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Gain and Loss of FLT3 Mutations in Patients with Acute Myeloid Leukemia: A Noninterventional Cohort Study (CLEVO)
Get PDFINTRODUCTION: FMS-like tyrosine kinase 3 (FLT3) mutations show variable detectability in relapse/refractory acute myeloid leukemia (AML) with unclear clonal evolution dynamics. METHODS: This prospective noninterventional study examined clonal evolution and outcomes from AML diagnosis to relapse/refractory disease occurrences. RESULTS: Of 650 patients included, 172 were FLT3-positive (FLT3pos) and 472 were FLT3-negative (FLT3neg; 99.1% testing rate; unknown FLT3 status, six patients). At first occurrence, the FLT3 testing rate decreased (57.0% [166/291]). Among tested patients, 45 had FLT3pos and 121 had FLT3neg AML. A gain or loss of mutations was seen in 15.6% (7/45) of patients with FLT3pos AML and 14.9% (18/121) of patients with FLT3neg AML. Median (95% confidence interval [CI]) overall survival was 22.8 (19.6, not estimable [NE]) months across patients (FLT3pos, NE;FLT3neg, 20.3 [15.2-23.7] months; hazard ratio [HR] [95% CI] 0.6 [0.5-0.8]). Median (95% CI) disease-free survival across patients was NE (26.3-NE) (FLT3pos, NE;FLT3neg, NE; HR [95% CI] 0.8 [0.6-1.1]). Median event-free survival (95% CI) was 11.8 (10.0-15.5) months in all patients (FLT3pos, 17.2 [11.0-NE] months;FLT3neg, 10.4 [8.4-13.2] months; HR [95% CI] 0.8 [0.6-1.0]). CONCLUSIONS: Dynamic changes in FLT3 mutation status were observed during these patients' disease course. FLT3pos status at baseline, but not at first occurrence, was associated with improved outcomes; other confounders should be considered. Timelier FLT3 mutation retesting may aid in personalizing treatment. Graphical abstract available for this article
Salience and sovereignty: the politics of taxing big tech in France and the United Kingdom
Get PDFWhat explains the passing of corporation tax reforms targeting tech multinationals in France and the United Kingdom at multiple levels? Focusing on policy developments in France and the United Kingdom from the second half of the 2010s to the signing of the OECD/G20 international tax agreement in October 2021, this research investigates the passing of five domestic unilateral reforms – France’s so-called ‘Google Tax’ and Digital Services Tax, the UK’s Diverted Profits Tax and Digital Services Tax, and the EU’s Digital Services Tax - and of two rounds of internationally coordinated tax reforms. The coexistence of these varied reform types within a short timeframe presents a puzzling case of public policy, in which governments pursued overlapping strategies to tax multinationals. It raises important questions about the drivers and constraints of tax policymaking in an era of digitalisation and economic globalisation. Drawing on qualitative process-tracing methodology, the research combines extensive elite interviews with documentary evidence and media coverage analysis to trace the causal mechanisms behind policy change. Through detailed case-studies of France, the UK, and OECD-led international negotiations, it shows how political salience created windows of opportunity for reform, while national economic interests shaped the scope and sustainability of policy change. The dissertation proposes a hybrid theoretical framework that integrates agenda-setting theories with interest-based models from comparative political economy. It suggests that political salience – raised and sustained by political entrepreneurs and media coverage – served as the primary catalyst for reform, transforming corporate tax policy from a technocratic matter into a politically urgent issue. It stresses the role of political intermediaries in the development and influence of political salience over public policy. The research challenges conventional explanations centered on partisanship and technocratic leadership, showing that these factors were secondary to the role of political salience in driving reform. It repositions international tax reform as a politically contingent – responsive to democratic accountability and domestic economic priorities even in complex, globally coordinated policy areas. This framework offers broader insights for understanding how states navigate competing pressures in other highly technical and politically salient domains, such as climate taxation, wealth regulation, and digital governance
Investigating the role of salient constructions in promoting generalization and preventing overgeneralization among young EFL learners: an artificial grammar learning study
Get PDFThis study explores the impact of +VLPR salient constructions — constructions containing verbs with lexically profiled roles — on the generalization and prevention of overgeneralization in children learning English as a Foreign Language (EFL). Through a controlled experiment employing an artificial grammar learning (AGL) design, the research compared the performance of children exposed to +VLPR salient constructions with those exposed to constructions containing verbs without lexically profiled roles (-VLPR). The results indicate that children exposed to +VLPR salient constructions demonstrated superior ability in generalizing novel constructions, as evidenced by higher production task scores. However, the study did not find conclusive evidence that +VLPR salient constructions reduce overgeneralization, partly due to a ceiling effect observed in the comprehension tasks. These findings underscore the importance of salience in language instruction, particularly in EFL contexts, and suggest that +VLPR salient constructions can enhance language learning by making grammatical structures more accessible and generalizable for young learners. Future research should address the limitations of sample size and explore strategies to mitigate ceiling effects to further understand the role of +VLPR salient constructions in language acquisition
Rapid Restoration of Circulating Vitamin B12 Levels by Using Oral Sucrosomial ® Vitamin B12 in Metformin-Associated B12 Deficiency: Results from a Double-Blind, Placebo-Controlled Randomized Clinical Trial
Get PDFBackground/Objectives: Vitamin B12 deficiency is common in individuals with type 2 diabetes mellitus (T2DM) receiving long-term metformin therapy, primarily due to impaired intestinal absorption. Conventional oral B12 supplementation is often associated with delayed or inconsistent biochemical correction. A lipid-based Sucrosomial® delivery system has been shown to improve circulatory vitamin B12 levels in healthy adults with deficiency, and the present study evaluates its performance in the clinically challenging context of metformin-treated individuals with T2DM, a population characterized by pharmacologically impaired intestinal vitamin B12 absorption. Methods: This multicentre, double-blind, placebo-controlled, parallel-group randomized clinical trial evaluated the efficacy, safety, and tolerability of a Sucrosomial® vitamin B12 formulation in adults with T2DM receiving metformin and presenting with vitamin B12 deficiency. Participants were randomized (1:1) to receive oral Sucrosomial® vitamin B12 (1000 µg daily; n = 25) or placebo (n = 25) for three weeks. Serum total vitamin B12 and holotranscobalamin (HoloTC), the biologically active fraction of vitamin B12, were assessed at baseline and during follow-up, with time-to-normalization and safety analyses performed. Results: Sucrosomial® vitamin B12 supplementation resulted in rapid and sustained increases in circulating vitamin B12 levels, with early separation from placebo, and a substantially higher proportion of participants achieved normalization of serum vitamin B12 concentrations within the three-week period. Parallel improvements in HoloTC levels indicated enhanced biologically active vitamin B12 availability, and the intervention was well tolerated with no clinically relevant safety concerns. Conclusions: These findings demonstrate that an oral Sucrosomial® vitamin B12 formulation can achieve rapid and reliable biochemical repletion of both total and biologically active vitamin B12 in metformin-treated adults with T2DM, despite pharmacologically impaired intestinal absorption, while maintaining a favourable safety and tolerability profile
Bonds or credits? Risk management and sovereign lending in the Euromarkets: evidence from Mexico, 1973-1982
Get PDFThis paper examines sovereign lending to Mexico in the Euromarkets during the decade preceding the 1982 international debt crisis, focusing on the interaction between syndicated bank credits and international bonds. While existing scholarship has largely treated Eurocredit and Eurobond markets as separate channels of sovereign finance, this article shows that, in Mexico’s case, they were closely intertwined and jointly shaped by the strategies of international banks. Drawing on original datasets covering all syndicated credits and Eurobond issues to Mexico during this period, complemented by bank-level evidence and archival material from Lloyds Bank International, we demonstrate that leading international banks arbitrated between bonds and credits in response to changes in country risk and macro-financial conditions. During periods of heightened distress, banks moved away from direct lending toward bond issuance, expanded syndicates, and reduced individual exposures as part of coordinated risk-management strategies. The analysis also uncovers a hierarchy in international lending in which leading market-making banks shaped access to sovereign finance while reallocating risk across instruments and institutions globally
Non-anomalous non-invertible symmetries in 1+1D from gapped boundaries of SymTFTs
Get PDFWe study the anomalies of non-invertible symmetries in 1+1D QFTs using gapped boundaries of its SymTFT. We establish the explicit relation between Lagrangian algebras which determine gapped boundaries of the SymTFT, and algebras which determine non-anomalous/gaugeable topological line operators in the 1+1D QFT. If the Lagrangian algebras in the SymTFT are known, this provides a method to compute algebras in all fusion categories that share the same SymTFT. We find necessary conditions that a line operator in the SymTFT must satisfy for the corresponding line operator in the 1+1D QFT to be non-anomalous. We use this constraint to show that a non-invertible symmetry admits a 1+1D trivially gapped phase if and only if the SymTFT admits a magnetic Lagrangian algebra. We define a process of transporting non-anomalous line operators between fusion categories which share the same SymTFT and apply this method to the three Haagerup fusion categories
Reduced order modelling of air‐puff test for corneal material characterisation
Get PDFModels of the fluid–structure interaction (FSI) model for the air‐puff test were analysed. Using Abaqus, the air‐puff test is applied to eyes with varying biomechanical parameters, such as material properties, corneal thickness, and radius. A reduced order model of the air puff (a turbulent impinging jet) has been acquired to decrease simulation time from 48 h for the FSI model to approximately 12 min for the finite element analysis (FEA) model alone. To further accelerate simulations and improve model accuracy, Physics‐Informed Neural Networks (PINNs) will be integrated with the reduced‐order model. This hybrid approach will help expand the model to a larger dataset, enhancing intraocular pressure (IOP) estimation accuracy and the corneal material properties algorithm through inverse FEA. Additionally, a neural network (NN) framework with embedded Gaussian‐modulated waveforms is proposed to model the pressure and deformation distributions on the corneal surface as functions of spatial and temporal parameters. By learning the relationship between corneal biomechanical inputs such as corneal central thickness (CCT), intraocular pressure (IOP), and baseline properties ( μ ), and the governing coefficients of pressure and deformation, the network accurately reconstructs the result that matches well with the high‐fidelity CFD data. This approach can quickly capture the distribution of pressure and deformation. It can also provide insights into the distinct spatial and temporal dynamics of pressure and deformation, giving a more comprehensive understanding of fluid–structure interaction phenomena in the air‐puff test
Ventilator weaning and extubation in acute brain injury: challenges and evidence-based approaches
No full textWeaning from invasive mechanical ventilation is a critical phase of intensive care management. While structured protocols, daily readiness assessments, and spontaneous breathing trials (SBTs) improve outcomes in general ICU populations, their application in patients with acute brain injury (ABI) is challenging. In these patients, respiratory mechanics are frequently preserved, whereas impaired consciousness, ineffective airway protective reflexes, and excessive secretions predominantly determine extubation readiness and success. This narrative review reframes Boles’s Six Stages of Weaning within a neurocritical care perspective, incorporating ABIspecific considerations including stabilization and pre-weaning optimization; suspicion that weaning may be possible; readiness assessment; performance of SBTs; extubation decisionmaking; and recognition and management of extubation failure. Across these stages, evidence consistently demonstrates that neurological factors, especially cough strength, swallowing function, ability to follow commands, and level of consciousness, are the main determinants of extubation success in ABI patients. In contrast, traditional respiratory predictors, such as rapid shallow breathing index (RSBI) or maximal inspiratory pressure (MIP)/negative inspiratory force (NIF), show limited discriminatory value in this population. Emerging data suggest that integrated models combining neurological and respiratory variables provide a more accurate framework for extubation decision-making in ABI. By highlighting the limitations of conventional weaning and extubation criteria, this review proposes practical, physiology-driven strategies to guide ventilator liberation in neurocritical care, with the goal of reducing extubation failure and minimizing secondary neurological injury
Synthesis, functionalization, and reactivity of vinyl sulfondiimidamides
No full textAcrylamides are the dominant electrophilic warheads used in bioactive covalent inhibitors. A limitation of acrylamides, and related unsaturated sulfonamides, is the narrow scope to modulate their electrophilicity, and hence reactivity, through simple structural modification. Here, we show that vinyl sulfondiimidamides are effective electrophilic motifs for reaction with both sulfur- and nitrogenbased biologically relevant nucleophiles. We demonstrate that the electrophilicity of these new reagents can be tuned through variation of the imidic N-substituents. Vinyl sulfondiimidamides are prepared via a short sequence that features a Cope elimination as the key alkene-forming step. A broad range of N-substituents can be installed
