History of smallpox vaccination and marked clinical expression of mpox among cases notified in France, from May to July 2022.

OBJECTIVES: The aim was to estimate the effect of reported history of smallpox vaccination prior to 1980 on clinical expression of mpox. METHODS: We included all confirmed mpox cases identified by the national mpox surveillance system in France between May and July 2022. Cases tested positive for monkeypox virus or orthopoxviruses by PCR. Cases were interviewed by phone using a questionnaire documenting demographics, symptoms and exposures. To estimate the effect of smallpox vaccination on presence of marked mpox symptoms (association of fever, lymphadenopathy and extensive mucocutaneous lesions), we estimated prevalence ratios (PR) and 95% confidence intervals (CI) using Poisson regression models with robust standard errors. RESULTS: There were 1,888 confirmed mpox cases with date of symptom onset between 7 May and 31 July 2022. Overall, 7% (93/1,394) presented marked mpox symptoms. Among cases who provided information about their vaccination status, 14% (207/1,469) reported smallpox vaccination prior to 1980. The proportion of cases with marked symptoms was 2% (3/170) among those reporting smallpox vaccination prior to 1980 and 8% (76/974) among those who reported no vaccination. The proportion of marked symptoms was four times lower among cases reporting previous smallpox vaccination than in cases reporting no vaccination (PR 0.24, 95%CI: 0.08-0.76). There was no evidence of an effect of smallpox vaccination on development of complications (PR 0.65, 95%CI: 0.35-1.22) or hospitalisation due to mpox (PR 0.64, 95%CI: 0.23-1.80). CONCLUSIONS: Our results suggest that smallpox vaccination during childhood attenuated the clinical expression of monkeypox virus infection, but there was no evidence of an effect on complications or hospitalisation.

Providing parents with HPV vaccine information from a male perspective may render them more inclined to have their daughters vaccinated.

OBJECTIVES: Several high-income countries have implemented a gender-neutral vaccination program against human papillomavirus (HPV) infections. The impact of a gender-neutral program (GNP) on parental intention to vaccinate their daughters has not been studied, especially in countries with low HPV vaccine coverage among girls. PATIENTS AND METHODS: In July 2019, before a GNP was implemented in France (2021), the French National Cancer Institute (INCa) conducted a survey on HPV vaccine acceptance among parents of children aged 11-19 years living in France. In the sample of girls' parents (n = 1424 parents, 1726 girls), we investigated whether parents who declared no initial intention to have their daughter(s) vaccinated changed their minds after reading information including a male perspective on HPV consisting in description of HPV-related disease among men and in ascertainment of the fact that in some countries, the HPV vaccine is recommended for boys, after which they were once again asked about their intentions "if the vaccine were recommended to boys and girls alike". RESULTS: As regards 295 (25.7 %) of the 1147 unvaccinated girls, their parents declared no intention to have them vaccinated, while 509 (44.4 %) were not sure. Among the parents of the 804 girls whose parents had not intended to have them vaccinated, 134 (16.7 %) changed their minds after reading about HPV among men. Fathers were more likely than mothers to change their minds, and finally intend to have their daughters vaccinated (adjusted relative risk, 1.74 [95 % confidence interval, 1.20,2.54]). CONCLUSIONS: These results suggest that parents, and fathers in particular, could be more motivated to have their daughters vaccinated against HPV if the information with which they were provided included a male perspective and a recommendation of vaccination for boys as well as girls.

Agent-based modelling of reactive vaccination of workplaces and schools against COVID-19.

With vaccination against COVID-19 stalled in some countries, increasing vaccine accessibility and distribution could help keep transmission under control. Here, we study the impact of reactive vaccination targeting schools and workplaces where cases are detected, with an agent-based model accounting for COVID-19 natural history, vaccine characteristics, demographics, behavioural changes and social distancing. In most scenarios, reactive vaccination leads to a higher reduction in cases compared with non-reactive strategies using the same number of doses. The reactive strategy could however be less effective than a moderate/high pace mass vaccination program if initial vaccination coverage is high or disease incidence is low, because few people would be vaccinated around each case. In case of flare-ups, reactive vaccination could better mitigate spread if it is implemented quickly, is supported by enhanced test-trace-isolate and triggers an increased vaccine uptake. These results provide key information to plan an adaptive vaccination rollout.

[Extension of HPV vaccination to boys: Survey of families and general practitioners]. / Extension de la vaccination contre les HPV aux garçons : enquête auprès de familles et de médecins généralistes.

INTRODUCTION: As part of an analysis on the extension of the HPV vaccination to French boys, the French National Cancer Institute (INCa) and the French National Authority for Health (HAS) have conducted in collaboration a survey on HPV vaccine acceptance in July 2019. This survey was completed by parents of children aged 11-19 and general practitioners (GPs). Questions focused on their representations, practices and intentions in the context of the future policy change allowing boys to get vaccinated against HPV. METHODS: The survey was conducted between June 20 and July 12, 2019. It focused on two populations: a nationally representative sample of parents with at least one girl aged 11-19 and/or one boy aged 11-14 (n=1984) and a representative sample of GPs in mainland France. Data were collected through a web-based questionnaire with a mean completion time of 10minutes for parents and GPs. The quota method was applied to ensure the representative nature of the samples based on (i) gender, age, children (girl aged 11-14 and/or boy aged 11-14) of the household, socio-professional category of the "head of the household", size of urban area and region for the parents' sample and based on (ii) gender, age, region and type of practice for the GPs' sample. RESULTS: Although most GPs were very favourable towards HPV vaccination (94%), they considered it one of the most challenging vaccinations to get parents to adhere to (82%). A notable percentage of parents have unfavourable opinions towards HPV vaccination (25%). The three main barriers cited by parents of non-vaccinated girls were: the fear of adverse effects, the lack of information, and the fact that the GP did not propose it. Regarding the extension of HPV vaccination to boys, 84 % of GPs would recommend this vaccination to boys if it was included in the vaccination schedule, and 88 % of those who did not routinely recommend HPV vaccination to girls would be more likely to offer it to girls if the extension was recommended.

A modelling study investigating short and medium-term challenges for COVID-19 vaccination: From prioritisation to the relaxation of measures.

BACKGROUND: The roll-out of COVID-19 vaccines is a multi-faceted challenge whose performance depends on pace of vaccination, vaccine characteristics and heterogeneities in individual risks. METHODS: We developed a mathematical model accounting for the risk of severe disease by age and comorbidity, and transmission dynamics. We compared vaccine prioritisation strategies in the early roll-out stage and quantified the extent to which measures could be relaxed as a function of the vaccine coverage achieved in France. FINDINGS: Prioritizing at-risk individuals reduces morbi-mortality the most if vaccines only reduce severity, but is of less importance if vaccines also substantially reduce infectivity or susceptibility. Age is the most important factor to consider for prioritization; additionally accounting for comorbidities increases the performance of the campaign in a context of scarce resources. Vaccinating 90% of ≥65 y.o. and 70% of 18-64 y.o. before autumn 2021 with a vaccine that reduces severity by 90% and susceptibility by 80%, we find that control measures reducing transmission rates by 15-27% should be maintained to remain below 1000 daily hospital admissions in France with a highly transmissible variant (basic reproduction number R0  = 4). Assuming 90% of ≥65 y.o. are vaccinated, full relaxation of control measures might be achieved with a vaccine coverage of 89-100% in 18-64 y.o or 60-69% of 0-64 y.o. INTERPRETATION: Age and comorbidity-based vaccine prioritization strategies could reduce the burden of the disease. Very high vaccination coverage may be required to completely relax control measures. Vaccination of children, if possible, could lower coverage targets necessary to achieve this objective.

Tratamento medicamentoso e não medicamentoso de usuários de um Centro de Atenção Psicossocial / Pharmacological and non-pharmacological treatment of a Psychosocial Care Center users

OBJETIVOS: Verificar o perfil de tratamento medicamentoso e não medicamentoso de usuários assistidos em um Centro de Atenção Psicossocial. MÉTODOS: Estudo epidemiológico com delineamento transversal, realizado em um Centro de Atenção Psicossocial de um município do Noroeste do Estado do Rio Grande do Sul. Foram incluídos todos os usuários assistidos no Centro, com idade superior a 18 anos, de ambos os gêneros. Foram excluídos aqueles com falta de informações sobre o tratamento. A coleta de dados foi realizada pelo acesso direto aos prontuários quanto às características sociodemográficas, informações relacionadas ao diagnóstico, internações hospitalares anteriores, tratamento medicamentoso e não medicamentoso. A análise dos dados foi realizada por meio do teste Qui-quadrado de Pearson e o nível de significância considerado foi p<0,05. RESULTADOS: Foram incluídos 448 pacientes, cuja média de idade foi 48,25±12,44 anos, sendo que 293 (65,4%) eram do gênero feminino, 266 (59,2%) viviam sem companheiro e 206 (46,0%) tinham ensino fundamental incompleto. Todos os usuários realizavam tratamento não medicamentoso e 445 (99,3%) faziam também uso de medicamentos. Entre as classes de medicamentos utilizados houve predomínio de antipsicóticos (78,3%) e dos antidepressivos (71,2%). O uso de quatro ou mais medicamentos foi associado à internação hospital anterior e ao uso de antipsicóticos, antidepressivos, antiepiléticos e ansiolíticos. CONCLUSÕES: Constatou-se um perfil sociodemográfico semelhante ao de usuários de Centros de Atenção Psicossocial em diferentes regiões brasileiras. A totalidade dos pacientes recebia tratamento não medicamentoso e quase a totalidade utilizava também medicamentos. Diante do elevado número de medicamentos e internações hospitalares anteriores identificadas emerge a necessidade de ampliação do escopo de terapêuticas não medicamentosas no tratamento de transtornos mentais, a fim de promover a integralidade e a resolubilidade do cuidado em saúde mental.

AIMS: To verify the profile of pharmacological and non-pharmacological treatment of patients assisted in a Psychosocial Care Center. METHODS: An epidemiological study with a cross-sectional design was carried out in a Psychosocial Care Center of a municipality in the Northwest of the State of Rio Grande do Sul. All patients assisted in the Center, aged over 18 years, of both genders, were included. Those for whom information about treatment was missing were excluded. Data collection was performed by direct access to medical records regarding sociodemographic characteristics, information on diagnosis, previous hospital admissions, pharmacological and non-pharmacological treatment. Data analysis was performed using the Pearson Chi-square test and the significance level was set at p<0.05. RESULTS: A total of 448 patients were included, whose mean age was 48.25±12.44 years, 293 (65.4%) were female, 266 (59.2%) lived without a partner and 206 (46.0%) had incomplete elementary education. All patients were receiving non-pharmacological treatment and 445 (99.3%) were also taking medications. Among the classes of drugs used, antipsychotics (78.3%) and antidepressants (71.2%) predominated. Using of four or more drugs was associated with previous hospitalization and with taking antipsychotics, antidepressants, antiepileptics and anxiolytics. CONCLUSIONS: A sociodemographic profile similar to that of users of Psychosocial Care Centers in different Brazilian regions was found. All patients received non-pharmacological treatment and almost all also used drugs. In view of the high number of medications and hospital admissions identified, there is a need to expand the scope of non-pharmacological therapies in the treatment of mental disorders, in order to promote the comprehensiveness and the resolubility of mental health care.

Mutation studies in ascidians: a review.

Historically, mutations have had a significant impact on the study of developmental processes and phenotypic evolution. Lesions in DNA are created by artificial methods or detected by natural genetic variation. Random mutations are then ascribed to genetic change by direct sequencing or positional cloning. Tunicate species of the ascidian genus Ciona represent nearly fully realized model systems in which gene function can be investigated in depth. Additionally, tunicates are valuable organisms for the study of naturally occurring mutations due to the capability to exploit genetic variation down to the molecular level. Here, we summarize the available information about how mutations are studied in ascidians with examples of insights that have resulted from these applications. We also describe notions and methodologies that might be useful for the implementation of easy and tight procedures for mutations studies in Ciona.

Fibroblast growth factor signalling controls nervous system patterning and pigment cell formation in Ciona intestinalis.

During the development of the central nervous system (CNS), combinations of transcription factors and signalling molecules orchestrate patterning, specification and differentiation of neural cell types. In vertebrates, three types of melanin-containing pigment cells, exert a variety of functional roles including visual perception. Here we analysed the mechanisms underlying pigment cell specification within the CNS of a simple chordate, the ascidian Ciona intestinalis. Ciona tadpole larvae exhibit a basic chordate body plan characterized by a small number of neural cells. We employed lineage-specific transcription profiling to characterize the expression of genes downstream of fibroblast growth factor signalling, which govern pigment cell formation. We demonstrate that FGF signalling sequentially imposes a pigment cell identity at the expense of anterior neural fates. We identify FGF-dependent and pigment cell-specific factors, including the small GTPase, Rab32/38 and demonstrated its requirement for the pigmentation of larval sensory organs.

Expression of a single prominin homolog in the embryo of the model chordate Ciona intestinalis.

Prominins are a family of pentaspan transmembrane glycoproteins, expressed in various types of cells, including stem and cancer stem cells in mammals. Prominin-1 is critical in generating and maintaining the structure of the photoreceptors in the eye since mutations in the PROM1 gene are associated with retinal and macular degeneration in human. In this study, we identified a single prominin homolog, Ci-prom1/2, in the model chordate the ascidian Ciona intestinalis and characterized Ci-prom1/2 expression profile in relation to photoreceptor differentiation during Ciona embryonic development. In situ hybridization experiments show Ci-prom1/2 transcripts localized in the developing central nervous system, predominantly in photoreceptor cell precursors as early as neurula stage and expression is maintained through larva stage in photoreceptor cells around the simple eye. We also isolated the regulatory region responsible for the specific spatio-temporal expression of the Ci-prom1/2 in photoreceptor cell lineage. Collectively, we report that Ci-prom1/2 is a novel molecular marker for ascidian photoreceptor cells and might represent a potential source to enlarge the knowledge about the function of prominin family in photoreceptor cell evolution and development.

The public health benefit of medicines: how it has been assessed in France? The principles and results of five years' experience.

Health technology assessment seeks to inform health policy- and decision-makers by promoting use of current best evidence and by addressing country specific factors, such as local context and values. In France, public health benefit (PHB) is one of the criteria used to inform decisions on the reimbursement of medicines. This article describes the methodological framework and the results after five years of assessment of PHB, by the French National Authority for Health. The semi-quantitative method used includes three dimensions that are: (1) the ability of a drug to improve the population's health status, (2) the drug's adequacy to cover public health needs, and; (3) the impact of the drug on the healthcare system. From 2005 to 2010, the PHB of 530 drugs was estimated, and 72% were assessed as having no PHB. The PHB was "low" for 88% of drugs expected to have a PHB, "medium" for 10%, and was considered to be "high" in only one case. The results of this experience show that it is feasible to assess the public health impact of drugs. But the high level of uncertainties at the time of a drug's first appraisal limits the assessment, which obviously has to be completed by reappraisal with post-marketing studies.

[French Health Authority (HAS) Guidance: the post-registration studies on health technologies (drugs, medical devices and instruments): principles and methods]. / Guide de la Haute autorité de santé (HAS) : les études post-inscription sur les technologies de santé (médicaments, dispositifs médicaux et actes) : principes et méthodes.

The assessment of a health technology is frequently accompanied by uncertainty about its impact, at short or long terms, on the health of the population. The Health Authorities may request additional « post-registration ¼ data that will allow a relevant reassessment of these technologies. The responsibility to collect this information lies with the industry and the HAS evaluates the methodology. This guideline provides practical benchmarks on methodological aspects of these studies. It describes the different types of studies to consider depending on the objectives, including the use of databases and cohorts and European studies. It emphasizes the importance of establishing a scientific committee, clearly defining the objectives of the study, justifying the methodological choices, documenting the representativeness or completeness of centers, investigators and patients, limiting the number of lost of follow-up patients and missing data, describing the statistical analysis methods, the bias and their possible impact on results. The publication of the results of these studies is strongly encouraged.

[Not Available]. / Guide de la Haute autorité de santé (HAS) : les études post-inscription sur les technologies de santé (médicaments, dispositifs médicaux et actes) : principes et méthodes.

The assessment of a health technology is frequently accompanied by uncertainty about its impact, at short or long terms, on the health of the population. The Health Authorities may request additional « post-registration ¼ data that will allow a relevant reassessment of these technologies. The responsibility to collect this information lies with the industry and the HAS evaluates the methodology. This guideline provides practical benchmarks on methodological aspects of these studies. It describes the different types of studies to consider depending on the objectives, including the use of databases and cohorts and European studies. It emphasizes the importance of establishing a scientific committee, clearly defining the objectives of the study, justifying the methodological choices, documenting the representativeness or completeness of centers, investigators and patients, limiting the number of lost of follow-up patients and missing data, describing the statistical analysis methods, the bias and their possible impact on results. The publication of the results of these studies is strongly encouraged.

FGF/MAPK/Ets signaling renders pigment cell precursors competent to respond to Wnt signal by directly controlling Ci-Tcf transcription.

FGF and Wnt pathways constitute two fundamental signaling cascades, which appear to crosstalk in cooperative or antagonistic fashions in several developmental processes. In vertebrates, both cascades are involved in pigment cell development, but the possible interplay between FGF and Wnt remains to be elucidated. In this study, we have investigated the role of FGF and Wnt signaling in development of the pigment cells in the sensory organs of C. intestinalis. This species possesses the basic features of an ancestral chordate, thus sharing conserved molecular developmental mechanisms with vertebrates. Chemical and targeted perturbation approaches revealed that a FGF signal, spreading in time from early gastrulation to neural tube closure, is responsible for pigment cell precursor induction. This signal is transmitted via the MAPK pathway, which activates the Ci-Ets1/2 transcription factor. Targeted perturbation of Ci-TCF, a downstream factor of the canonical Wnt pathway, indicated its contribution to pigment cell differentiation Furthermore, analyses of the Ci-Tcf regulatory region revealed the involvement of the FGF effector, Ci-Ets1/2, in Ci-Tcf transcriptional regulation in pigment cell precursors. Our results indicate that both FGF and the canonical Wnt pathways are involved in C. intestinalis pigment cell induction and differentiation. Moreover, we present a case of direct transcriptional regulation exerted by the FGF signaling cascade, via the MAPK-ERK-Ets1/2, on the Wnt downstream gene Ci-Tcf. Several examples of FGF/Wnt signaling crosstalk have been described in different developmental processes; however, to our knowledge, FGF-Wnt cross-interaction at the transcriptional level has never been previously reported. These findings further contribute to clarifying the multitude of FGF-Wnt pathway interactions.

Natural variation of model mutant phenotypes in Ciona intestinalis.

BACKGROUND: The study of ascidians (Chordata, Tunicata) has made a considerable contribution to our understanding of the origin and evolution of basal chordates. To provide further information to support forward genetics in Ciona intestinalis, we used a combination of natural variation and neutral population genetics as an approach for the systematic identification of new mutations. In addition to the significance of developmental variation for phenotype-driven studies, this approach can encompass important implications in evolutionary and population biology. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a preliminary survey for naturally occurring mutations in three geographically interconnected populations of C. intestinalis. The influence of historical, geographical and environmental factors on the distribution of abnormal phenotypes was assessed by means of 12 microsatellites. We identified 37 possible mutant loci with stereotyped defects in embryonic development that segregate in a way typical of recessive alleles. Local populations were found to differ in genetic organization and frequency distribution of phenotypic classes. CONCLUSIONS/SIGNIFICANCE: Natural genetic polymorphism of C. intestinalis constitutes a valuable source of phenotypes for studying embryonic development in ascidians. Correlating genetic structure and the occurrence of abnormal phenotypes is a crucial focus for understanding the selective forces that shape natural finite populations, and may provide insights of great importance into the evolutionary mechanisms that generate animal diversity.

Primary cultures of nervous system cells from the larva of the ascidian Ciona intestinalis.

The ascidian Ciona intestinalis is a useful model for the study of nervous system development and function. The larva of this animal represents a 'primitive' vertebrate form that contains only about 100 neurons in the CNS. Although embryos can be easily subjected to genetic manipulation, the nervous system cells are not easily accessible for neurophysiological study at the larval stage. To remedy this problem, we have developed a method to obtain primary cell cultures from the larval stage of Ciona. Light microscopy and electrophysiology discriminate several types of cells including neurons and photoreceptors. The results show that in Ciona primary cultures different types of neurons as well as neurite sprouting and synapse formation can be visualised. Ciona primary cell cultures will be very useful to study the biochemical, molecular and biophysical properties of individual cells in the larval nervous system of C. intestinalis.

[Performance evaluation of a tool for institutional protocol quality assurance]. / Evaluation de la performance d'un outil d'assurance qualité des protocoles institutionnels.

BACKGROUND: Few data are available on the quality of the protocols promoted by the University Hospital Centers (CHU) in France, and there is no standardised method for evaluating protocol quality. The Clinical Research Centre (CIC) of Nancy developed a checklist-based tool aimed at evaluating the quality of institutional protocols. OBJECTIVE: The objective of this study was to evaluate the performance of this tool for assessing the quality of the protocols promoted by the CHU. METHODS: A prospective parallel-group study design, controlled with cluster randomisation, was used. The checklist was applied within the Directions of Clinical Research (DRC) for 4 months. Sixty four protocols were analysed. RESULTS: Before intervention there was no significant difference in quality scores between the two groups. Compared with baseline, there was a significant improvement of the methodological and regulation median score (81.7 +/- 13.7 vs 90.4 +/- 9.2) only in the intervention group (p = 0.040). Changes in the two groups over time were not significantly different from each other using analysis of variance (p = 0.501). CONCLUSION: In an observation limited to 12 CHU in France, the quality of the promoted protocols was judged as suboptimal and able to be improved. Initiation of quality assurance tools, such as the one used in this study, was associated with some spontaneous improvement, but did not improve the result significantly.

Characterization of sea urchin transglutaminase, a protein regulated by guanine/adenine nucleotides.

Transglutaminases (TGs) are calcium-dependent enzymes that catalyze the transamidation of glutamine residues to form intermolecular isopeptide bonds. Nine distinct TGs have been identified in mammals, and three of them (types 2, 3, and 5) are regulated by GTP/ATP and are able to hydrolyze GTP, working as bifunctional enzymes. We have isolated a cDNA clone encoding a TG from a cDNA library prepared from the blastula stage of sea urchin Paracentrotus lividus (PlTG). The cDNA sequence has an open reading frame coding for a protein of 738 amino acids, including a Cys active site and two other residues critical for catalytic activity, His and Asp. We have studied its expression pattern by in situ hybridization and have also demonstrated that the in vitro expressed PlTG had GTP- and ATP-hydrolyzing activity; moreover, GTP inhibited the transamidating activity of this enzyme as it does that of human TG2, TG3, and TG5.