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Abstract Background Maternal short-term outcomes of postpartum depression (PPD) were widely examined, but little is known about its long-term association with multiple chronic diseases (multimorbidity) in women’s later life. This study aims to assess the association of PPD with chronic diseases and multimorbidity in women’s mid-late life. Methods This prospective cohort study included female participants in UK Biobank who attended online follow-up assessment and reported their history of PPD. A total of 36 chronic diseases were assessed and multimorbidity was defined as the co-existence of two or more of these diseases. Participants were followed from the baseline recruitment to the onset of two or more chronic diseases, death, or the end of follow-up (2023). Logistic regression models, Cox proportional hazard models, quasi-Poisson mixed effects models, and linear mixed models were conducted to examine the association of PPD with chronic diseases and multimorbidity at baseline and during follow-up. Results Among all 54,885 participants, 5106 (9.3%) participants experienced PPD, 13,928 (25.4%) participants had multimorbidity at baseline, and 14,135 (25.8%) participants developed two or more diseases during a median follow-up of 15 years. Women with a PPD history had higher odds of having multimorbidity at baseline (odds ratio = 1.35, 95% confidence interval [CI] = 1.27–1.44) and higher risk of developing multimorbidity during follow-up (hazard ratio = 1.13, 95% CI = 1.08–1.20). PPD was associated with increased number of chronic diseases, with the relatively new-onset number of diseases during follow-up being 8% higher for those with PPD (relative risk = 1.08, 95% CI = 1.05–1.12). Chronic diseases also accumulated at a faster annual rate for women with a history of PPD (b = 0.009, 95% CI = 0.007–0.011), compared to those without. We observed no interaction or mediation effects of physical activity, smoking, alcohol drinking, and dietary factors on the association between PPD and multimorbidity; however, women’s body mass index at baseline contributed to the association, with the mediation proportion of 6.38% (2.56–10.20%). Conclusions PPD was associated with higher risks of chronic diseases and multimorbidity in women’s mid-late life. This finding supports the importance of perinatal and postpartum mental health care, and its role in the prevention of chronic diseases and multimorbidity throughout women’s life course.

Despite the recognition of the importance of both formal and natural supports for adults with developmental disabilities, there is limited research on how organizations integrate these supports in the Canadian context. Using a collective case study design, this study explored how three organizations in British Columbia, Canada, facilitate the integration of formal and natural supports to improve the lives of adults with developmental disabilities. Data were collected through a comprehensive document review, interviews, and focus groups. The analysis was conducted in multiple phases, focusing initially on individual cases and then on cross-case themes. This research revealed both similarities and differences across three organizational approaches to integrating formal and natural supports for adults with developmental disabilities and their families. Key themes were identified, including the importance of relationships in this work, the creation of natural supports through formal supports and brokered community connections, systemic changes and innovative approaches, and the impact of funding models on organizational support. The findings highlight the critical need for organizations to build trust-based relationships between staff and the people they serve and to provide flexible support that adapts to changing needs and circumstances, facilitated by funders allowing for such flexibility. This study also underlines the value of formal supports in establishing natural networks and the necessity for cross-organizational partnerships to foster innovation and implement effective changes in the provision of services for people with developmental disabilities and their families.

Abstract Background Orbital Castleman's disease is a rare benign lymphoproliferative disorder of extranodal origin. Case presentation A 72-year-old man presented with bilateral upper eyelid swelling. Radiology revealed enlarged lacrimal glands in both eyes. Castleman's disease (plasma cell type) was confirmed by histo-immunochemical examinations after excision of the left orbital mass. No extraorbital involvement was found in systemic evaluation. Postoperatively, corticosteroid therapy was given. After 1 year of follow-up, there was no recurrence in the left orbit, and the swelling of the right eyelid was improved. Conclusions Here, we report a case of orbital Castleman's disease involving the lacrimal gland bilaterally and summarize previously reported cases. For bilateral orbital masses, the possibility of Castleman's disease should be considered. Before the diagnosis, it is necessary to fully distinguish from other diseases such as IgG4-related eye diseases.

Abstract Background Postoperative neurocognitive disorders (PNDs) frequently occur following orthopedic surgery and are closely associated with adverse prognosis. PNDs are an emerging concept that includes both postoperative cognitive dysfunction (POCD) and postoperative delirium (POD). The prevention of combined use of peripheral nerve block (PNB) and general anesthesia (GA) on POCD and/or POD incidence following orthopedic surgery remains unknown. We aimed to investigate the effect of this combined anesthesia method on POCD/POD incidence after orthopedic surgery, compared with GA. Methods The databases of PubMed, Web of Science, Embase via Ovid, and the Cochrane Central Register of Controlled Trials were searched for all available randomized controlled trials (RCTs). The incidence of POD/POCD was the primary outcome. Continuous and dichotomous outcomes are represented as standardized mean differences [SMD, 95% confidence interval (CI)] and risk ratios [RR, 95%CI], respectively. Results Meta-analysis of twelve RCTs with a total of 1488 patients revealed that compared with GA, PNB plus GA decreased the incidence of POCD (RR: 0.58, 95%CI: 0.35 to 0.95, P = 0.03, I2 = 0%), while the incidence of POD had no significant difference (RR: 0.87, 95%CI: 0.54 to 1.40, P = 0.57, I2 = 67%). Compared with GA alone, a significant decrease of intraoperative and postoperative opioid consumption (SMD: -1.54, 95%CI: -2.26 to -0.82, P

Abstract Background Physical activity and sleep are established modifiable lifestyle factors, but the optimal time of the day of these behaviours for health is unknown. This study examined the independent and joint associations of diurnal patterns of physical activity and sleep with all-cause mortality. Methods This prospective cohort study included 6,673 participants who have attended the accelerometer assessment in the 2011–2014 National Health and Nutrition Examination Surveys (NHANES). Diurnal patterns of accelerometer-measured physical activity and sleep were identified using K-means clustering analysis. All-cause mortality was ascertained from the accelerometer measurement to December 31, 2019 (median follow-up 6.8 years). Survey-weighted Cox proportional hazard models were performed to estimate the independent and joint associations of diurnal patterns of physical activity and sleep with all-cause mortality. Results Diurnal patterns identified were: early-morning (32.4%), midday (42.5%), and late-afternoon (25.1%) for physical activity; and irregular sleep (37.4%), morning lark (33.6%), and night owl (29.0%) for sleep. After adjusting for volume of physical activity, sleep duration and other potential covariates, the early-morning physical activity pattern (hazard ratio 1.36, 95% confidence interval 1.13–1.64) and irregular sleep pattern (1.42, 1.01–1.99) were independently associated with higher risk of all-cause mortality, compared with midday physical activity and morning lark sleep patterns, respectively. In addition, participants with the combined pattern of early-morning physical activity and irregular sleep had higher risk of all-cause mortality compared to those with midday physical activity combined with a morning lark sleep pattern (1.92, 1.33–2.78). Several sociodemographic differences were observed in the strength of these associations. Conclusions Wearable activity-rest monitoring data showed that peak physical activity in the early morning and irregular sleep diurnal patterns are associated with increased mortality risk, and the combination of these patterns further exaggerated the risk. Public health program should acknowledge that the diurnal patterns of physical activity and sleep, in addition to their duration and frequency, may play a crucial role in lifestyle-based health promotion and management strategies.

PurposeTo evaluate clinical presentation and imaging characteristics of leiomyosarcomas of the inferior vena cava (IVC LMS) using contrast-enhanced CT (CECT), ultrasonography (US), magnetic resonance imaging (MRI), and to identify features that facilitate early and accurate pre-operative diagnosis.Materials and methodsOur study enrolled 21 patients with pathologically confirmed IVC LMS from October 2015 to June 2022. All participants underwent CECT, and additionally, 12 participants had US examinations and 3 had MRI. Images were independently reviewed by two experienced radiologists. The clinical presentations and diagnostic characteristics were recorded.ResultsThe study involved 16 female and 5 male patients, with an average age of 55 ± 11 years (ranging from 34 to 80 years). Common clinical symptoms included abdominal pain, back pain, leg discomfort, abdominal distension, jaundice, and the presence of an abdominal mass. On CT scans, a large, lobulated, heterogeneous mass with progressive enhancement was typically seen in 13 of the 21 patients (61.9%). Ultrasonography revealed that IVC LMS typically presented as a lobulated, heterogeneous, hypoechoic mass. Color Doppler imaging evaluated lumen obstruction in 8 of the 12 patients (66.7%), and high velocity flow signals were detected by Pulsed wave Doppler in 4 of the 12 patients (33.3%). On MRI, IVC LMS presented as a heterogeneous mass that exhibited intermediate intensity on T1-weighted images, slightly high intensity on T2-weighted images and high intensity on diffusion-weighted images.ConclusionSeveral diagnostic characteristics on CECT, US and MRI could aid in the diagnosis of IVC LMS. The detection of a heterogeneous mass with progressive enhancement along the inferior vena cava on CECT was strongly indicative of IVC LMS. Both CT and US are effective in accurately indicating the location of the tumor within the IVC.

Abstract. Introduction:. Chronic pain is associated with single cardiometabolic diseases (CMDs). Less is known about the association of chronic pain with the co-occurrence of multiple CMDs, known as cardiometabolic multimorbidity (CMM). Objectives:. This study aims to examine the association between chronic pain and incidence of CMM and if it existed, to what extent chronic pain relates to the progression of specific CMD-related multimorbidity (MM). Methods:. We pooled individual-level data of 59,134 participants from 4 cohort studies across 18 countries between 2010 and 2020. Participants aged 45 years or older, free of CMDs (diabetes, heart diseases, and stroke), and with self-reported chronic pain status at baseline were included. Multinomial logistic regression was performed on the association of chronic pain with incident CMM and the progression of specific CMD-related MM. Results:. One-third (21,204) of participants reported chronic pain at baseline. After 8 to 9 years, 1344 (2.3%) developed CMM. Chronic pain was associated with the onset of each CMD (odds ratio [OR] range 1.12–1.37) and CMM combinations (OR range 1.57–2.09). It is also linked with the increased odds of more CMDs (1, 2, and 3) during the follow-up. For example, OR increased from 1.31 for individuals with one CMD, to 1.57 for those with 2 CMDs, to 2.09 for those with 3 CMDs. Chronic pain was also associated with developing all CMD-related MM (OR range 1.26–1.88). Compared with those with diabetes only, participants with chronic pain were more likely to progress to diabetes and heart diseases, as well as diabetes, heart diseases, and stroke. Conclusion:. Chronic pain is associated with incidence and progression of CMM, whose management should be considered in primary and secondary prevention of CMM among middle-aged and older populations.

Summary: Background: In China, rising chronic diseases has coincided with the increasing burden of multimorbidity, particularly for vulnerable populations. Limited primary data are available to understand the prevalence and patterns of multimorbidity, especially in resource-limited rural areas. This study aims to conduct robust evaluations of the prevalence and patterns of multimorbidity among rural adults in China, and to compare the differences in prevalence and patterns when using primary data alone versus in combination with routinely collected data. Methods: This cross-sectional study was conducted in three provinces in China, with two counties per province and 40 villages per county, resulted in a total of 240 villages. Participants were randomly selected and stratified by sex and age in each village. Multimorbidity, defined as the coexistence of two or more diseases in same individual, was assessed through data collection involving primary data (face-to-face questionnaire, physical examination and fasting blood sample collection) and routinely collected data (health insurance claims, hospital electronic records and infectious disease surveillance system). Multimorbidity prevalence and patterns were compared based on 1) primary data alone and 2) primary data complemented by routinely collected data. Findings: A total of 6474 individuals participated in this study (50.9% women, mean age 57.1). Combining routinely collected data with the primary data increased the prevalence of all single disease conditions. Multimorbidity prevalence rose from 35.7% with primary data alone to 44.4% with the addition of routinely collected data. The top three dyad multimorbidity patterns (hypertension with heart disease, stroke, or chronic digestive diseases) remained consistent between the two ascertainment methods, while triad pattern rankings had a substantial shift. According to blood pressure measurements, over 40% of participants had elevated blood pressure and may have undiagnosed hypertension. Over 20% may have undiagnosed mental health disorders base on the questionnaires, and nearly 10% with undiagnosed chronic kidney disease as indicated by blood testing. Interpretation: The utilisation of primary data combined with routinely collected data provided a robust estimation of multimorbidity burden in three rural regions in China. Yet, the prevalence may still have been underestimated due to inaccuracies in self-reported data and underdiagnosis of diseases. Future research should incorporate routinely collected data for more robust epidemiological evidence of multimorbidity. Funding: Harbin Medical University Leading Talent Grant (31021220002) and National Natural Science Foundation of China (72074065 and 72474063).

Chemotherapy is important in the systemic therapy for breast cancer. However, after chemotherapy, the left living tumour cells are more progressive. There is an urgent need to study the underlying mechanism which is still unclear to further improve the therapeutic efficacy of chemotherapy in breast cancer. Here we find a pro-tumour effect of the apoptotic cells induced by the chemotherapy, which is mediated by a new subset of macrophages undergoing LC3-associated phagocytosis (LAP). By transferring exosomal S100A11 into the living tumour cells after chemotherapy, the macrophage exhibits a more pro-tumour phenotype than classic M2-type macrophages. Moreover, S100A11 binds to IFITM3, inducing Akt phosphorylation of living tumour cells after chemotherapy, which promotes tumour progression. Of note, Akt inhibitor can enhance the therapeutic effcicay of chemotherapy in breast cancer. This study provides a novel mechanistic link between tumour-associated macrophages and breast cancer, uncovering Akt as a potential therapeutic target to improve chemotherapy efficacy.

The convincing performances of deep neural networks (DNNs) can be degraded tremendously under malicious samples, known as adversarial examples. Besides, with the widespread edge platforms, it is essential to reduce the DNN model size for efficient deployment on resource-limited edge devices. To achieve both adversarial robustness and model sparsity, we propose a robustness-aware search framework, an Adversarial Neural Architecture Search by the Pruning policy (ANAS-P). The layer-wise width is searched automatically via the binary convolutional mask, titled Depth-wise Differentiable Binary Convolutional indicator (D2BC). By conducting comprehensive experiments on three classification data sets (CIFAR-10, CIFAR-100, and Tiny-ImageNet) utilizing two adversarial losses TRADES (TRadeoff-inspired Adversarial DEfense via Surrogate-loss minimization) and MART (Misclassification Aware adveRsarial Training), we empirically demonstrate the effectiveness of ANAS in terms of clean accuracy and adversarial robust accuracy across various sparsity levels. Our proposed approach, ANAS-P, outperforms previous representative methods, especially in high-sparsity settings, with significant improvements.

Dilated cardiomyopathy (DCM) remains an enigmatic myocardial disorder characterized either by enlargement of either the left or right ventricle or both and reduced contractility, posing a significant burden on pediatric populations as a leading cause of cardiac-related mortality and morbidity. This paper presents a compelling case of DCM in a Han Chinese child whose genomic analysis unveiled a novel LMNA-C.185G>C (p.Arg62Pro) variant. Over a meticulous 3-year clinical follow-up, spanning ten outpatient consultations and hospital admissions since the initial diagnosis, the patient exhibited a progressive emergence of various cardiac conduction anomalies closely mirroring LMNA-associated phenotypes. Delving into a comprehensive review of the patient's 14-year medical journey and familial history, antecedent signs of muscular dystrophy (MD) predated DCM onset. Familial scrutiny revealed a lineage marred by muscular atrophy, with the patient's maternal grandmother having a history of muscular dystrophy and an episode of DCM, necessitating cardiac transplantation in the patient's uncle at age 37. This scenario illuminates the intricate interplay between LMNA-associated diseases and genetic predisposition. Timely identification of etiological triggers stands paramount in DCM management. Beyond conventional genetic scrutiny, leveraging novel serum biomarkers such as anti-heart muscle antibodies (AHA) remarkably enhanced diagnostic precision. Notably, personalized therapeutic interventions comprising prednisolone regimens and intravenous immunoglobulin infusions precipitated marked amelioration in heart failure symptoms and serum biomarker profiles. It is noteworthy to identify this novel genetic locus within the Han Chinese populace, underscoring the imperative of expanding the LMNA mutation repository within this demographic cohort. Early recognition of clinical manifestations and etiological cues in pediatric DCM heralds a paradigm shift in risk prognostication and individualized therapeutic interventions, underscoring the profound significance of precision medicine in combating rare familial cardiomyopathies.

Abstract Background Root resorption of adjacent teeth due to impacted canines is common, and orthodontic treatment often leads to secondary resorption or even loss of adjacent roots. Clinical reports of long-term stability after treatment are rare. Case presentation This study reports two cases of maxillary impacted canines resulting in severe root resorption of the adjacent lateral incisors. Surgical exposure, orthodontic retraction, and alignment of the impacted canines were successful in both cases, and the resorbed lateral incisors were stable with no significant loosening and normal pulp vitality after treatment and at the 5- and 10-year follow-up appointments. Conclusions Light orthodontic force may be used to move adjacent teeth with root resorption due to tooth obstruction. The path and direction in which the teeth are moved must be specifically designed so that the adjacent roots are not resorbed and so long-term stability can be achieved.

Seeds are the most basic and important means of production for agriculture. During the production and processing of seeds, they may undergo potential mechanical damages and mildew alterations, which might jeopardize their germination viability. Hence, checking the quality of seeds before sowing is of paramount importance for the benefit of the sower and the safety of agricultural production. In order to achieve an efficient detection of maize seed quality, our experiment assembled a dataset composed of 2,128 seeds with four different health statuses of maize: healthy, broken, moth-eaten, and mildewed. In this paper, we proposed a lightweight maize seed quality detection model for small objects based on improved YOLOv8: I-YOLOv8. Firstly, we introduced a multi-scale attention mechanism called EMA to efficiently retain information across channels and reduce computational load. Next, we chosen the SPD-Conv module for low-resolution images and small objects, and applied it to the backbone, which addressed the loss of fine-grained information and the less efficient learning of feature representations present in YOLOv8. Lastly, we reduced the large detection layer, which directed the network to pay more attention to the location, channel, and dimensional information of smaller objects, and we also replaced the loss function with WIoUv3. We validated our model using ablation studies and compared it with YOLOv5, YOLOv6, and YOLOv8. The mAP (Mean Average Precision) of the improved model I_YOLOv8 reaches 98.5%, which is 6.7% higher than YOLOv8. The average recognition time per image was 163.9fps, a boost of 5.2fps compared to YOLOv8. This study lays a theoretical foundation for the efficient, convenient, and rapid detection of maize quality, while also offering a technical basis for advancing automated maize quality detection means.

T cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy. Emerging evidence has shown that interferon-gamma (IFNγ) could enhance CXCL9 secretion from macrophages to recruit T cells, but Siglec15 expressed on TAMs can attenuate T cell proliferation. Therefore, targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues. We herein developed reduction-responsive nanoparticles (NPs) made with poly (disulfide amide) (PDSA) and lipid-poly (ethylene glycol) (lipid-PEG) for systemic delivery of Siglec15 siRNA (siSiglec15) and IFNγ for enhanced cancer immunotherapy. After intravenous administration, these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages (TAMs). With the highly concentrated glutathione (GSH) in the cytoplasm to destroy the nanostructure, the loaded IFNγ and siSiglec15 could be rapidly released, which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation, leading to significant inhibition of hepatocellular carcinoma (HCC) growth when combining with the immune checkpoint inhibitor. The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Land cover maps with high accuracy are essential for environmental protection and climate change research. The 30-meter-resolution maps, with their better resolution and longer historical records, are extensively utilized to assess changes in land cover and their effects on carbon storage, land–atmosphere energy balance, and water cycle processes. However, current data products use different classification methods, resulting in significant classification inconsistency and triggering serious disagreements among related studies. Here, we compared four mainstream land cover products in China, namely GLC_FCS30, CLCD, Globeland30, and CNLUCC. The result shows that only 50.34% of the classification results were consistent across the four datasets. The differences between pairs of datasets ranged from 21.10% to 37.53%. Importantly, most inconsistency occurs in transitional zones among land cover types sensitive to climate change and human activities. Based on the accuracy evaluation, CLCD is the most accurate land cover product, with an overall accuracy reaching 86.98 ± 0.76%, followed by CNLUCC (81.38 ± 0.87%) and GLC_FCS30 (77.83 ± 0.80%). Globeland30 had the lowest accuracy (75.24 ± 0.91%), primarily due to misclassification between croplands and forests. Misclassification diagnoses revealed that vegetation-related spectral confusion among land cover types contributed significantly to misclassifications, followed by slope, cloud cover, and landscape fragmentation, which affected satellite observation angles, data availability, and mixed pixels. Automated classification methods using the random forest algorithm can perform better than those that depend on traditional human–machine interactive interpretation or object-based approaches. However, their classification accuracy depends more on selecting training samples and feature variables.

Urban historical heritage areas serve as vital repositories of urban culture and history, playing a crucial role in cultural inheritance and the promotion of urban development. The protection and development of these heritage areas are essential for preserving the cultural characteristics and architectural styles of cities. Despite the growing body of research, a comprehensive review of the dynamic evolution, research frontiers, and future trajectories in this field remains absent. To bridge this gap, this study draws on the Web of Science Core Collection database, selecting 828 papers published between 2000 and 2024 that focus on urban historical heritage conservation and development. By employing Python programming and network analysis tools, this study conducted a systematic analysis of research structures and trends over the past 25 years. The results indicate that countries such as China and Italy, along with their respective research institutions, are at the forefront of global research in this area. Furthermore, this study identified research hotspots, including historic districts, sustainable urban development, urban regeneration, risk assessment, 3D modeling, digital documentation, and cultural tourism. This research not only discusses the challenges faced in the field but also explores future development trends, providing new theoretical perspectives and practical guidance for subsequent studies.

Abstract Background Whether a transthoracic (TT) procedure by a thoracic surgeon or a transabdominal (TA) by a gastrointestinal surgeon is best for Siewert type II esophagogastric junction adenocarcinoma (EGJA) remains unknown. Survival and perioperative outcomes were compared between the two groups in this meta-analysis to clarify this argument. Methods We searched 7 databases for eligible studies comparing TT and TA procedures for Siewert type II EGJA. The final analyzed endpoints included intraoperative and hospitalization outcomes, recurrence, complication, and survival. Results Seventeen studies involving 10,756 patients met the inclusion criteria. The TA group had higher rates of overall survival (OS) (HR: 1.31 [1.20 ~ 1.44], p

Community-based rehabilitation (CBR) is a multi-sectoral strategy that addresses the human rights and inclusion of persons with disabilities. Justice is a core component within the social pillar of the CBR Matrix, however, there is limited understanding of how CBR and Community-Based Inclusive Development (CBID) programs are implementing this component globally. The CBR Global Network and partners facilitated five online dialogues in different regions of the world to understand current practices and the future of the field as it relates to justice, choice, and power in CBR/CBID. Analysis was completed both deductively and inductively, to explore the trends and issues and any similarities or differences in practice across the regions. Participants discussed (i) challenges in policy implementation and law enforcement; (ii) the role of CBR/CBID programs; (iii) the role of family (as both facilitator and barrier to accessing justice); and (iv) engagement of people with disabilities. Findings detail important experiences of the CBR/CBID stakeholders around the globe, and may inform future funding, practice, and advocacy.

Abstract Background The impact of multimorbidity on long-term care (LTC) use is understudied, despite its well-documented negative effects on functional disabilities. The current study aims to assess the association between multimorbidity and informal LTC use in China. We also explored the socioeconomic and regional disparities. Methods The study included 10,831 community-dwelling respondents aged 45 years and older from the China Health and Retirement Longitudinal Study in 2011, 2015, and 2018 for analysis. We used a two-part model with random effects to estimate the association between multimorbidity and informal LTC use. Heterogeneity of the association by socioeconomic position (education and income) and region was explored via a subgroup analysis. We further converted the change of informal LTC hours associated with multimorbidity into monetary value and calculated the 95% uncertainty interval (UI). Results The reported prevalence of multimorbidity was 60·0% (95% CI: 58·9%, 61·2%) in 2018. We found multimorbidity was associated with an increased likelihood of receiving informal LTC (OR = 2·13; 95% CI: 1·97, 2·30) and more hours of informal LTC received (IRR = 1·20; 95% CI: 1·06, 1·37), ceteris paribus. Participants in the highest income quintile received more hours of informal LTC care (IRR = 1·62; 95% CI: 1·31, 1·99). The estimated monetary value of increased informal LTC hours among participants with multimorbidity was equivalent to 3·7% (95% UI: 2·2%, 5·4%) of China’s GDP in 2018. Conclusion Our findings substantiate the threat of multimorbidity to LTC burden. It is imperative to strengthen LTC services provision, especially among older adults with multimorbidity and ensure equal access among those with lower income.

Abstract Background Migrant and left-behind families are vulnerable in health services utilization, but little is known about their disparities in immunization of non-National Immunization Program (NIP) vaccines. This study aims to evaluate the immunization coverage, knowledge, satisfaction, and associated factors of non-NIP vaccines among local and migrant families in the urban areas and non-left-behind and left-behind families in the rural areas of China. Methods A cross-sectional survey was conducted in urban areas of Zhejiang and rural areas of Henan in China. A total of 1648 caregivers of children aged 1–6 years were interviewed face-to-face by a pre-designed online questionnaire, and their families were grouped into four types: local urban, migrant, non-left-behind, and left-behind. Non-NIP vaccines included Hemophilus influenza b (Hib) vaccine, varicella vaccine, rotavirus vaccine, enterovirus 71 vaccine (EV71) and 13-valent pneumonia vaccine (PCV13). Log-binomial regression models were used to calculate prevalence ratios (PRs) and 95% confidence intervals (CIs) for the difference on immunization coverage of children, and knowledge and satisfaction of caregivers among families. The network models were conducted to explore the interplay of immunization coverage, knowledge, and satisfaction. Logistic regression models with odds ratios (ORs) and 95% CIs were used to estimate the associated factors of non-NIP vaccination. Results The immunization coverage of all non-NIP vaccines and knowledge of all items of local urban families was the highest, followed by migrant, non-left-behind and left-behind families. Compared with local urban children, the PRs (95% CIs) for getting all vaccinated were 0.65 (0.52–0.81), 0.29 (0.22–0.37) and 0.14 (0.09–0.21) among migrant children, non-left-behind children and left-behind children, respectively. The coverage-knowledge-satisfaction network model showed the core node was the satisfaction of vaccination schedule. Non-NIP vaccination was associated with characteristics of both children and caregivers, including age of children (> 2 years-OR: 1.69, 95% CI: 1.07–2.68 for local urban children; 2.67, 1.39–5.13 for migrant children; 3.09, 1.23–7.76 for non-left-behind children); and below caregivers’ characteristics: family role (parents: 0.37, 0.14–0.99 for non-left-behind children), age (≤ 35 years: 7.27, 1.39–37.94 for non-left-behind children), sex (female: 0.49, 0.30–0.81 for local urban children; 0.31, 0.15–0.62 for non-left-behind children), physical health (more than average: 1.58, 1.07–2.35 for local urban children) and non-NIP vaccines knowledge (good: 0.45, 0.30–0.68 for local urban children; 7.54, 2.64–21.50 for left-behind children). Conclusions There were immunization disparities in non-NIP vaccines among migrant and left-behind families compared with their local counterparts. Non-NIP vaccination promotion strategies, including education on caregivers, and optimization of the immunization information system, should be delivered particularly among left-behind and migrant families. Graphical Abstract

Abstract Background We aimed to explore the associations of adherence to an overall healthy lifestyle with cardiometabolic diseases (CMDs) among schoolteachers in China. Methods We conducted a cross‐sectional analysis among 2983 teachers (aged 39.8 ± 9.3 years, 73.8% women) in Zhejiang Province, China. A healthy lifestyle score (0–7) was constructed based on seven low‐risk factors: healthy diet, noncurrent smoking, noncurrent drinking, regular exercise, normal body mass index (BMI), adequate sleep duration, and limited sedentary behavior. CMDs included self‐reported hyperlipidemia, hypertension, diabetes, coronary heart disease, and stroke. Multivariable‐adjusted logistic regression models were used to evaluate the associations between healthy lifestyle and CMD. Results A total of 493 (16.5%) participants had at least one CMD, with hyperlipidemia, hypertension, and diabetes being the three leading CMDs. Each point increment in a healthy lifestyle score was associated with 20% lower odds of having CMD (p‐trend

Abstract Objectives Development of endovenous treatment and sclerotherapy technology makes it feasible for clinicians to treat varicose veins (VV) through day surgery (DS). Superficial venous thrombosis (SVT) of lower extremities is a common complication of VV. This study aimed to investigate whether the existence of SVT below knee affect the safety and efficacy of DS for VV patients. Methods This is a single-center retrospective study. Clinical data of 593 VV patients was retrospectively analyzed. Raw data were matched by the using of propensity score matching model. Operation time, technical failure, postoperative DVT, skin burns, saphenous nerve injury, subcutaneous induration, and bleeding were compared between the groups. Also, we compared VV recurrence, SVT formation, DVT events and the change of VCSS score with 12 months. Results Fifty-nine patients complicated with SVT below knee were matched with 118 patients had VV only. Perioperative and follow-up outcomes were similar in both groups except for the number of incisions (median = 6 [5, 7] VS median = 4 [4, 5], P

Transcription factors (TFs) are key players in the regulation of gene transcription in mammalian cells. Although high‐throughput screening can be used to identify differentially expressed genes between comparable groups, the precision of the corresponding datasets is far from optimal. Here, we establish Target Finder of Transcription Factor (TFoTF), a method for the prediction of TF‐targeted genes from genomic and cancer‐related transcriptomic data. TFoTF can identify potential TF‐targeted genes in large cancer datasets and efficiently estimate correlations between TFs and their targeted genes with a significant level of specificity, sensitivity, and precision. Overall, TFoTF is an easy‐to‐use tool that can be utilized to generate testable hypotheses in the context of cancer research projects.

Abstract Background Little is known about the relationship between early life body size and occurrence of life-course multiple chronic diseases (multimorbidity). We aim to evaluate associations of birth weight, childhood body size, and their changes with the risks of chronic diseases and multimorbidity. Methods This prospective cohort study included 246,495 UK Biobank participants (aged 40–69 years) who reported birth weight and childhood body size at 10 years old. Birth weight was categorized into low, normal, and high; childhood body size was reported as being thinner, average, or plumper. Multimorbidity was defined as having two or more of 38 chronic conditions retrieved from inpatient hospital data until 31 December, 2020. The Cox regression and quasi-Poisson mixed effects models were used to estimate the associations. Results We show that 57,071 (23.2%) participants develop multimorbidity. Low birth weight (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.26–1.33), high birth weight (HR 1.02, 95% CI > 1.00–1.05), thinner (HR 1.21, 95% CI 1.18–1.23) and plumper body size (HR 1.06, 95% CI 1.04–1.09) are associated with higher risks of multimorbidity. A U-shaped relationship between birth weight and multimorbidity is observed. Changing to be thinner or plumper is associated with multimorbidity and many conditions, compared to changing to be average. Conclusions Low birth weight, being thinner and changing to have a thinner body size in childhood are associated with higher risks of developing multimorbidity and many chronic conditions in adulthood. Early monitoring and maintaining a normal body size in childhood could have life-course benefits for preventing multimorbidity above and beyond individual conditions.

Abstract Purpose Eyelid sebaceous gland carcinoma (SGC) is a malignancy with fatal risk, high recurrence rate, and pagetoid spread. Thus, recurrence risk prediction and prompt treatment are extremely important. This study aimed to develop a nomogram to predict SGC recurrence based on potential risk factors. Methods We conducted a retrospective study to train and test a nomogram based on the clinical data of 391 patients across our hospital (304) and other grass‐roots hospitals (87). After Cox regression, predictors included in the nomogram were selected, and sensitivity, specificity, concordance index (C‐index), etc., were calculated to test their discrimination ability. Results After a median follow‐up period of 4.12 years, SGC recurred in 52 (17.11%) patients. The 1‐, 2‐, and 5‐year recurrence‐free survival rates were 88.3%, 85.4%, and 81.6%, respectively. We examined five risk factors, such as lymph node metastasis at initial diagnosis (hazard ratio [HR], 2.260; 95% confidence interval [CI], 1.021–5.007), Ki67 (HR, 1.036; 95% CI, 1.020–1.052), histology differentiation degree (HR, 2.274; 95% CI, 1.063–4.865), conjunctival pagetoid infiltration (HR, 2.100; 95% CI, 1.0058–4.167), and orbital involvement (HR, 4.764; 95% CI, 1.436–15.803). The model had good discrimination in both internal and external test sets. The model had good discrimination in both internal and external test sets. The sensitivity of the internal test and external test set were 0.722 and 0.806, respectively, and specificity of the internal test and external test set were 0.886 and 0.893, respectively. Conclusion We examined the potential risk factors for eyelid SGC recurrence and constructed a nomogram, which complements the TNM system in terms of prediction, indicating that our nomogram has the potential to reach clinical significance. This nomogram has the potential to assist healthcare practitioners in promptly detecting patients who are at an elevated risk and in tailoring clinical interventions to meet their individualized needs.

Abstract Background Protocell refers to the basic unit of life and synthetic molecular assembly with cell structure and function. The protocells have great applications in the field of biomedical technology. Simulating the morphology and function of cells is the key to the preparation of protocells. However, some organic solvents used in the preparation process of protocells would damage the function of the bioactive substance. Perfluorocarbon, which has no toxic effect on bioactive substances, is an ideal solvent for protocell preparation. However, perfluorocarbon cannot be emulsified with water because of its inertia. Methods Spheroids can be formed in nature even without emulsification, since liquid can reshape the morphology of the solid phase through the scouring action, even if there is no stable interface between the two phases. Inspired by the formation of natural spheroids such as pebbles, we developed non-interfacial self-assembly (NISA) of microdroplets as a step toward synthetic protocells, in which the inert perfluorocarbon was utilized to reshape the hydrogel through the scouring action. Results The synthetic protocells were successfully obtained by using NISA-based protocell techniques, with the morphology very similar to native cells. Then we simulated the cell transcription process in the synthetic protocell and used the protocell as an mRNA carrier to transfect 293T cells. The results showed that protocells delivered mRNAs, and successfully expressed proteins in 293T cells. Further, we used the NISA method to fabricate an artificial cell by extracting and reassembling the membrane, proteins, and genomes of ovarian cancer cells. The results showed that the recombination of tumor cells was successfully achieved with similar morphology as tumor cells. In addition, the synthetic protocell prepared by the NISA method was used to reverse cancer chemoresistance by restoring cellular calcium homeostasis, which verified the application value of the synthetic protocell as a drug carrier. Conclusion This synthetic protocell fabricated by the NISA method simulates the occurrence and development process of primitive life, which has great potential application value in mRNA vaccine, cancer immunotherapy, and drug delivery. Graphical Abstract

Abstract Impacts occur everywhere, and they pose a serious threat to human health and production safety. Flexible materials with efficient cushioning and energy absorption are ideal candidates to provide protection from impacts. Despite the high demand, the cushioning capacity of protective materials is still limited. In this study, an integrated bionic strategy is proposed, and a bioinspired structural composite material with highly cushioning performance is developed on the basis of this strategy. The results demonstrated that the integrated bionic material, an S‐spider web‐foam, has excellent energy storage and dissipation as well as cushioning performance. Under impact loading, S‐spider web‐foam can reduce peak impact forces by a factor of 3.5 times better than silicone foam, achieving unprecedented cushioning performance. The results of this study deepen the understanding of flexible cushioning materials and may provide new strategies and inspiration for the preparation of high‐performance flexible cushioning materials.

IntroductionThe coronavirus (COVID-19) became a global pandemic in March 2020 and impacted nations worldwide not only because of the disease but also because the containment measures-imposed created ripple effects for the populations in each country. The COVID-19 pandemic disproportionately affected vulnerable groups, such as persons with disabilities. This study aimed to understand the impact of COVID-19 on the function of Community-Based Rehabilitation (CBR)/Community-Based Inclusive Development (CBID) across nations and for their target communities-persons with disabilities. The current article also described some measures CBR/CBID programs took in light of service closure to facilitate access to needed services for persons with disabilities.MethodsWe conducted a secondary analysis of qualitative data to understand the impact of COVID-19 on the functioning of CBR/CBID programs and their target communities. The original qualitative data were collected through online dialogues among CBR/CBID partners across five regions of the world, facilitated for understanding of their practices on five other topics.FindingsCOVID-19 significantly impacted the function of CBR/CBID programs across the world. Many services were halted due to public health measures, such as maintaining social distancing or lockdowns. The COVID-19 pandemic also had a negative impact on access to health, education and livelihood support for persons with disabilities. Additionally, many people with disabilities did not have access to COVID-19 related information and services like vaccines. However, we found that technology played a significant role in revitalizing CBR/CBID programs during COVID-19. CBR/CBID service providers across five regions used online platforms to disseminate information about COVID-19. Professionals also used technology to provide rehabilitation and educational services to people with disabilities through online platforms.ConclusionOur findings suggest that technology can play a vital role in continuing many services (e.g., CBR/CBID) that cannot be offered in person during crises like COVID-19. However, it is important to remember that technology may not be accessible to many individuals with disabilities, specifically those who reside in rural areas and who experience adverse situations like financial constraints. Additionally, many persons with disabilities may not have the necessary knowledge and skills to use technology. CBR personnel must consider that before adopting technology to provide services under CBR programs.

BackgroundAngiogenesis response plays a crucial role in the occurrence and development of Crohn’s disease (CD) and may involve the mechanism of infliximab non-response. However, the role of angiogenesis-related genes in Crohn’s disease has not been comprehensively studied. This study aimed to explore the expression profiles of angiogenesis-related genes in CD patients and construct models for disease diagnosis and prediction of infliximab non-response.MethodsCD-related microarray datasets were collected from the GEO database. Unsupervised consensus clustering analysis was performed based on differentially expressed angiogenesis-related genes to divide CD samples into two distinct clusters. Weighted gene co-expression network analysis (WGCNA) was conducted on the clusters to identify angiogenesis-related module. Based on the differentially expressed genes in the module, machine learning algorithms were employed to further identify hub genes and construct a disease diagnostic model. Subsequently, treatment outcome-related genes were extracted from these hub genes, and a predictive model for infliximab non-response in CD patients was ultimately built.ResultsBased on angiogenesis-related genes, we identified two distinct CD clusters (C1 and C2). Compared to C1, the metabolic pathways in C2 were significantly upregulated, and there was a higher abundance of cell clusters such as M1 macrophages and plasma cells. Additionally, C2 showed a poorer response to infliximab. Furthermore, a predictive model for infliximab non-response in CD patients was constructed based on the hub genes, and it was successfully validated using an external dataset.ConclusionComprehensive analysis of angiogenesis-related genes revealed different clusters of CD, which exhibited differential response rates to infliximab. The construction of models provides a reference for disease diagnosis and drug selection, aiding in clinical decision-making.

Introduction: Cardiometabolic multimorbidity (CMM) and depression are risk factors for cognitive decline and dementia. We investigated the independent and synergistic associations of CMM and depression on longitudinal cognitive deterioration in two Asian cohorts of elderly at varying cognitive status with differed underlying neuropathology. Methods: Eligible memory clinic (Harmonization) and stroke patients (Coast) aged ≥50 completed cognitive and clinical assessments at baseline and up to 5 follow-up visits in 6 years. Cardiometabolic diseases (CMDs), including hypertension, hyperlipidemia, diabetes mellitus, stroke and other cardiovascular diseases were assessed. Presence of CMM was defined as having two or more CMDs. Depression was defined by Geriatric Depression Scale (GDS) of ≥5. Biomarkers including cerebral beta-amyloid, cerebrovascular disease and ApoE genotype, were assessed by MRI and laboratory tests. Cognitive outcomes included cognitive trajectory patterns identified by the group-based trajectory model (GBTM) and the rate of change of global cognitive z-score. Multivariable logistic models and mixed models were conducted to assess the associations of CMM(+) and depression(+) with longitudinal cognitive decline. Stratification analysis by demographics and biomarkers was conducted. Results: Among a total of 809 (Harmonization: 586, Coast: 223) participants, three cognitive trajectories were identified by the GBTM in each cohort. CMM(+) was independently associated with longitudinal cognitive decline. There was a significant interaction among CMM, depression and time with longitudinal cognition in both cohorts (ps of β(CMM*depression*time) < 0.05). Compared with reference group, CMM(+) and depression(+) were associated with patterns of rapid decline (OR=3.58, =95%CI=(1.64,7.81)) and slow decline (OR=3.32, 95%CI=(1.20,9.19)) in Harmonization, and decline/low stable (OR=4.01, 95%CI=(1.03,15.50)) in Coast. Participants with CMM(+) and depression(+) had a 0.24 (95%CI= -0.49, -0.01) and 0.13 (95%CI=-0.24,-0.01) units decline per year on global cognitive z-scores in Harmonization and Coast, respectively, compared with those with CMM(-) and depression(-). The combined effect between CMM and depression was more pronounced among older and male participants, as well as APOEε4 carriers. Discussion: Our study demonstrated a synergistic effect between CMM and depression on longitudinal cognitive decline among elderly with differed underlying neuropathology. Targeting both CMM and depression in preventing cognitive decline may lead to greater effectiveness.

Water inrush disaster is one of the most severe problems during the construction of sea tunnels, primarily due to faults, karst, and weathered zones. Once a water inrush disaster occurs, it can lead to construction delays, traffic disruptions, and major economic losses, as well as potential consequences such as seawater intrusion, casualties, project suspension, and tunnel closure. Thus, advanced geological prediction is indispensable. During the construction of the Shantou Bay subsea tunnel, a sudden water inrush accident occurred in the sea–land transition section. To prevent such incidents and ensure safety, an integrated approach was employed. Firstly, the cross-hole resistivity method was used to predict water content in front of the tunnel, as it is highly sensitive to water. Subsequently, borehole ground-penetrating radar was applied to finely characterize the geological structure. By combining these two methods, the size, scale, location, water content, and spatial distribution of water-bearing structures in front of the tunnel were identified. With the above measures, the Shantou Bay subsea tunnel passed through the detection section successfully. Herein, we present a case study and offer a valuable reference for similar projects concerning subsea tunnel construction.

Summary: Age-related functional impairments (ARFIs) contribute to the loss of independence in older adults, but their progressions, interrelations, and combined relations with mortality are largely unknown. We conducted a prospective study among 17,914 participants in the Health and Retirement Study (2000–2020). The incidence rates of visual impairment, hearing impairment, physical frailty, and cognitive impairment increased exponentially with age, while those of restless sleep and depression increased relatively slowly. These ARFIs were associated with each other in temporal sequence and constituted a hazard network. We observed a dose-response relationship between the number of ARFIs and mortality risk, and the dyads involving physical frailty demonstrated the strongest associations with mortality. Our findings may assist in the identification of individuals at higher mortality risk and highlight the potential for future investigations to explore the impact of multiple ARFIs in aging.

BackgroundAlthough well-documented, the causal relationships between diet-derived circulating antioxidants, oxidative stress, and osteoarthritis (OA) are equivocal. The objective of this study is to employ two-sample Mendelian randomization (MR) to investigate possible causal relationships among dietary-derived circulating antioxidants, oxidative stress damage indicators, and OA risk.MethodsSingle-nucleotide polymorphisms for diet-derived circulating antioxidants (ascorbate, β-carotene, lycopene, retinol, and α-and γ-tocopherol), assessed as absolute levels and metabolites, as well as oxidative stress injury biomarkers (GSH, GPX, CAT, SOD, albumin, and total bilirubin), were retrieved from the published data and were used as genetic instrumental variables. Summary statistics for gene–OA associations were obtained from publicly available and two relatively large-scale GWAS meta-analyses to date. The inverse-variance weighting method was utilized as the primary MR analysis. Moreover, multivariable MR was used to determine if mediators (BMI and smoking) causally mediated any connection. Furthermore, for each exposure, MR analyses were conducted per outcome database and then meta-analyzed.ResultsGenetically predicted absolute retinol level was causally associated with hip OA risk [odds ratios (ORs) = 0.40, 95% confidence interval (CI) = 0.24–0.68, FDR-corrected p = 0.042]. Moreover, genetically predicted albumin level was causally associated with total OA risk (OR = 0.80, 95% CI = 0.75–0.86, FDR-corrected p = 2.20E-11), as well as the risk of hip OA (OR = 0.75, 95% CI = 0.68–0.84, FDR-corrected p = 1.38E-06) and knee OA (OR = 0.82, 95% CI = 0.76–0.89, FDR-corrected p = 4.49E-06). In addition, MVMR confirmed that the effect of albumin on hip OA is independent of smoking initiation, alcoholic drinks per week, and moderate-to-vigorous physical activity levels but may be influenced by BMI.ConclusionEvidence from our study supports a potentially protective effect of high levels of retinol and albumin on OA risk.

Abstract This study aims to give a new perspective to the biomarkers in the lung adenocarcinoma (LUAD) brain metastasis, pathways involved and potential therapeutics. We performed a comprehensive single-cell level transcriptomic analysis on one LUAD patient with circulating tumor cells (CTCs), primary tumor tissue and metastatic tumor tissue using scRNA-seq approach to identify metastasis related biomarkers. Further scRNA-seq were performed on 7 patients to validate the cancer metastatic hallmark. with single cells collected from either metastatic or primary LUAD tissues. Pathological and functional studies were also performed to evidence the critical role of RAC1 in the LUAD metastasis. Hallmark gene was verified based on immunohistochemistry staining, cytological experiment, survival information from The Cancer Genome Atlas (TCGA), and staining results from Human Protein Atlas (HPA) databases. PCA analysis revealed that CTCs were in the intermediate place between the metastatic group and primary group. In the unsupervised clustering analysis CTCs were closer to one of the metastatic tumor cells, implying heterogeneity of the metastatic tumor and origin of the CTCs were from metastatic site. Transitional phase related gene analysis identified RAC1 was enriched in metastatic tumor tissue (MTT) preferred gene set functioning as regulated cell death and apoptosis as well as promoted macromolecule organization. Compared with normal tissue, expression levels of RAC1 increased significantly in LUAD tissue based on HPA database. High expression of RAC1 predicts worse prognosis and higher-risk. EMT analysis identified the propensity of mesenchymal state in primary cells while epithelial signals were higher in the metastatic site. Functional clustering and pathway analyses suggested genes in RAC1 highly expressed cells played critical roles in adhesion, ECM and VEGF signaling pathways. Inhibition of RAC1 attenuates the proliferation, invasiveness and migration ability of lung cancer cells. Besides, through MRI T2WI results, we proved that RAC1 can promote brain metastasis in the RAC1-overexpressed H1975 cell burden nude mouse model. RAC1 and its mechanisms might promote drug design against LUAD brain metastasis.

Abstract Aim To develop health literacy assessment instrument for patients with chronic pain. Design Qualitative methods based on Delphi technique, assessed against the CREDES checklist. Methods A 2‐round Delphi method was adopted in this study. The panel consisted of 19 experts. Results The health literacy assessment instrument for chronic pain patients was constructed, which contained 3 dimensions (functional health literacy, interactive health literacy and critical health literacy) and 41 items. The positive coefficients of two rounds Delphi were 100.00% and 89.5%, respectively. The authority coefficient of experts was 0.848 and 0.858, respectively. The coordination coefficients of dimension and items were 0.222 and 0.364, respectively. Conclusions The health literacy assessment instrument dimensions and items for patients with chronic pain based on a Delphi method are valid. This instrument is suitable for investigating the health literacy level of patients with chronic pain.

It is often challenging for youth with disabilities to access university education in Africa, and for those who manage to make it to university, while there, their experiences are still not barrier-free. The purpose of this study was to uncover the experiences of the barriers and facilitators to inclusion for youth with disabilities in universities in South Africa, Ghana and Ethiopia. This qualitative project applied a critical, participatory research approach to exploring youth experiences. Youth with disabilities and their colleagues conducted seven focus group discussions, with an average of five students in each focus group, and we used a qualitative descriptive method to analyze data. The findings uncovered similarities and differences in the barriers and facilitators to inclusive education among students with disabilities across all sites. Participants noted limited financial support and university services, and how inaccessible spaces and harmful attitudes are all barriers that hinder their access to education and inclusion. The identified facilitators include support systems and self-directed facilitation. Although the students self-advocated and reported some support to assist in their inclusion in university, it was still insufficient. Notably, some universities are making a concerted effort toward inclusion and accessibility, but more work needs to be done.

BackgroundHerein, we applied bioinformatics methods to analyze the crosstalk between septic shock (SS) and venous thromboembolism (VTE), focusing on the correlation with immune infiltrating cells.MethodsExpression data were obtained from the Gene Expression Omnibus (GEO) database, including blood samples from SS patients (datasets GSE64457, GSE95233, and GSE57065) and VTE patients (GSE19151). We used the R package “limma” for differential expression analysis (p value

BackgroundThe role of certain biomarkers in the development of single cardiometabolic disease (CMD) has been intensively investigated. Less is known about the association of biomarkers with multiple CMDs (cardiometabolic multimorbidity, CMM), which is essential for the exploration of molecular targets for the prevention and treatment of CMM. We aimed to systematically synthesize the current evidence on CMM-related biomarkers.MethodsWe searched PubMed, Embase, Web of Science, and Ebsco for relevant studies from inception until August 31st, 2022. Studies reported the association of serum/plasma biomarkers with CMM, and relevant effect sizes were included. The outcomes were five progression patterns of CMM: (1) no CMD to CMM; (2) type 2 diabetes mellitus (T2DM) followed by stroke; (3) T2DM followed by coronary heart disease (CHD); (4) T2DM followed by stroke or CHD; and (5) CHD followed by T2DM. Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess the quality of the included studies. A meta-analysis was conducted to quantify the association of biomarkers and CMM.ResultsA total of 68 biomarkers were identified from 42 studies, which could be categorized into five groups: lipid metabolism, glycometabolism, liver function, immunity, and others. Lipid metabolism biomarkers were most reported to associate with CMM, including TC, TGs, HDL-C, LDL-C, and Lp(a). Fasting plasma glucose was also reported by several studies, and it was particularly associated with coexisting T2DM with vascular diseases. According to the quantitative meta-analysis, HDL-C was negatively associated with CHD risk among patients with T2DM (pooled OR for per 1 mmol/L increase = 0.79, 95% CI = 0.77–0.82), whereas a higher TGs level (pooled OR for higher than 150 mg/dL = 1.39, 95% CI = 1.10–1.75) was positively associated with CHD risk among female patients with T2DM.ConclusionCertain serum/plasma biomarkers were associated with the progression of CMM, in particular for those related to lipid metabolism, but heterogeneity and inconsistent findings still existed among included studies. There is a need for future research to explore more relevant biomarkers associated with the occurrence and progression of CMM, targeted at which is important for the early identification and prevention of CMM.

Porcine epidemic diarrhea virus (PEDV) is an acute enteric coronavirus, inducing watery diarrhea and high mortality in piglets, leading to huge economic losses in global pig industry. Ivermectin (IVM), an FDA-approved antiparasitic agent, is characterized by high efficacy and wide applicability. However, the poor bioavailability limits its application. Since the virus is parasitized inside the host cells, increasing the intracellular drug uptake can improve antiviral efficacy. Hence, we aimed to develop nanostructured lipid carriers (NLCs) to enhance the antiviral efficacy of IVM. The findings first revealed the capacity of IVM to inhibit the infectivity of PEDV by reducing viral replication with a certain direct inactivation effect. The as-prepared IVM-NLCs possessed hydrodynamic diameter of 153.5 nm with a zeta potential of −31.5 mV and high encapsulation efficiency (95.72%) and drug loading (11.17%). IVM interacted with lipids and was enveloped in lipid carriers with an amorphous state. Furthermore, its encapsulation in NLCs could enhance drug internalization. Meanwhile, IVM-NLCs inhibited PEDV proliferation by up to three orders of magnitude in terms of viral RNA copies, impeding the accumulation of reactive oxygen species and mitigating the mitochondrial dysfunction caused by PEDV infection. Moreover, IVM-NLCs markedly decreased the apoptosis rate of PEDV-induced Vero cells. Hence, IVM-NLCs showed superior inhibitory effect against PEDV compared to free IVM. Together, these results implied that NLCs is an efficient delivery system for IVM to improve its antiviral efficacy against PEDV via enhanced intracellular uptake.

Abstract Background Ocular mucosa-associated lymphoid tissue (MALT) lymphoma involving orbit and conjunctiva usually has an indolent clinical course with “salmon patch” mass as typical presentation. This study is to report a series of rare cases and investigate the clinical and pathological features of ocular MALT lymphoma that involved uveal tissue primarily and presented as posterior scleritis. Methods This retrospective, observational study was conducted at Beijing Tongren Hospital. From 2018 to 2020, 3 cases of 3 eyes (2 female patients and 1 male patient) with ocular MALT lymphoma that involved uveal tissue primarily and presented as posterior scleritis were included in the study. All patients had complaints of red eyes with blurred vision. The average age was 56.33 ± 2.08 years old and the average time from initial diagnosis to pathological diagnosis was 3.00 ± 1.73 months. Ophthalmic examinations including best-corrected visual acuity (BCVA), intraocular pressure (IOP), slit lamp microscope examinations, fundus photography, B-scan ultrasonography, ultrasound biomicroscope (UBM), optical coherence tomography (OCT), fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were conducted. Systemic workups including orbital magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT) and blood autoimmune antibody tests were also conducted. Pathological tissue from patients were obtained through surgeries. Biopsy examinations were performed to accurately determine pathological diagnosis. All the information of clinical, imaging and pathological changes were collected and analyzed. Results At the initial diagnosis, the BCVA of involved eyes decreased seriously while the IOP were normal. All involved eyeball showed extensive hyperemia and local thickening in the wall of eyeballs. B-scan ultrasonography showed mass with abundant blood and irregular cysts inside the eyeball wall and in the retrobulbar orbit, surrounding the ocular wall and optic nerve. UBM showed solid lesions with low and medium echo under the conjunctiva and inside the ciliary body of 2 cases. OCT showed posterior polar wavy rise of RPE and local neuroepithelial detachment in all cases. FFA and ICGA showed vascular abnormalities (patch-like strong fluorescence and fluorescence leakage) and local thickening in retina and choroid (Rectangle-like weak fluorescence below the macula). The posterior wall of the eyeball was thickened and enhanced in MRI. PET-CT also showed thickening of posterior wall of eyeballs and increased metabolic activity but there was no sign of autoimmune disease. All patients were diagnosed as MALT lymphoma through pathologic examinations of biopsy tissue. Conclusions The onset of primary ocular MALT lymphoma in uvea is hidden. The early clinical manifestations are lack of specificity and misleading. B-scan ultrasonography has characteristic manifestations and is valuable in diagnosis. However, pathological diagnosis through tissue biopsy is irreplaceable.

Objectives: To summarize the evidence on the association between sleep problems and multimorbidity.Methods: Six electronic databases (PubMed, Web of Science, Embase, China National Knowledge Infrastructure, VIP, and Wan fang) were searched to identify observational studies on the association between sleep problems and multimorbidity. A random-effects model was used to estimate the pooled odds ratios (ORs) and 95% confidence intervals for multimorbidity.Results: A total of 17 observational studies of 133,575 participants were included. Sleep problems included abnormal sleep duration, insomnia, snoring, poor sleep quality, obstructive sleep apnea (OSA) and restless legs syndrome (RLS). The pooled ORs (95% CIs) for multimorbidity were 1.49 (1.24–1.80) of short sleep duration, 1.21 (1.11–1.44) of long sleep duration and 2.53 (1.85–3.46) for insomnia. The association of other sleep problems with multimorbidity was narratively summarized due to limited number of comparable studies.Conclusion: Abnormal sleep duration and insomnia are associated with higher odds of multimorbidity, while the evidence on association of snoring, poor sleep quality, obstructive sleep apnea and restless legs syndrome with multimorbidity remains inconclusive. Interventions targeting sleep problems should be delivered for better management of multimorbidity.

Abstract Angiotensin II (AngII) causes endothelial dysfunction. Eucommia ulmoides extract (EUE) is documented to manipulate AngII, but its impact on cardiac microvascular endothelial cell (CMVEC) function remains unknown. This study determines the effects of EUE on AngII-treated CMVECs. CMVECs were treated with different concentrations of AngII or EUE alone and/or the p53 protein activator, WR-1065, before AngII treatment, followed by examinations of the apoptotic, migratory, proliferative, and angiogenic capacities and nitric oxide (NO), p53, von Willebrand factor (vWF), endothelin (ET)-1, endothelial NO synthase (eNOS), manganese superoxide dismutase (MnSOD), hypoxia-inducible factor (HIF)-1α, and vascular endothelial growth factor (VEGF) levels. AngII induced CMVEC dysfunction in a concentration-dependent manner. EUE enhanced the proliferative, migratory, and angiogenic capacities and NO, MnSOD, and eNOS levels but repressed apoptosis and vWF and ET-1 levels in AngII-induced dysfunctional CMVECs. Moreover, AngII increased p53 mRNA levels, p-p53 levels in the nucleus, and p53 protein levels in the cytoplasm and diminishes HIF-1α and VEGF levels in CMVECs; however, these effects were counteracted by EUE treatment. Moreover, WR-1065 abrogated the mitigating effects of EUE on AngII-induced CMVEC dysfunction by activating p53 and decreasing HIF-1α and VEGF expression. In conclusion, EUE attenuates AngII-induced CMVEC dysfunction by upregulating HIF-1α and VEGF levels via p53 inactivation.

Abstract Exosomes are membranous vesicles containing RNA and proteins that are specifically secreted in vivo. Exosomes have many functions, such as material transport and signal transduction between cells. Many studies have proven that exosomes can not only be used as biomarkers for disease diagnosis but also as carriers to transmit information between cells. Exosomes participate in a variety of physiological and pathological processes, including the immune response, antigen presentation, cell migration, cell differentiation, and tumour development. Differences in exosome functions depend on cell type. In recent years, exosome origin, cargo composition, and precise regulatory mechanisms have been the focus of research. Although exosomes have been extensively reported in digestive tumours, few articles have reviewed their roles in inflammatory diseases of the digestive system, especially inflammatory-related diseases (such as reflux oesophagitis, gastritis, inflammatory bowel disease, hepatitis, and pancreatitis). This paper briefly summarizes the roles of exosomes in inflammatory diseases of the digestive system to provide a basis for research on the mechanism of inflammatory diseases of the digestive system targeted by exosomes.

Abstract Chemoresistance is often a cause of the failure of chemotherapy in cancer treatment. Sorcin (SRI) is a soluble resistance-related calcium-binding protein involved in chemoresistant processes and is overexpressed in many chemoresistant cancer cells, including paclitaxel (PTX)-resistant ovarian cancer. Increased SRI can reduce the concentration of calcium ions in the cytosol and mitochondria and the decrease of calcium ion concentration prevents the occurrence of apoptosis. Here we examined the SRI expression in multiple cancers using a human TissueArray and found that SRI expression was significantly higher in malignant tumor tissues. Furthermore, SRI was overexpressed, while intracellular calcium concentration was decreased, in chemoresistant cancer cells. To restore intracellular calcium homeostasis and overcome chemoresistance, we developed lipid-coated albumin-PTX nanoparticles loaded with SRI-siRNA (LANP-PTX-siSRI) for PTX and SRI-siRNA co-delivery. LANP-PTX-siSRI had dual-target roles in the regulation of SRI and the delivery of PTX into chemoresistant cells. The LANP-PTX-siSRI inhibited the expression of SRI and enhanced intracellular calcium, leading to the induction of apoptosis and the inhibition of the growth of PTX-resistant cancer cells in vitro and in vivo. In addition, the mechanism study revealed that the overexpression of SRI was associated with an impaired TGF-β signaling pathway. The administration of TGF-β1 inhibited two calcium-binding proteins SRI and S100A14. In conclusion, our data unveil that restoring intracellular calcium ion homeostasis via reducing SRI expression can reverse chemoresistance. Thus, the fabricated LANP-PTX-siSRI has a potentially therapeutical application.

Abstract Bacterial vaginosis (BV) is a genital infection that frequently presents in women infected with human papillomavirus (HPV), but the correlation between BV, HPV and cervical intraepithelial neoplasia (CIN) development is still elusive. We organized a cross-sectional analysis which enrolled 624 participants and obtained 423 samples of vaginal secretions from them, including 193 HPV-negative samples and 230 HR-HPV-positive samples. We used 16S rRNA sequencing to measure the vaginal microbiota diversity in women with different BV, HPV and CIN status, and then calculated risk factors for CIN by logistic regression. We found that the diversity of vaginal microbiota was significantly increased after BV, HPV and BV-infected CIN group. The Observed species and Chao1 index of H.C group showed little difference with normal group, while its Shannon index was considerable higher than normal group. L. iners enriched in HPV infection group compared with others significantly. BV (OR = 0.358; 95% CI = 0.195–0.656; P

Anesthesia and surgery are likely causing cognitive dysfunction in patients, especially the elderly. However, the underlying pathogenic mechanisms largely remain unclear. Accumulating evidence suggest that signaling between Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) plays an important role in the pathogenesis and treatment of brain dysfunction, while sulforaphane (SFN), a natural compound acting as an Nrf2 agonist, can improve brain function. In the present study, we used 9-month-old mice to perform tibial fracture surgery under isoflurane general anesthesia. Hierarchical cluster analysis of Morris water maze test (MWMT) analysis was performed to classify mice into post-operative cognitive dysfunction (POCD) versus non-POCD phenotypes. Expression levels of Keap1 and Nrf2 were significantly decreased in the medial prefrontal cortex (mPFC), hippocampus and liver, but not in the nucleus accumbens, muscle and gut of POCD mice compared to control and non-POCD mice. Interestingly, both pretreatment and posttreatment with SFN significantly improved the abnormal behaviors of mice in the MWMT, in parallel with the up-regulated levels of Keap1-Nrf2 signaling in the mPFC, hippocampus and liver. In conclusion, these results suggest that decreased Keap1-Nrf2 signaling in the mPFC, hippocampus and liver may contribute to the onset of POCD, and that SFN exerts facilitating effects on POCD symptoms by increasing Keap1-Nrf2 signaling.

Microorganisms play very important roles in carcinogenesis, tumor progression, and resistance upon treatment. Due to the challenge of accurately acquiring samples and quantifying low-biomass tissue microorganisms, most studies have focused on the effect of gut microorganisms on cancer treatments, especially the efficacy of immunotherapy. Although recent publications reveal the potential interactions between intratumor microorganisms and the immune microenvironment, whether and to what extent the intratumor microorganism could affect progression and treatment outcome remain controversial. This study is aiming to evaluate the associations among intratumor microorganisms, DNA methylation cancer driver genes, immune response, and clinical outcomes from a pan-cancer perspective, using 6,876 TCGA samples across 21 cancer types. We revealed that tumor microorganism dysbiosis is closely associated with the abnormal tumor methylome and/or tumor microenvironment, which might serve to enhance the proliferation ability and fitness for the therapy of tumors. These findings shed the light on a better understanding of the interactions between tumor cells and carcinogens during and after tumor formation, as well as microorganism-associated methylation alterations that could further serve as biomarkers for clinical outcome assessment.

N6-methyladenosine (m6A) modification has been demonstrated to exhibit a crucial prognostic effect on colorectal cancer (CRC). Nonetheless, potential mechanism of m6A in survival rate and immunotherapeutic response remains unknown. Here we investigated the genes associated with m6A regulators and developed a risk score for predicting the overall survival (OS) of CRC patients. RNA-seq transcriptomic profiling data of COAD/READ samples were obtained from The Cancer Genome Atlas (TCGA) database. Absolute Shrinkage and Selection Operator (LASSO)- Cox regression analysis was conducted to identify the m6A-related gene expression signatures and the selected genes were inputted into stepwise regression to develop a prognostic risk score in TCGA, and its predictive performance of CRC survival was further validated in Gene Expression Omnibus (GEO) datasets. According to our results, the risk score comprising 18 m6A-related mRNAs was significantly associated with CRC survival in both TCGA and GEO datasets. And the stratified analysis also confirmed that high-risk score acted as a poor factor in different age, sex, T stage, and tumour, node, metastasis (TNM) stages. The m6A-related prognostic score in combination with clinical characteristics yielded time-dependent area under the receiver operating characteristic curve (AUCs) of 0.85 (95%CI: 0.79–0.91), 0.84 (95%CI: 0.79–0.90) and 0.80 (95%CI: 0.71–0.88) for the prediction of the 1-, 3-, 5-year OS of CRC in TCGA cohort. Furthermore, mutation of oncogenes occurred more frequently in the high-risk group and the composition of immune cells in tumour microenvironment (TME) was significantly distinct between the low- and high-risk groups. The low-risk group had a lower microsatellite instability (MSI) score, T-cell exclusion score and dysfunction score, implying that low-risk patients may have a better immunotherapy response than high-risk patients. In summary, a prognostic risk score derived from m6A-related gene expression signatures could serve as a potential prognostic predictor for CRC survival and indicator for predicting immunotherapy response in CRC patients.