Antitumor efficacy and potential mechanism of FAP-targeted radioligand therapy combined with immune checkpoint blockade.

Radiotherapy combined with immune checkpoint blockade holds great promise for synergistic antitumor efficacy. Targeted radionuclide therapy delivers radiation directly to tumor sites. LNC1004 is a fibroblast activation protein (FAP)-targeting radiopharmaceutical, conjugated with the albumin binder Evans Blue, which has demonstrated enhanced tumor uptake and retention in previous preclinical and clinical studies. Herein, we demonstrate that 68Ga/177Lu-labeled LNC1004 exhibits increased uptake and prolonged retention in MC38/NIH3T3-FAP and CT26/NIH3T3-FAP tumor xenografts. Radionuclide therapy with 177Lu-LNC1004 induced a transient upregulation of PD-L1 expression in tumor cells. The combination of 177Lu-LNC1004 and anti-PD-L1 immunotherapy led to complete eradication of all tumors in MC38/NIH3T3-FAP tumor-bearing mice, with mice showing 100% tumor rejection upon rechallenge. Immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and TCR sequencing revealed that combination therapy reprogrammed the tumor microenvironment in mice to foster antitumor immunity by suppressing malignant progression and increasing cell-to-cell communication, CD8+ T-cell activation and expansion, M1 macrophage counts, antitumor activity of neutrophils, and T-cell receptor diversity. A preliminary clinical study demonstrated that 177Lu-LNC1004 was well-tolerated and effective in patients with refractory cancers. Further, scRNA-seq of peripheral blood mononuclear cells underscored the importance of addressing immune evasion through immune checkpoint blockade treatment. This was emphasized by the observed increase in antigen processing and presentation juxtaposed with T cell inactivation. In conclusion, our data supported the efficacy of immunotherapy combined with 177Lu-LNC1004 for cancer patients with FAP-positive tumors.

Hypoxia-mediated programmed cell death is involved in the formation of wooden breast in broilers.

BACKGROUND: Wooden breast (WB) myopathy is a common myopathy found in commercial broiler chickens worldwide. Histological examination has revealed that WB myopathy is accompanied by damage to the pectoralis major (PM) muscle. However, the underlying mechanisms responsible for the formation of WB in broilers have not been fully elucidated. This study aimed to investigate the potential role of hypoxia-mediated programmed cell death (PCD) in the formation of WB myopathy. RESULTS: Histological examination and biochemical analysis were performed on the PM muscle of the control (CON) and WB groups. A significantly increased thickness of the breast muscle in the top, middle, and bottom portions (P<0.01) was found along with pathological structure damage of myofibers in the WB group. The number of capillaries per fiber in PM muscle, and the levels of pO2 and sO2 in the blood, were significantly decreased (P < 0.01), while the levels of pCO2 and TCO2 in the blood were significantly increased (P < 0.05), suggesting hypoxic conditions in the PM muscle of the WB group. We further evaluated the PCD-related pathways including autophagy, apoptosis, and necroptosis to understand the consequence response to enhanced hypoxic conditions in the PM muscle of birds with WB. The ratio of LC3 II to LC3 I, and the autophagy-related factors HIF-1α, BNIP3, Beclin1, AMPKα, and ULK1 at the mRNA and protein levels, were all significantly upregulated (P < 0.05), showing that autophagy occurred in the PM muscle of the WB group. The apoptotic index, as well as the expressions of Bax, Cytc, caspase 9, and caspase 3, were significantly increased (P < 0.05), whereas Bcl-2 was significantly decreased (P < 0.05) in the WB-affected PM muscle, indicating the occurrence of apoptosis mediated by the mitochondrial pathway. Additionally, the expressions of necroptosis-related factors RIP1, RIP3, and MLKL, as well as NF-κB and the pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6, were all significantly enhanced (P < 0.05) in the WB-affected PM muscle. CONCLUSIONS: The WB myopathy reduces blood supply and induces hypoxia in the PM muscle, which is closely related to the occurrence of PCD including apoptosis, autophagy, and necroptosis within myofibers, and finally leads to abnormal muscle damage and the development of WB in broilers.

Model-based bioequivalence approach for sparse pharmacokinetic bioequivalence studies: Model selection or model averaging?

Conventional pharmacokinetic (PK) bioequivalence (BE) studies aim to compare the rate and extent of drug absorption from a test (T) and reference (R) product using non-compartmental analysis (NCA) and the two one-sided test (TOST). Recently published regulatory guidance recommends alternative model-based (MB) approaches for BE assessment when NCA is challenging, as for long-acting injectables and products which require sparse PK sampling. However, our previous research on MB-TOST approaches showed that model misspecification can lead to inflated type I error. The objective of this research was to compare the performance of model selection (MS) on R product arm data and model averaging (MA) from a pool of candidate structural PK models in MBBE studies with sparse sampling. Our simulation study was inspired by a real case BE study using a two-way crossover design. PK data were simulated using three structural models under the null hypothesis and one model under the alternative hypothesis. MB-TOST was applied either using each of the five candidate models or following MS and MA with or without the simulated model in the pool. Assuming T and R have the same PK model, our simulation shows that following MS and MA, MB-TOST controls type I error rates at or below 0.05 and attains similar or even higher power than when using the simulated model. Thus, we propose to use MS prior to MB-TOST for BE studies with sparse PK sampling and to consider MA when candidate models have similar Akaike information criterion.

Development and anatomy of petals with specialized nectar holder and pollen container in Fumarioideae (Papaveraceae).

MAIN CONCLUSION: Petal developmental characteristics in Fumarioideae were similar at early stages, and the specialized nectar holder/pollen container formed by the outer/inner petals. The micro-morphology of these two structures, however, shows diversity in seven species. Elaborate petals have been modified to form different types, including petal lobes, ridges, protuberances, and spurs, each with specialized functions. Nectar holder and pollen container presumably have a function in plant-pollinator interactions. In Fumarioideae, four elaborate petals of the disymmetric/zygomorphic flower present architecture forming the "nectar holder" and "pollen container" structure at the bottom and top separately. In the present study, the petals of seven species in Fumarioideae were investigated by scanning electron microscopy, light microscope, and transmission electron microscopes. The results show that petal development could divided into six stages: initiation, enlargement, adaxial/abaxial differentiation, elaborate specializations (sacs, spurs, and lobes formed), extension, and maturation, while the specialized "nectar holder" and "pollen container" structures mainly formed in stage 4. "Nectar holder" is developed from the shallow sac/spur differentiated at the base of the outer petal, eventually forming a multi-organized complex structure, together with staminal nectaries (1-2) with individual sizes. A semi-closed ellipsoidal "pollen container" is developed from the apical part of the 3-lobed inner petals fused by middle lobes and attain different sizes. The adaxial epidermis cells are specialized, with more distinct punctate/dense columnar protrusions or wavy cuticles presented on obviously thickening cell walls. In addition, a large and well-developed cavity appears between the inner and outer epidermis of the petals. As an exception, Hypecoum erectum middle lobes present stamen mimicry. Elaborate petal structure is crucial for comprehending the petal diversity in Fumarioideae and provides more evidence for further exploration of the reproductive study in Papaveraceae.

Efficacy of transcutaneous electrical nerve stimulation combined with mirabegron therapy compared with mirabegron monotherapy for overactive bladder: a prospective randomized controlled study.

PURPOSE: The objective was to evaluate the efficacy of transcutaneous electrical nerve stimulation (TENS) combined with mirabegron therapy compared with mirabegron monotherapy in the treatment of female patients with overactive bladder (OAB). METHODS: In this randomized controlled study, 100 female outpatients with OAB were screened. Among these patients, 86 who met the inclusion criteria were randomly divided into the TENS combined with mirabegron treatment group and mirabegron monotherapy treatment group, with 43 patients in each group. The voiding diary, Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Symptom Bother Score (OAB-q SBS), total health-related quality of life (OAB-q HRQoL), and treatment satisfaction-visual analog scale (TS-VAS) score before and after treatment were recorded to evaluate the efficacy of OAB treatment. Seventy-nine of the 86 patients (40 in the TENS plus mirabegron group and 39 in the mirabegron monotherapy group) completed 12 weeks of treatment. RESULTS: TENS combined with mirabegron therapy was superior to mirabegron monotherapy in improving the primary endpoints, including the daily number of micturition episodes and the daily MVV/micturition and secondary endpoints, including the daily number of urgency episodes, the OABSS, the OAB-q SBS, the HRQoL score and TS-VAS score. There were no statistically significant differences in urgency urinary incontinence and nocturia between the groups. Some minor adverse effects were observed, including muscle pain, local paresthesia and constipation. CONCLUSIONS: The combination of TENS and mirabegron was more effective than mirabegron alone in the treatment of female patients with OAB. TRIAL REGISTRATION NUMBER: ChiCTR2400080528 (31.01.2024, retrospectively registered).

Predicting drug-Protein interaction with deep learning framework for molecular graphs and sequences: Potential candidates against SAR-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the COVID-19 disease, which represents a new life-threatening disaster. Regarding viral infection, many therapeutics have been investigated to alleviate the epidemiology such as vaccines and receptor decoys. However, the continuous mutating coronavirus, especially the variants of Delta and Omicron, are tended to invalidate the therapeutic biological product. Thus, it is necessary to develop molecular entities as broad-spectrum antiviral drugs. Coronavirus replication is controlled by the viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme, which is required for the virus's life cycle. In the cases of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV), 3CLpro has been shown to be a promising therapeutic development target. Here we proposed an attention-based deep learning framework for molecular graphs and sequences, training from the BindingDB 3CLpro dataset (114,555 compounds). After construction of such model, we conducted large-scale screening the in vivo/vitro dataset (276,003 compounds) from Zinc Database and visualize the candidate compounds with attention score. geometric-based affinity prediction was employed for validation. Finally, we established a 3CLpro-specific deep learning framework, namely GraphDPI-3CL (AUROC: 0.958) achieved superior performance beyond the existing state of the art model and discovered 10 molecules with a high binding affinity of 3CLpro and superior binding mode.

Accountability analysis of health benefits related to National Action Plan on Air Pollution Prevention and Control in China.

China is one of the largest producers and consumers of coal in the world. The National Action Plan on Air Pollution Prevention and Control in China (2013-2017) particularly aimed to reduce emissions from coal combustion. Here, we show whether the acute health effects of PM2.5 changed from 2013 to 2018 and factors that might account for any observed changes in the Beijing-Tianjin-Hebei (BTH) and the surrounding areas where there were major reductions in PM2.5 concentrations. We used a two-stage analysis strategy, with a quasi-Poisson regression model and a random effects meta-analysis, to assess the effects of PM2.5 on mortality in the 47 counties of BTH. We found that the mean daily PM2.5 levels and the SO42- component ratio dramatically decreased in the study period, which was likely related to the control of coal emissions. Subsequently, the acute effects of PM2.5 were significantly decreased for total and circulatory mortality. A 10 µg/m3 increase in PM2.5 concentrations was associated with a 0.16% (95% CI: 0.08, 0.24%) and 0.02% (95% CI: -0.09, 0.13%) increase in mortality from 2013 to 2015 and from 2016 to 2018, respectively. The changes in air pollution sources or PM2.5 components appeared to have played a core role in reducing the health effects. The air pollution control measures implemented recently targeting coal emissions taken in China may have resulted in significant health benefits.

Salience Interest Option: Temporal abstraction with salience interest functions.

Reinforcement Learning (RL) is a significant machine learning subfield that emphasizes learning actions based on environment to obtain optimal behavior policy. RL agents can make decisions at variable time scales in the form of temporal abstractions, also known as options. The issue of discovering options has seen a considerable research effort. Most notably, the Interest Option Critic (IOC) algorithm first extends the initial set to the interest function, providing a method for learning options specialized to certain state space regions. This approach offers a specific attention mechanism for action selection. Unfortunately, this method still suffers from the classic issues of poor data efficiency and lack of flexibility in RL when learning options end-to-end through backpropagation. This paper proposes a new approach called Salience Interest Option Critic (SIOC), which chooses subsets of existing initiation sets for RL. Specifically, these subsets are not learned by backpropagation, which is slow and tends to overfit, but through particle filters. This approach enables the rapid and flexible identification of critical subsets using only reward feedback. We conducted experiments in discrete and continuous domains, and our proposed method demonstrate higher efficiency and flexibility than other methods. The generated options are more valuable within a single task and exhibited greater interpretability and reusability in multi-task learning scenarios.

Multi-omics reveal the gut microbiota-mediated severe foraging environment adaption of small wild ruminants in the Three-River-Source National Park, China.

The Tibetan antelope (Pantholops hodgsonii), blue sheep (Pseudois nayaur), and Tibetan sheep (Ovis aries) are the dominant small ruminants in the Three-River-Source National Park (TRSNP). However, knowledge about the association between gut microbiota and host adaptability remains poorly understood. Herein, multi-omics sequencing approaches were employed to investigate the gut microbiota-mediated forage adaption in these ruminants. The results revealed that although wild ruminants (WR) of P. hodgsoni and P. nayaur were faced with severe foraging environments with significantly low vegetation coverage and nutrition, the apparent forage digestibility of dry matter, crude protein, and acid detergent fiber was significantly higher than that of O. aries. The 16s rRNA sequencing showed that the gut microbiota in WR underwent convergent evolution, and alpha diversity in these two groups was significantly higher than that in O. aries. Moreover, indicator species, including Bacteroidetes and Firmicutes, exhibited positive relationships with apparent forage digestibility, and their relative abundances were enriched in the gut of WR. Enterotype analysis further revealed that enterotype 1 belonged to WR, and the abundance of fatty acid synthesis metabolic pathway-related enzyme genes was significantly higher than enterotype 2, represented by O. aries. Besides, the metagenomic analysis identified 14 pathogenic bacterial species, among which 10 potentially pathogenic bacteria were significantly enriched in the gut microbiota of O. aries. Furthermore, the cellulolytic strains and genes encoding cellulase and hemicellulase were significantly enriched in WR. In conclusion, our results provide new evidence of gut microbiota to facilitate wildlife adaption in severe foraging environments of the TRSNP, China.

Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options.

Drug resistance represents a significant obstacle in cancer treatment, underscoring the need for the discovery of novel therapeutic targets. Ubiquitin-specific proteases (USPs), a subclass of deubiquitinating enzymes, play a pivotal role in protein deubiquitination. As scientific research advances, USPs have been recognized as key regulators of drug resistance across a spectrum of treatment modalities, including chemotherapy, targeted therapy, immunotherapy, and radiotherapy. This comprehensive review examines the complex relationship between USPs and drug resistance mechanisms, focusing on specific treatment strategies and highlighting the influence of USPs on DNA damage repair, apoptosis, characteristics of cancer stem cells, immune evasion, and other crucial biological functions. Additionally, the review highlights the potential clinical significance of USP inhibitors as a means to counter drug resistance in cancer treatment. By inhibiting particular USP, cancer cells can become more susceptible to a variety of anti-cancer drugs. The integration of USP inhibitors with current anti-cancer therapies offers a promising strategy to circumvent drug resistance. Therefore, this review emphasizes the importance of USPs as viable therapeutic targets and offers insight into fruitful directions for future research and drug development. Targeting USPs presents an effective method to combat drug resistance across various cancer types, leading to enhanced treatment strategies and better patient outcomes.

Fibroblast Activation Protein Inhibitor Tracers and Their Preclinical, Translational, and Clinical Status in China.

Quinoline-based fibroblast activation protein (FAP) inhibitors (FAPIs) have recently emerged as a focal point in global nuclear medicine, underscored by their promising applications in cancer theranostics and the diagnosis of various nononcological conditions. This review offers an in-depth summary of the existing literature on the evolution and use of FAPI tracers in China, tracing their journey from preclinical to clinical research. Moreover, this review also assesses the diagnostic accuracy of FAPI PET for the most common cancers in China, analyzes its impact on oncologic management paradigms, and investigates the potential of FAP-targeted radionuclide therapy in patients with advanced or metastatic cancer. This review also summarizes studies using FAPI PET for nononcologic disorders in China. Thus, this qualitative overview presents a snapshot of China's engagement with FAPI tracers, aiming to guide future research endeavors.

Vacancy-Driven High-Performance Metabolic Assay for Diagnosis and Therapeutic Evaluation of Depression.

Depression is one of the most common mental illnesses and is a well-known risk factor for suicide, characterized by low overall efficacy (<50%) and high relapse rate (40%). A rapid and objective approach for screening and prognosis of depression is highly desirable but still awaits further development. Herein, a high-performance metabolite-based assay to aid the diagnosis and therapeutic evaluation of depression by developing a vacancy-engineered cobalt oxide (Vo-Co3O4) assisted laser desorption/ionization mass spectrometer platform is presented. The easy-prepared nanoparticles with optimal vacancy achieve a considerable signal enhancement, characterized by favorable charge transfer and increased photothermal conversion. The optimized Vo-Co3O4 allows for a direct and robust record of plasma metabolic fingerprints (PMFs). Through machine learning of PMFs, high-performance depression diagnosis is achieved, with the areas under the curve (AUC) of 0.941-0.980 and an accuracy of over 92%. Furthermore, a simplified diagnostic panel for depression is established, with a desirable AUC value of 0.933. Finally, proline levels are quantified in a follow-up cohort of depressive patients, highlighting the potential of metabolite quantification in the therapeutic evaluation of depression. This work promotes the progression of advanced matrixes and brings insights into the management of depression.

Quantifying uncertainty in graph neural network explanations.

In recent years, analyzing the explanation for the prediction of Graph Neural Networks (GNNs) has attracted increasing attention. Despite this progress, most existing methods do not adequately consider the inherent uncertainties stemming from the randomness of model parameters and graph data, which may lead to overconfidence and misguiding explanations. However, it is challenging for most of GNN explanation methods to quantify these uncertainties since they obtain the prediction explanation in a post-hoc and model-agnostic manner without considering the randomness of graph data and model parameters. To address the above problems, this paper proposes a novel uncertainty quantification framework for GNN explanations. For mitigating the randomness of graph data in the explanation, our framework accounts for two distinct data uncertainties, allowing for a direct assessment of the uncertainty in GNN explanations. For mitigating the randomness of learned model parameters, our method learns the parameter distribution directly from the data, obviating the need for assumptions about specific distributions. Moreover, the explanation uncertainty within model parameters is also quantified based on the learned parameter distributions. This holistic approach can integrate with any post-hoc GNN explanation methods. Empirical results from our study show that our proposed method sets a new standard for GNN explanation performance across diverse real-world graph benchmarks.

Discovery and characterization of a novel pathogen Erwinia pyri sp. nov. associated with pear dieback: taxonomic insights and genomic analysis.

In 2022, a novel disease similar to pear fire blight was found in a pear orchard in Zhangye City, Gansu Province, China. The disease mainly damages the branches, leaves, and fruits of the plant. To identify the pathogen, tissue isolation and pathogenicity testing (inoculating the potential pathogen on healthy plant tissues) were conducted. Furthermore, a comprehensive analysis encompassing the pathogen's morphological, physiological, and biochemical characteristics and whole-genome sequencing was conducted. The results showed that among the eight isolates, the symptoms on the detached leaves and fruits inoculated with isolate DE2 were identical to those observed in the field. Verifying Koch's postulates confirmed that DE2 was the pathogenic bacterium that causes the disease. Based on a 16S rRNA phylogenetic tree, isolate DE2 belongs to the genus Erwinia. Biolog and API 20E results also indicated that isolate DE2 is an undescribed species of Erwinia. Isolate DE2 was negative for oxidase. Subsequently, the complete genome sequence of isolate DE2 was determined and compared to the complete genome sequences of 29 other Erwinia species based on digital DNA-DNA hybridization (dDDH) and average nucleotide identity (ANI) analyses. The ANI and dDDH values between strain DE2 and Erwinia species were both below the species thresholds (ANI < 95-96%, dDDH<70%), suggesting that isolate DE2 is a new species of Erwinia. We will temporarily name strain DE2 as Erwinia pyri sp. nov. There were 548 predicted virulence factors in the genome of strain DE2, comprising 534 on the chromosome and 5 in the plasmids. The whole genome sequence of strain DE2 has been submitted to the NCBI database (ASM3075845v1) with accession number GCA_030758455.1. The strain DE2 has been preserved at the China Center for Type Culture Collection (CCTCC) under the deposit number CCTCC AB 2024080. This study represents the initial report of a potentially new bacterial species in the genus Erwinia that causes a novel pear dieback disease. The findings provide a valuable strain resource for the study of the genus Erwinia and establish a robust theoretical foundation for the prevention and control of emerging pear dieback diseases.

Predicting the association of different levels of physical activity on postoperative pulmonary complications using the international physical activity questionnaire in patients undergoing thoracoscopic lung surgery under general anaesthesia: protocol for a prospective cohort study.

INTRODUCTION: Postoperative pulmonary complications (PPCs) occur frequently in patients undergoing lung surgery under general anaesthesia and are strongly associated with longer postoperative hospital stays and increased mortality. The existing literature has shown that a higher level of preoperative physical activity (PA) plays a positive role in the low incidence of postoperative complications and the quality of life in patients undergoing lung surgery. However, the association between preoperative PA levels and the incidence of PPCs has rarely been studied, particularly in thoracoscopic lung surgery. This study aims to evaluate PA levels in patients undergoing thoracoscopic lung surgery using the International Physical Activity Questionnaire and to investigate the association between PA levels and the incidence of PPCs. METHODS AND ANALYSIS: A total of 204 participants aged 18-80 years undergoing thoracoscopic lung surgery (thoracoscopic wedge resection, thoracoscopic segmentectomy and thoracoscopic lobectomy) will be included in the study. The primary outcome is the incidence of PPCs within the first 5 postoperative days. The secondary outcomes include the number of PPCs, the incidence of PPCs 1 month postoperatively, the arterial blood levels of inflammatory markers, the incidence of postoperative adverse events within the first 5 postoperative days, extubation time, unplanned admission to the intensive care unit, postoperative length of stay and mortality 1 month postoperatively. ETHICS AND DISSEMINATION: The study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Shandong First Medical University on 31 March 2022 (YXLL-KY-2022(014)) and is registered at ClinicalTrials.gov. We plan to disseminate the data and findings of this study in international and peer-reviewed journals. TRIAL REGISTRATION NUMBER: The trial has been prospectively registered at the clinicaltrials.gov registry (NCT05401253).

Organophosphate esters in milk across thirteen countries from 2020 to 2023: Concentrations, sources, temporal trends and ToxPi priority to humans.

Recent increases in organophosphate ester (OPE) application have led to their widespread presence, yet little is known about their temporal trends in food. This study collected milk samples from 13 countries across three continents during 2020-2023, finding detectable OPEs in all samples (range: 2.25-19.7; median: 7.06 ng/g ww). Although no statistical temporal differences were found for the total OPEs during the 4-year sampling campaign, it was interesting to observe significant variations in the decreasing trend for Cl-OPEs and concentration variations for aryl-OPEs and alkyl-OPEs (p < 0.05), indicating changing OPE use patterns. Packaged milk exhibited significant higher OPE levels than those found in directly collected raw unpackaged milk, and milk with longer shelf-life showed higher OPE levels, revealing packaging material as a contamination source. No significant geographical differences were observed in milk across countries (p > 0.05), but Shandong Province, a major OPE production site in China, showed relatively higher OPE concentrations. The Monte Carlo simulation of estimated daily intakes indicated no exposure risk from OPEs through milk consumption. The molecular docking method was used to assess human hormone binding affinity with OPEs, amongst which aryl-OPEs had the highest binding energies. The Toxicological-Priority-Index method which integrated chemical property, detection frequency, risk quotients, hazardous quotients and endocrine-disrupting effects was employed to prioritize OPEs. Aryl-OPEs showed the highest scores, deserving attention in the future.

The temporal trends of prevalence and years lived with disability of anaemia in China, Japan, and South Korea, from 1990 to 2021: Results from the Global Burden of Disease Study 2021.

Background: Studies have shown that the disease burden of anaemia varies globally, yet they have not yet determined its exact extent in East Asian countries specifically. We thus aimed to investigate the prevalence and years lived with disability (YLDs) due to anaemia from 1990 to 2021 in China, Japan, and South Korea. Methods: We extracted the prevalence and YLDs with their age-standardised rates (ASRs) in China, Japan, and South Korea from the Global Burden of Disease Study 2021, stratified by sex, age, and causes. We then examined the temporal trend of anaemia burden from 1990 to 2021 using joinpoint analysis and the association of anaemia burden with the Human Development Index and Universal Health Index through Spearman's correlation analysis. Results: In 2021, anaemia affected 136 million people in China (95% uncertainty interval (UI) = 131, 141), with ASRs of prevalence of 8.9% (95% UI = 8.6, 9.3), and accounted for 3.0 million YLDs (95% UI = 2.0, 4.4). It affected 13.6 million people in Japan (95% UI = 11.8, 16.0), with ASRs of prevalence of 7.4% (95% UI = 6.1, 9.0), and caused 181 thousand YLDs (95% UI = 108, 282). It also affected 2.7 million individuals in South Korea (95% UI = 2.4, 3.0), with ASRs of prevalence of 5.2% (95% UI = 4.6, 5.7), and led to 34 thousand YLDs (95% UI = 22, 55). We observed a significant gender discrepancy in the anaemia burden in these three countries, with the prevalence and YLD rates in women being almost twice as high as those in men. Moreover, the peak age of the anaemia burden shifted toward higher age groups in all three countries, particularly in Japan. Chronic kidney disease was responsible for a growing share of anaemia cases and YLDs, especially in adults aged more than 60 years in Japan and South Korea. Haemoglobinopathies were another noticeable cause of anaemia in China, though dietary iron deficiency remained the leading cause. Both socioeconomic development and essential health service coverage showed negative associations with the anaemia burden in the three countries in the past three decades, though with differential patterns. Conclusions: Anaemia remains a major public health issue in China, Japan, and South Korea; targeted surveillance and interventions are recommended for high-risk populations and cause-specific anaemia.

The Real-World Data on Patients With Cardiac Stage IIIb AL Amyloidosis.

BACKGROUND: Morbidity and mortality of patients with immunoglobulin light chain (AL) amyloidosis are strongly associated with the severity of cardiac involvement, especial in patients with cardiac stage IIIb, but the real-world data on these patients is still limited. PATIENTS AND METHODS: A retrospective analysis was conducted on 77 patients diagnosed with cardiac stage IIIb AL amyloidosis at our center. We analyzed the clinical characteristics, treatment and outcome of the patients. RESULTS: The median age of patients was 57 years and 49.4% were male. Median serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponin T (cTnT) were 13,384 ng/L and 0.166 ug/L, and 42 (54.5%) patients had heart failure at diagnosis. Fifty-seven (74.0%) patients received antiplasma cell treatment, and the main treatment options include bortezomib or thalidomide combined with dexamethasone. The hematologic overall response rate was 70% (28/40), and at 6-month landmark analysis, patients with hematologic responses had a higher survival rate. Cardiac and renal responses were achieved in 14 (37.8%) and 13 (32.5%) patients, respectively. After a median follow-up of 10 months (range 1-115 months), median overall survival (OS) was 18 months, and the estimated survival rates at 3, 6, and 12 months were 79.9%, 75.6%, and 54.5%, respectively. In Cox regression models, age, hypotension and cTnT were independently predictive of mortality after adjusting for heart failure. CONCLUSION: The hematologic, cardiac and renal responses were relative lower in patients with cardiac stage IIIb AL amyloidosis. The overall prognosis of patients was poor, and age, hypotension, and cTnT can be used to predict mortality.

Multi-resource dynamic coordinated planning of flexible distribution network.

The flexible distribution network presents a promising architecture to accommodate highly integrated distributed generators and increasing loads in an efficient and cost-effective way. The distribution network is characterised by flexible interconnections and expansions based on soft open points, which enables it to dispatch power flow over the entire system with enhanced controllability and compatibility. Herein, we propose a multi-resource dynamic coordinated planning method of flexible distribution network that allows allocation strategies to be determined over a long-term planning period. Additionally, we establish a probabilistic framework to address source-load uncertainties, which mitigates the security risks of voltage violations and line overloads. A practical distribution network is adopted for flexible upgrading based on soft open points, and its cost benefits are evaluated and compared with that of traditional planning approaches. By adjusting the acceptable violation probability in chance constraints, a trade-off between investment efficiency and operational security can be realised.

A review on fermented vegetables: Microbial community and potential upgrading strategy via inoculated fermentation.

Fermentation is a traditional method utilized for vegetable preservation, with microorganisms playing a crucial role in the process. Nowadays, traditional spontaneous fermentation methods are widely employed, which excessively depend on the microorganisms attached to the surface of raw materials, resulting in great difficulties in ideal control over the fermentation process. To achieve standardized production and improve product quality, it is essential to promote inoculated fermentation. In this way, starter cultures can dominate the fermentation processes successfully. Unfortunately, inoculated fermentation has not been thoroughly studied and applied. Therefore, this paper provides a systematic review of the potential upgrading strategy of vegetable fermentation technology. First, we disclose the microbial community structures and succession rules in some typical spontaneously fermented vegetables to comprehend the microbial fermentation processes well. Then, internal and external factors affecting microorganisms are explored to provide references for the selection of fermented materials and conditions. Besides, we widely summarize the potential starter candidates with various characteristics isolated from spontaneously fermented products. Subsequently, we exhibited the inoculated fermentation strategies with those isolations. To optimize the product quality, not only lactic acid bacteria that lead the fermentation, but also yeasts that contribute to aroma formation should be combined for inoculation. The inoculation order of the starter cultures also affects the microbial fermentation. It is equally important to choose a proper processing method to guarantee the activity and convenience of starter cultures. Only in this way can we achieve the transition from traditional spontaneous fermentation to modern inoculated fermentation.