Université Paris Cité

There is limited data regarding the rare and aggressive colorectal neuroendocrine carcinoma (CR-NEC). In this large prospective study, molecular-clinical characteristics and treatment outcomes following palliative chemotherapy are reported for 163 metastatic CR-NEC patients, with a comparison to a population-based prospective cohort of 263 metastatic colorectal adenocarcinoma (CR-AC) patients. Eighty-three percent of CR-NEC received first-line platinum-etoposide, while 98% of CR-AC patients received first-line fluorouracil-based chemotherapy. Disease control rate across all first-line regimens in CR-NEC and CR-AC was 43% vs. 74%, immediate progressive disease 46% vs. 15%, progression-free survival 2.4 months (m) (95% CI 2.1-3.3) vs. 7.7 m (95% CI 6.9-8.5), and overall survival 6.7 m (95% CI 5.6-8.8) vs. 16.8 m (95% CI 13.7-20.3), all, p < .001. CR-NEC more often had synchronous metastases, worse performance status, and symptom burden at treatment initiation than CR-AC (all, p < .001). Two-year survival was 9% vs. 37% in CR-NEC and CR-AC (p < .001). BRAF mutations were frequent in CR-NEC and CR-AC (26% vs. 20%, p = .153) and associated with shorter OS in CR-NEC and CR-AC (p = .025 and p = .003). KRAS mutations were less frequent in CR-NEC than CR-AC (34% vs. 45%, p = .041), but only associated with shorter OS in rectal NEC (p = .04). The frequencies of APC and TP53 mutations were similar between the cohorts and did not impact survival. Metastatic CR-NEC and CR-AC are clinically distinct, with NEC demonstrating more aggressive features, limited treatment effect, and worse prognosis. Although they share important driver mutations, the underlying reason for their marked clinical differences remains unclear.

The principles underpinning Equity, Diversity and Inclusivity (EDI) are seen by many as being essential in contemporary society while others consider it disparaging and claim it can negatively affect meritocracy. In the USA, EDI is referred to as DEI (Diversity, Equity and Inclusivity) and appears to be under attack by the present governmental agencies. Indeed, multinational companies and other governments are responding in various ways, including partial compliance and outright resistance. Wherever one stands politically on the matter, the International Federation of Anatomical Associations (IFAA) has promulgated a strong statement of intent concerning the importance of EDI and the IFAA Executive, through its Federative International Committee for Equality and Diversity in Anatomy (FICEDA), has also provided guidelines for EDI based on the results of a survey of the IFAA's member associations. The findings of that survey are presented in this article and show a clear recognition by virtually all member associations of the importance of EDI, while highlighting some areas lacking diversity and inclusivity.

Erythropoietin (EPO) is a glycoprotein hormone primarily known for its central role in red blood cell production, but it is now also recognized for its immunomodulatory effects on a range of immune effectors. Several studies indicate that EPO helps regulate intestinal barrier integrity, although its effect on intraepithelial lymphocytes (IELs) is still unknown. Using multiparameter flow cytometry and both conventional and unsupervised analyses, we conducted an in-depth phenotypic assessment of IELs from the murine duodenum, jejunum, ileum and colon. Our results revealed that in EPO-treated C57BL/6 mice, the absolute IEL count in the colonic epithelium was more than twice that observed in control mice without changes in the frequencies of the various subpopulations, indicating a global increase. This was accompanied by integrin α4β7 overexpression. Furthermore, EPO treatment alters the intestinal microbiota, increasing bacterial load while reducing diversity, with a notable decrease in Muribaculaceae, a taxon involved in microbial cross-feeding. This alteration may contribute to epithelial imbalance and indirectly to the observed increase in IEL density. Importantly, EPO treatment did not trigger colonic mucosal inflammation, although the affected IELs show a microbiota-dependent decrease in CD8αα expression (known to downregulate IEL activity). The present study is the first to provide a phenotypic mapping of IEL populations in the digestive tract of C57BL/6 mice and highlighted a novel regulatory role of EPO on colonic IELs. These results raise important questions about the impact of exogenous EPO supplementation and endogenous EPO fluctuations on intestinal immune responses - particularly in the context of inflammatory diseases.

International audience

Convergent thinking, the ability to find a single optimal solution to a well-defined problem, is considered a core component of creativity, and is often assumed to rely on controlled, deliberative processes. We tested this assumption using the Compound Remote Associates (CRA) test, where participants have to find a word that connects three seemingly unrelated words (e.g., "river, note, account"; solution: "bank"). We implemented a two-response paradigm wherein participants provided an initial, intuitive response (under cognitive load and time constraints to minimize deliberation), followed by a final, deliberate response. Our findings reveal that, in most cases, extended deliberation was not necessary for sound thinking-correct final responses were typically preceded by accurate intuitive responses produced under time pressure and cognitive load. By using large language models and semantic network modeling, we found that items with a smaller semantic search space are better solved intuitively, and that participants with a more efficient and flexible semantic memory structure display higher intuitive performance on the CRA. These results suggest that effective problem-solving in creative tasks may often rely on fast, automatic associative processes within semantic memory, without necessarily requiring extended deliberation.

Observations of Titan were performed on the 4 November 2022 with the Near Infra- Red Spectrometer (NIRSpec) onboard the James Webb Space Telescope (JWST). The observation is a spectro-image of Titan taken about two and a half years before the northern autumnal equinox. This spectro-image at low phase angle covers a spectral range between 0.95 to 5 . 27 μ m and has a spectral resolving power R= λ / Δ λ =2700. Titan was resolved with about eight pixels across the disk, corresponding to a spatial resolution of 643 km at the centre of Titan. However, the data was resampled to obtain a final spectro-image with thirty pixels across the disk. In this study, we retrieved the distribution of the photochemical haze (above 80 km) and the condensate mist layer (below 80 km) as a function of latitude and altitude. Due to the high NIRSpec spectral resolution, we can distinguish five mist sublayers. We found a haze distribution with extinctions increasing from the north to the south, consistent with the direction of stratospheric meridional winds. The distribution of the mist layer depends on both the circulation and the thermodynamic conditions relating to cloud formation. We found an upper mist layer, above 40 km, having a latitudinal distribution similar to the haze with an increase from north to south. The lower mist, below 40 km, has a minimum around 10 ° N and increases toward the north and the south. The retrieved mist layer also presents a significant increase in extinction that emerges from the background at an altitude of around 50 to 60 km in the southern hemisphere. Finally, we retrieved the surface reflectivity that varies with latitude but is always spectrally consistent with the reflectivity of water ice grains with radius 100 μ m . These results yield important constraints for climate models and, in return, climate models such as the Titan Planetary Climate Model (PCM) will help to fully understand the meaning of our results.

Chronic hepatitis B (CHB) affects an estimated 254 million people globally. Historically, WHO and professional society guidelines have recommended treatment for individuals at high risk of disease progression, including those with hepatitis B virus (HBV) DNA concentrations >20 000 IU/mL. Whether individuals at lower risk, including those with HBV DNA <20 000 IU/mL and normal alanine aminotransferase concentrations, benefit from treatment remains uncertain. To inform 2024 WHO guidelines and the potential expansion of treatment threshold recommendations, we conducted two linked systematic reviews and meta-analyses; this analysis examines the incidence of clinical outcomes in untreated adults with non-cirrhotic CHB stratified by baseline HBV DNA and ALT concentrations. In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, and the Cochrane Library for longitudinal prospective and retrospective cohort studies, randomised controlled trials, and non-randomised studies of interventions, published in any language, from Jan 1, 2000, to Feb 6, 2023. We also reviewed the reference lists of included studies and systematic reviews and consulted networks of experts to identify other data sources. Included studies followed up adults (≥18 years) with non-cirrhotic CHB who had no history of antiviral therapy at enrolment, had baseline HBV DNA quantification and ALT measurement, had a follow-up period of at least 48 weeks, and assessed one or more of six key clinical outcomes (hepatocellular carcinoma, cirrhosis, liver-related mortality, all-cause mortality, liver decompensation, and indication for liver transplantation) or six additional outcomes (advanced liver fibrosis, progression of liver fibrosis, becoming eligible for antiviral treatment, hepatitis flare, and HBsAg and HBeAg seroclearance). Outcomes were required to be stratified by HBV DNA concentrations (<200 IU/mL, <2000 IU/mL, 2000-19 999 IU/mL, 20 000-199 999 IU/mL, and ≥200 000 IU/mL) or ALT concentrations (less than the upper limit of normal [ULN], 1·0-1·9 × ULN, and ≥2·0 × ULN). We excluded studies that focused solely on individuals who were pregnant; were co-infected with HIV, hepatitis C virus, or hepatitis D virus; or had another underlying condition other than CHB. We extracted aggregate data and used random-effects meta-analysis to pool incidence rates per 100 person-years. This study was registered with PROSPERO (CRD42023431652). Of 13 231 studies screened, 71 met the inclusion criteria. A concentration-response relationship was observed between single baseline HBV DNA measurements and hepatocellular carcinoma incidence rates per 100 person-years: 0·131 (95% CI 0·097 to 0·177, I2=0%) for HBV DNA concentrations <200 IU/mL, 0·176 (0·117-0·266, I2=88%) for <2000 IU/mL, 0·311 (0·245-0·393, I2=13%) for 2000-19 999 IU/mL, 0·862 (0·725-1·026, I2=0%) for 20 000-199 999 IU/mL, and 0·941 (0·668-1·324, I2=58%) for ≥200 000 IU/mL (p<0·0001 for between-group difference). Similar concentration-response patterns were observed for development of cirrhosis (0·298 [95% CI 0·214-0·415], two studies, for <200 IU/mL; 0·300 [0·146-0·616], I2=88%, for <2000 IU/mL; 0·712 [0·624-0·814], I2=46%, for 2000-19 999 IU/mL; 1·436 [0·991-2·082], I2=76%, for 20 000-199 999 IU/mL; and 2·193 [1·690-2·846], I2=82%, for ≥200 000 IU/mL) and liver-related mortality (0·086 [95% CI 0·054-0·136], one study; 0·083 [0·015-0·451], I2=0%; 0·303 [0·228-0·402], I2=0%; 0·766 [0·591-0·993], one study; and 1·118 [0·951-1·314], two studies), but no concentration-response relationship was observed between a single baseline HBV DNA assessment and all-cause mortality or liver decompensation. Compared with ALT below the ULN, incidence rates of hepatocellular carcinoma, cirrhosis, and liver-related mortality were higher in individuals with baseline ALT concentrations 1·0-1·9 × ULN or ≥2·0 × ULN. A similar pattern was not found for all-cause mortality, and other outcomes were not meta-analysed due to small numbers. Within the HBV DNA strata of <2000 IU/mL, 2000-19 999 IU/mL, and ≥200 000 IU/mL, hepatocellular carcinoma incidence rates were 2-3 times higher in individuals with ALT 1·0-1·9 × ULN than in those with ALT concentrations less than the ULN. Individuals with persistently low HBV DNA concentrations (<2000 IU/mL) or persistently normal ALT concentrations across multiple assessments had slightly lower hepatocellular carcinoma incidence rates compared with those assessed by a single measurement. Our risk of bias assessment found 15 (21%) of 71 studies to be rated as good quality, 40 (56%) as fair quality, and 16 (23%) as poor quality. These findings, alongside the linked systematic review and meta-analysis of antiviral treatment efficacy, supported the 2024 WHO guidelines expansion of treatment criteria to include individuals with HBV DNA concentrations >2000 IU/mL and ALT concentrations above the ULN. For those with HBV DNA concentrations <2000 IU/mL and persistently normal ALT concentrations, treatment can be deferred. WHO.