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The Pacific Arctic shelf is undergoing significant environmental changes that are expected to impact the functioning of Arctic benthic ecosystem. By utilizing trait-based methods, we can better understand the effects of environmental changes on the functional structure of macrobenthic communities, offering a more detailed interpretation that complements traditional biodiversity assessments based on community structure. Using Biological Trait Analysis (BTA), we investigated shifts in the functional composition of macrobenthic communities across the subarctic to Arctic regions of the Pacific Arctic shelf, examining how these communities are responding to various environmental gradients. The study analyzed data from 14 environmental variables and 355 taxa, using 13 functional traits coded with 51 modalities collected from 78 boxcore stations. Multivariate statistics, including fuzzy correspondence analysis (FCA) and RLQ/fourth-corner combined analysis, were utilized. We find that the northern Bering Sea (NB) and southeastern Chukchi Sea (SEC) shelves exhibit shared functional similarities (e.g., small, chitinous skeletons, gregarious behavior, and low body flexibility) and significant regional differences from other subregions. The analysis revealed that sediment characteristics and sea ice cover influenced macrobenthic trait composition. The ongoing retreat of sea ice is expected to lead to rapid functional shifts in the Pacific Arctic shelves, potentially causing the migration of smaller, deposit-feeding, shorter-lived taxa to the Arctic seas. This could result in structural transformation in Arctic communities characterized by greater longevity, suspension-feeding, and larger size. These findings can inform future polar environmental management and help develop adaptive management strategies.

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Purpose: The goal of the study was to create a nomogram based on clinical risk factors to forecast the rate of locoregional recurrence-free survival (LRFS) in patients with esophageal squamous cell carcinoma (ESCC) who underwent radiotherapy (RT). Methods: In this study, 574 ESCC patients were selected as participants. Following radiotherapy, subjects were divided into training and validation groups at a 7:3 ratio. The nomogram was established in the training group using Cox regression. Performance validation was conducted in the validation group, assessing predictability through the C-index and AUC curve, calibration via the Hosmer-Lemeshow (H-L) test, and evaluating clinical applicability using decision curve analysis (DCA). Results: T stage, N stage, gross tumor volume (GTV) dose, location, maximal wall thickness (MWT) after RT, node size (NS) after RT, Δ computer tomography (CT) value, and chemotherapy were found to be independent risk factors that impacted LRFS by multivariate cox analysis, and the findings could be utilized to create a nomogram and forecast LRFS. the area under the receiver operating characteristic (AUC) curve and C-index show that for training and validation groups, the prediction result of LRFS using nomogram was more accurate than that of TNM. The LRFS in both groups was consistent with the nomogram according to the H-L test. The DCA curve demonstrated that the nomogram had a good prediction effect both in the groups for training and validation. The nomogram was used to assign ESCC patients to three risk levels: low, medium, or high. There were substantial variations in LRFS between risk categories in both the training and validation groups (p<0.001, p=0.003). Conclusions: For ESCC patients who received radiotherapy, the nomogram based on clinical risk factors could reliably predict the LRFS.

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PURPOSE: This study aimed to compare the clinical outcomes and differences in biomechanical characteristics between the femoral neck system (FNS) and cannulated cancellous screws (CCSs) in the treatment of femoral neck fractures. METHODS: This study retrospectively analysed a cohort of 38 registered cases of femoral neck fractures treated surgically with either the FNS (n = 17) or CCSs (n = 21) between January 2020 and December 2023. Indicators such as fluoroscopy frequency, length of hospital stay, and fracture healing time were compared between the two groups. Functional status was evaluated via the Harris hip score (HHS) and visual analogue scale (VAS), whereas prognosis was assessed based on changes in the neck shaft angle and femoral neck shortening. Additionally, six sets of femoral neck fracture models were developed based on Pauwels angles of 30°, 40°, 50°, 60°, 70°, and 80°. Two experimental groups, FNS and CCS, were established, and a joint reaction force of 1800 N was applied to the proximal femur. The displacement, stress, and stiffness of the components of interest in the different models were tested and compared. RESULTS: The distributions of all the baseline characteristics were similar between the two groups (p > 0.05). The FNS group presented significantly shorter fluoroscopy frequency, length of hospital stay, and fracture healing time (p < 0.05). Harris and VAS scores were higher in the FNS group than in the CCS group (p < 0.05). Postoperative changes in the neck shaft angle and femoral neck shortening were significantly lower in the FNS group than in the CCS group (p < 0.05). The results of the finite element analysis indicated that the maximum stress on the femoral head and varus angle were generally lower in the FNS group than in the CCS group and that the maximum displacement of the femoral head and FNS was generally lower in the FNS group than in the CCS group. However, the superiority of FNS over CCS decreased with increasing Pauwels angle. Additionally, the effectiveness of FNS in limiting displacement of the femoral neck upper wall was not as favourable as that of CCS. CONCLUSIONS: The treatment of femoral neck fractures with FNS is superior and contributes to improved hip joint function. Biomechanical research has confirmed its structural stability and advantages in resisting femoral head varus. However, challenges to its fixation efficacy persist, particularly at higher Pauwels angles.

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Background: Prior studies indicate that lactylation regulates various biological mechanisms within cancer. However, lactylation-related genes (LRGs) have been found to have limited value in predicting the prognosis of hepatocellular carcinoma (HCC). The aim of this study was to review HCC LRGs using data from The Cancer Genome Atlas (TCGA). Methods: The RNA sequencing data and related clinical information of patients with HCC patients were collected from the TCGA database. A total of 20 LRGs were selected and bioinformatics analysis was performed. A consistency cluster analysis was conducted to classify the HCC tumors. Using a lactylation-related model of HCC, prognosis, immune cell infiltration, and immunotherapy was evaluated. Results: A total of 4,378 genes were associated with prognosis. Twenty LRGs (i.e., ACIN1, RAN, PPP1CB, ALDOB, SUMO2, THOC2, HDAC1, SF3A1, SF3B1, HNRNPM, PPP1CC, SRRM1, PRPF6, HDAC2, H2AFV, ALYREF, H2AFZ, H2AFX, HNRNPK, and MAGOH) were identified. The 20 LRGs were used to divide TCGA-HCC patients into low-risk (G1) and high-risk (G2) categories. The upregulated genes in the G1 group primarily participate in the p53 signaling pathway, focal adhesion, extracellular matrix (ECM)-receptor interaction, and cell cycle, while the downregulated genes primarily participate in the glycolysis/gluconeogenesis, carbon metabolism, and biosynthesis of amino acids. The box plots showed a significant difference in the immune cell populations, with a higher abundance of B cells, CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and myeloid dendritic cells in the G1 than the G2 HCC samples. Further, the box plots showed higher expression levels of seven of the eight immune checkpoint inhibitor (ICI)-related genes in the G1 HCC samples than the G2 samples. There was a significant disparity in the cancer stem cell (CSC) scores between the G1 and G2 TCGA-HCC patients. Additionally, the G1 TCGA-HCC patients had higher tumor immune dysfunction and exclusion (TIDE) scores than the G2 TCGA-HCC patients. The prognosis of the HCC patients was also predicted using a six-LRG model, comprising HDAC2, SRRM1, SF3B1, HDAC1, THOC2, and PPP1CB. Conclusions: Strong correlation between LRGs and tumor classification as well as immunity in patients with HCC was identified. LRG signatures serve as reliable prognostic markers for HCC.

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The periosteum contains skeletal stem/progenitor cells that contribute to bone fracture healing. However, the in vivo identity of periosteal skeletal stem cells (P-SSCs) remains unclear, and membrane protein markers of P-SSCs that facilitate tissue engineering are needed. Here, we identified integral membrane protein 2A (Itm2a) enriched in SSCs using single-cell transcriptomics. Itm2a+ P-SSCs displayed clonal multipotency and self-renewal and sat at the apex of their differentiation hierarchy. Lineage-tracing experiments showed that Itm2a selectively labeled the periosteum and that Itm2a+ cells were preferentially located in the outer fibrous layer of the periosteum. The Itm2a+ cells rarely expressed CD34 or Osx, but expressed periosteal markers such as Ctsk, CD51, PDGFRA, Sca1, and Gli1. Itm2a+ P-SSCs contributed to osteoblasts, chondrocytes, and marrow stromal cells upon injury. Genetic lineage tracing using dual recombinases showed that Itm2a and Prrx1 lineage cells generated spatially separated subsets of chondrocytes and osteoblasts during fracture healing. Bone morphogenetic protein 2 (Bmp2) deficiency or ablation of Itm2a+ P-SSCs resulted in defects in fracture healing. ITM2A+ P-SSCs were also present in the human periosteum. Thus, our study identified a membrane protein marker that labels P-SSCs, providing an attractive target for drug and cellular therapy for skeletal disorders.

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AIMS: Extended fasting-postprandial switch intermitting time has been shown to affect Alzheimer's disease (AD). Few studies have investigated the cerebral perfusion response to fasting-postprandial metabolic switching (FMS) in AD patients. We aimed to evaluate the cerebral perfusion response to FMS in AD patients. METHODS: In total, 30 AD patients, 32 mild cognitive impairment (MCI) patients, and 30 healthy control individuals (HCs) were included in the quantification of cerebral perfusion via cerebral blood flow (CBF). The cerebral perfusion response to FMS was defined as the difference (ΔCBF) between fasting and postprandial CBF. RESULTS: Patients with AD had a regional negative ΔCBF in the anterior temporal lobe, part of the occipital lobe and the parietal lobe under FMS stimulation, whereas HCs had no significant ΔCBF. The AD patients had lower ΔCBF values in the right anterior temporal lobe than the MCI patients and HCs. ΔCBF in the anterior temporal lobe was negatively correlated with cognitive severity and cognitive reserve factors in AD patients. CONCLUSIONS: AD patients exhibited a poor ability to maintain cerebral perfusion homeostasis under FMS stimulation. The anterior temporal lobe is a distinct area that responds to FMS in AD patients and negatively correlates with cognitive function.

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As a major immune cell type in the tumor microenvironment, tumor-associated macrophages secrete suppressive factors that can inhibit antitumor immunity and promote tumor progression. One approach trying to utilize macrophages for immunotherapy has been to block the CD47-SIRPα axis, which mediates inhibitory signaling, to promote phagocytosis of tumor cells. Many CD47-targeted agents, namely, anti-CD47 antibodies and SIRPα fusion proteins, were associated with a diverse spectrum of toxicities that limit their use in clinical settings. Universal expression of CD47 also leads to a severe "antigen sink" effect of CD47-targeted agents. Given that the CD47 receptor, SIRPα, has a more restricted expression profile and may have CD47-independent functions, targeting SIRPα is considered to have distinct advantages in improving clinical efficacy with a better safety profile. We have developed ES004-B5, a potentially best-in-class pan-allelic human SIRPα-blocking antibody using hybridoma technology. ES004-B5 binds to major human SIRPα variants through a unique epitope with high affinity. By blocking CD47-induced inhibitory "don't-eat-me" signaling, ES004-B5 exerts superior antitumor activity in combination with anti-tumor-associated antigen antibodies in vitro and in vivo. Unlike CD47-targeted agents, ES004-B5 exhibits an excellent safety profile in nonhuman primates. ES004-B5 has potential to be an important backbone for SIRPα-based combination therapy and/or bispecific antibodies, which will likely overcome the limitations of CD47-targeted agents encountered in clinical settings.

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Efficient and precise calculations of thermal transport properties and figures of merit, alongside a deep comprehension of thermal transport mechanisms, are essential for the practical utilization of advanced thermoelectric materials. In this study, we explore the microscopic processes governing thermal transport in the distinguished crystalline material Tl9SbTe6 by integrating a unified thermal transport theory with machine learning-assisted self-consistent phonon calculations. Leveraging machine learning potentials, we expedite the analysis of phonon energy shifts, higher-order scattering mechanisms, and thermal conductivity arising from various contributing factors, such as population and coherence channels. Our finding unveils an exceptionally low thermal conductivity of 0.31 W m-1 K-1 at room temperature, a result that closely correlates with experimental observations. Notably, we observe that the off-diagonal terms of heat flux operators play a significant role in shaping the overall lattice thermal conductivity of Tl9SbTe6, where the ultralow thermal conductivity resembles that of glass due to limited group velocities. Furthermore, we achieve a maximum ZT value of 3.17 in the c-axis orientation for p-type Tl9SbTe6 at 600 K and an optimal ZT value of 2.26 in the a-axis and b-axis direction for n-type Tl9SbTe6 at 500 K. The crystalline Tl9SbTe6 not only showcases remarkable thermal insulation but also demonstrates impressive electrical properties owing to the dual-degeneracy phenomenon within its valence band. These results not only elucidate the underlying reasons for the exceptional thermoelectric performance of Tl9SbTe6 but also suggest potential avenues for further experimental exploration.

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BACKGROUND: Deep learning reconstruction (DLR) with denoising has been reported as potentially improving the image quality of magnetic resonance imaging (MRI). Multi-modal MRI is a critical non-invasive method for tumor detection, surgery planning, and prognosis assessment; however, the DLR on multi-modal glioma imaging has not been assessed. PURPOSE: To assess multi-modal MRI for glioma based on the DLR method. MATERIAL AND METHODS: We assessed multi-modal images of 107 glioma patients (49 preoperative and 58 postoperative). All the images were reconstructed with both DLR and conventional reconstruction methods, encompassing T1-weighted (T1W), contrast-enhanced T1W (CE-T1), T2-weighted (T2W), and T2 fluid-attenuated inversion recovery (T2-FLAIR). The image quality was evaluated using signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and edge sharpness. Visual assessment and diagnostic assessment were performed blindly by neuroradiologists. RESULTS: In contrast with conventionally reconstructed images, (residual) tumor SNR for all modalities and tumor to white/gray matter CNR from DLR images were higher in T1W, T2W, and T2-FLAIR sequences. The visual assessment of DLR images demonstrated the superior visualization of tumor in T2W, edema in T2-FLAIR, enhanced tumor and necrosis part in CE-T1, and fewer artifacts in all modalities. Improved diagnostic efficiency and confidence were observed for preoperative cases with DLR images. CONCLUSION: DLR of multi-modal MRI reconstruction prototype for glioma has demonstrated significant improvements in image quality. Moreover, it increased diagnostic efficiency and confidence of glioma.

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BACKGROUND: Persistent infection with human papillomavirus (HPV) significantly contributes to the development of cervical cancer. Thus, it is urgent to develop rapid and accurate methods for HPV detection. Herein, we present an ultrasensitive CRISPR/Cas12a-based electrochemiluminescent (ECL) imaging technique for the detection of HPV-18 DNA. RESULT: The ECL DNA sensor array is constructed by applying black hole quencher (BHQ) and polymer dots (Pdots) co-labeled hairpin DNA (hpDNA) onto a gold-coated indium tin oxide slide (Au-ITO). The ECL imaging method involves an incubation process of target HPV-18 with a mixture of crRNA and Cas12a to activate Cas12a, followed by an incubation of the active Cas12a with the ECL sensor. This interaction causes the indiscriminate cleavage of BHQ from Pdots by digesting hpDNA on the sensor surface, leading to the restoration of the ECL signal of Pdots. The ECL brightness readout demonstrates superior performance of the ECL imaging technique, with a linear detection range of 10 fM-500 pM and a limit-of-detection (LOD) of 5.3 fM. SIGNIFICANCE: The Cas12a-based ECL imaging approach offers high sensitivity and a broad detection range, making it highly promising for nucleic acid detection applications.

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Amyotrophic lateral sclerosis is a neurodegenerative disorder. Despite extensive studies, it remains challenging to treat ALS. Recent ALS studies have shown dysbiosis (e.g., loss of microbial diversity and beneficial function in the gut microbiota) is correlated with intestinal inflammation and change of intestinal integrity in ALS. The novel concepts and the roles of microbiome and microbial metabolites through the gut-microbiome-neuron axis in ALS pathogenesis have been slowly recognized by the neurology research field. Here, we will discuss the recent progress of microbiome, including bacteria, fungi, and viruses, in the ALS research. We will discuss our understanding of microbial metabolites in ALS. Micronutrition refers to the intake of essential vitamins, minerals, and other micronutrients. We will summarize the literation related to micronutrition and ALS. Furthermore, we will consider the mutual interactions of microbiome and micronutrition in the ALS progression and treatment. We further propose that the mechanistic and translational studies that shift from suspension of disbelief to cogent ingenuity, and from bench study to bed-side application, should allow new strategies of diagnosis and treatment for ALS.

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Deep vein thrombosis (DVT) is a serious health issue that often leads to considerable morbidity and mortality. Diagnosis of DVT in a clinical setting, however, presents considerable challenges. The fusion of metabolomics techniques and machine learning methods has led to high diagnostic and prognostic accuracy for various pathological conditions. This study explored the synergistic potential of dual-platform metabolomics (specifically, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS)) to expand the detection of metabolites and improve the precision of DVT diagnosis. Sixty-one differential metabolites were identified in serum from DVT patients: 22 from GC-MS and 39 from LC-MS. Among these, five key metabolites were highlighted by SHapley Additive exPlanations (SHAP)-guided feature engineering and then used to develop a stacking diagnostic model. Additionally, a user-friendly interface application system was developed to streamline and automate the application of the diagnostic model, enhancing its practicality and accessibility for clinical use. This work showed that the integration of dual-platform metabolomics with a stacking machine learning model enables faster and more accurate diagnosis of DVT in clinical environments.

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Osteogenesis imperfecta (OI) is a disorder of low bone mass and increased fracture risk due to a range of genetic variants that prominently include mutations in genes encoding type I collagen. While it is well known that OI reflects defects in the activity of bone-forming osteoblasts, it is currently unclear whether OI also reflects defects in the many other cell types comprising bone, including defects in skeletal vascular endothelium or the skeletal stem cell populations that give rise to osteoblasts and whether correcting these broader defects could have therapeutic utility. Here, we find that numbers of skeletal stem cells (SSCs) and skeletal arterial endothelial cells (AECs) are augmented in Col1a2oim/oim mice, a well-studied animal model of moderate to severe OI, suggesting that disruption of a vascular SSC niche is a feature of OI pathogenesis. Moreover, crossing Col1a2oim/oim mice to mice lacking a negative regulator of skeletal angiogenesis and bone formation, Schnurri 3 (SHN3), not only corrected the SSC and AEC phenotypes but moreover robustly corrected the bone mass and spontaneous fracture phenotypes. As this finding suggested a strong therapeutic utility of SHN3 inhibition for the treatment of OI, a bone-targeting AAV was used to mediate Shn3 knockdown, rescuing the Col1a2oim/oim phenotype and providing therapeutic proof-of-concept for targeting SHN3 for the treatment of OI. Overall, this work both provides proof-of-concept for inhibition of the SHN3 pathway and more broadly addressing defects in the stem/osteoprogenitor niche as is a strategy to treat OI.

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A circular non-touch mode capacitive pressure sensor can operate in both transverse and normal uniform loading modes, but the elastic behavior of its movable electrode plate is different under the two different loading modes, making its input-output analytical relationships between pressure and capacitance different. This suggests that when such a sensor operates, respectively, in transverse and normal uniform loading modes, the theory of its numerical design and calibration is different, in other words, the theory for the transverse uniform loading mode (available in the literature) cannot be used as the theory for the normal uniform loading mode (not yet available in the literature). In this paper, a circular non-touch mode capacitive pressure sensor operating in normal uniform loading mode is considered. The elastic behavior of the movable electrode plate of the sensor under normal uniform loading is analytically solved with the improved governing equations, and the improved analytical solution obtained can be used to mathematically describe the movable electrode plate with larger elastic deflections, in comparison with the existing two analytical solutions in the literature. This provides a larger technical space for developing the circular non-touch mode capacitive pressure sensors used for measuring the static gas pressure (belonging to normal uniform loading).

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In the age of information explosion, the exponential growth of digital data far exceeds the capacity of current mainstream storage media. DNA is emerging as a promising alternative due to its higher storage density, longer retention time, and lower power consumption. To date, commercially mature DNA synthesis and sequencing technologies allow for writing and reading of information on DNA with customization and convenience at the research level. However, under the disconnected and nonspecialized mode, DNA data storage encounters practical challenges, including susceptibility to errors, long storage latency, resource-intensive requirements, and elevated information security risks. Herein, we introduce a platform named DNA-DISK that seamlessly streamlined DNA synthesis, storage, and sequencing on digital microfluidics coupled with a tabletop device for automated end-to-end information storage. The single-nucleotide enzymatic DNA synthesis with biocapping strategy is utilized, offering an ecofriendly and cost-effective approach for data writing. A DNA encapsulation using thermo-responsive agarose is developed for on-chip solidification, not only eliminating data clutter but also preventing DNA degradation. Pyrosequencing is employed for in situ and accurate data reading. As a proof of concept, DNA-DISK successfully stored and retrieved a musical sheet file (228 bits) with lower write-to-read latency (4.4 min of latency per bit) as well as superior automation compared to other platforms, demonstrating its potential to evolve into a DNA Hard Disk Drive in the future.

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Importance: In several randomized clinical trials, endovascular thrombectomy led to better functional outcomes than conventional treatment at 90 days poststroke in patients with acute basilar artery occlusion. However, the long-term clinical outcomes of these patients have not been well delineated. Objective: To evaluate 1-year clinical outcomes in patients with acute basilar artery occlusion following endovascular thrombectomy vs control. Design, Setting, and Participants: This study is an extension of the ATTENTION trial, a multicenter, randomized clinical trial. Patients were included between February 2021 and January 2022, with 1-year follow-up through April 2023. This multicenter, population-based study was conducted at 36 comprehensive stroke sites. Patients with acute basilar artery occlusion within 12 hours of estimated symptom onset were included. Of the 342 patients randomized in the ATTENTION trial, 330 (96.5%) had 1-year follow-up information available. Exposures: Endovascular thrombectomy (thrombectomy group) vs best medical treatment (control group). Main Outcomes and Measures: The primary outcome was defined as a score of 0 to 3 on the modified Rankin Scale (mRS) at 1 year. Secondary outcomes were functional independence (mRS score 0-2), excellent outcome (mRS score 0-1), level of disability (distribution of all 7 mRS scores), mortality, and health-related quality of life at 1 year. Results: Among 330 patients who had 1-year follow-up data, 227 (68.8%) were male, and the mean (SD) age was 67.0 (10.7) years. An mRS score 0 to 3 at 1 year was achieved by 99 of 222 patients (44.6%) in the thrombectomy group and 21 of 108 (19.4%) in the control group (adjusted rate ratio, 2.23; 95% CI, 1.51-3.29). Mortality at 1 year compared with 90 days was more frequent in both the thrombectomy group (101 of 222 [45.5%] vs 83 of 226 [36.7%]) and the control group (69 of 108 [63.9%] vs 63 of 114 [55.3%]). Excellent outcome (mRS score 0-1) at 1 year compared with 90 days increased in the thrombectomy group (62 of 222 [27.9%] vs 45 of 226 [19.9%]) but not in the control group (9 of 108 [8.3%] vs 9 of 114 [7.9%]) resulting in a magnified treatment benefit. Conclusions and Relevance: Among patients with basilar artery occlusion within 12 hours of onset, the benefits of endovascular thrombectomy at 1 year compared with 90 days were sustained for favorable (mRS score 0-3) outcome and enhanced for excellent (mRS score 0-1) outcome.

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BACKGROUND: Severe heart failure (HF) has a higher mortality during vulnerable period while targeted predictive tools, especially based on drug exposures, to accurately assess its prognoses remain largely unexplored. Therefore, this study aimed to utilize drug information as the main predictor to develop and validate survival models for severe HF patients during this period. METHODS: We extracted severe HF patients from the MIMIC-IV database (as training and internal validation cohorts) as well as from the MIMIC-III database and local hospital (as external validation cohorts). Three algorithms, including Cox proportional hazards model (CoxPH), random survival forest (RSF), and deep learning survival prediction (DeepSurv), were applied to incorporate the parameters (partial hospitalization information and exposure durations of drugs) for constructing survival prediction models. The model performance was assessed mainly using area under the receiver operator characteristic curve (AUC), brier score (BS), and decision curve analysis (DCA). The model interpretability was determined by the permutation importance and Shapley additive explanations values. RESULTS: A total of 11,590 patients were included in this study. Among the 3 models, the CoxPH model ultimately included 10 variables, while RSF and DeepSurv models incorporated 24 variables, respectively. All of the 3 models achieved respectable performance metrics while the DeepSurv model exhibited the highest AUC values and relatively lower BS among these models. The DCA also verified that the DeepSurv model had the best clinical practicality. CONCLUSIONS: The survival prediction tools established in this study can be applied to severe HF patients during vulnerable period by mainly inputting drug treatment duration, thus contributing to optimal clinical decisions prospectively.

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The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.

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Objective: Nontyphoidal Salmonella infection is one of the most common foodborne illnesses, and its oncogenic potential has been documented in animal models. The primary goal of this study was to examine whether individuals who were exposed to enteric Salmonella infection are more likely to develop colorectal cancer (CRC) than the general population through the linkage of 2 statewide public health surveillance databases. Materials and Methods: We designed a 2-stage probabilistic linkage, starting with 17,587 records of enteric salmonellosis reported to Michigan Department of Health and Human Services between 1992 and 2020. These records did not include unique identifiers (such as Social Security number [SSN]). The initial linkage to LexisNexis address history was conducted to obtain information to calculate each person's time in Michigan as well as SSN for the second linkage. The linkage to the state cancer registry was performed to obtain the observed number of CRC cases, while the expected number of CRC cases was calculated according to corresponding state CRC incidence by age, sex, and calendar year. Results: Ninety-three percent of the initially identified salmonellosis records were sent to LexisNexis linkage, which returned address history, death, and SSN for 97% of the records. Further linkage to the statewide cancer registry identified 98 incident CRC cases. Overall, the observed-to-expected (O/E) ratio was not different from unity (0.833; 95% CI, 0.627-1.003). Conclusions: While the new linkage strategy was found effective and should be applicable to other health conditions, we cannot rule out bias due to incomplete or underreporting of the infection in estimating the risk of CRC.

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