Circulating B Cell-Derived Small RNA Delivered by Extracellular Vesicles: A Dialogue Mechanism for Long-Range Targeted Renal Mitochondrial Injury in Obesity.

The intricate processes that govern the interactions between peripatetic immune cells and distal renal injury in obesity are not fully understood. Employing transcriptomic analysis of circulating extracellular vesicles (EVs), a marked amplification of small RNA (miR-3960) is discerned within CD3-CD19+ B cells. This RNA is found to be preferentially augmented in kidney tissues, contrasting with its subdued expression in other organs. By synthesizing dual-luciferase reporter assay with co-immunoprecipitation analysis, it is pinpointed that miR-3960 specifically targets the nuclear gene TRMT5, a pivotal actor in the methylation of mitochondrial tRNA. This liaison instigates aberrations in the post-transcriptional modifications of mitochondrial tRNA, engendering deficiencies within the electron respiratory chain, primarily attributable to the diminution of the mitochondrial bioenergetic compound (NDUFA7) complex I. Such perturbations lead to a compromised mitochondrial respiratory capacity in renal tubular cells, thereby exacerbating tubular injury. In contrast, EV blockade or miR-3960 depletion markedly alleviates renal tubular injury in obesity. This investigation unveils a hitherto unexplored pathway by which obesity-induced circulating immune cells remotely manipulate mitochondrial metabolism in target organs. The strategic targeting of obese EVs or infiltrative immune cells and their specifically secreted RNAs emerges as a promising therapeutic avenue to forestall obesity-related renal afflictions.

Association of preserved ratio impaired spirometry with mortality and cardiovascular diseases: a systematic review and meta-analysis.

BACKGROUND: Preserved ratio impaired spirometry (PRISm) is a type of abnormal lung function. PRISm and mortality have been explored in several studies, but a comprehensive evaluation of the associations is limited. The current study aims to conduct a systematic review and meta-analysis in order to investigate the mortality and cardiovascular diseases in patients with PRISm. METHODS: PubMed, Embase, and Web of Science databases, as well as gray literature sources, were searched for relevant studies published up to 7 September 2023 without language restrictions. This review included all published observational cohort studies that investigated the association of PRISm with mortality in the general population, as well as subgroup analyses in smokers and pre-bronchodilation spirometry studies. The outcomes of interest were all-cause mortality, cardiovascular mortality, and respiratory-related mortality. The Newcastle-Ottawa scale assessed study quality. Sensitivity and subgroup analyses explored heterogeneity and robustness. Publication bias was assessed with Egger's and Begg's tests. RESULTS: Overall, eight studies were included in this meta-analysis. The pooled HR was 1.60 (95% CI, 1.48-1.74) for all-cause mortality, 1.68 (95% CI, 1.46-1.94) for CVD mortality, and 3.09 (95% CI, 1.42-6.71) for respiratory-related mortality in PRISm group compared to normal group. In the subgroup analysis, participants with PRISm had a higher effect (HR, 2.11; 95% CI, 1.74-2.54) on all-cause mortality among smokers relative to participants with normal spirometry. Furthermore, the association between PRISm and mortality risk was consistent across several sensitivity analyses. CONCLUSIONS: People with PRISm were associated with an increased risk of all-cause mortality, CVD mortality, and respiratory-related mortality as compared to those with normal lung function in the general population. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023426872.

Rapid detection and quantification of melamine, urea, sucrose, water, and milk powder adulteration in pasteurized milk using Fourier transform infrared (FTIR) spectroscopy coupled with modern statistical machine learning algorithms.

There is an evident requirement for a rapid, efficient, and simple method to screen the authenticity of milk products in the market. Fourier transform infrared (FTIR) spectroscopy stands out as a promising solution. This work employed FTIR spectroscopy and modern statistical machine learning algorithms for the identification and quantification of pasteurized milk adulteration. Comparative results demonstrate modern statistical machine learning algorithms will improve the ability of FTIR spectroscopy to predict milk adulteration compared to partial least square (PLS). To discern the types of substances utilized in milk adulteration, a top-performing multiclassification model was established using multi-layer perceptron (MLP) algorithm, delivering an impressive prediction accuracy of 97.4 %. For quantification purposes, bayesian regularized neural networks (BRNN) provided the best results for the determination of both melamine, urea and milk powder adulteration, while extreme gradient boosting (XGB) and projection pursuit regression (PPR) gave better results in predicting sucrose and water adulteration levels, respectively. The regression models provided suitable predictive accuracy with the ratio of performance to deviation (RPD) values higher than 3. The proposed methodology proved to be a cost-effective and fast tool for screening the authenticity of pasteurized milk in the market.

TULIPs decorate the three-dimensional genome of PFA ependymoma.

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

An Improved U-Net Infrared Small Target Detection Algorithm Based on Multi-Scale Feature Decomposition and Fusion and Attention Mechanism.

Infrared small target detection technology plays a crucial role in various fields such as military reconnaissance, power patrol, medical diagnosis, and security. The advancement of deep learning has led to the success of convolutional neural networks in target segmentation. However, due to challenges like small target scales, weak signals, and strong background interference in infrared images, convolutional neural networks often face issues like leakage and misdetection in small target segmentation tasks. To address this, an enhanced U-Net method called MST-UNet is proposed, the method combines multi-scale feature decomposition and fusion and attention mechanisms. The method involves using Haar wavelet transform instead of maximum pooling for downsampling in the encoder to minimize feature loss and enhance feature utilization. Additionally, a multi-scale residual unit is introduced to extract contextual information at different scales, improving sensory field and feature expression. The inclusion of a triple attention mechanism in the encoder structure further enhances multidimensional information utilization and feature recovery by the decoder. Experimental analysis on the NUDT-SIRST dataset demonstrates that the proposed method significantly improves target contour accuracy and segmentation precision, achieving IoU and nIoU values of 80.09% and 80.19%, respectively.

Detection strip of anti-NGAL antibody coupled with fluorescent microspheres-A novel tool for reliable and accurate prediction of renal injury.

OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) has been identified by the International Nephrology Association (INA) as a promising biomarker for the early evaluation of renal injury. This study aimed to develop and evaluate NGAL test strips as a rapid, simple, and economical method for the early diagnosis of acute kidney injury (AKI). METHODS: Recombinant prokaryotic expression vectors, purified NGAL protein, and anti-NGAL monoclonal antibodies were prepared. NGAL test strips were developed, and serum samples were collected from healthy individuals and patients with early-stage kidney injury at the Third Affiliated Hospital of Sun Yat-sen University between January 2023 and May 2024. Samples were tested using both the self-made strips and commercially available reagents. RESULTS: The NGAL test strip comprised a conjugate pad containing 0.2 µL of fluorescent microspheres conjugated with anti-NGAL monoclonal antibody (McAb7#), a test line containing 1 mg/mL of a different anti-NGAL monoclonal antibody (McAb3#), and a control line containing 0.5 mg/mL of goat anti-mouse IgG. The test utilized 60 µL of sample (30 µL serum diluted with 30 µL of sample diluent) and was completed within 15 min at 25 °C and 35 %-85 % relative humidity. The developed strip accurately detected NGAL, demonstrating good linearity within the range of 0-160 ng/mL (R2 = 0.9943). The sensitivity and specificity of the NGAL strip for AKI diagnosis were 86.1 % and 78.8 %, respectively, comparable to the performance of commercially available testing reagents. CONCLUSION: The developed test strip, utilizing anti-NGAL antibodies coupled with fluorescent microspheres, effectively detected trace amounts of NGAL protein in serum samples.

Neuroimmune modulating and energy supporting nanozyme-mimic scaffold synergistically promotes axon regeneration after spinal cord injury.

Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.

Targeting CD73 limits tumor progression and enhances anti-tumor activity of anti-PD-1 therapy in intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Patients with intrahepatic cholangiocarcinoma (iCCA) respond poorly to immune checkpoint blockades (ICBs). In this study, we aimed to dissect the potential mechanisms underlying poor response to ICBs and explore a rational ICB-based combination therapy in iCCA. METHODS: scRNA-seq dataset GSE151530 was analyzed to investigate the differentially expressed genes in malignant cells following ICBs therapy. RNA-seq analysis and western blot assays were performed to examine the upstream and downstream signaling pathways of CD73. Subcutaneous tumor xenograft models were utilized to investigate the impact of CD73 on iCCA growth. Plasmid AKT/NICD-induced spontaneous murine iCCAs were used to explore the therapeutic efficacy of CD73 enzymatic inhibitor AB680 combined with PD-1 blockade. Time-of-flight mass cytometry (CyTOF) was conducted to identify the tumor-infiltrating immune cell populations and their functional changes in murine iCCAs treated with AB680 in combination with PD-1 antibody. RESULTS: scRNA-seq analysis identified elevated CD73 expression in malignant cells in response to ICBs therapy. Mechanistically, ICBs therapy upregulated CD73 expression in malignant cells via TNF-α/NF-κB signaling pathway. In vivo studies revealed that CD73 inhibition suppressed the growth of subcutaneous tumors, and achieved synergistic depression effects with gemcitabine and cisplatin (GC). Adenosine produced by CD73 activates AKT/GSK3ß/ß-catenin signaling axis in iCCA cells. CD73 inhibitor AB680 potentiates anti-tumor efficacy of PD-1 antibody in murine iCCAs. CyTOF analysis showed that AB680 combined with anti-PD-1 therapy promoted the infiltration of CD8+ T, CD4+ T cells, and NK cells in murine iCCAs, while simultaneously decreased the proportions of macrophages and neutrophils. Moreover, AB680 combined with anti-PD-1 significantly upregulated the expression of Granzyme B, Tbet and co-stimulatory molecule ICOS in infiltrating CD8+ T cells. CONCLUSIONS: CD73 inhibitor AB680 limits tumor progression and potentiates therapeutic efficacy of GC chemotherapy or anti-PD-1 treatment in iCCA. AB680 combined with anti-PD-1 therapy effectively elicits anti-tumor immune response.

Global burden and risk factors of chronic kidney disease in adolescents and young adults: a study from 1990 to 2019.

Background: Few studies have evaluated the global burden of chronic kidney disease (CKD) in adolescents and young adults (AYAs). Methods: Age-standardized rates of incidence (ASIR), mortality (ASMR), and disability-adjusted life-years (ASDR) were used to describe the CKD burden in AYAs. The estimated annual percentage changes (EAPCs) were calculated to evaluate the temporal trends from 1990 to 2019. Risk factors were calculated by population attributable fractions. Results: In 2019, the ASIR, ASMR, and ASDR of CKD in AYAs were 32.21 (95% uncertainty interval [UI], 23.73-40.81) per 100,000, 2.86 (2.61-3.11) per 100,000 and 236.85 (209.03-268.91) per 100,000, respectively. The ASIR was higher among females than males, whereas the ASMR was higher among males than females in 2019. From 1990 to 2019, significant increases in ASIR were found for CKD (EAPC, 0.98%; 95% confidence interval [CI], 0.95%-1.01%), although the ASMR had decreased (EAPC, -0.40%; 95% CI, -0.56% to -0.24%). The largest increase in ASIR was observed in countries with a middle sociodemographic index (SDI) (EAPC, 1.30%; 95% CI, 1.28%-1.33%), while the largest increase in ASMR was observed in high SDI. Globally, the proportional contribution of risk factors for CKD mortality varied across regions, with the highest proportions of high fasting plasma glucose being 14.04% in low SDI, compared with 24.01% in high SDI. Conclusion: CKD is a growing global health problem in AYAs, especially in countries with a middle SDI. Targeted measures are needed to address the rising burden of CKD in AYAs, focusing on prevention, early diagnosis, and reducing disparities.

Development and Internal Validation of the Cleveland Clinic Bleeding Model to Predict Major Bleeding Risk at Admission in Medical Inpatients.

BACKGROUND: Guidelines recommend pharmacological VTE prophylaxis for acutely ill medical patients at acceptable bleeding risk, but only the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) model has been validated for bleeding risk assessment. OBJECTIVE: We developed and internally validated a risk assessment model (RAM) to predict major in-hospital bleeding using risk factors at admission and compared our model to IMPROVE. METHODS: We selected patients admitted to medical services at 10 hospitals in the Cleveland Clinic Health System from 2017 to 2020. We identified major bleeding according to the International Society on Thrombosis and Hemostasis criteria, using a combination of diagnostic codes and laboratory values, and confirmed events with chart review. We fit a LASSO logistic regression model in the training set and compared the discrimination and calibration of our model and IMPROVE in the validation set. RESULTS: Among 46,314 admissions, 268 (0.58%) had a major bleed. The final RAM included 16 risk factors, of which prior bleeding (OR = 4.83), peptic ulcer (OR = 3.82), history of sepsis (OR = 3.26), and steroid use (OR = 2.59) were the strongest. The Cleveland Clinic Bleeding Model (CCBM) had better discrimination than IMPROVE (AUC = 0.85 vs. 0.70, p < .001) and, at equivalent sensitivity (52%), categorized fewer patients as high-risk (7.2% vs. 11.8%, p < .001). Calibration was adequate (Brier score = 0.0057). CONCLUSION: Using a large population of medical inpatients with verified major bleeding events, we developed and internally validated a RAM for major bleeding whose performance surpassed the IMPROVE model.

New information about the cyclable capacity fading process of a pouch cell with Li-rich layered oxide cathodes.

Most studies investigate the cyclable capacity fading mechanism of Li-rich layered oxides (LLOs) from the microscopic structure level, lacking discussions about how the structure degradation influences the performance of the pouch cell precisely and quantitatively. Based on the analysis of the evolution of key parameters during the whole cycling period, a new transition-type fading mechanism is proposed. From the early-to-middle stage of the cycling period, polarization increases, most of which is interface-related, causing about 67% of the whole capacity loss. From the middle-to-late stage of the cycling period, active material losses turn out to be the dominating factor, inducing about 61% of the total capacity loss. Diffusion-related polarization, replacing the interface type, is responsible for most of the increased overpotential. Relative analysis confirms that during the early stage, the increase of the charge transfer resistance, induced by CEI (cathode electrolyte interface) growth and initial surface layered-structure degradation, is the main source of interface polarization. As the cycling evolves to the late stage, severe bulky structure degradation, including lattice-oxygen release, Li/Ni mixture and generation of a new spinel phase, turns out to be the major factor, causing further capacity fading.

Human umbilical cord mesenchymal stem cells attenuate diabetic nephropathy through the IGF1R-CHK2-p53 signalling axis in male rats with type 2 diabetes mellitus. / 人脐带间å 质干细胞通过IGF1R-CHK2-p53信号轴减轻2åž‹ç³–å°¿ç— é›„æ€§å¤§é¼ ç³–å°¿ç— è‚¾ç— .

Diabetes mellitus (DM) is a disease syndrome characterized by chronic hyperglycaemia. A long-term high-glucose environment leads to reactive oxygen species (ROS) production and nuclear DNA damage. Human umbilical cord mesenchymal stem cell (HUcMSC) infusion induces significant antidiabetic effects in type 2 diabetes mellitus (T2DM) rats. Insulin-like growth factor 1 (IGF1) receptor (IGF1R) is important in promoting glucose metabolism in diabetes; however, the mechanism by which HUcMSC can treat diabetes through IGF1R and DNA damage repair remains unclear. In this study, a DM rat model was induced with high-fat diet feeding and streptozotocin (STZ) administration and rats were infused four times with HUcMSC. Blood glucose, interleukin-6 (IL-6), IL-10, glomerular basement membrane, and renal function were examined. Proteins that interacted with IGF1R were determined through coimmunoprecipitation assays. The expression of IGF1R, phosphorylated checkpoint kinase 2 (p-CHK2), and phosphorylated protein 53 (p-p53) was examined using immunohistochemistry (IHC) and western blot analysis. Enzyme-linked immunosorbent assay (ELISA) was used to determine the serum levels of 8-hydroxydeoxyguanosine (8-OHdG). Flow cytometry experiments were used to detect the surface markers of HUcMSC. The identification of the morphology and phenotype of HUcMSC was performed by way of oil red "O" staining and Alizarin red staining. DM rats exhibited abnormal blood glucose and IL-6/10 levels and renal function changes in the glomerular basement membrane, increased the expression of IGF1 and IGF1R. IGF1R interacted with CHK2, and the expression of p-CHK2 was significantly decreased in IGF1R-knockdown cells. When cisplatin was used to induce DNA damage, the expression of p-CHK2 was higher than that in the IGF1R-knockdown group without cisplatin treatment. HUcMSC infusion ameliorated abnormalities and preserved kidney structure and function in DM rats. The expression of IGF1, IGF1R, p-CHK2, and p-p53, and the level of 8-OHdG in the DM group increased significantly compared with those in the control group, and decreased after HUcMSC treatment. Our results suggested that IGF1R could interact with CHK2 and mediate DNA damage. HUcMSC infusion protected against kidney injury in DM rats. The underlying mechanisms may include HUcMSC-mediated enhancement of diabetes treatment via the IGF1R-CHK2-p53 signalling pathway.

Synthesis and Characterization of Emulsifiers Based on the Maillard Reaction and Its Application in Stabilized DHA Algal Oil Nanoemulsions.

The aim of this study was to optimize the formation of sodium caseinate (CS) and gum arabic (GA) complexes through the Maillard reaction and to evaluate their effectiveness in improving the emulsification properties and stability of docosahexaenoic acid (DHA) nanoemulsions. First, the best target polysaccharides were selected, and the best modification conditions were determined using orthogonal experiments. Secondly, the response surface experiments were used to optimize the preparation process of the emulsion. The stability, in vitro digestion characteristics, and rheological characteristics of the emulsion prepared by means of CS-GA were compared with the emulsion prepared using a whey protein isolate (WPI). After the orthogonal test, the optimal modification conditions were determined to be a reaction time of 96 h, a CS-GA mass ratio of 1:2, a reaction temperature of 60 °C, and a degree of grafting of 44.91%. Changes in the infrared (IR), Raman, ultraviolet (UV), and endogenous fluorescence spectra also indicated that the complex structure was modified. The response surface test identified the optimal preparation process as follows: an emulsifier concentration of 5 g/L, an oil-phase concentration of 5 g/L, and a homogenization frequency of five, and the emulsion showed good stability. Therefore, the use of a nanoemulsion as a nanoscale DHA algal oil delivery system is very promising for extending the shelf life and improving the stability of food.

Genomics- and Transcriptomics-Guided Discovery of Clavatols from Arctic Fungi Penicillium sp. MYA5.

Clavatols exhibit a wide range of biological activities due to their diverse structures. A genome mining strategy identified an A5cla cluster from Penicillium sp. MYA5, derived from the Arctic plant Dryas octopetala, is responsible for clavatol biosynthesis. Seven clavatols, including one new clavatol derivate named penicophenone F (1) and six known clavatols (2-7), were isolated from Penicillium sp. MYA5 using a transcriptome mining strategy. These structures were elucidated by comprehensive spectroscopic analysis. Antibacterial, aldose reductase inhibition, and siderophore-producing ability assays were conducted on compounds 1-7. Compounds 1 and 2 demonstrated inhibitory effects on the ALR2 enzyme with inhibition rates of 75.3% and 71.6% at a concentration of 10 µM, respectively. Compound 6 exhibited antibacterial activity against Staphylococcus aureus and Escherichia coli with MIC values of 4.0 µg/mL and 4.0 µg/mL, respectively. Additionally, compounds 1, 5, and 6 also showed potential iron-binding ability.

Serum 25-hydroxyvitamin D level and erectile dysfunction: a causal relationship? Findings from a two-sample Mendelian randomization study.

Background: Serum 25-hydroxyvitamin D level is associated with erectile dysfunction (ED) in observational studies. However, whether there is a causal association between them remains uncertain. Objective: Conduct a two-sample Mendelian randomization (MR) analysis to investigate the causal effect between serum 25-hydroxyvitamin D level and ED risk. Method: Genome-wide association study (GWAS) data of serum 25-hydroxyvitamin D levels comprising 6,896,093 single nucleotide polymorphisms (SNP) from 496,949 people of European ancestry were regarded as exposure for the MR analysis. Additional GWAS data involving 9,310,196 SNPs of 6,175 European ED cases and 217,630 controls were used as outcome data. The MR-Egger, inverse variance weighted (IVW) method, weighted median, simple mode, and weighted mode were employed to evaluate causal effects, among which IVW was the primary MR analysis method. The stability of the MR analysis results was confirmed by a heterogeneity test, a horizontal pleiotropy test, and the leave-one-out method. Result: There were 103 SNPs utilized as instrumental variables (p < 5 × 10-8). The results of MR analysis showed no causal effects of serum 25(OH) D concentration on ED risks (IVW; OR = 0.9516, 95% CI = 0.7994 to 1.1328, p = 0.5772). There was no heterogeneity and pleiotropy in the statistical models. Conclusion: The present MR study did not support a causal association for genetically predicted serum 25-hydroxyvitamin D concentration in the risk of ED in individuals of European descent.

Mobilization and activation of tumor-infiltrating dendritic cells inhibits lymph node metastasis in intrahepatic cholangiocarcinoma.

Lymph node metastasis (LNM) facilitates distant tumor colonization and leads to the high mortality in patients with intrahepatic cholangiocarcinoma (ICC). However, it remains elusive how ICC cells subvert immune surveillance within the primary tumor immune microenvironment (TIME) and subsequently metastasize to lymph nodes (LNs). In this study, scRNA-seq and bulk RNA-seq analyses identified decreased infiltration of dendritic cells (DCs) into primary tumor sites of ICC with LNM, which was further validated via dual-color immunofluorescence staining of 219 surgically resected ICC samples. Tumor-infiltrating DCs correlated with increased CD8+ T cell infiltration and better prognoses in ICC patients. Mechanistically, ß-catenin-mediated CXCL12 suppression accounted for the impaired DC recruitment in ICC with LNM. Two mouse ICC cell lines MuCCA1 and mIC-23 cells were established from AKT/NICD or AKT/YAP-induced murine ICCs respectively and were utilized to construct the footpad tumor LNM model. We found that expansion and activation of conventional DCs (cDCs) by combined Flt3L and poly(I:C) (FL-pIC) therapy markedly suppressed the metastasis of mIC-23 cells to popliteal LNs. Moreover, ß-catenin inhibition restored the defective DC infiltration into primary tumor sites and reduced the incidence of LNM in ICC. Collectively, our findings identify tumor cell intrinsic ß-catenin activation as a key mechanism for subverting DC-mediated anti-tumor immunity in ICC with LNM. FL-pIC therapy or ß-catenin inhibitor could merit exploration as a potential regimen for mitigating ICC cell metastasis to LNs and achieving effective tumor immune control.

Perspectives for capillary refill time in clinical practice for sepsis.

BACKGROUND: Capillary refill time (CRT) is defined as the time taken for color to return to an external capillary bed after pressure is applied to cause blanching. Recent studies demonstrated the benefits of CRT in guiding fluid therapy for sepsis. However, lack of consistency among physicians in how to perform and interpret CRT has led to a low interobserver agreement for this assessment tool, which prevents its availability in sepsis clinical settings. OBJECTIVE: To give physicians a concise overview of CRT and explore recent evidence on its reliability and value in the management of sepsis. RESEARCH DESIGN: A narrative review. RESULTS: This narrative review summarizes the factors affecting CRT values, for example, age, sex, temperature, light, observation techniques, work experience, training level and differences in CRT measurement methods. The methods of reducing the variability of CRT are synthesized. Based on studies with highly reproducible CRT measurements and an excellent inter-rater concordance, we recommend the standardized CRT assessment method. The threshold of normal CRT values is discussed. The application of CRT in different phases of sepsis management is summarized. CONCLUSIONS: Recent data confirm the value of CRT in critically ill patients. CRT should be detected by trained physicians using standardized methods and reducing the effect of ambient-related factors. Its association with severe infection, microcirculation, tissue perfusion response, organ dysfunction and adverse outcomes makes this approach a very attractive tool in sepsis. Further studies should confirm its value in the management of sepsis. IMPLICATIONS FOR CLINICAL PRACTICE: As a simple assessment, CRT deserves more attention even though it has not been widely applied at the bedside. CRT could provide nursing staff with patient's microcirculatory status, which may help to develop individualized nursing plans and improve the patient's care quality and treatment outcomes.

On-chip photonic convolution by phase-change in-memory computing cells with quasi-continuous tuning.

Matrix multiplication acceleration by on-chip photonic integrated circuits (PICs) is emerging as one of the attractive and promising solutions, offering outstanding benefits in speed and bandwidth as compared to non-photonic approaches. Incorporating nonvolatile phase-change materials into PICs or devices enables optical storage and computing, surpassing their electrical counterparts. In this paper, we propose a design of on-chip photonic convolution for optical in-memory computing by integrating the phase change chalcogenide of Ge2Sb2Se4Te1 (GSST) into an asymmetric directional coupler for constructions of an in-memory computing cell, marrying the advantages of both the large bandwidth of Mach-Zehnder interferometers (MZIs) and the small size of micro-ring resonators (MRRs). Through quasi-continuous electro-thermal tuning of the GSST-integrated in-memory computing cells, numerical calculations about the optical and electro-thermal behaviors during GSST phase transition confirm the tunability of the programmable elements stored in the in-memory computing cells within [-1, 1]. For proof-of-concept verification, we apply the proposed optical convolutional kernel to a typical image edge detection application. As evidenced by the evaluation results, the prototype achieves the same accuracy as the convolution kernel implemented on a common digital computer, demonstrating the feasibility of the proposed scheme for on-chip photonic convolution and optical in-memory computing.

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial.

Importance: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. Objective: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. Design, Setting, and Participants: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Exposures: Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Main Outcomes and Measures: Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Results: Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. Conclusions and Relevance: In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.