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Despite significant progress in cancer prevention, screening, and treatment, the still limited number of therapeutic options is an obstacle towards increasing the cancer cure rate. In recent years, many efforts were put forth to develop therapeutics that selectively target different components of the oncogenic Wnt/β-catenin signaling pathway. These include small molecule inhibitors, antibodies, and more recently, gene-based approaches. Although some of them showed promising outcomes in clinical trials, the Wnt/β-catenin pathway is still not targeted in routine clinical practice for cancer management. As for most anticancer treatments, a critical limitation to the use of Wnt/β-catenin inhibitors is their therapeutic index, i.e., the difficulty of combining effective anticancer activity with acceptable toxicity. Protecting healthy tissues from the effects of Wnt/β-catenin inhibitors is a major issue due to the vital role of the Wnt/β-catenin signaling pathway in adult tissue homeostasis and regeneration. In this review, we provide an up-to-date summary of clinical trials on Wnt/β-catenin pathway inhibitors, examine their anti-tumor activity and associated adverse events, and explore strategies under development to improve the benefit/risk profile of this therapeutic approach.

This study compares recent CO, NOx, NMVOC, SO2, BC, and OC anthropogenic emissions from several state‐of‐the‐art top‐down estimates to global and regional bottom‐up inventories and projections from five Shared Socioeconomic Pathways (SSPs) in several regions. Results show that top‐down emissions derived in several recent studies exhibit similar uncertainty as bottom‐up inventories in some regions for certain species and even less in the case of Chinese CO emissions. In general, the largest discrepancies are found outside of regions such as the United States, Europe, and Japan where the most accurate and detailed information on emissions is available. In some regions such as China, which has recently undergone dynamical economic growth and changes in air quality regulations, the top‐down estimates better capture recent emission trends than global bottom‐up inventories. These results show the potential of top‐down estimates to complement bottom‐up inventories and to aide in the development of emission scenarios, particularly in regions where global inventories lack the necessary up‐to‐date and accurate information regarding regional activity data and emission factors such as Africa and India. Areas of future work aimed at quantifying and reducing uncertainty are also highlighted. A regional comparison of recent CO and NOx trends in the five SSPs indicate that SSP126, a strong pollution control scenario, best represents the trends from the top‐down and regional bottom‐up inventories in the United States, Europe, and China, while SSP460, a low‐pollution control scenario, lies closest to actual trends in West Africa. This analysis can be useful for air quality forecasting and near‐future pollution control/mitigation policy studies. Key Points Top‐down emissions from several recent studies are within the range of bottom‐up inventories and exhibit a similar level of uncertainty for some regions and species In China, the United States, and Europe emission trends in the last decade from SSP126 match most closely actual trends from bottom‐up and top‐down estimates In Western Africa and India recent emission trends from low pollution control scenarios (SSP460 and SSP370, respectively) match most closely actual trends

•Severe aortic atheroma was an independent risk factor for 2-year MACCE following TAVR.•Severe aortic atheroma was associated with periprocedural ischemic stroke and CV death (≤30 d), and late stroke (>1 y post-TAVR).•Severe aortic atheroma constitutes a major harmful factor associated with periprocedural events and can affect late stroke post-TAVR. Although aorta atheroma morphology is associated with acute outcomes post-transcatheter aortic valve replacement (TAVR), its association with long-term outcomes post-TAVR remains unknown. This study evaluates the impact of severe aortic atheroma on long-term outcomes following TAVR. We enrolled 977 patients who underwent TAVR between February 2010 and May 2019, with available contrast-enhanced computed tomography data. Severe aortic atheroma was defined as protruding atheroma of ≥3mm thickness with protruding components, ulcerated atheroma with ulcer-like intimal disruption, and atheroma of ≥5mm thickness. The primary endpoint was 2-year major adverse cardiac and cerebrovascular event (MACCE), defined as a composite of cardiovascular death, myocardial infarction, ischemic stroke, and heart failure, events classified as periprocedural (≤30 days), early (30 days to 1 year), and late (>1-year post-TAVR). Patients with severe aortic atheroma (n = 274, 28%) had a higher cumulative incidence of 2-year MACCE than those without (40.6% vs 28.9%, log-rank p = 0.0002), which was attributed to increased risks of ischemic stroke (13.8% vs 6.8%, log-rank p = 0.0012) and cardiovascular death (18.6% vs 10.8%, log-rank p = 0.0009). Severe aortic atheroma was an independent risk factors for 2-year MACCE (adjusted hazard ratio [aHR], 1.49, 95% CI 1.16 to 1.90). In the landmark analysis, severe aortic atheroma was independently associated with periprocedural ischemic stroke and cardiovascular death (aHR, 2.12, 95% CI 1.15 to 3.90 and aHR, 3.29, 95% CI 1.70 to 6.37, respectively), and late ischemic stroke (aHR, 3.71, 95% CI 1.35 to 10.2). Patients with severe aortic atheroma have an increased risk of 2-year MACCE post-TAVR.

Background: Vascular closure of the femoral artery during transcatheter aortic valve implantation (TAVI) remains a critical step prone to complications, despite advancements in introducer technology. The traditional technique involves using two ProGlide® suture closure devices (2P), but alternative approaches, such as employing a single ProGlide® device (1P), have emerged. Aims: We sought to evaluate the efficacy and safety of the 1P strategy compared to the standard 2P closure technique during transfemoral TAVI procedures. Methods: A registry-based study was conducted at the University Hospitals of Strasbourg, France, from January 2020 to December 2023. Consecutive patients who underwent TAVI via the transfemoral approach were deemed eligible. Results: The study cohort consisted of 1303 patients, with a mean age of 81.7 years and 47% female. The 1P strategy was used in 733 cases (56.3%), while the 2P technique was employed in 570 patients (43.7%). Hemostasis was achieved in the catheterization laboratory without additional devices in 30.4% of the single-ProGlide® pre-closing cases. Vascular complication rates were similar in both groups, at 11.3% for the 1P technique and 11.4% for the 2P technique (p = 0.964). However, vascular closure device failure was significantly less frequent in the 1P group (1.6%) compared to the 2P group (5.3%). Conclusions: The 1P strategy for pre-closing during TAVI is as effective and safe as the conventional 2P approach. The 1P method offers potential advantages in terms of simplicity and cost-effectiveness.

Background Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. Methods The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. Discussion This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. Trial registration ClinicalTrials.gov NCT02384876 . Registered on March 2015.

The geographic range of plant pests can be modified by the use of glasshouses. Bemisia tabaci, originating from warm to hot climates, has been shown to be a complex of distinct genetic groups with very limited gene flow. The genetic structure of this pest was studied in glasshouses in southern France, a region beyond the northern limit of its open-field development area in Europe. Seven microsatellite loci were scored in 22 populations sampled from various regions over 3 years. Two genetic groups were distinguished using a Bayesian clustering method and were assigned to the so-called biotypes B and Q using the gene sequence of cytochrome oxidase 1 (CO1). All but one population corresponded to biotype Q, even though only biotype B was previously reported. Despite the enclosed environment of glasshouses and their expected isolation due to low outdoor survival during the winter, only limited differentiation among biotype Q glasshouses was observed. A single sample site was notable for a decrease in expected heterozygosity and the mean number of alleles over the years. The lack of spatial genetic structure among biotype Q populations was indicative of a recent colonization event combined with large dispersal at all spatial scales. This migration pattern of biotype Q populations was further supported by additional CO1 sequences, since individuals from France, Asia and America exhibited 100% nucleotide identity. The evolution of genetic diversity observed in glasshouses in France is part of the worldwide invasion of biotype Q, which is discussed in light of human activities.

Bemisia tabaci is a complex of putative species that exhibit a strong geographical pattern. Crossing experiments have revealed various degrees of reproductive isolation between these nascent species, ranging between fertile first‐generation hybrids (F1) and no F1 at all. However, the relevance of these results under natural conditions is generally not known. The worldwide invasion of the putative species Middle East‐Asia Minor 1 (MEAM1) has caused secondary contacts between allopatric species, which in turn provide an opportunity to detect potential hybrids in nature. A total of 346 female B. tabaci were collected in 2003 and 2005 in the North East of Morocco and assigned to MEAM1 (119), Mediterranean (Med) (225) and a new putative species (2) using mitochondrial cytochrome oxidase (mtCOI) gene sequences. MEAM1 and Med individuals were characterized at seven microsatellite loci. MEAM1 and Med were found to be sympatric in 11 of 12 samples (6 fields/year). As previously reported from Spain, MEAM1 frequency decreased over time. The genetic data are consistent with a recent introduction of MEAM1. A Bayesian clustering analysis (Structure) distinguished two groups, which were 100% consistent with the mtCOI groups. From several lines of evidence, two individuals were identified as hybrids. Assignment profiles using NewHybrids and allele composition indicated that they were not F1 hybrids. The results are discussed in relation to the secondary endosymbiont infection status determined on a sample of individuals, and the contrasting outcomes of the reported crossing experiments between MEAM1 and Med. The whitefly Bemisia tabaci – one of the most damaging pests of open field and protected cropping globally – displays a complex of putative species, which can coexist locally. We show here that gene flow between the two most invasive putative species is rare but did exist under natural conditions. The results are discussed in relation to the secondary endosymbiont infection status determined on a sub‐sample of individuals, and the contrasting outcomes of previously reported crossing experiments between these putative species.

B emisia tabaci is a complex of putative species that exhibit a strong geographical pattern. Crossing experiments have revealed various degrees of reproductive isolation between these nascent species, ranging between fertile first‐generation hybrids ( F 1) and no F 1 at all. However, the relevance of these results under natural conditions is generally not known. The worldwide invasion of the putative species M iddle E ast‐ A sia M inor 1 ( MEAM 1) has caused secondary contacts between allopatric species, which in turn provide an opportunity to detect potential hybrids in nature. A total of 346 female B . tabaci were collected in 2003 and 2005 in the N orth E ast of M orocco and assigned to MEAM 1 (119), Mediterranean (Med) (225) and a new putative species (2) using mitochondrial cytochrome oxidase (mt COI ) gene sequences. MEAM 1 and M ed individuals were characterized at seven microsatellite loci. MEAM 1 and M ed were found to be sympatric in 11 of 12 samples (6 fields/year). As previously reported from S pain, MEAM 1 frequency decreased over time. The genetic data are consistent with a recent introduction of MEAM 1. A B ayesian clustering analysis ( Structure ) distinguished two groups, which were 100% consistent with the mt COI groups. From several lines of evidence, two individuals were identified as hybrids. Assignment profiles using NewHybrids and allele composition indicated that they were not F 1 hybrids. The results are discussed in relation to the secondary endosymbiont infection status determined on a sample of individuals, and the contrasting outcomes of the reported crossing experiments between MEAM 1 and M ed.

[fre] Progrès technique, emploi et exclusion du marché du travail. . Cet article étudie l'impact de la croissance sur l'emploi, le chômage et l'exclusion du marché du travail dans un cadre où les chômeurs subissent des pertes de capital humain relativement aux travailleurs employés, de telle sorte que, s'ils dépassent une certaine ancienneté dans le chômage, ils peuvent devenir inemployables. Les interdépendances entre le processus de déclassement des chômeurs et les décisions de créations d'emplois peuvent entraîner l'existence d'équilibres multiples. En outre, l'impact d'une augmentation du taux de croissance sur l'exclusion et l'emploi dépend de la valeur du taux de croissance. Une croissance plus élevée accentue l'exclusion et diminue l'emploi pour des faibles taux de croissance, mais atténue l'exclusion et accroît l'emploi lorsque le taux de croissance est lui-même suffisamment élevé. [eng] Growth, unemployment and poverty. . This paper is devoted to the analysis of the consequences of growth on employment and exclusion from the labor market in a framework in which unemployed workers loss human capital relative to the employed one. In such a framework, long-term unemployed have a too low relative productivity to be hired: They are excluded from labor force. It is shown that this exclusion mechanism can entail multiple equilibria and that economic growth has an ambiguous impact on unemployment and exclusion. A growth rate increase raises the share of excluded individuals and diminishes the employment rate, if the growth rate is sufficiently low, but has opposite effects if the growth rate is high.