Target (United States)

Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)-particularly when TB < 0.6 times the upper limit of normal (× ULN)-is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.

Copper is an essential trace element that is requiredat optimallevels to support physiological functions in the cerebrovascular system.Copper deficiency reduces vascular elasticity, potentially worseningthe ischemic stroke. Epidemiological evidence has linked higher copperintake with reduced stroke risk. This study aimed to investigate Elesclomol(ES) as a vector for delivering copper to the brain in models of ischemicstroke. 64Cu-ES showed excellent serum stability in vitro. PET/CT imaging revealed that 64Cu-ESexhibited longer brain retention compared to 64Cu-ATSM,likely due to its higher lipophilicity. Ex vivo biodistributionresults were consistent with the imaging data. In normal SD rats, 64Cu-ES showed the highest uptake in the cingulate cortex,followed by the striatum, cerebral cortex, hippocampus, thalamus,and pons, with the lowest levels in the cerebellum and amygdala. Inischemic SD rats, there was no significant difference in the 64Cu-ES uptake between the ischemic region and the contralateralside up to 24 h post-administration. These results provide directevidence that ES can facilitate delivery of copper to the brain, supportingits potential as a therapeutic candidate for copper supplementationin ischemic stroke patients.

In chickens and humans, classical class I molecules of the major histocompatibility complex (MHC) can have a hierarchy of correlated properties, including cell surface expression and peptide repertoire. Chicken BF2 alleles that are less well-expressed on the cell surface and bind a very wide range of peptides are expressed by MHC haplotypes that confer protection from a variety of economically-important infectious diseases, while certain human HLA-B alleles that are well-expressed and bind a narrow range of peptides lead to slow progression from HIV infection to AIDS. Understanding the impact of these promiscuous generalists and fastidious specialists is of considerable interest. The promiscuous BF2 molecule from the chicken B21 haplotype, BF2*21:01, binds a wide range of peptides by remodelling the peptide-binding site, allowing co-variation of the anchor residues at peptide positions P2 and Pc-2, and binding of an anchor residue at Pc. By using in vitro refolding assays with peptides and peptide libraries, determining thermostability and crystal structures, and analysing a chicken B21 cell line by immunopeptidomics, we found that BF2*21:01 will accommodate many possible combinations at P2 and Pc-2, as well as several hydrophobic amino acids at Pc. However, marked preferences for particular peptide lengths, particular amino acids at the three anchor residues, combinations of amino acids at P2 and Pc-2, and amino acids at P3 and Pc-3 affecting stability lead to high frequencies of major peptides while still allowing the possibility of presenting a wide peptide repertoire. These simplifying principles may eventually allow predictions of pathogen peptides with stable binding for this iconic promiscuous class I molecule, as well as providing the data for more sophisticated peptide prediction methods.

We reported a 52-year-old man with thymus nonkeratinized squamous carcinoma presenting with acute superior vena cava syndrome (SVCS) who received 177 Lu-FAP-2286 treatment and followed by low-dose chemotherapy. 68 Ga-FAP-2286 PET/CT revealed significantly less intensity of the mediastinal mass comparing to pretherapy scan, as well as significant relief of SVCS. No adverse effects were observed.

ABSTRACT With the rapid advancement of communication technologies, space‐air‐ground integrated networks (SAGIN) have become a pivotal research frontier in current and future communication domains. To tackle critical challenges in SAGIN scenarios, such as excessive task‐related energy consumption and insufficient communication‐computing resources, this paper proposes a three‐tier edge computing architecture integrating satellites, unmanned aerial vehicle (UAV) swarms, and ground systems. Aiming to minimize the system's weighted energy consumption and latency, we investigate the joint optimization of task allocation, user‐UAV association, UAV deployment, and resource allocation between UAVs and low‐earth orbit (LEO) satellites. Formulated as a non‐convex mixed‐integer nonlinear combinatorial optimization problem, this work integrates the branch‐and‐bound method, multi‐start global optimization, and gray wolf optimization (GWO) to develop a suboptimal solution based on block coordinate descent (BCD), which decouples the original problem into three subproblems for independent solving and iterative approximation of the optimal solution. Experimental results show that the proposed algorithm reduces the total system cost by 7.81%, 11.99%, and 45.69% compared with baseline algorithms with random user‐UAV association, random UAV positioning, and random task assignment, respectively, effectively cutting down overall energy consumption and task latency.

Video frame interpolation in ultra-high-definition extreme motion scenes remains highly challenging due to large displacements, nonlinear motion, and occlusions that disrupt spatio-temporal symmetry. To address this issue, this study proposes a frame interpolation method for extreme motion scenes based on dual alignment and region-adaptive interaction from the perspectives of cross-frame localization and adaptive reconstruction. Specifically, we design a two-stage motion information alignment strategy that obtains two types of motion information via optical flow estimation and offset estimation, and it progressively guides reference pixels for accurate long-range cross-frame localization, mitigating structural misalignment caused by limited receptive fields while simultaneously alleviating spatiotemporal asymmetry caused by inconsistent inter-frame motion speed and direction. Based on this, we introduce a region-adaptive interaction module that automatically adapts motion representations for different regions through cross-frame interaction and leverages distinct attention pathways to accurately capture both the global context and local high-frequency motion details. This achieves a dynamic feature fusion tailored to regional characteristics, significantly enhancing the model’s ability to perceive the overall structure and texture details in extreme motion scenarios. In addition, the introduction of a motion compensation module explicitly captures pixel motion relationships by constructing a global correlation matrix that compensates for the positioning errors of the dual alignment module in extreme motion or occlusion areas. The experimental results demonstrate that the proposed method achieves excellent overall performance in ultra-high-definition extreme motion scenes, with a PSNR improvement of 0.05 dB over state-of-the-art methods. In multi-frame interpolation tasks, it achieves an average PSNR gain of 0.31 dB, demonstrating strong cross-scene interpolation capability.

I.K.M. is the Chair of the Centre for Research and Improvement at the Royal College of Anaesthetists (London, UK). The data that support the findings of this study are not openly available, but may be made available for legitimate secondary analyses subject to data sharing policies.