Impact of COVID-19 pandemic and lockdowns on the consumption of anxiolytics, hypnotics and antidepressants according to age groups: a French nationwide study.

BACKGROUND: Previous studies have shown a negative impact of the COVID-19 pandemic and its associated sanitary measures on mental health, especially among adolescents and young adults. Such a context may raise many concerns about the COVID-19 pandemic long-term psychological effects. An analysis of administrative databases could be an alternative and complementary approach to medical interview-based epidemiological surveys to monitor the mental health of the population. We conducted a nationwide study to describe the consumption of anxiolytics, antidepressants and hypnotics during the first year of the COVID-19 pandemic, compared to the five previous years. METHODS: A historic cohort study was conducted by extracting and analysing data from the French health insurance database between 1 January 2015 and 28 February 2021. Individuals were classified into five age-based classes. Linear regression models were performed to assess the impact of the COVID-19 pandemic period on the number of drug consumers, in introducing an interaction term between time and COVID-19 period. RESULTS: Since March 2020, in all five age groups and all three drug categories studied, the number of patients reimbursed weekly has increased compared to the period from January 2015 to February 2020. The youngest the patients, the more pronounced the magnitude. CONCLUSIONS: Monitoring the consumption of psychiatric medications could be of great interest as reliable indicators are essential for planning public health strategies. A post-crisis policy including reliable monitoring of mental health must be anticipated.

[Impact of the suicidal crisis intervention training program on the confidence and skills of hospital professionals in the Hauts-de-France region]. / Impact de la formation à l'intervention de crise suicidaire sur la confiance et les aptitudes des professionnels hospitaliers des Hauts-de-France.

INTRODUCTION: Suicide is a major public health issue given its huge human and economic consequences. Symptoms prior to suicide are often not specific. Nevertheless, the majority of suicidal people express suicidal thoughts, and nearly one in two meet a health professional in the period preceding the act. Being able to recognize the warnings and intervene during the suicidal crisis, defined as a mental crisis where the major risk is suicide, is to seize the opportunity to postpone the suicidal plan and to gain time to implement in place lasting strategies to combat suffering. Thus, the training for suicidal crisis intervention is a major axis of the suicide prevention strategy. Recently, crisis intervention training programs have been updated with knowledge accumulated since the early 2000's. In France, one of the countries most concerned by suicide, the Hauts-de-France region is one of the most impacted. In this context, the Regional Health Agency of Hauts-de-France included in its Regional Health Program of 2018-2023 the training of healthcare workers who work with high suicidal risk patients. The suicidal crisis intervention training program (SCIT) has been introduced to hospital staffs in Hauts-de-France. The purpose of this study was to evaluate this program. METHODS: Eight training sessions with 15 to 21 participants were carried out from 2019 November to 2021 January in the Hauts-de-France region. Participants were volunteer healthcare professionals in direct contact with suicidal crisis patients. The training included three modules. The first one concerned the suicidal crisis intervention training: definition of the suicidal crisis, typology of the crisis, vulnerability development, crisis evaluation and crisis intervention practice. The second concerned the evaluation with the RED scale (Risk-Emergency-Danger) and the adequate patient orientation to a psychiatric unit. The third was dedicated to the Gatekeeper training with the constitution of a Gatekeeper network to enhance the capacity to detect suicidal risk and to orient the concerned person towards an adequate evaluation or care organization. We evaluated the first two levels of the Kirkpatrick's model: level 1) the participant's satisfaction (rated out of 10), and level 2) the degree of confidence in their professional abilities (rated out of 10) and their skills in responding to a person in a suicidal crisis (using the SIRI-2-VF - French version of the Suicide Intervention Response Inventory-2). The participants were interviewed before (T0), just after (T1) and at one month of training (T2). RESULTS: Among the 141 health professionals who followed the training, 139 answered the questionnaire at least one time (13 psychologists, 22 doctors, 97 nurses and 7 head nurses). The participation rates were 99.3 % at T0, 96.4 % at T1 and 46.0 % at T2. Most of the participants were nurses (69.8 %), and 33.1 % of the respondents declared they had already followed a suicidal crisis training. The satisfaction with the training was evaluated at 8.6 (± 1.3) out of 10. There was no significant difference among the professions, neither between those having already received or not a previous training. The self-perceived capacity to manage a suicidal crisis was rate 6.8 (± 1.8) out of 10 at T0. There was a significant increase just after the training (8.1±1.2 vs 6,8±1,8, p<0,001) which persisted at 1 month (8.1±1.1 vs 6.8±1.8, P<0.001). The score at the SIRI-2-VF was 15.0 (± 4.2) out of 30 at T0. There was a significant increase just after the training (17.5±3.5 vs 15.0±4.2, P<0.001), which persisted at 1 month (17.0±4.0 vs 15.0±4.2, P<0.001). DISCUSSION: This is the first evaluation of the suicidal crisis intervention training program. This program increased and homogenized the competency of the participants to manage suicidal ideation and behaviors. Those who followed a previous training maintained higher scores than the others, which shows the importance of repeated training to maintain a satisfying level of knowledge over the long term. One of the strengths of this training is the use of roleplay which enhances the learning and abilities to interact with people at suicidal risk. It seems important to integrate a suicidal crisis intervention training in the cursus of health students to avoid suicide and the dramatic consequences for the entourage and the health professionals who are confronted with it. CONCLUSION: The SCIT program showed encouraging results in terms of confidence and capacity of the healthcare professionals to intervene in suicidal crisis.

Contribution of women authors in French medical journals from 1983 to 2019.

PURPOSE: Despite the feminization of the medical profession, the academic world remains largely male-dominated. Several studies conducted in the English-speaking world have shown that women are published less than men. Our goal is to define the evolution of the role of women in five French medical journals. MATERIALS AND METHODS: The articles from five French journals (Revue du Praticien, Bulletin du Cancer, Exercer, Presse Médicale, Cancer/Radiothérapie) published in February between 1983 and 2019 were included. We selected twelve years from that period of time. The analysis was completed using Cochran-Armitage tests with a significance level of<0,05. Among the authors, 4397 were included in total and we were able to determine the gender of 4309 of them. RESULTS: The percentage of female authors went from 16% in 1983 to 36.4% in 2019 (p<0.001). This rise is more significant for those specializing in surgery than for those specializing in medicine, with a percentage going from 14% to 38.5% (p<0.001) against 16.8% to 35.4% (p<0.001) respectively. In 2019, women still only represent 30.2% of the last authors, 27.6% of editorial authors and 30.6% of corresponding authors. CONCLUSION: Our study underlines a significant increase in the number of female authors and highlights that their position as authors remains on the margins of the most prestigious authorial positions. While we can celebrate this increase, we nevertheless notice that there are fewer female authors than female practitioners.

Effects at 3 months of a large-scale simulation-based training for first year medical residents on the knowledge of suicide.

BACKGROUND: Suicide is a leading yet underestimated cause of death in the world and in France. The goal of our study was to determine the impact at 3 months of a large-scale simulation program on suicide risk assessment for first-year medical residents. METHODS: All the first-year medical residents participated in the simulation program that included a session on suicide risk assessment. The scenario was carried out by a standardized patient (professional actor) who had a normal check-up at the ER after a chest pain. He verbalized suicidal thoughts to an ER nurse due to a recent divorce and social difficulties, who then reported it to the resident. The latter had to assess suicide risk on his own. The QECS "Questionnaire de connaissances relatives au suicide" was used to assess knowledge of suicide before the training session (T0) and 3 months later (T1). A pre/post comparison was performed with a paired t-test. RESULTS: 420 residents participated in this study. A total of 273 matching questionnaires was obtained. A statistically significant theoretical knowledge improvement was found at 3 months of the session for all the residents. LIMITATIONS: The absence of a control group and data loss were some of the major limitations of our study. Another limitation corresponds to the lack of additional questions, such as levels of interest, former and recent training, level of experience, attitudes, and self-competency in suicide risk assessment before and after the simulation program that could have helped to interpret the obtained results and their variation. Moreover, the exact effects of this increased knowledge on clinical practice has not been measured in our study. CONCLUSION: This is an unprecedented, large-scale attempt in France to allow all the medical residents to practice suicide risk assessment. This simulation-based training had a positive impact at 3 months on the knowledge of suicide in medical residents.

[Impact of an educational video on the representations of electroconvulsive therapy among psychiatrists in Hauts-de-France and Occitanie]. / Impact d'une vidéo pédagogique sur les croyances et représentations relatives à l'électro-convulsivothérapie chez les psychiatres des Hauts-de-France et d'Occitanie.

INTRODUCTION: Despite its effectiveness and good tolerance, electro-convulsive therapy (ECT) is under-used in current clinical practice probably because of stigma and the negative image of this treatment. The main objective of this study was to evaluate the impact of an educational video on the representations of ECT among psychiatrists and psychiatric residents in the North and in Occitanie districts of France. METHOD: We evaluated the representations of ECT through the Questionnaire on Attitudes and Knowledge of ECT (QuAKE) before (T0) and after (T1) viewing a short educational video. Scores at T0 and T1 were compared with a paired t-test. Factors associated with the improvement of the representations were investigated using a logistic regression model. RESULTS: In all, 195 responses were obtained. The QuAKE score at T1 was significantly better than at T0 (29.4 at T1 vs. 31.5 at T0, P<0.001). The more negative the representations were at T0, the higher the probability of a decrease in the score at T1 (OR=1.07 [1.02-1.13], P=0.003). DISCUSSION: Our study showed a beneficial effect of a short educational video on psychiatrists' representations of ECT. The wide use of this type of media, allowing information and destigmatization, could considerably optimize access to ECT for patients.

Effectiveness of a French Program to Prevent Suicide Reattempt (VigilanS).

AIM: Brief contact interventions (such as letters, green cards, telephone calls or postcards) for reducing suicide reattempt (SR) and suicide have been evaluated since the 1980s, but results have been inconsistent. VigilanS is one of these programs that has benefited patients hospitalized for suicide attempt (SA) after discharge in 2 departments of northern France since 2015. The purpose of this study is to demonstrate its effectiveness in reducing SR. METHODS: Patients exposed to VigilanS in 2016 were recruited from the medical administrative database of the program, and the nonexposed patients from a database of the medico-surgical ward outside the scope of the program. First, a Cox model was used to compare the probability of SR during the 12-month follow-up period between the 2 groups. Second, a propensity score using the variables sex, age, source, SA history and SA method was used to match the VigilanS-exposed and the nonexposed patients. A Cox model propensity score adjusted analysis was reiterated on the matched data. RESULTS: The exposed and nonexposed groups included 3,068 and 3,694 individuals, respectively. In the bivariate analyses, the cumulative probability of SR at 12 months was significantly lower in the exposed group (6.0%, 95% confidence interval (CI): 5.5-6.5%) than in the nonexposed group (16.8%, 95% CI: 15.9-17.7%; p < 0.001). In the Cox model, the hazard ratio of SR was 0.38 in the exposed patients (95% CI: 0.36-0.40, p < 0.001). After matching, the cumulative probability of SR at 12 months was 5.2% in exposed versus 22.2% in nonexposed patients (p < 0.001). In the propensity score-adjusted Cox model, the hazard ratio of SR in the exposed patients was 0.19 (95% CI: 0.14-0.24, p < 0.001). CONCLUSION: The results suggest the effectiveness of this real-life program for reducing SR. However, VigilanS only benefits a portion of the patients hospitalized for SA and therefore could be extended.

Noxa/HSP27 complex delays degradation of ubiquitylated IkBα in airway epithelial cells to reduce pulmonary inflammation.

IFN-γ is known as a pro-inflammatory cytokine, but can also block inflammation in certain chronic diseases although the underlying mechanisms are poorly understood. We found that IFN-γ rapidly induced Noxa expression and that extent of inflammation by repeated house dust mite exposure was enhanced in noxa-/- compared with noxa+/+ mice. Noxa expression blocked transforming necrosis factor alpha (TNF-α)-induced nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and the production of pro-inflammatory cytokines. Noxa did not affect TNF-α-induced IκBα phosphorylation but the degradation of 48-chain-ubiquitylated IκBα. The Cys25 of Noxa was cross-linked with Cys137 of phospho-HSP27 and both proteins were required for blocking the degradation of ubiquitylated IκBα. Because phospho-HSP27 is present in airway epithelial cells and not in fibroblasts or thymocytes, we generated transgenic mice that inducibly expressed Noxa in airway epithelia. These mice showed protection from allergen-induced inflammation and mucous cell metaplasia by blocking nuclear translocation of NF-κB. Further, we identified a Noxa-derived peptide that prolonged degradation of 48-chain-ubiquitylated IκBα, blocked nuclear translocation of NF-κB, and reduced allergen-induced inflammation in mice. These results suggest that the anti-inflammatory role of the Noxa protein may be restricted to airway epithelial cells and the use of Noxa for therapy of chronic lung diseases may be associated with reduced side effects.

Virus infection induces the assembly of coordinately activated transcription factors on the IFN-beta enhancer in vivo.

We have identified a virus-activated factor (VAF) that binds to a regulatory element shared by different virus-inducible genes. We provide evidence that VAF contains two members of the interferon regulatory factor (IRF) family of transcriptional activator proteins (IRF-3 and IRF-7), as well as the transcriptional coactivator proteins p300 and CBP. Remarkably, VAF, as well as recombinant IRF-3 and IRF-7 proteins, binds very weakly to the interferon-beta (IFN-beta) gene promoter in vitro. However, in virus-infected cells, both proteins are recruited to the endogenous IFN-beta promoter as part of a protein complex that includes ATF-2/c-Jun and NF-kappa B. These observations provide a unique example of the coordinate activation of multiple transcriptional activator proteins and their highly cooperative assembly into a transcriptional enhancer complex in vivo.

Expression cloning of an interferon-inducible 17-kDa membrane protein implicated in the control of cell growth.

Interferon-inducible membrane proteins of approximately 17 kDa have been suggested to play a role in the antiproliferative activity of interferons based on (1) their pattern of induction in interferon-sensitive and -resistant cell lines and (2) the ability of a membrane fraction enriched in 17-kDa proteins to inhibit cell growth. To gain insight into the nature of the proteins that mediate the antiproliferative activity of interferons, a monoclonal antibody, 13A5, was generated that reacted specifically with a 17-kDa interferon-inducible cell surface protein. The expression pattern of this 17-kDa protein by human cell lines correlated with sensitivity to the antiproliferative activity of interferons. To obtain information regarding the structure of this protein, the 13A5 antibody was used to screen COS cells transfected with a human cDNA expression library. Sequence analysis of a full-length cDNA clone revealed identity with the 9-27 cDNA, previously isolated on the basis of its interferon inducibility by differential screening. In addition, the 17-kDa protein encoded by the 9-27 gene was shown to be identical to the Leu-13 antigen. Leu-13 was previously identified as a 16-kDa interferon-inducible protein in leukocytes and endothelial cells and is a component of a multimeric complex involved in the transduction of antiproliferative and homotypic adhesion signals. These results suggest a novel level of cellular regulation by interferons involving a membrane protein, encoded by the interferon-inducible 9-27 gene, which associates with other proteins at the cell surface, forming a complex relaying growth inhibitory and aggregation signals.

Regulation of gene expression by cytokines and virus in human cells lacking the type-I interferon locus.

A number of genes that are induced by type-I interferons are also activated by one or more other inducers, including double-stranded RNA, viruses, interferon-gamma, interleukin-1 and tumor necrosis factor. However, these inducers can also activate the expression of type-I interferons. Thus, the activation of type-I interferon-inducible genes by these other inducers could be direct, or a secondary consequence of the induction of interferon. To distinguish between these possibilities, we have used cell lines lacking all type-I interferon genes to study the direct effect of potential inducers on the expression of 14 interferon-inducible human genes. We show that double-stranded RNA, virus, interferon-gamma or tumor necrosis factor-alpha can act directly to induce specific subsets of type-I interferon-inducible genes in the absence of any possible type-I interferon involvement. The cis-acting element which confers inducibility by type-I interferon has been shown in some cases to confer inducibility by interferon-gamma, double-stranded RNA or virus as well. However, not all promoters containing such an element respond to both interferon and other inducers. Thus, the ability of a given gene to respond to different inducers most likely depends on the exact nature and specific combination of cis-acting elements present in its promoter.

The interferon- and virus-inducible IFI-56K and IFI-54K genes are located on human chromosome 10 at bands q23-q24.

IFI-56K and IFI-54K are two human genes that are strongly induced by interferon and viruses. These genes are closely related at the protein, RNA, and promoter levels. By means of the somatic cell hybrid technique, the two genes have been previously located on chromosome 10. Using in situ hybridization, we show here that both IFI-54K and IFI-56K genes map to 10q23-q24. This result does not confirm the previous localization of the IFI-56K gene at the junction of the 10q25 and 10q26 bands.

CD69 is expressed on Daudi cells in response to interferon-alpha.

An approach to obtain monoclonal antibodies directed against cell surface proteins induced by interferon has been developed in order to characterize such proteins and determine their role. Hybridomas obtained by fusion of murine myeloma cells and spleen cells of mice immunized with interferon-alpha-treated Daudi cells were screened for the production of antibodies reacting differentially with interferon-alpha-treated and untreated Daudi cells. One such hybridoma, 2D5, produced an antibody reacting with a 28/32 kDa homodimeric protein (p28/32) expressed at the surface of Daudi cells in response to IFN-alpha treatment. IFN-alpha treatment also increased the basal level of p28/32 detected on peripheral blood leukocytes (PBL). 2D5 Antibody was used to probe the expression of p28/32 on different cells and in response to various inducers. It appears that 2D5 reacted in fact with CD69, a marker of leukocyte activation and that, following IFN-alpha treatment, CD69 was not induced on all cultured cell lines tested. Interestingly, IFN-gamma was also able to induce CD69 expression on a restricted number of cell lines but the induction pattern only partially overlapped that of IFN-alpha. As expected, activation of cells with phorbol myristate acetate (PMA) resulted in a notable increase in the level of CD69 on all cell lines considered except for the epithelial and fibroblastic types.

Human thymosin-beta 4/6-26 gene is part of a multigene family composed of seven members located on seven different chromosomes.

We have isolated a cDNA encoding the human interferon-inducible gene 6-26, by screening a cDNA library with an oligodeoxynucleotide probe. Its sequence was found to be identical to that of the human thymosin-beta 4 cDNA, which encodes a protein present in most cell types, but whose function is not clear at present. By hybridization of the thymosin-beta 4/6-26 cDNA to the DNA of a panel of human-rodent somatic cell hybrids, we found that at least seven genes homologous to this cDNA are present in the human genome. We localized these genes, some of which might be pseudogenes, to seven distinct chromosomes, namely, chromosomes 1, 2, 4, 9, 11, 20, and X.

Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment.

Recombinant human interferon-alpha (IFN-alpha) can induce a hematologic remission in patients with chronic myeloid leukemia. However, some patients are resistant and others develop late resistance to the IFN-alpha treatment. To understand the molecular mechanism of this resistance, we have analyzed the expression of 10 IFN-inducible genes in the cells of three resistant patients, two responsive patients, and six healthy controls. Northern blot hybridizations showed that all the genes were induced in in vitro IFN-alpha treated peripheral blood cells of the patients and healthy controls. These genes were also inducible in peripheral blood and bone marrow cells of two out of two resistant patients administered an injection of IFN-alpha. We conclude that the resistance to the IFN-alpha treatment of the chronic myeloid leukemia patients we studied is not due to (1) the absence of induction of any of the 10 IFN-inducible genes we studied, including the low-molecular-weight 2'-5'oligoadenylate synthetase; (2) the presence of an antagonist of IFN-alpha in the peripheral blood or bone marrow cells; and (3) the presence of neutralizing anti-IFN-alpha antibodies.

Cloning and sequence analyses of cDNAs for interferon- and virus-induced human Mx proteins reveal that they contain putative guanine nucleotide-binding sites: functional study of the corresponding gene promoter.

The human protein p78 is induced and accumulated in cells treated with type I interferon or with some viruses. It is the human homolog of the mouse Mx protein involved in resistance to influenza virus. A full-length cDNA clone encoding the human p78 protein was cloned and sequenced. It contained an open reading frame of 662 amino acids, corresponding to a polypeptide with a predicted molecular weight of 75,500, in good agreement with the Mr of 78,000 determined on sodium dodecyl sulfate gels for the purified natural p78 protein. The cloned gene was expressed in vitro and corresponded in size, pI, antigenic determinant(s), and NH2 terminus sequence to the natural p78 protein. A second cDNA was cloned which encoded a 633-amino-acid protein sharing 63% homology with human p78. This p78-related protein was translated in reticulocyte lysates where it shared an antigenic determinant(s) with p78. A putative 5' regulatory region of 83 base pairs contained within the gene promoter region upstream of the presumed p78 mRNA cap site conferred human alpha interferon (IFN-alpha) inducibility to the cat reporter gene. The p78 protein accumulated to high levels in cells treated with IFN-alpha. In contrast, the p78-related protein was not expressed at detectable levels. The rate of decay of p78 levels in diploid cells after a 24-h treatment with IFN-alpha was much slower than the rate of decay of the antiviral state against influenza A virus and vesicular stomatitis virus, suggesting that the p78 protein is probably not involved in an antiviral mechanism. Furthermore, we showed that these proteins, as well as the homologous mouse Mx protein, possess three consensus elements in proper spacing, characteristic of GTP-binding proteins.

Chromosomal localization of two human genes inducible by interferons, double-stranded RNA, and viruses.

Human IFI-15K and 6-16 genes are transcriptionally stimulated by interferons, double-stranded RNA, and viruses. By screening a cDNA library with oligodeoxynucleotide probes, we have isolated complete copies corresponding to these two genes. These cDNA clones allowed us to localize the IFI-15K and 6-16 genes on human chromosome 1 by somatic cell hybridization.

2-Aminopurine selectively blocks the transcriptional activation of cellular genes by virus, double-stranded RNA and interferons in human cells.

Interferons, double-stranded RNA and viruses induce the transcription of partly overlapping sets of cellular genes. We have studied the regulation of 11 interferon-inducible genes by these agents and found that four of them were also directly inducible by virus and double-stranded RNA, and two by virus only. We have investigated whether an inhibitor of interferon-beta gene activation, 2-aminopurine, would block this induction process. Induction of these genes by virus and double-stranded RNA was indeed blocked by 2-aminopurine. Since a single cis-acting element can confer inducibility both to interferons, and to virus and double-stranded RNA, we tested the effect of 2-aminopurine on gene activation by interferon-alpha and interferon-gamma. Remarkably, in all the cell lines tested, these induction processes and the establishment of an antiviral state were blocked by the drug. These observations contrast with previous reports. The inhibitory effect of this drug on gene induction was exerted in a selective fashion and at the transcriptional level. This indicate that for the virus-, double-stranded-RNA-, and interferons-mediated gene induction, an early and similar step in signal transduction was affected by 2-aminopurine.

Identification of a translation inhibitory element (TIE) in the 3' untranslated region of the human interferon-beta mRNA.

We have previously reported that the 3' untranslated region (UTR) of the human interferon-beta mRNA has an inhibitory effect on the mRNA translation both in vitro, in a rabbit reticulocyte lysate, and in vivo, in the Xenopus oocyte. In the present study, we identify the sequence in the 3' UTR which is responsible for this translation inhibition. We show that this sequence is located between the 100th and 161st nucleotides downstream from the translation stop codon. It contains several repeats of the A + U-rich consensus octanucleotide UUAUUUAU, which is also present in the 3' UTR of several mRNAs involved in the inflammatory response. We also demonstrate here that the inhibitory effect of the sequence on the mRNA translation does not depend on its position in relation to the termination codon. However, no inhibition of translation is observed when this sequence is inserted in the 5' UTR of the mRNA. The removal of the translation inhibitory sequence not only improves the mRNA translation in Xenopus oocytes but it also strongly decreases the IFN-beta mRNA stability in those cells. This suggests that, in this system at least, the mRNA degradation is linked to its translational efficiency.