Centre Nouvelle Aquitaine-Bordeaux

AIMS: Clinical trials constitute the gold standard to assess the efficacy and safety of new medicines. However, because they are conducted in standardized conditions far from the real world of prescription and use, discrepancies in patient selection or treatment conditions may alter both the effectiveness and risks. On the basis of three examples, our objectives were to study the differences between the characteristics of treated populations and treatment patterns in clinical trials and in postmarketing settings and to discuss the potential consequences on actual efficacy and safety. METHODS: Treated populations were compared with patients included in premarketing clinical trials. Comparisons were made on the basis of demographic characteristics and treatment patterns. RESULTS: Whatever the indicator and the drug studied, differences were observed: from 0.04% to 63% for tacrine, from 0% to 37% for celecoxib and from 6% to 52% for simvastatin, with possible consequences on the effectiveness and safety of the drug concerned. Our results confirm the under-representation of women and elderly patients in premarketing clinical trials, e.g. an M : F ratio of 4.6 in clinical trails of simvastatin vs 1.0 in the joint population. Moreover, the concomitant use of medicines was made extremely restrictive by the protocols of these trials while this was not the case in the postmarketing phase. This has possible consequences on the effectiveness and safety of the drug concerned. CONCLUSIONS: These results plead for systematic ad hoc observational postmarketing studies for any novel and/or expensive medicine to assess the relevance of premarketing data.

Reducing production of type B trichothecenes by Fusarium graminearum on cereals is necessary to control contamination, prevent yield reduction and protect human and animal health. Thus, an understanding of how trichothecene biosynthesis is induced is essential. The effect of ambient pH on fungal growth, toxin biosynthesis and expression of TRI genes was studied during in vitro liquid culture of F. graminearum on minimal medium. Fungal development stopped at day 3 after a sharp pH drop in the medium. At the same time, induction of TRI gene expression was observed and toxin began accumulating 1 day later. Acidification seems a determinant of induction, as neither the toxin nor the TRI genes were detected when the pH was maintained neutral. Shifting from neutral to acidic pH by mycelium transfer induced TRI gene expression and toxin accumulation. The regulation of toxin production by ambient pH appears to be specific to some TRI genes since TRI5, located in the core FgTRI5 cluster, showed an immediate induction while TRI101, located elsewhere in the genome, showed a more progressive response. The regulation of trichothecene biosynthesis by the ambient pH appears to be a general mechanism, independent of strain or chemotype, as all tested strains, including F. graminearum and F. culmorum species, showed a regulation of toxin production in response to the ambient pH. We conclude that, in vitro, external acidification is required for induction of TRI gene expression.

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Skin conditions such as acne, atopic dermatitis, skin toxicity from oncology treatment, and scars are among the most common health conditions and negatively impact quality of life (QoL). Yet the physician perception of this impact often varies greatly from the patient perception. This is important because patient illness perception is closely linked with seeking help and treatment adherence behaviors. The objective of this review is to better understand the impact of these four highly prevalent skin conditions on QoL including their health-related economic factors to improve treatment outcomes. The literature search included literature published on QoL with acne, atopic dermatitis, scars (from any cause) and skin toxicities on PubMed between 2015 and 2020. We found that patients with skin conditions have a much higher frequency of altered QoL and psychological distress than those without. Also, skin conditions negatively impact self-image and can cause feelings of isolation, loneliness, lower self-esteem, and lower body satisfaction. Additionally, physical discomfort adds to the psychological distress. These physical and psychological impacts are an enormous financial burden on patients, their families and society. We found evidence that holistic treatment including treating the skin condition itself, providing wider peer and psychological support as well as shared decision-making, therapeutic patient education and dermatologist involvement improves outcomes. Holistic history-taking, checklists, or the use of more formal QoL scoring tools can be incorporated into routine consultations to better assess patient well-being and provide clinicians with important information for adapting treatment to individual patient requirements. In conclusion, this review highlights the overall impact of skin conditions (including psychological and QoL impacts) and the importance of providing holistic care to optimize treatment outcomes. A comprehensive QoL screening tool would be useful to help provide patient-centered treatment.

Stable aqueous dispersions of fatty acids can now be obtained and yield multiple applications.

OBJECTIVE: To characterize the role of interleukin-1β (IL-1β) and microvascular endothelial cells (MVECs) in the generation of alternatively activated macrophages in the skin, and to explore their role in the development of skin fibrosis in patients with systemic sclerosis (SSc; scleroderma). METHODS: Conditioned medium prepared with MVECs purified from the skin of healthy donors and the skin of SSc patients was used to generate monocyte-derived macrophages. Flow cytometry, multiplex protein assessment, real-time quantitative polymerase chain reaction, and tissue immunofluorescence were used to characterize MVEC-induced polarization of alternatively activated macrophages. Coculture experiments were conducted to assess the role of MVEC-induced alternatively activated macrophages in fibroblast activation. Alternatively activated macrophages were characterized in the skin of healthy donors and SSc patients using multiparametric immunofluorescence and multiplex immunostaining for gene expression. Based on our in vitro data, we defined a supervised macrophage gene signature score to assess correlation between the macrophage score and clinical features in patients with SSc, using the Spearman's test. RESULTS: IL-1β-activated MVECs from SSc patients induced monocytes to differentiate into DC-SIGN+ alternatively activated macrophages producing high levels of CCL18, CCL2, and CXCL8 but low levels of IL-10. DC-SIGN+ alternatively activated macrophages showed significant enhancing effects in promoting the production of proinflammatory fibroblasts and were found to be enriched in perivascular regions of the skin of SSc patients who had a high fibrosis severity score. A novel skin transcriptomic macrophage signature, defined from our in vitro findings, correlated with the extent of skin fibrosis (Spearman's r = 0.6, P = 0.0018) and was associated with early disease manifestations and lung involvement in patients with SSc. CONCLUSION: Our findings shed new light on the vicious circle implicating unabated IL-1β secretion, MVEC activation, and the generation of DC-SIGN+ alternatively activated macrophages in the development of skin fibrosis in patients with SSc.

Decision-making in humans is known to be subject to several biases. For instance, when facing bets, humans demonstrate some asymmetry concerning their preference for the riskiest option depending on whether stakes involve potential gains or potential losses. They are indeed risk-averse for bets involving gains but risk seeking for bets involving losses. They also exhibit a distorted perception of probabilities. It is not clear whether non-human primates exhibit the same biases. Setting up a protocol that allowed two rhesus monkeys to make choices between lotteries involving either gains or losses, we demonstrated that rhesus monkeys facing bets exhibited an asymmetry in the treatment of gains and losses comparable with that of humans.

We aimed to estimate the prevalence of depressive disorder in people living with HIV (PLWH) and evaluate its association with non-HIV-specific and HIV-specific factors in PLWH and in PLWH compared to the general population (GP). We used cross-sectional data from the QuAliV study, conducted within the ANRS-CO3 Aquitaine-AQUIVIH-NA cohort of PLWH in Nouvelle-Aquitaine (2018-2020), and a nationally-representative survey in the GP (EHIS-ESPS, 2014-2015), we included all participants aged ≥ 18 years old who had completed the Patient Health Questionnaire-8 (PHQ-8). Depressive disorder was defined as Patient Health Questionnaire-8 score greater or equal to 10. Its association with non-HIV-specific (demographic, socio-economic, behavioral, health status), HIV-specific factors (immuno-viral markers, antiretrovirals, level of perceived HIV-stigma), and HIV-status was assessed using Poisson regression models with robust variance in women and men separately. We included 914 PLWH (683 men/231 women). More than one in five PLWH had depressive disorder. It was strongly associated with being younger and experiencing severe pain in both sexes. Unemployment in women, being single, and lack of family ties in men were also associated with depressive disorder. More than 30% of our sample reported HIV-stigma, with a dose-response relationship between level of perceived HIV-stigma and depressive disorder. The crude prevalence of depressive disorder was 2.49 (95%CI 1.92-3.22) and 4.20 (95%CI 3.48-5.05) times higher in women and men living with HIV respectively compared to GP counterparts and 1.46 (95%CI 1.09-1.95) and 2.45 (95%CI 1.93-3.09) times higher after adjustment for non-HIV specific factors. The adjusted prevalence ratio of depressive disorder was not significantly different in HIV-stigma free women, but remained twice as high in HIV-stigma free men. The prevalence of depressive disorder compared to the GP tended to decrease with age in PLWH. Excess depressive disorder remains a major concern in PLWH. Our findings reaffirm the importance of regular screening. Tackling social inequalities and HIV-stigma should be prioritized to ensure that PLWH achieve good mental as well as physical health outcomes.

Marine ecosystems are affected by diverse pressures and consequently may undergo significant changes that can be interpreted as regime shifts. In this study we used integrated trend analysis (ITA) that combines multivariate statistics and methodologies to identify abrupt changes in time-series, in order to test a hypothesis about the occurrence of regime shifts in the Portuguese continental shelf ecosystem (PCSE). We used two types of data describing ecosystem drivers (fishing mortality and environmental/climatic indices) and ecosystem state (observed and modelled biomass and ecosystem indices). Modelled biomass and ecosystem indices were outputs of Ecopath with Ecosim temporal model parametrised for PSCE between 1986 and 2017. The analyses indicated that the regime shifts in the PCSE have occurred during three periods in the last three decades: “early regime” until the mid-1990s, followed by “transition regime” in-between and “late regime” since the mid-2010s. The detected regime shifts are characterised by changes in the pelagic community that became more dominant when compared to the demersal community and shifted from sardine, the main fishing resource, abundant in the “early regime”, to other less valuable pelagic fishes such as chub mackerel that dominated the “late regime”. The “early regime” was characterised by high catch, a larger proportion of demersal species, and higher diversity while, the “late regime” was represented by lower catch, an increase in higher trophic level (TL) predatory fish and lower diversity. Moreover, the “late regime” showed lower resilience and reduced maturity when compared to the “early regime”. Changes described in the ecosystem were probably related to (1) the shift in the north Atlantic environmental conditions that affected small pelagic fish (SPF) and lower TLs groups, (2) reduction in fishing pressure, and (3) internal triggers, related to the indirect trophic interactions that might have benefited higher TL fish and impacted the pelagic community. In the context of PCSE management, this study highlighted a need to consider the possibility of regime shifts in the management process. For example, regime specific harvest rates and environmental reference points should be considered when an indication of abrupt change in the ecosystem exists.

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Highly prevalent comorbidities associated with metabolic syndrome, such as abdominal obesity, nonalcoholic fatty liver disease (NAFLD) and insulin-resistance/Type 2 diabetes (IR/T2D) share alterations in gut microbiota composition as a potential triggering factor. Recent studies put the attention in the potential usage of postbiotics (inactivated probiotics) on these metabolic alterations. This review summarizes the current evidence regarding the efficacy of postbiotic administration in both, preclinical and clinical studies, for the management of obesity, NAFLD and IR/T2D. Data from preclinical studies (rodents) suggest that postbiotic administration effectively prevents obesity, whereas clinical studies corroborate these benefits also in overweight/obese subjects receiving inactivated bacteria. As for NAFLD, although preclinical studies indicate that postbiotic administration improves different liver markers, no data obtained in humans have been published so far since all the studies are ongoing clinical trials. Finally, while the administration of inactivated bacteria demonstrated to be a promising approach for the management of IR/T2D in rodents, data from clinical trials indicates that in humans, this approach is more effective on IR than in T2D. In conclusion, the available scientific data indicate that postbiotic administration not only is safer, but also as effective as probiotic administration for the management of obesity associated prevalent metabolic alterations.

PURPOSE: To evaluate the real-world effectiveness of intravitreal ranibizumab 0.5 mg (Lucentis) in improving visual acuity (VA) in adults with decreased VA due to diabetic macular edema (DME). PATIENTS AND METHODS: Real-world prospective observational 24-month study. Ranibizumab-naïve patients (n=116) were enrolled, treated and followed up according to investigators' usual procedures. Outcomes included change from baseline to month 24 in best-corrected VA (BCVA; primary outcome), central retinal thickness (CRT), treatment exposure and safety. RESULTS: Overall, 62.9% of patients completed the study per protocol, 68.6% completed the induction phase (first three injections one month apart). On average, patients had 12.5 ophthalmologist visits and 5.74 injections in year 1, decreasing to 4.6 visits and 1.94 injections in year 2. Mean baseline BCVA was 58.4 letters, mean gain at M24 was +6.08 letters (95% CI: 2.95, 9.21). Gains were higher for patients who completed induction, and for patients who did not switch treatment. Mean CRT improved by 149.17 μm at M24. There were no new safety signals. BCVA variation of ≥6 letters by M3 was predictive of BCVA gains at M24 (p=0.007), as was hypertension medication at baseline (p=0.022). CONCLUSION: Real-world ranibizumab treatment improved VA in DME patients, despite fewer injections than recommended.

OBJECTIVE: The aim of this study was to compare differences in clinical response, drug survival, and adverse event rates between anakinra and canakinumab in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: This multicenter international study includes patients with VEXAS from France, Israel, and Italy treated with interleukin-1 inhibition. Global response (GR) was defined as the absence of inflammatory symptoms and ≥50% decrease in steroid dose and C-reactive protein. Multiple regression analysis was performed to identify associated variables. Drug survival was analyzed using Kaplan-Meier plots and log-rank test, with Cox regression models for associated factors. RESULTS: We included 47 male patients with VEXAS; 44 received anakinra and 9 received canakinumab, with 6 patients using both at different time points. GR at 1 month was 34% for anakinra and 100% for canakinumab (P < 0.001) and 22% and 78% at 3 months, respectively (P = 0.001). Treatment with canakinumab was associated with a higher odds ratio (OR) of achieving GR at 3 months (OR 28.8, 95% confidence interval 3.0-273.9; P = 0.004) in a multivariable analysis. Median drug survival was 54 (interquartile range [IQR] 30-56) months for canakinumab at 300 mg/month compared with 7 (IQR 4-8) months for canakinumab 150 mg/month and 1 (IQR 1-2.5) months for anakinra (P = 0.01). Injection-site reactions were only recorded for the anakinra group (47 vs 0%; P = 0.006), whereas infections were more frequent in the anakinra group (31% and 11%; P = 0.3). CONCLUSION: Canakinumab demonstrated superior clinical response and drug survival with fewer adverse events compared with anakinra. Monthly canakinumab 300 mg may be considered as an effective steroid-sparing therapeutic option for patients with VEXAS.

Raising awareness on marine environmental issues is crucial to deepen students’ knowledge on ocean sustainability. Nonetheless, ocean-related topics have not been adequately addressed through formal education curricula, thus non-formal learning activities were developed to promote Ocean Literacy among students. These include visits to the local fish market and hands-on activities of fish biological sampling. A mixed methodology with closed and open-self questionnaires and interviews, was used to assess the activities’ effect in student’s learning and to evaluate their implementation and importance. Results showed the activities contribution to the increased learning while promoting a more active citizenship regarding ocean conservancy.

INTRODUCTION: Systemic sclerosis (SSc) is a rare autoimmune disease currently classified into two subgroups based on skin extension. The aim of this study was to determine in a large cohort whether the determination of autoantibody (AAb) profile among a full antinuclear AAbs panel including nine specificities had a higher impact than skin phenotype on stratifying the risk of organ involvement and mortality in SSc. METHODS: Data for patients with SSc followed in seven French university hospitals were retrospectively analysed in terms of skin phenotype, AAbs (anti-topoisomerase I (ATA), anticentromere (ACA), anti-RNA polymerase III (anti-RNAPIII), anti-U1RNP, anti-U3RNP, anti-Pm/Scl, anti-Ku, anti-Th/To, anti-NOR90), organ involvement and mortality. Multivariate analyses were performed to identify independent factors associated with organ involvement and mortality. RESULTS: We included 1605 patients with SSc (367 with diffuse cutaneous SSc). On multivariate analysis, ATAs were associated with interstitial lung disease and mortality (OR=3.27 (95% CI 2.42 to 4.42); HR=1.9 (95% CI 1.01 to 3.58)), anti-RNAPIII with scleroderma renal crisis and mortality (OR=7.05 (95% CI 2.98 to 16.72); HR=2.35 (95% CI 1.12 to 4.93)), anti-U1RNP with arthritis (OR=3.79 (95% CI 2.16 to 6.67)), anti-Pm/Scl and anti-Ku with myositis (OR=7.09 (95% CI 3.87 to 12.98) and 7.99 (95% CI 2.41 to 26.46)). The skin phenotype was not associated with survival or organ involvement on multivariate analysis without stepwise selection. CONCLUSION: This study unravels, by contrast with skin phenotype, a strong association between AAbs specificities, organ involvement and outcome in SSc and suggests that patients' classification based on only skin extension is not sufficient for defining prognosis and phenotype.

Understanding food webs environmental condition is a challenging task since evaluations are limited by data on key ecosystem elements, by the availability of indicators that incorporate relevant guilds and by the difficulty in establishing cause-effect relations between pressures and health status, as multiple overlapping pressures can affect taxonomic elements differently. The present work aims to investigate food webs assessment under the Marine Strategy Framework Directive (MSFD), revealing gaps and future research needs in the North Eastern Atlantic. To understand reporting patterns, information on the criteria employed and the resulting assessment trends of Descriptor 4—Food webs were surveyed from the MSFD reports. A multivariate analysis was applied to food webs assessment status and spatially overlapping anthropogenic pressures to understand if the assessment was detecting pressures, considering fish elements. Results revealed that reporting strategies varied between Member States. High reporting effort was exhibited by the United Kingdom in opposition to Ireland or France. Reporting of other groups other than fish and plankton was limited to the United Kingdom due to the availability of monitoring programs and data. The analysis applied to criteria considering fish elements reinforced that reporting strategies and trends differed between countries, although some similarities were found for the Bay of Biscay and Iberian coast and the Celtic Seas. Food webs assessment trends for fish were variable in Spain and were stable or increased in Portugal and the United Kingdom. Anthropogenic drivers significantly influencing food web trends for fish elements were fishing, and climate anomalies in the southern Bay of Biscay and Iberian coast, while eutrophication and chemical contamination had effects on trends in the Celtic Sea and the North Sea. Results allowed to establish a relation between anthropogenic effects and food web patterns, however, these were limited since food webs assessment is incongruent in terms of criteria used and data is still limited at relevant scales. This study reinforced the necessity to increase Member States harmonization and calibration to improve our understanding of food webs environmental status.

A dedicated mission to investigate exoplanetary atmospheres represents a major milestone in our quest to understand our place in the universe by placing our Solar System in context and by addressing the suitability of planets for the presence of life. EChO -the Exoplanet Characterisation Observatory- is a mission concept specifically geared for this purpose. EChO will provide simultaneous, multi-wavelength spectroscopic observations on a stable platform that will allow very long exposures. EChO will build on observations by Hubble, Spitzer and groundbased telescopes, which discovered the first molecules and atoms in exoplanetary atmospheres. EChO will simultaneously observe a broad enough spectral region -from the visible to the mid-IR- to constrain from one single spectrum the temperature structure of the atmosphere and the abundances of the major molecular species. The spectral range and resolution are tailored to separate bands belonging to up to 30 molecules to retrieve the composition and temperature structure of planetary atmospheres. The target list for EChO includes planets ranging from Jupiter-sized with equilibrium temperatures Teq up to 2000 K, to those of a few Earth masses, with Teq ~300 K. We have baselined a dispersive spectrograph design covering continuously the 0.4-16 micron spectral range in 6 channels (1 in the VIS, 5 in the IR), which allows the spectral resolution to be adapted from several tens to several hundreds, depending on the target brightness. The instrument will be mounted behind a 1.5 m class telescope, passively cooled to 50 K, with the instrument structure and optics passively cooled to ~45 K. EChO will be placed in a grand halo orbit around L2. We have also undertaken a first-order cost and development plan analysis and find that EChO is easily compatible with the ESA M-class mission framework.

Abstract Several micro-founded macroeconomic models with rational expectations address the issue of money emergence, by characterizing it as a coordination game. These models have in common the use of agents who dispose of perfect or near-perfect information on the global state of the economy and who display full-fledged computational abilities. Several experimental studies have shown that a simple trial-and-error learning process could constitute an explanation for how agents coordinate on a single mean of exchange. However, these studies provide subjects with full information regarding the state of the economy while restricting the number of goods in circulation to three. In this study, by the mean of multi-agent simulations and human experiments, we test the hypothesis according to which coordination over a unique medium of exchange is possible in the context of information scarcity. In our experimental design, subjects and artificial agents are only aware of the outcome of their own decisions. We provide results for economies with 3 and 4 goods to evaluate to which extent it is possible to generalize results obtained with 3 goods to $$n$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>n</mml:mi></mml:math> goods. Our findings show that in an economy à la Iwai, commodity money can emerge under drastic information restrictions with three goods in circulation, but generalization to four or more goods is not guaranteed.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common treatable disease often diagnosed in patients with risk factors after a prolonged period with suggestive symptoms. Our qualitative study aimed to identify barriers to establishing diagnosis in the natural history of this condition. METHODS: An inductive thematic analysis was performed on structured interviews with patients, general practitioners (GPs) and pulmonologists in France. Inclusion depended on criteria to generate two purposive samples (patients and physicians). Recruitment occurred online. Data collection proceeded until 15 patients and 15 physicians (eight pulmonologists, seven GPs) were interviewed. Data saturation was checked and achieved. The interviews were transcribed and coded in NVivo and triangulated between two researchers. The article respects the consolidated criteria for reporting qualitative research guidelines. RESULTS: Three phases in the patients' clinical pathway to diagnosis and 12 barriers were found: Phase 1 (symptoms before consultation; n=4), lack of COPD knowledge, symptom denial, fear of lung cancer, and delayed general practice consultations; Phase 2 (primary care; n=3), letting bronchitis become chronic, priority to diseases with similar symptoms and/or more serious diseases, lack of COPD screening devices, time and curative treatments; Phase 3 (specialised medicine; n=5), treatment before diagnosis, late referral to pulmonologists, difficulty in accessing specialists and examination results, patient's reluctance to undergo further examinations, and need for additional tests to confirm a diagnosis. CONCLUSION: People unaware of their COPD condition can encounter up to 12 barriers, which may combine before obtaining a formal diagnosis. Patients, GPs, pulmonologists and the state health authorities share responsibility for addressing these barriers and enhancing the care pathway.

BACKGROUND: Alteration in metabolic activities is a critical step in cancer progression. Myriad metabolic-based therapy options are increasingly being proposed for human tumours. However, emerging evidence highlights interpatient metabolic heterogeneity and underscores the importance of metabolic phenotyping in cancer treatment. OBJECTIVES: To investigate metabolic heterogeneity in cutaneous squamous cell carcinoma (cSCC) and its impact on cSCC characteristics and treatment responses. METHODS: We applied combined proteomic and bioenergetic analyses to patient samples representing various stages of cSCC, ranging from precancerous actinic keratosis to metastatic cSCC. To investigate the functional impacts of the identified metabolic heterogeneities on tumour characteristics and treatment responses, we used patient-derived tumour cell (PDC) and patient-derived xenograft (PDX) models by transplanting tumour cells and freshly resected patient tumours into immunocompromised mice. RESULTS: Three subgroups with low, medium and high metabolic scores, respectively, were identified across all stages of carcinogenesis. Functional analyses indicated that, in both models (PDC and PDX), the sensitivities of tumours to leflunomide, an inhibitor of dihydroorotate dehydrogenase (DHODH), were inversely correlated with their metabolic scores and directly correlated with DHODH protein expression level. Moreover, DHODH overexpression in nonresponding groups rendered them sensitive to leflunomide. CONCLUSIONS: The findings demonstrate the relevance of metabolic profiling and scoring in the design of therapeutic approaches targeting the bioenergetic vulnerabilities of tumours and suggest DHODH as a promising therapeutic target in the low metabolic score subgroup of cSCC.