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A number of case studies describing hypnotherapy in the treatment of anxiety disorder patients have already been published. Only a few randomized controlled trials (RCTs) investigated the efficacy of hypnotherapy but focused mainly on symptoms rather than specific mental disorders. The goal of this study was to investigate whether hypnotherapy (HT) was superior to a waitlist control group (WL) in the reduction of agoraphobia-related symptoms. Further goals were to report the feasibility of hypnotherapy as well as attrition and completion rates and detect (epi-)genetic variables, which might play a role in treatment outcome. This pilot study was based on a monocentric two-armed randomized controlled rater-blind clinical trial that was conducted between 2018 and 2020 with a waitlist control group. A total of 36 patients diagnosed with agoraphobia were randomized to either HT or WL. Patients in HT received individual outpatient treatment with hypnotherapy with 8 to 12 sessions for a period of 3 months. Patients in WL received HT after 3 months. Agoraphobia-related symptoms were assessed at baseline, after the treatment, and 3 months later in both groups with a clinician rating. The primary hypothesis concerning the difference between groups in the individual percentage symptom reduction could be confirmed in the intention-to-treat, not the per-protocol sample. Additionally, we applied repeated-measures analyses of variance and found a higher symptom decrease in HT compared with WL patients in three of the five imputed datasets. The dropout rate was low, and satisfaction with the treatment was high. HT patients experienced a strong symptom reduction after receiving hypnotherapy. WL patients improved slightly during the waiting period. The COMT Val108/158Met genotype had an effect on the agoraphobia-related symptoms as well as on COMT DNA methylation levels. This is the first study to indicate that hypnotherapy performed better than a waitlist control group regarding the reduction in anxiety symptoms in an RCT. Future studies should confirm the efficacy of hypnotherapy and compare the treatment with a standard treatment for anxiety disorders in a larger trial. Future studies should also investigate whether hypnotic susceptibility is associated with COMT Val108/158Met genotype and could predict treatment success for HT.Clinical trial registrationhttps://classic.clinicaltrials.gov/ct2/show/NCT03684577, identifier: NCT03684577.

Congenital heart diseases (CHDs) are the most common congenital malformations. The objective of our study was to evaluate the prenatal screening accuracy of congenital heart disease (CHD) in Southern France and to evaluate the impact of a prenatal diagnosis on pregnancies outcomes and neonatal outcomes. We performed a bicentric, retrospective observational study in the southern region over 4 years was conducted between 1 January 2014 and 31 December 2017. All foetuses and children under one year of age with CHD monitored in the UTHs (University Teaching Hospitals) in Marseille and Nice were included. CHD cases were divided into 3 groups: group 1, those with no possible options for anatomical repair; group 2, those with anatomical repair possibilities but that may require neonatal cardiologic management; and group 3, those with anatomical repair possibilities that do not require an emergency neonatal procedure. Among the 249070 deliveries during the study period, 677 CHD cases were included in the study. The overall prenatal screening rate was 71.5%. The screening rates were 97.8%, 63.6%, and 65.9% for groups 1, 2 and 3, respectively. Among group 2 CHD cases, 80% of the transpositions of the great arteries, 56% of the aortic coarctations, and 20% of the total anomalous pulmonary venous returns were detected during the prenatal period. A genetic anomaly was found in 16% of CHD cases. The overall mortality rate was 11.3% with a higher death rate in cases of prenatal screening (17.2% versus 2.1%; p < 0.001). However, when focusing only on children who died of CHD, prenatal screening did not create an impact (56.6% versus 100%, p = 0,140). Our data showed that the prenatal screening rate of CHD appears satisfactory in Southern France. Nevertheless, it could be improved for some CHD. This study did not find any benefit in terms of mortality from prenatal screening for CHD.

Control of invasive species relies partly on permanent surveillance at international points of entry. We report the exceptional trapping of one adult mosquito (Diptera: Culicidae) in the port of Marseille, France, in July 2018, during a routine survey conducted according to International Health Regulations. Morphological and molecular identification classified the specimen as a female Aedes (Stegomyia) aegypti (L.), vector of many arboviruses, absent from Europe and the Mediterranean rim since the 1950s. A world reference panel of approximately 23,000 genome-wide single nucleotide polymorphisms determined that the mosquito originated from Cameroon, west Africa. Cross-reference of this geographic location with boats traveling from Central Africa to Marseille during the trapping period suggests that the mosquito travelled within an identified merchant ship, a vehicles carrier connecting Douala, Cameroon to Marseille, France. This ship left Douala on June 25, 2018 and arrived 20 days later in Marseille on July 15. The mosquito was captured 350 m away from the dock. The interception of a propagule of an invasive species is a rare event that must be considered a priority to prevent its successful establishment.

Abstract Background Urban malaria can be a serious public health problem in Africa. Human-landing catches of mosquitoes, a standard entomological method to assess human exposure to malaria vector bites, can lack sensitivity in areas where exposure is low. A simple and highly sensitive tool could be a complementary indicator for evaluating malaria exposure in such epidemiological contexts. The human antibody response to the specific Anopheles gSG6-P1 salivary peptide have been described as an adequate tool biomarker for a reliable assessment of human exposure level to Anopheles bites. The aim of this study was to use this biomarker to evaluate the human exposure to Anopheles mosquito bites in urban settings of Dakar (Senegal), one of the largest cities in West Africa, where Anopheles biting rates and malaria transmission are supposed to be low. Methods One cross-sectional study concerning 1,010 (505 households) children (n = 505) and adults (n = 505) living in 16 districts of downtown Dakar and its suburbs was performed from October to December 2008. The IgG responses to gSG6-P1 peptide have been assessed and compared to entomological data obtained in or near the same district. Results Considerable individual variations in anti-gSG6-P1 IgG levels were observed between and within districts. In spite of this individual heterogeneity, the median level of specific IgG and the percentage of immune responders differed significantly between districts. A positive and significant association was observed between the exposure levels to Anopheles gambiae bites, estimated by classical entomological methods, and the median IgG levels or the percentage of immune responders measuring the contact between human populations and Anopheles mosquitoes. Interestingly, immunological parameters seemed to better discriminate the exposure level to Anopheles bites between different exposure groups of districts. Conclusions Specific human IgG responses to gSG6-P1 peptide biomarker represent, at the population and individual levels, a credible new alternative tool to assess accurately the heterogeneity of exposure level to Anopheles bites and malaria risk in low urban transmission areas. The development of such biomarker tool would be particularly relevant for mapping and monitoring malaria risk and for measuring the efficiency of vector control strategies in these specific settings.

Abstract Background The evaluation of malaria transmission intensity is a crucial indicator for estimating the burden of malarial disease. In this respect, entomological and parasitological methods present limitations, especially in low transmission areas. The present study used a sensitive multiplex assay to assess the exposure to Plasmodium falciparum infection in children living in an area of low endemicity. In three Senegalese villages, specific antibody (IgG) responses to 13 pre-erythrocytic P. falciparum peptides derived from Lsa1, Lsa3, Glurp, Salsa, Trap, Starp, Csp and Pf11.1 proteins were simultaneously evaluated before (June), at the peak (September) and after (December) the period of malaria transmission, in children aged from 1 to 8 years. Results Compared to other antigens, a high percentage of seropositivity and specific antibody levels were detected with Glurp, Salsa1, Lsa3NR2, and Lsa1J antigens. The seropositivity increased with age for all tested antigens. Specific IgG levels to Glurp, Salsa1, Lsa3NR2, and Lsa1J were significantly higher in P. falciparum infected children compared to non-infected and this increase is significantly correlated with parasite density. Conclusion The multiplex assay represents a useful technology for a serological assessment of rapid variations in malaria transmission intensity, especially in a context of low parasite rates. The use of such combined serological markers (i.e. Glurp, Lsa1, Lsa3, and Salsa) could offer the opportunity to examine these variations over time, and to evaluate the efficacy of integrated malaria control strategies.

Abstract Background Human populations exposed to low malaria transmission present particular severe risks of malaria morbidity and mortality. In addition, in a context of low-level exposure to Anopheles vector, conventional entomological methods used for sampling Anopheles populations are insufficiently sensitive and probably under-estimate the real risk of malaria transmission. The evaluation of antibody (Ab) responses to arthropod salivary proteins constitutes a novel tool for estimating exposure level to insect bites. In the case of malaria, a recent study has shown that human IgG responses to the gSG6-P1 peptide represented a specific biomarker of exposure to Anopheles gambiae bites. The objective of this study was to investigate if this biomarker can be used to estimate low-level exposure of individuals to Anopheles vector. Methods The IgG Ab level to gSG6-P1 was evaluated at the peak and at the end of the An. gambiae exposure season in children living in Senegalese villages, where the Anopheles density was estimated to be very low by classical entomological trapping but where malaria transmission occurred during the studied season. Results Specific IgG responses to gSG6-P1 were observed in children exposed to very low-level of Anopheles bites. In addition, a significant increase in the specific IgG Ab level was observed during the Anopheles exposure season whereas classical entomological data have reported very few or no Anopheles during the studied period. Furthermore, this biomarker may also be applicable to evaluate the heterogeneity of individual exposure. Conclusion The results strengthen the hypothesis that the evaluation of IgG responses to gSG6-P1 during the season of exposure could reflect the real human contact with anthropophilic Anopheles and suggest that this biomarker of low exposure could be used at the individual level. This promising immuno-epidemiological marker could represent a useful tool to assess the risk to very low exposure to malaria vectors as observed in seasonal, urban, altitude or travellers contexts. In addition, this biomarker could be used for the surveillance survey after applying anti-vector strategy.

Abstract Background During blood feeding, the mosquito injects saliva into the vertebrate host. This saliva contains bioactive components which may play a role in pathogen transmission and in host-vector relationships by inducing an immune response in the vertebrate host. The evaluation of human immune responses to arthropod bites might also represent a research direction for assessing individual exposure to the bite of a malaria vector. Methods The present study examined the antibody (Ab) IgG response during the season of exposure to Anopheles gambiae bites in young children living in a malaria endemic area. Immunoblots were performed with An. gambiae saliva to detect anti-saliva Ab bands and the evolution of immunogenic bands at the peak of, and following, the transmission period. Results The results showed that anti-Anopheles Ab was directed against a limited number of salivary proteins (175, 115, 72 and 30 kDa bands). Specific IgG responses to mosquito salivary proteins were variable among exposed individuals; nevertheless, two major bands (175 and 72 kDa) were observed in all immune-responder children. Analysis of the intensity of immunogenic bands revealed that IgG levels against the 175 kDa band were significantly higher during the peak period compared to the end period malaria transmission. Conclusion This preliminary work supports the potential of using anti-saliva immune responses as a measure of exposure to Anopheles bites. The use of immunoblots coupled with evaluation of band intensity could be an adequate tool for distinguishing immunogenic salivary proteins as candidate markers of bite exposure. Furthermore, this study may open the way to design new epidemiological tools for evaluating the risk of malaria exposure.

Background: Long-lasting insecticidal bed nets (LLINs) are a key measure for preventing malaria and their evaluation is coordinated by the World Health Organization Pesticide Evaluation Scheme (WHOPES). LifeNet® was granted WHOPES time-limited interim recommendation in 2011 after successful Phase I and Phase II evaluations. Here, we evaluated the durability and community acceptance of LifeNet® in a Phase III trial from June 2014 to June 2017 in Benin rural area., Methods: A prospective longitudinal, cluster-randomized, controlled trial with households as the unit of observation was designed to assess the performance of LifeNet® over a three-year period, using a WHOPES fully recommended LLIN (PermaNet® 2.0) as a positive control. The primary outcomes were the bioassay performance using WHO cone assays and tunnel tests, the insecticide content and physical integrity., Results: At baseline, 100% of LLINs were within the tolerance limits of their target deltamethrin concentrations. By 36 months only 17.3% of LifeNet® and 8.5% of PermaNet® LLINs still were within their target deltamethrin concentrations. Despite these low rates, 100% of both LLINs meet WHO efficacy criteria (≥ 80% mortality or ≥ 95% knockdown or tunnel test criteria of ≥ 80% mortality or ≥ 90% blood-feeding inhibition) after 36 months using WHO cone bio-assays and tunnel tests. The proportion of LLINs in good physical condition was 33% for LifeNet® and 29% for PermaNet® after 36 months. After 36 M the survivorship was 21% and 26% for LifeNet® and PermaNet® respectively. Although both LLINs were well accepted by the population, complaints of side effects were significantly higher among LifeNet® users than PermaNet® ones., Conclusion: LifeNet® LLINs did meet WHO criteria for bio-efficacy throughout the study period and were well accepted by the population. This is an important step towards getting a full WHO recommendation for use in malaria endemic countries., Competing Interests: The authors declare that they have no competing interests, (Copyright: © 2023 Djènontin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Malaria control is heavily reliant on insecticides, especially pyrethroids. Resistance of mosquitoes to insecticides may threaten the effectiveness of insecticide-based vector control and lead to a resurgence of malaria in Africa., Methods: In 21 villages in Southern Benin with high levels of insecticide resistance, the resistance status of local vectors was measured at the same time as the prevalence of malaria infection in resident children., Results: Children who used LLINs had lower levels of malaria infection [odds ratio = 0.76 (95% CI 0.59, 0.98, p = 0.033)]. There was no evidence that the effectiveness of nets was different in high and low resistance locations (p = 0.513). There was no association between village level resistance and village level malaria prevalence (p = 0.999)., Conclusions: LLINs continue to offer individual protection against malaria infection in an area of high resistance. Insecticide resistance is not a reason to stop efforts to increase coverage of LLINs in Africa.

Background: The estimates of risk of malaria in early childhood are imprecise given the current entomologic and parasitological tools. Thus, the utility of anti-Anopheles salivary gSG6-P1 peptide antibody responses in measuring exposure to Anopheles bites during early infancy has been assessed., Methods: Anti-gSG6-P1 IgG and IgM levels were evaluated in 133 infants (in Benin) at three (M3), six (M6), nine (M9) and 12 (M12) months of age. Specific IgG levels were also assessed in their respective umbilical cord blood (IUCB) and maternal blood (MPB)., Results: At M3, 93.98 and 41.35% of infants had anti-gSG6-P1 IgG and IgM Ab, respectively. Specific median IgG and IgM levels gradually increased between M3 and M6 (p < 0.0001 and p < 0.001), M6-M9 (p < 0.0001 and p = 0.085) and M9-M12 (p = 0.002 and p = 0.03). These levels were positively associated with the Plasmodium falciparum infection intensity (p = 0.006 and 0.003), and inversely with the use of insecticide-treated bed nets (p = 0.003 and 0.3). Levels of specific IgG in the MPB were positively correlated to those in the IUCB (R = 0.73; p < 0.0001) and those at M3 (R = 0.34; p < 0.0001)., Conclusion: The exposure level to Anopheles bites, and then the risk of malaria infection, can be evaluated in young infants by assessing anti-gSG6-P1 IgM and IgG responses before and after 6-months of age, respectively. This tool can be useful in epidemiological evaluation and surveillance of malaria risk during the first year of life.

Background: The widespread use of insecticide-treated nets (LLINs) leads to the development of vector resistance to insecticide. This resistance can reduce the effectiveness of LLIN-based interventions and perhaps reverse progress in reducing malaria morbidity. To prevent such difficulty, it is important to know the real impact of resistance in the effectiveness of mosquito nets. Therefore, an assessment of LLIN efficacy was conducted in malaria prevention among children in high and low resistance areas., Methods: The study was conducted in four rural districts and included 32 villages categorized as low or high resistance areas in Plateau Department, south-western Benin. Larvae collection was conducted to measure vector susceptibility to deltamethrin and knockdown resistance (kdr) frequency. In each resistance area, around 500 children were selected to measure the prevalence of malaria infection as well as the prevalence of anaemia associated with the use of LLINs., Results: Observed mortalities of Anopheles gambiae s.s population exposed to deltamethrin ranged from 19 to 96%. Knockdown resistance frequency was between 38 and 84%. The prevalence of malaria infection in children under five years was 22.4% (19.9-25.1). This prevalence was 17.3% (14.2-20.9) in areas of high resistance and 27.1% (23.5-31.1) in areas of low resistance (p=0.04). Eight on ten children that were aged six - 30 months against seven on ten of those aged 31-59 months were anaemic. The anaemia observed in the six to 30-month old children was significantly higher than in the 31-59 month old children (p=0.00) but no difference associated with resistance areas was observed (p=0.35). The net use rate was 71%. The risk of having malaria was significantly reduced (p<0.05) with LLIN use in both low and high resistance areas. The preventive effect of LLINs in high resistance areas was 60% (95% CI: 40-70), and was significantly higher than that observed in low resistance areas (p<0.05)., Conclusion: The results of this study showed that the resistance of malaria vectors seems to date not have affected the impact of LLINs and the use of LLINs was highly associated with reduced malaria prevalence irrespective of resistance.

Cytosine-phosphate-guanine (CpG) motifs in bacterial DNA are known to activate the mammalian immune system, and this activation is thought to depend on the Toll-like receptor 9 (TLR9) signaling pathway. Previous studies strongly suggested that TLR9 is involved as the specific receptor for CpG motifs but did not provide direct evidence of their interaction. In this study, we demonstrate for the first time that murine TLR9 binds an unmethylated CpG-containing plasmid. This interaction is sequence-specific and is influenced by the methylation status of the plasmid. Furthermore, we demonstrate that this interaction leads to the activation of the NF-kappaB pathway in mTLR9-expressing cells. Our results provide a molecular basis for the interaction between CpG-DNA and TLR9.

Objective: Unmethylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotides are highly frequent motifs in bacterial DNA and rare in the mammalian genome. They are potent inducers of inflammatory cytokines and act synergistically with lipopolysaccharide (LPS) for the induction of tumor necrosis factor alpha (TNF-alpha) production in vivo. It has therefore been suggested that innate immune reaction to bacterial unmethylated CpG motifs might contribute to the development of septic shock. We designed this study to assess the sensitization role of CpG motifs in LPS-induced shock using the D-galactosamine (D-GalN)-sensitized mouse model., Design: A prospective, randomized in vivo animal laboratory study., Setting: Experimental research laboratory., Intervention: We performed experiments in which CpG, LPS and D-GalN were administrated sequentially in various orders or simultaneously in 8 week-old BALB/c mice., Measurements and Results: Cytosine-phosphate-guanine treatment potentiated LPS action only if injected prior to LPS. A combination of predefined sublethal doses of CpG (1 nmol/mouse) and LPS (1 ng/mouse) not only had a synergetic effect on TNF-alpha production (20.3+/-9.2 IU/ml versus 2.5+/-1.4 IU/ml and 5.6+/-3.4 IU/ml for CpG and LPS groups, respectively, p<0.05), but also led to animal death (5/5). An CpG effect requires de novo mRNA synthesis, since the sensitizing effect was inhibited by co-administration of mRNA transcription inhibitors such as D-GalN and pentoxifylline, which is a specific TNF-alpha transcription inhibitor. Furthermore, CpG treatment provoked a strong TNF-alpha mRNA production in the liver that was dramatically reduced by pre-treatment with D-GalN., Conclusion: Our findings indicate that CpG motifs act synergistically with LPS by initializing the synthesis of TNF-alpha and/or TNF-alpha regulating factors, thereby acting as a sensitizing agent.