropriateness method Delphi study was conducted between October 2019 and September 2020. METHODS: A multidisciplinary steering committee conducted a literature review and developed a list of 96 recommendations. These recommendations were submitted in a two-round Delphi electronic survey to a panel of 49 experienced practicing nurses from five mental health hospitals in France. Each recommendation was rated for its appropriateness and applicability in clinical practice on a 9-point Likert scale. Consensus among nurses was evaluated. The steering committee discussed the results after each round and approved the final set of recommendations. RESULTS: A final set of 79 specific recommendations were accepted for their appropriateness and applicability in clinical practice. Recommendations were classified in five domains: legal and quality assurance aspects, nurse-patient relationship, hygiene, pharmacology, and injection technique. CONCLUSION: The established recommendations placed patients at the heart of the decisions concerning the intramuscular injection and underlined the need for specific training programs. Future research should focus on the integration of these recommendations in clinical practice, by both before-and-after studies and regular assessments of professional practices with relevant indicators. IMPACT: The recommendations developed for good nursing practices explored not only the technical aspects but integrated the nurse-patient relationship. These recommendations may impact usual practices of administration of long-acting injectable antipsychotics and most of them could be applied in many countries. NO PATIENT OR PUBLIC CONTRIBUTION: Due to the study design.

Change in Hemoglobin Was Not a Reliable Diagnostic Screening Test for Postpartum Hemorrhage: A French Prospective Multicenter Cohort Study (HERA Study).

Changes between pre- and postpartum hemoglobin might be useful for optimizing the postpartum diagnosis of postpartum hemorrhage (PPH), defined as a blood loss exceeding 500 mL. This study's principal objective was to estimate the mean change in hemoglobin (between pre/post-delivery hemoglobin) among women with vaginal deliveries and PPH. The secondary objectives were to analyze: hemoglobin changes according to blood volume loss, the appropriateness of standard thresholds for assessing hemoglobin loss, and the intrinsic and extrinsic performances of these threshold values for identifying PPH. French maternity units (n = 182) participated in the prospective HERA cohort study. Women with a vaginal delivery at or after a gestation of 22 weeks with a PPH (n = 2964) were eligible. The principal outcome was hemoglobin loss in g/L. The mean hemoglobin change was 30 ± 14 g/L among women with a PPH. Overall, hemoglobin decreased by at least 10% in 90.4% of women with PPH. Decreases ≥ 20 g/L and ≥40 g/L were found, respectively, in 73.9% and 23.7% of cases. Sensitivity and specificity values for identifying PPH were always <65%, the positive predictive values were between 35% and 94%, and the negative predictive values were between 14% and 84%. Hemoglobin decrease from before to after delivery should not be used as a PPH diagnostic screening test for PPH diagnosis for all vaginal deliveries.

Farnesoid X receptor alpha ligands inhibit HDV in vitro replication and virion infectivity.

BACKGROUND AND AIMS: HDV, a satellite of HBV, is responsible for the most severe form of human viral hepatitis, for which curative therapy is still awaited. Both HBV and HDV use the hepatic transporter of bile acids (ie, Na+-taurocholate cotransporting polypeptide) to enter hepatocytes. We have previously shown that ligands of the farnesoid-X-receptor alpha (FXR), a master regulator of bile acids metabolism, inhibit HBV replication. Here we asked whether FXR ligands can also control HDV infection. APPROACH AND RESULTS: In vitro HDV monoinfections or HDV/HBV coinfections and superinfections were performed in differentiated HepaRG cells (dHepaRG) and primary human hepatocytes. Following treatment with FXR ligands, HDV RNAs and antigens were analyzed by RT-qPCR, northern blot, immunofluorescence, and western blot. Virus secretion was studied by RNA quantification in supernatants, and the infectivity of secreted HDV particles was measured by reinfection of naive HuH7.5-Na+-taurocholate cotransporting polypeptide cells. In HDV/HBV superinfection models, a 10-day treatment with FXR ligand GW4064 decreased intracellular HDV RNAs by 60% and 40% in dHepaRG cells and primary human hepatocytes, respectively. Both HDV genomic and antigenomic RNAs were affected by treatment, which also reduced the amount of intracellular delta antigen. This antiviral effect was also observed in HDV monoinfected dHepaRG cells, abolished by FXR loss of function, and reproduced with other FXR ligands. In HBV/HDV coinfected dHepaRG cells, HDV secretion was decreased by 60% and virion-specific infectivity by >95%. CONCLUSIONS: FXR ligands both inhibit directly (ie, independently of anti-HBV activity) and indirectly (ie, dependently of anti-HBV activity) the replication, secretion, and infectivity of HDV. The overall anti-HDV activity was superior to that obtained with interferon-α, highlighting the therapeutic potential of FXR ligands in HDV-infected patients.

A severe case of PLOD1-related kyphoscoliotic Ehlers-Danlos syndrome associated with several arterial and venous complications: A case report.

Kyphoscoliotic Ehlers-Danlos syndrome (kEDS) is a rare genetic disorder combining congenital hypotonia, congenital/early onset and progressive kyphoscoliosis, and generalized joint hypermobility. Vascular fragility is another characteristic of the disease rarely described. We report a severe case of kEDS-PLOD1 with several vascular complications leading to difficulties in disease management.

Opti'care protocol: a randomised control trial to evaluate the impact of a mobile antenatal care clinic in isolated rural areas on prenatal follow-up.

INTRODUCTION: Rural residence appears to be a factor of vulnerability among pregnant women with poor clinical antenatal care. Our principal objective is to assess the impact of an infrastructure for a mobile antenatal care clinic on the completion of antenatal care for women identified as geographically vulnerable in a perinatal network. METHODS AND ANALYSIS: Controlled cluster-randomised study in two parallel arms comparing an intervention group with an open-label control group. This study will concern the population of pregnant women who must live in one of the municipalities covered by the perinatal network and considered to be an area of geographic vulnerability. The cluster randomisation will take place according to the municipality of residence. The intervention will be the implementation of pregnancy monitoring by a mobile antenatal care clinic. The completion of antenatal care between the intervention and control groups will be a binary criterion: 1 will be attributed to each antenatal care that includes all visits and supplementary examinations. Sample size has been estimated to be 330 at least with an 80% participation rate.The univariate analyses will compare the follow-up rates (with Fisher's exact test), and all individual characteristics collected (Fisher's exact test, Student's t-test) between the two groups. The multivariate analysis will use a mixed linear model analysis and consider the cluster effect as random; the initial model will include known confounders from the literature, confounders identified in univariate analyses, and the clinically relevant prognostic factors. All of these factors will be taken into account in the model as a fixed effect. ETHICS AND DISSEMINATION: The Patient Protection Committee North-West II approved this study on 4 February 2021 (IRB 2020-A02247-32). The results will be the subject of scientific communications and publications. TRIAL REGISTRATION NUMBER: NCT04823104.

Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms.

BACKGROUND & AIMS: Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients. METHODS: Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays. RESULTS: Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2. CONCLUSIONS: Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. IMPACT AND IMPLICATIONS: Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.

Does the type of pushing at delivery influence pelvic floor function at 2 months postpartum? A pragmatic randomized trial-The EOLE study.

INTRODUCTION: Maternal pushing techniques during the second stage of labor may affect women's pelvic floor function. Our main objective was to assess the impact of the type of pushing used at delivery on the mother's medium-term pelvic floor function. MATERIAL AND METHODS: This is a secondary analysis of a randomized clinical trial (clinicaltrials.gov: NCT02474745) that took place in four French hospitals from 2015 through 2017 (n = 250). Women in labor with a singleton fetus in cephalic presentation at term who had undergone standardized training in both of these types of pushing were randomized after cervical dilation ≥7 cm. The exclusion criteria were a previous cesarean, a cesarean delivery in this pregnancy or a fetal heart rate anomaly. In the intervention group, open-glottis (OG) pushing was defined as a prolonged exhalation contracting the abdominal muscles to help move the fetus down the birth canal. Closed-glottis (CG) pushing was defined as Valsalva pushing. The principal outcome was the stage of pelvic organ prolapse (POP) assessed by the Pelvic Organ Prolapse-Quantification 2 months after delivery. A secondary outcome was incidence of urinary incontinence (UI). The results of our multivariable, modified intention-to-treat analysis are reported as crude relative risks (RRs) with their 95% confidence intervals. RESULTS: Our analysis included 207 women. Mode of birth was similar in both groups. The two groups did not differ for stage II POP: 10 of 104 (9.4%) in the OG group compared with 7 of 98 (7.1%) in the CG group, for a RR 1.32, 95% confidence interval [CI] 0.52-3.33, and an adjusted RR of 1.22, 95% CI 0.42-3.6. Similarly, the incidence of UI did not differ: 26.7% in the OG group and 28.6% in the CG group (aRR 0.81, 95% CI 0.42-1.53). Subgroup analysis suggests that for secundiparous and multiparous women, OG pushing could have a protective effect on the occurrence of UI (RR 0.33, 95% CI 0.13-0.80). CONCLUSIONS: The type of directed pushing used at delivery did not impact the occurrence of pelvic organ prolapse 2 months after delivery. OG pushing may have a protective effect against UI among secundiparous and multiparous women.

Assessment of arterial damage in vascular Ehlers-Danlos syndrome: A retrospective multicentric cohort.

Background: Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder due to pathogenic variants in COL3A1 leading to medium-size-artery (MSA) dissection, aneurysm, rupture. Aortic lesions are rarer and less investigated. The objective was to describe the distribution of MSA and aortic lesions and the type of COL3A1 variants in a multicentric cohort of 330 adult vEDS patients. Methods: At the time of the study, 87% were alive, 60.3% were index cases, and 60.0% were women. COL3A1 variants were identified using NGS and/or Sanger sequencing and classified according to functional consequences: 80.6% leading to dominant-negative (DN) and 19.4% leading to haploinsufficiency (HI). Imaging was systematically performed during the initial workup. Carotid mechanics were assessed by echo tracking in a subgroup of patients. Results: Arterial lesions were reported in 82.4% of the patients (N = 272): 83.5% had MSA lesions alone, 3.3% had aortic lesions alone, and 13.2% both. DN variants were associated with a higher prevalence of arterial lesions (P < 0.044), especially in supra-aortic trunks and renal arteries. The prevalence of aortic lesions in HI patients with arterial lesions was higher than that in patients with DN (P 0.027), but not anymore when adjusted for age (P < 0.559). Carotid Young's modulus was lower in patients with DN, in association with the higher incidence of MSA lesions in this group. Conclusion: The prevalence of aortic lesions is not influenced by the COL3A1 genotype when adjusted for age. Patients with DN variant vEDS have a higher frequency of MSA lesions, especially in supra-aortic trunks associated with lower carotid stiffness. These results support optimized care and follow-up for these vulnerable patients.

Prediction of Iron Deficiency Anemia in Third Trimester of Pregnancy Based on Data in the First Trimester: A Prospective Cohort Study in a High-Income Country.

Background: Systematic iron supplementation may be harmful in pregnant women with non-depleted iron. Our objectives were to estimate the prevalence of anemia at the third trimester of pregnancy (T3) and to identify the parameters at the first trimester (T1), which best predict anemia at T3. Methods: This prospective cohort study in France included pregnant women at T1 without non-iron deficiency anemia. Clinical and social characteristics, health-related quality of life, blood count, and a frozen blood sample were collected at T1 and/or T3. Secondly, a matched nested case−control study was built for women with anemia at T3 but not at T1. Multivariate analyses and ROC curves were used to identify the best predictive parameter(s) of anemia at T3. Results: The prevalence of anemia at T3 in the cohort (629 women) was 21.9% (95% CI 18.7−25.2%). In the matched nested case−control study (256 women), hemoglobin (Hb), serum ferritin (SF) and the SF/soluble transferrin receptor ratio at T1 were predictive of anemia at T3 (p < 0.001); however, clinical and social characteristics, as serum hepcidin were not. In multivariate analyses, Hb at T1 was the best predictive biomarker of anemia at T3 with a cut-off value of 120 g/L (specificity 87.5%). Conclusions: The prevalence of anemia at the end of pregnancy remained high in a High-Income Country. Clinical, social, and biochemical parameters did not seem useful to predict anemia at T3 and could not guide iron supplementation. We suggest systematically performing a simple blood count in the first trimester of pregnancy and offering oral iron supplementation for women with Hb < 120 g/L.

Workplace Lactation Support: A Cross-Sectional Study in a University Hospital and a Perinatal Network.

Return to work negatively affects the initiation and duration of breastfeeding. Our study's objective was to assess the percentage of departments in Auvergne with an appropriate space for pumping milk at work. Our cross-sectional survey investigated the arrangements for facilitating the continuation of breastfeeding on return to work at all departments at the Clermont-Ferrand University Hospital Center and perinatal (obstetric and pediatric) departments in this region. Our principal endpoint was the percentage of departments reporting that they had a lactation room­a room where nursing mothers can express milk­and whether it met the criteria defined by the French Labor Code. Among 98 respondents, 44 departments (44.9%) did not offer lactation rooms; of the remaining 54 departments, only 11 rooms met the legal requirements. All perinatal departments offered lactation rooms. The availability of a lactation room was associated with other breastfeeding support, such as a break period for expressing milk (p < 0.0001) and the availability of a refrigerator to store it (p = 0.01). Almost half the responding departments did not offer a lactation room where mothers could breastfeed or pump their milk. Measures must be envisioned to facilitate the pumping of breast milk by French women returning to work.

Cross-Cultural Adaptation and Psychometric Properties of the French Version of the EXIT to Measure Women's Experiences of Induction of Labor.

BACKGROUND: In France, more than 20% of women require induction of labor (IOL), which can be psychologically and emotionally challenging for patients. It is important to assess how they feel about their IOL experiences. Our aim was to cross-culturally adapt and evaluate the psychometric properties of a French version of the EXIT to assess women's experiences of IOL. METHODS: The EXIT was cross-culturally adapted by conducting forward and backward translations following international guidelines. A cross-sectional study was conducted to assess the psychometric properties of the ten French EXIT items: data completeness, factor analysis, internal consistency, score distribution, floor and ceiling effects, inter-subscale correlations, convergent validity, and test-retest reliability. RESULTS: The EXIT was successfully cross-culturally adapted to the French context and any IOL method. The results obtained from 163 patients requiring IOL showed good acceptability. Exploratory factor analysis resulted in a three-factor solution with subscales reflecting the experiential aspects of time taken to give birth, discomfort with IOL, and subsequent contractions. Good internal consistency (Cronbach's alpha or Spearman correlation coefficients ranging from 0.55 to 0.84) and good test-retest reliability (intraclass correlation coefficients ranging from 0.66 to 0.85) for the three identified subscales were found. CONCLUSIONS: The ten-item French EXIT is a valid and reliable instrument for the self-assessment of women's experiences of IOL in the three weeks following delivery for any method of IOL used. As a patient-reported outcome measure, it would allow the comparison of experiential outcomes across IOL studies in order to include women's preferences in decisions regarding their care.

Does the Quality of Postpartum Hemorrhage Local Protocols Improve the Identification and Management of Blood Loss after Vaginal Deliveries? A Multicenter Cohort Study.

Substandard care, which can result from a delayed recognition of the severity of blood loss, can increase maternal morbidity. Our objectives were to assess the incidence of postpartum hemorrhage (PPH) and of second-line procedures in maternity units according to the quality of their PPH protocol. We used a mixed design, a prospective cohort (3442 women with PPH after vaginal delivery; February−July 2011), and an audit of the written protocols (177 French maternity units; September 2010−June 2011). A quality score was calculated for the protocol of each unit. Maternity units were classified into three categories according to this score: category 1 (total score: 0−8), category 2 (9−12.5), and category 3 (>12.5). The PPH incidence (>500 mL) was 3.2%, 3.3% and 4.6% among maternity units in categories 1, 2 and 3, respectively (p < 0.0001). The incidence of severe maternal morbidity (surgery and/or artery embolization and/or blood transfusion) was higher among maternity units in category 1 (54.8%; 95% CI: 51.9, 57.7) than in either category 2 (50.1%; 95% CI: 47.8, 52.5) or 3 (38.0%; 95% CI: 33.8, 42.4]) (p < 0.0001). The risks of severe maternal morbidity were lower for category 3 than category 1 and 2 (respectively, adjusted RR 0.68, 95% CI 0.60−0.86 and 0.77, 95% CI 0.68−0.87). Finally, maternity units with higher scores identified PPH better and used fewer curative second-line procedures.

Atypical variants in COL1A1 and COL3A1 associated with classical and vascular Ehlers-Danlos syndrome overlap phenotypes: expanding the clinical phenotype based on additional case reports.

The vast majority of reported (likely) pathogenic missense variants in the genes coding for the fibrillar collagens leads to the substitution of one of the obligatory glycine residues in the Gly-Xaa-Yaa repeat sequence of the triple helical domain. Their phenotypic consequences and deleterious effects have been well-documented. However, with increasing access to molecular diagnostic testing based on next-generation sequencing techniques, such as sequencing of multi-gene panels and whole-exome sequencing, non-glycine substitutions are more frequently identified in individuals suspected to have a heritable collagen disorder, but their pathogenic effect is often difficult to predict.Some specific non-glycine substitutions in the proα1(I)- (p.(Arg312Cys)) and proα1(III)- (glutamic acid to lysine at different positions) collagen chain have been identified in a number of individuals presenting a phenotype showing features of both classical and vascular Ehlers-Danlos syndrome. The number of reported individuals with these defects is currently very low, and several of these non-glycine substitutions had initially been categorised as variants of unknown significance (VUS), complicating early diagnosis, accurate counselling, management guidelines, and correct classification. This collaborative study reports on the phenotype of 22 and 7 individuals harbouring these rare variants in COL1A1 and COL3A1, respectively, expanding our knowledge on clinical presentation, phenotypic variability, and natural history, and informing on the risk for potentially life-threatening events, such as vascular, gastro-intestinal, and pregnancy-related complications.

Comparative therapeutic strategies for preventing aortic rupture in a mouse model of vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome is a rare inherited disorder caused by genetic variants in type III collagen. Its prognosis is especially hampered by unpredictable arterial ruptures and there is no therapeutic consensus. We created a knock-in Col3a1+/G182R mouse model and performed a complete genetic, molecular and biochemical characterization. Several therapeutic strategies were also tested. Col3a1+/G182R mice showed a spontaneous mortality caused by thoracic aortic rupture that recapitulates the vascular Ehlers-Danlos syndrome with a lower survival rate in males, thin non-inflammatory arteries and an altered arterial collagen. Transcriptomic analysis of aortas showed upregulation of genes related to inflammation and cell stress response. Compared to water, survival rate of Col3a1+/G182R mice was not affected by beta-blockers (propranolol or celiprolol). Two other vasodilating anti-hypertensive agents (hydralazine, amlodipine) gave opposite results on aortic rupture and mortality rate. There was a spectacular beneficial effect of losartan, reversed by the cessation of its administration, and a marked deleterious effect of exogenous angiotensin II. These results suggest that blockade of the renin angiotensin system should be tested as a first-line medical therapy in patients with vascular Ehlers-Danlos syndrome.

Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity in vitro.

BACKGROUND & AIMS: HDV superinfection of chronically HBV-infected patients is the most aggressive form of chronic viral hepatitis, with an accelerated progression towards fibrosis/cirrhosis and increased risk of liver failure, hepatocellular carcinoma, and death. While HDV infection is not susceptible to available direct anti-HBV drugs, suboptimal responses are obtained with interferon-α-based therapies, and the number of investigational drugs remains limited. We therefore analyzed the effect of several innate immune stimulators on HDV replication in infected hepatocytes. METHODS: We used in vitro models of HDV and HBV infection based on primary human hepatocytes (PHHs) and the non-transformed HepaRG cell line that are relevant to explore new innate immune therapies. RESULTS: We describe here, for the first time, anti-HDV effects of Pam3CSK4 and BS1, agonists of Toll-like receptor (TLR)-1/2, and the lymphotoxin-ß receptor (LTßR), respectively. Both types of agonists induced dose-dependent reductions of total intracellular HDV genome and antigenome RNA and of HDV protein levels, without toxicity in cells monoinfected with HDV or co/superinfected with HBV. Moreover, both molecules negatively affected HDV progeny release and strongly decreased their specific infectivity. The latter effect is particularly important since HDV is thought to persist in humans through constant propagation. CONCLUSIONS: Immune-modulators inducing NF-κB pathways in hepatocytes can inhibit HDV replication and should be further evaluated as a possible therapeutic approach in chronically HBV/HDV-infected patients. LAY SUMMARY: Hepatitis delta virus causes the most severe form of viral hepatitis. Despite positive recent developments, effective treatments remain a major clinical need. Herein, we show that immune-modulators that trigger the NF-κB pathways could be effective for the treatment of hepatitis delta infections.

Immediate consequences and solutions used to maintain medical education during the COVID-19 pandemic for residents and medical students: a restricted review.

BACKGROUND: The COVID-19 outbreak has dramatically impacted medical education, both bedside and academic teaching had to be adapted to comply with the reorganisation of care and social distancing measures. OBJECTIVES: To overview the impact of the pandemic on medical education, including the pedagogical responses adopted and their assessment by medical students and residents. MATERIAL AND METHODS: This restricted systematic review was performed using Rayyan QCRI, to select observational or interventional articles and field experience reports assessing the impact of the COVID-19 pandemic on medical education for medical students and residents. Study design, study population, geographical origin, use of an educational tools (including softwares and social media), their type and assessment, were recorded. For studies evaluating a specific tool the Medical Education Research Study Quality Instrument (MERSQI) was used to assess study quality. RESULTS: The literature search identified 1480 references and 60 articles were selected. Most articles focused on residents (41/60; 69%), and half (30/60; 50%) involved surgical specialties. Online courses were the most frequently used pedagogical tool (52/60; 88%). Simulation tools were used more frequently in articles involving surgical specialties (15/29; 52%) compared with medical specialties (2/14; 12%) (p=0.01). Only four studies reported the assessment of pedagogical tools by medical students, their MERSQI scores ranged from 5.5/18 to 9.0/18. CONCLUSION: Medical education was highly impacted by the COVID-19 pandemic particularly in surgical specialties. Online courses were the most frequently attempted solution to cope with social distancing constraints. Medical students' assessment of pedagogical tools was mostly positive, but the methodological quality of those studies was limited.

Cardiovascular and connective tissue disorder features in FLNA-related PVNH patients: progress towards a refined delineation of this syndrome.

BACKGROUND: FLNA Loss-of-Function (LoF) causes periventricular nodular heterotopia type 1 (PVNH1), an acknowledged cause of seizures of various types. Neurological symptoms are inconstant, and cardiovascular (CV) defects or connective tissue disorders (CTD) have regularly been associated. We aimed at refining the description of CV and CTD features in patients with FLNA LoF and depicting the multisystemic nature of this condition. METHODS: We retrospectively evaluated FLNA variants and clinical presentations in FLNA LoF patient with at least one CV or CTD feature, from three cohorts: ten patients from the French Reference Center for Rare Vascular Diseases, 23 patients from the national reference diagnostic lab for filaminopathies-A, and 59 patients from literature review. RESULTS: Half of patients did not present neurological symptoms. Most patients presented a syndromic association combining CV and CTD features. CV anomalies, mostly aortic aneurysm and/or dilation were present in 75% of patients. CTD features were present in 75%. Variants analysis demonstrated an enrichment of coding variants in the CH1 domain of FLNA protein. CONCLUSION: In FLNA LoF patients, the absence of seizures should not be overlooked. When considering a diagnosis of PVNH1, the assessment for CV and CTD anomalies is of major interest as they represent interlinked features. We recommend systematic study of FLNA within CTD genes panels, regardless of the presence of neurological symptoms.

Measuring the readiness to screen and manage intimate partner violence: Cross-cultural adaptation and psychometric evaluation of the PREMIS tool for perinatal care providers.

INTRODUCTION: Pregnancy and perinatal periods are significant risk factors of intimate partner violence (IPV), a major public health problem that could begin or intensify during these periods. Perinatal care providers have a major role in the identification and the management of IPV. This study aimed to cross-culturally adapt into French the Physician Readiness to Manage Intimate Partner Violence Survey (PREMIS) tool, a reliable instrument to assess the knowledge, attitudes and preparedness to address IPV, and to evaluate its psychometric properties. METHODS: The PREMIS was cross-culturally adapted by conducting forward and backward translations, following international guidelines. An online cross-sectional study was conducted to assess the psychometric properties of the PREMIS-French in perinatal care providers: data completeness, factor analysis, score distribution, floor and ceiling effects, internal consistency, item-total correlations, inter-subscale correlations and test-retest reliability. RESULTS: The PREMIS was successfully translated and cross-culturally adapted to the context of metropolitan France. The results obtained from 360 perinatal care providers showed good acceptability. Exploratory factor analysis of the "Opinions" items resulted in a six-factor solution with six of the eight subscales of the original structure identified. Good internal consistency (Cronbach's alpha ranging from 0.54 to 0.97) and good test-retest reliability (intraclass correlation coefficients ranging from 0.46 to 0.92) for the "Background" and "Opinions" subscales were found. DISCUSSION: This study provides evidence of the good psychometric properties of the PREMIS-French. This valid instrument will help to understand perinatal care providers' barriers to IPV screening and management and will help to focus on specific lacks of knowledge for developing IPV education programs.