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.

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.

Tracing the vertical migration of exogenous cadmium in soil by seasonal freeze-thaw event using rare earth elements.

Environmental behaviors of heavy metal in soil are strongly influenced by seasonal freeze-thaw events at the mid-high altitudes. However, the potential impact mechanisms of freeze-thaw cycles on the vertical migration of heavy metal are still poor understood. This study aimed to explore how exogenous cadmium (Cd) migrated and remained in soil during the in-situ seasonal freeze-thaw action using rare earth elements (REEs) as tracers. As a comparison, soil which was incubated in the controlled laboratory (25 °C) was employed. Although there was no statistically significant difference in the Cd levels of different soil depths under different treatments, the original aggregate sources of Cd in the 5-10 cm and 10-15 cm soil layers differed. From the distributions of REEs in soil profile, it can be known that Cd in the subsurface of field incubated soil was mainly from the breakdown of >0.50 mm aggregates, while it was mainly from the <0.106 mm aggregates for the laboratory incubated soil. Furthermore, the dissolved and colloidal Cd concentrations were 0.47 µg L-1 and 0.62 µg L-1 in the leachates from field incubated soil than those from control soil (0.21 µg L-1 and 0.43 µg L-1). Additionally, the colloid-associated Cd in the leachate under field condition was mainly from the breakdown of >0.25 mm aggregates and the direct migration of <0.106 mm aggregates, while it was the breakdown of >0.50 mm and the direct migration of <0.106 mm aggregates for the soil under laboratory condition. Our results for the first time provided insights into the fate of exogenous contaminants in seasonal frozen regions using the rare earth element tracing method.

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.

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.

Facilitating the coping and development of college students with mental disorders: a positive clinical psychology approach.

In serving college students with mental disorders, on-campus mental health professionals have been lacking integrative theoretical frameworks to guide their missions of prevention, remedy, and development facilitation. In the current paper, we propose the positive clinical psychology as a theoretically and practically valuable framework for these missions by narratively reviewing the preventive, remedial, and developmental mechanisms derived from the theory and summarizing the most recent empirical evidence that supports each mechanism. We further discuss why and how these mechanisms and findings can be applied to on-campus mental health services to facilitate the resilience and optimal development of college students with mental disorders. Particularly, the use of resilience-focused and strength-based intervention strategies are promoted for services.

Endogenous Retroviruses Unveiled: A Comprehensive Review of Inflammatory Signaling/Senescence-Related Pathways and Therapeutic Strategies.

Endogenous retroviruses (ERVs), a subset of genomic transposable elements (TEs) in a broader sense, have remained latent within mammalian genomes for tens of millions of years. These genetic elements are typically in a silenced state due to stringent regulatory mechanisms. However, under specific conditions, they can become activated, triggering inflammatory responses through diverse mechanisms. This activation has been shown to play a potential role in various neurological disorders, tumors, and cellular senescence. Consequently, the regulation of ERV expression through various methods holds promise for clinical applications in disease treatment. ERVs also engage in interactions with a variety of exogenous viruses, thereby influencing the outcomes of viral infectious diseases. This article comprehensively reviews the pathogenic cascade of ERVs, encompassing activation, inflammation, associated diseases, senescence, and interplay with viruses. Additionally, it outlines therapeutic strategies targeting ERVs with the aim of offering novel research directions for understanding the relationship between ERVs and diseases, along with corresponding treatment modalities.

Neratinib stimulates senescence of mammary cancer cells by reducing the levels of SIRT1.

Neratinib, a typical small-molecule, pan-human tyrosine kinase inhibitor (TKI), has been licensed for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the underlying pharmacological mechanism is still unknown. In the current study, we report a novel function of Neratinib by showing that its treatment stimulates senescence of the mammary cancer AU565 cells. Our results demonstrate that Neratinib induces mitochondrial injury by increasing mitochondrial reactive oxygen species (ROS) and reducing intracellular adenosine triphosphate (ATP). Also, we found that Neratinib induced DNA damage by increasing the levels of 8-Hydroxy-desoxyguanosine (8-OHdG) and γH2AX in AU565 cells. Additionally, Neratinib reduced the levels of telomerase activity after 7 and 14 days incubation. Importantly, the senescence-associated-ß-galactosidase (SA-ß-Gal) assay revealed that Neratinib stimulated senescence of AU565 cells. Neratinib decreased the gene levels of human telomerase reverse transcriptase (hTERT) but increased those of telomeric repeat-binding factor 2 (TERF2) in AU565 cells. Further study displayed that Neratinib upregulated the expression of K382 acetylation of p53 (ac-K382) and p21 but reduced the levels of sirtuin-1 (SIRT1). However, overexpression of SIRT1 abolished the effects of Neratinib in cellular senescence. These findings provide strong preclinical evidence of Neratinib's treatment of breast cancer.

Evidence of nuclide migration from high-level radioactive waste glass via geogas.

Characteristics of high-level radioactive waste transport in glass as gases were studied. A transmission electron microscope was used to observe the morphology of the substance after penetrating the high-level radioactive waste glass and the bentonite soil column, and the composition of the substance was analyzed using electron probe energy spectroscopy. The results show that the radionuclides in the high-level radioactive waste glass were transported out of the glass, the bentonite was penetrated by the geogas, and the transported substance occurred as nanometer-size particles and particle aggregates.

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.

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.

ABHD5 regulates midgut-specific lipid homeostasis in Bombyx mori.

Lipids are an important energy source and are utilized as substrates for various physiological processes in insects. Comparative gene identification 58 (CGI-58), also known as α/ß hydrolase domain-containing 5 (ABHD5), is a highly conserved and multifunctional gene involved in regulating lipid metabolism and cellular energy balance in many organisms. However, the biological functions of ABHD5 in insects are poorly understood. In the current study, we describe the identification and characterization of the ABHD5 gene in the lepidopteran model insect, Bombyx mori. The tissue expression profile investigated using quantitative reverse transcription polymerase chain reaction (RT-qPCR) reveals that BmABHD5 is widely expressed in all tissues, with particularly high levels found in the midgut and testis. A binary transgenic CRISPR/Cas9 system was employed to conduct a functional analysis of BmABHD5, with the mutation of BmABHD5 leading to the dysregulation of lipid metabolism and excessive lipid accumulation in the larval midgut. Histological and physiological analysis further reveals a significant accumulation of lipid droplets in the midgut of mutant larvae. RNA-seq and RT-qPCR analysis showed that genes related to metabolic pathways were significantly affected by the absence of BmABHD5. Altogether, our data prove that BmABHD5 plays an important role in regulating tissue-specific lipid metabolism in the silkworm midgut.

A sono-responsive antibacterial nanosystem co-loaded with metformin and bone morphogenetic protein-2 for mitigation of inflammation and bone loss in experimental peri-implantitis.

Background: Dental implants have become an increasingly popular option for replacing missing teeth, and the prevalence of peri-implantitis has also increased, which is expected to become a public health problem worldwide and cause high economic and health burdens. This scenario highlights the need for new therapeutic options to treat peri-implantitis. Methods: In this study, we proposed a novel sono-responsive antibacterial nanosystem co-loaded with metformin (Met) and bone morphogenetic protein-2 (BMP-2) to promote efficacy in treating peri-implantitis. We introduced the zeolitic imidazolate framework-8 (ZIF-8) as a carrier for hematoporphyrin monomethyl ether (HMME) to enhance the antibacterial effect of sonodynamic antibacterial therapy and tested its reactive oxygen species (ROS) production efficiency and bactericidal effect in vitro. Afterward, HMME-loaded ZIF-8, BMP-2-loaded polylactic acid-glycolic acid (PLGA), and Met were incorporated into gelatin methacryloyl (GelMA) hydrogels to form HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels, and the biocompatibility of which was determined in vitro and in vivo. A bacterial-induced peri-implantitis model in the maxilla of rats was established to detect the effects of the composite hydrogels with adjunctive use of ultrasound on regulating inflammation and promoting bone tissue repair in vivo. Results: The results indicated that HMME@ZIF-8 with ultrasound stimulation demonstrated more better ROS production efficiency and antimicrobial efficacy. The composite hydrogels had good biocompatibility. Ultrasound-assisted application of the composite hydrogels reduced the release of the inflammatory factors IL-6 and TNF-α and reduced bone loss around the implant in rats with bacterial-induced peri-implantitis. Conclusion: Our observations suggest that HMME@ZIF-8 may be a new good sonosensitizer material for sonodynamic antibacterial therapy. The use of HMME@ZIF-8/Met/BMP-2@PLGA/GelMA composite hydrogels in combination with ultrasound can provide a novel option for treating peri-implantitis in the future.

Dual-mode nanoprobe strategy integrating ultrasound and near-infrared light for targeted and synergistic arterial thrombolysis.

Efficient thrombolysis in time is crucial for prognostic improvement of patients with acute arterial thromboembolic disease, while limitations and complications still exist in conventional thrombolytic treatment methods. Herein, our study sought to investigate a novel dual-mode strategy that integrated ultrasound (US) and near-infrared light (NIR) with establishment of hollow mesoporous silica nanoprobe (HMSN) which contains Arginine-glycine-aspartate (RGD) peptide (thrombus targeting), perfluoropentane (PFP) (thrombolysis with phase-change and stable cavitation) and indocyanine green (ICG) (thrombolysis with photothermal conversion). HMSN is used as the carrier, the surface is coupled with targeted RGD to achieve high targeting and permeability of thrombus, PFP and ICG are loaded to achieve the collaborative diagnosis and treatment of thrombus by US and NIR, so as to provide a new strategy for the integration of diagnosis and treatment of arterial thrombus. From the in vitro and in vivo evaluation, RGD/ICG/PFP@HMSN can aggregate and penetrate at the site of thrombus, and finally establish the dual-mode directional development and thrombolytic treatment under the synergistic effect of US and NIR, providing strong technical support for the accurate diagnosis and treatment of arterial thrombosis.

Effect of carbon source on carbon and nitrogen metabolism of common heterotrophic nitrification-aerobic denitrification pathway.

Pseudomonas sp. ZHL02, removing nitrogen via ammonia nitrogen (NH4+) → hydroxylamine (HN2OH) → nitrite (NO2-) → nitrate (NO3-) → NO2- → nitric oxide (NO) → nitrous oxide (N2O) pathway was employed for getting in-depth information on the heterotrophic nitrification-aerobic denitrification (HNAD) pathway from carbon oxidation, nitrogen conversion, electron transport process, enzyme activity, as well as gene expression while sodium succinate, sodium citrate, and sodium acetate were utilized as the carbon sources. The nitrogen balance analysis results demonstrated that ZHL02 mainly removed NH4+-N through assimilation. The carbon source metabolism resulted in the discrepancies in electron transport chain and nitrogen removal between different HNAD bacteria. Moreover, the prokaryotic strand-specific transcriptome method showed that, amo and hao were absent in ZHL02, and unknown genes may be involved in ZHL02 during the HNAD process. As a fascinating process for removing nitrogen, the HNAD process is still puzzling, and the relationship between carbon metabolism and nitrogen metabolism among different HNAD pathways should be studied further.

Achievement of Guideline-Recommended Targets for Secondary Prevention of Cardiovascular Disease in 38 Low-Income and Middle-Income Countries.

BACKGROUND: This study aimed to estimate the prevalence of achieving the secondary prevention targets recommended in the World Health Organization (WHO) guidelines for cardiovascular disease (CVD) in 38 low-income and middle-income countries (LMICs). METHODS: We pooled nationally representative cross-sectional surveys from 38 LMICs between 2013 and 2020. Treatment, metabolic and lifestyle targets were assessed for individuals with a self-reported history of CVD according to WHO's recommendations. Associations between the prevalence of guideline adherence and sociodemographic characteristics were assessed using multivariate Poisson regression models. RESULTS: The pooled sample included 126 106 participants, of whom 9821 (6.8% [95% CI 6.4-7.2]) reported a history of CVD. Overall, the prevalence of achieving treatment targets in patients with CVD was 22.7% (95% CI, 21.0-24.5%) for antihypertensive drugs, 19.6% (17.9-21.4%) for aspirin, and 13.6% (12.0-15.44%) for statins. The prevalence of achieving metabolic targets was 54.9% (52.5-57.3%) for BMI, 39.9% (37.7-42.2%) for blood pressure, 46.1% (43.6-48.6%) for total cholesterol, and 84.9% (83.1-86.5%) for fasting blood glucose. The prevalence of achieving lifestyle targets was 83.2% (81.5-84.7%) for not smoking, 83.1% (81.2-84.9%) for not drinking, 65.5% (63.1-67.7%) for sufficient physical activity and 16.2% (14.5-18.0%) for healthy diet. Only 6.1% (5.1-7.4%) achieved three treatment targets, 16.0% (14.3-17.9%) achieved four metabolic targets, and 6.9% (5.8-8.0%) achieved four lifestyle targets. Upper-middle income countries were better than low-income countries at achieving the treatment, non-drinking and dietary targets. Being younger and female were associated with poorer achievement of metabolic targets. CONCLUSION: In LMICs, achieving the targets recommended in the guideline for treatment, metabolism and healthy lifestyles for patients with CVD is notably low. This highlights an urgent need for effective, systematic secondary prevention strategies to improve CVD management.

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.

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.