The EPRS-ATF4-COLI pathway axis is a potential target for anaplastic thyroid carcinoma therapy.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is recognized as the most aggressive and malignant form of thyroid cancer, underscoring the critical need for effective therapeutic strategies to curb its progression and improve patient prognosis. Halofuginone (HF), a derivative of febrifugine, has displayed antitumor properties across various cancer types. However, there is a paucity of published research focused on the potential of HF to enhance the clinical efficacy of treating ATC. OBJECTIVE: In this study, we thoroughly investigated the antitumor effects and mechanisms of HF in ATC, aiming to discover lead compounds for treating ATC and reveal novel therapeutic targets for ATC tumors. METHODS: A series of assays, including CCK8, colony formation, tumor xenograft models, and ATC tumor organoid experiments, were conducted to evaluate the anticancer properties of HF both in vitro and in vivo. Techniques such as drug affinity responsive target stability (DARTS), western blot, immunofluorescence, and immunohistochemistry were employed to pinpoint HF target proteins within ATC. Furthermore, we harnessed the GEPIA and GEO databases and performed immunohistochemistry to validate the therapeutic potential of the glutamyl-prolyl-tRNA-synthetase (EPRS)- activating transcription factor 4 (ATF4)- type I collagen (COLI) pathway axis in the context of ATC. The study also incorporated RNA sequencing analysis, confocal imaging, and flow cytometry to delve into the molecular mechanisms of HF in ATC. RESULTS: HF exhibited a substantial inhibitory impact on cell proliferation in vitro and on tumor growth in vivo. The DARTS results highlighted HF's influence on EPRS within ATC cells, triggering an amino acid starvation response (AASR) by suppressing EPRS expression, consequently leading to a reduction in COLI expression in ATC cells. The introduction of proline mitigated the effect of HF on ATF4 and COLI expression, indicating that the EPRS-ATF4-COLI pathway axis was a focal target of HF in ATC. Analysis of the expression levels of the EPRS, ATF4, and COLI proteins in thyroid tumors, along with an examination of the relationship between COLI expression and thyroid tumor stage, revealed that HF significantly inhibited the growth of ATC tumor organoids, demonstrating the therapeutic potential of targeting the EPRS-ATF4-COLI pathway axis in ATC. RNA sequencing analysis revealed significant differences in the pathways associated with metastasis and apoptosis between control and HF-treated cells. Transwell assays and flow cytometry experiments provided evidence of the capacity of HF to impede cell migration and induce apoptosis in ATC cells. Furthermore, HF hindered cell metastasis by suppressing the epithelial-mesenchymal transition (EMT) pathway, acting through the inhibition of FAK-AKT-NF-κB/Wnt-ß-catenin signaling and restraining angiogenesis via the VEGF pathway. HF also promoted apoptosis through the mitochondrial apoptotic pathway. CONCLUSION: This study provided inaugural evidence suggesting that HF could emerge as a promising therapeutic agent for the treatment of ATC. The EPRS-ATF4-COLI pathway axis stood out as a prospective biomarker and therapeutic target for ATC.

Causal effect of gut microbiota of Defluviitaleaceae on the clinical pathway of "Influenza-Subacute Thyroiditis-Hypothyroidism".

Introduction: Hypothyroidism has been found to be influenced by gut microbiota. However, it remains unclear which a taxon of gut microbiota plays a key role in this function. Identifying the key bacteria affects hypothyroidism and through what mechanism will be helpful for the prevention of hypothyroidism through specific clinical pathways. Materials and methods: In Study A, 35 families and 130 genera of gut microbiota are used as exposures, with hypothyroidism as the outcome. The causal effect of the gut microbiota on hypothyroidism is estimated through two-sample Mendelian randomization. Combining the results of the two taxonomical levels, key taxa are selected, which in Study B are investigated for their causal association with multiple generally admitted causes of hypothyroidism and their more upstream factors. For validating and revealing the potential mechanism, enrichment analyses of the related genes and interacting transcription factors were performed. Results: In Study A, Defluviitaleaceae (OR: 0.043, 95% CI: 0.005-0.363, P = 0.018)/Defluviitaleaceae_UCG_011 (OR: 0.385, 95% CI: 0.172-0.865, P = 0.021) are significantly causally associated with hypothyroidism at both taxonomical levels. In Study B, Defluviitaleaceae family and Defluviitaleaceae_UCG_011 genus show the causal association with decreased thyroiditis (Family: OR: 0.174, 95% CI: 0.046-0.653, P = 0.029; Genus: OR: 0.139, 95% CI: 0.029-0.664, P = 0.043), decreased subacute thyroiditis (Family: OR: 0.028, 95% CI: 0.004-0.213, P = 0.007; Genus: OR: 0.018, 95% CI: 0.002-0.194, P = 0.013), decreased influenza (Family: OR: 0.818, 95% CI: 0.676-0.989, P = 0.038; Genus: OR: 0.792, 95% CI: 0.644-0.974, P = 0.027), and increased anti-influenza H3N2 IgG levels (Family: OR: 1.934, 95% CI: 1.123-3.332, P = 0.017; Genus: OR: 1.675, 95% CI: 0.953-2.943, P = 0.073). The results of the enrichment analysis are consistent with the findings and the suggested possible mechanisms. Conclusion: Defluviitaleaceae of the gut microbiota displays the probability of causally inhibiting the clinical pathway of "Influenza-Subacute Thyroiditis-Hypothyroidism" and acts as the potential probiotics to prevent influenza, subacute thyroiditis, and hypothyroidism.

MTFN: multi-temporal feature fusing network with co-attention for DCE-MRI synthesis.

BACKGROUND: Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) plays an important role in the diagnosis and treatment of breast cancer. However, obtaining complete eight temporal images of DCE-MRI requires a long scanning time, which causes patients' discomfort in the scanning process. Therefore, to reduce the time, the multi temporal feature fusing neural network with Co-attention (MTFN) is proposed to generate the eighth temporal images of DCE-MRI, which enables the acquisition of DCE-MRI images without scanning. In order to reduce the time, multi-temporal feature fusion cooperative attention mechanism neural network (MTFN) is proposed to generate the eighth temporal images of DCE-MRI, which enables DCE-MRI image acquisition without scanning. METHODS: In this paper, we propose multi temporal feature fusing neural network with Co-attention (MTFN) for DCE-MRI Synthesis, in which the Co-attention module can fully fuse the features of the first and third temporal image to obtain the hybrid features. The Co-attention explore long-range dependencies, not just relationships between pixels. Therefore, the hybrid features are more helpful to generate the eighth temporal images. RESULTS: We conduct experiments on the private breast DCE-MRI dataset from hospitals and the multi modal Brain Tumor Segmentation Challenge2018 dataset (BraTs2018). Compared with existing methods, the experimental results of our method show the improvement and our method can generate more realistic images. In the meanwhile, we also use synthetic images to classify the molecular typing of breast cancer that the accuracy on the original eighth time-series images and the generated images are 89.53% and 92.46%, which have been improved by about 3%, and the classification results verify the practicability of the synthetic images. CONCLUSIONS: The results of subjective evaluation and objective image quality evaluation indicators show the effectiveness of our method, which can obtain comprehensive and useful information. The improvement of classification accuracy proves that the images generated by our method are practical.

Circulating small extracellular vesicle-based miRNA classifier for follicular thyroid carcinoma: a diagnostic study.

BACKGROUND: The diagnosis of follicular thyroid carcinoma (FTC) prior to surgery remains a major challenge in the clinic. METHODS: This multicentre diagnostic study involved 41 and 150 age- and sex-matched patients in the training cohort and validation cohort, respectively. The diagnostic properties of circulating small extracellular vesicle (sEV)-associated and cell-free RNAs were compared by RNA sequencing in the training cohort. Subsequently, using a quantitative real-time polymerase chain reaction (qRT‒PCR) assay, high-quality candidates were identified to construct an RNA classifier for FTC and verified in the validation cohort. The parallel expression, stability and influence of the RNA classifier on surgical strategy were also investigated. RESULTS: The diagnostic properties of sEV long RNAs, cell-free long RNAs and sEV microRNAs (miRNAs) were comparable and superior to those of cell-free miRNAs in RNA sequencing. Given the clinical application, the circulating sEV miRNA (CirsEV-miR) classifier was developed from five miRNAs based on qRT‒PCR data, which could well identify FTC patients (area under curve [AUC] of 0.924 in the training cohort and 0.844 in the multicentre validation cohort). Further tests revealed that the CirsEV-miR score was significantly correlated with the tumour burden, and the levels of sEV miRNAs were also higher in sEVs from the FTC cell line, organoid and tissue. Additionally, circulating sEV miRNAs remained constant after different treatments, and the addition of the CirsEV-miR classifier as a biomarker improves the current surgical strategy. CONCLUSIONS: The CirsEV-miR classifier could serve as a noninvasive, convenient, specific and stable auxiliary test to help diagnose FTC following ultrasonography.

Dynamics of The Γδtcr Repertoires During The Dedifferentiation Process and Pilot Implications for Immunotherapy of Thyroid Cancer.

γδ T cells are evolutionarily conserved T lymphocytes that manifest unique antitumor efficacy independent of tumor mutation burden (TMB) and conventional human leukocyte antigen (HLA) recognition. However, the dynamic changes in their T cell receptor (TCR) repertoire during cancer progression and treatment courses remain unclear. Here, a comprehensive characterization of γδTCR repertoires are performed in thyroid cancers with divergent differentiation states through cross-sectional studies. The findings revealed a significant correlation between the differentiation states and TCR repertoire diversity. Notably, highly expanded clones are prominently enriched in γδ T cell compartment of dedifferentiated patients. Moreover, by longitudinal investigations of the γδ T cell response to various antitumor therapies, it is found that the emergence and expansion of the Vδ2neg subset may be potentially associated with favorable clinical outcomes after post-radiotherapeutic immunotherapy. These findings are further validated at single-cell resolution in both advanced thyroid cancer patients and a murine model, underlining the importance of further investigations into the role of γδTCR in cancer immunity and therapeutic strategies.

Mapping global new-onset, worsening, and resolution of diabetes following partial pancreatectomy: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Partial pancreatectomy, commonly used for chronic pancreatitis, or pancreatic lesions, has diverse impacts on endocrine and metabolism system. The study aims to determine the global prevalence of new-onset, worsening, and resolution of diabetes following partial pancreatectomy. METHODS: The authors searched PubMed, Embase, Web of Science, and Cochrane Library from inception to October, 2023. DerSimonian-Laird random-effects model with Logit transformation was used. Sensitivity analysis, meta-regression, and subgroup analysis were employed to investigate determinants of the prevalence of new-onset diabetes. RESULTS: A total of 82 studies involving 13 257 patients were included. The overall prevalence of new-onset diabetes after partial pancreatectomy was 17.1%. Univariate meta-regression indicated that study size was the cause of heterogeneity. Multivariable analysis suggested that income of country or area had the highest predictor importance (49.7%). For subgroup analysis, the prevalence of new-onset diabetes varied from 7.6% (France, 95% CI: 4.3-13.0) to 38.0% (UK, 95% CI: 28.2-48.8, P <0.01) across different countries. Patients with surgical indications for chronic pancreatitis exhibited a higher prevalence (30.7%, 95% CI: 21.8-41.3) than those with pancreatic lesions (16.4%, 95% CI: 14.3-18.7, P <0.01). The type of surgical procedure also influenced the prevalence, with distal pancreatectomy having the highest prevalence (23.7%, 95% CI: 22.2-25.3, P <0.01). Moreover, the prevalence of worsening and resolution of preoperative diabetes was 41.1 and 25.8%, respectively. CONCLUSIONS: Postoperative diabetes has a relatively high prevalence in patients undergoing partial pancreatectomy, which calls for attention and dedicated action from primary care physicians, specialists, and health policy makers alike.

Increasing trends of overweight and obesity in treatment-naive people living with HIV in Shenzhen from 2014 to 2020: an emerging health concern.

Background: With the early initiation of antiretroviral therapy (ART) in China, the demographics of treatment-naïve people living with HIV (PLWH) are moving closer to those of the general population, which is characterized by a gradual increase in metabolic indicators. However, the epidemic trends of overweight and obesity over the past decade in treatment-naïve PLWH ready to initiate ART have not yet been investigated. Methods: A cross-sectional study was conducted, including 12,135 consecutive treatment-naïve PLWH ready to initiate ART in Shenzhen, using data retrieved from the China National Free Antiretroviral Treatment Program database from 2014 to 2020. The chi-square test was used to examine the trends of overweight and obesity between age groups, and multivariate logistic regression was used to identify the association of overweight and obesity with hyperglycemia and dyslipidemia. Results: During the 7-year study period, 12,135 treatment-naïve PLWH ready to initiate ART were included, among whom 1,837 (15.1%) were overweight and 388 (3.2%) were obese. The prevalence of overweight rose from 11.4 to 17.3% (Z = -4.58, P for trend <0.01) and that of obesity from 2.0% to 4.2% (Z = -6.45, P for trend <0.01) from 2014 to 2020. The annual prevalence of overweight was the highest in the age group of participants >35 years compared to prevalence in other age groups during the period 2014-2020. Compared with those who were not overweight or obese, PLWH who were overweight or obese were more likely to have hyperglycemia (aOR 1.84, 95% CI: 1.37-2.49 for overweight; aOR 2.68, 95% CI: 1.62-4.44 for obesity), higher ALT level (aOR 2.70, 95% CI: 2.33-3.13 for overweight; aOR 3.85, 95% CI: 2.93-5.05 for obesity), higher TG levels (aOR 1.89, 95% CI 1.63-2.19 for overweight; aOR 2.56, 95% CI 1.97-3.32 for obesity), and lower HDL levels (aOR 1.67, 95% CI 1.44-1.95 for overweight; aOR 2.06, 95% CI 1.54-2.77 for obesity). Conclusion: The prevalence of overweight and obesity in treatment-naive PLWH increased steadily from 2014 to 2020 in Shenzhen. Overweight and obese in treatment-naive PLWH ready to initiate ART were associated with dyslipidemia and hyperglycemia. Public health authorities should take proactive steps to address these issues by implementing targeted screening, intervention programs including lifestyle modifications, and integrated healthcare services.

Excitatory purinergic and cholinergic expression changed in a partial bladder outlet obstruction-induced overactive bladder rat model.

Overactive bladder (OAB) is a common, long-term symptom complex with a high prevalence in women worldwide. OAB has caused a social burden, and effective treatments are urgently needed. However, the pathogenesis of OAB has yet to be elucidated. Model rats underwent bladder outlet obstruction surgery. In the 2nd, 3rd, and 4th weeks after surgery, metabolic cages were used to detect the 12 h urine volume of rats in the sham and model groups. The urodynamic parameters bladder leak point pressure (BPLL), maximum voiding pressure (MVP), residual volume (RV), maximum bladder capacity (MBC), bladder compliance (BC), voided efficiency (VE), and non-voiding contractions (NVCs) were also detected. Moreover, the contractile responses of isolated detrusor muscles to electrical and carbachol stimulation were examined at the abovementioned time points. At the 4th week after surgery, the bladders of both groups were obtained for hematoxylin-eosin (H&E) and Masson's trichrome staining. Real-time qPCR and Western blot were performed to quantify the expression of choline acetyltransferase (ChAT) and solute carrier family 17 member 9 (SLC17A9). At week 4, compared with the sham group, the 12 h urine volume of PBOO group increased significantly. The BLPP, MVP, VE, MBC, and NVCs increased significantly, and the VE was significantly reduced in 4-week PBOO group. The contractile responses of isolated detrusor muscles to electrical and carbachol stimulation significantly increased in 4-week PBOO group. In the 4-week PBOO group, the bladder wall and the ratio of bladder muscle to collagen within the bladder smooth muscle layer wall were significantly higher than those in the sham group. ChAT and SLC17A9 mRNA and protein expression in the OAB model rats significantly increased. At 4 weeks after PBOO, the OAB model was successfully established. The gene and protein expression levels of ChAT and SLC17A9 increased in the bladder of the OAB model, suggesting that OAB may be related to increased excitatory purinergic and cholinergic expression.

The cyclooxygenase-expressing mesenchyme resists intestinal epithelial injury by paracrine signaling.

Paracrine signals play pivotal roles in organ homeostasis. Mesenchymal stromal cells (MSCs) play a key role in regulating epithelium homeostasis in the intestine while their paracrine effects are poorly characterized. Here, we identified prostaglandin E2 (PGE2) secreted by cyclooxygenase (COX)-expressing MSCs as a vital factor to maintain the intestinal mucosal barrier. We found that MSCs-induced organoid swelling through paracrine effect in vitro, a process due to enhanced water adsorption and is mediated by the COX-PGE2-EP4 axis. To further explore the regulatory effect of this axis on the intestinal epithelial barrier in vivo, we established the conditional knockout mouse model to specifically delete COX in MSCs and found that PGE2 reduction downregulated the gene Muc2 and induced a gastric metaplasia-like phenotype. Moreover, PGE2 defects increased the susceptibility of intestinal epithelium to colitis. Our study uncovers the paracrine signaling of COX-expressing MSCs in intestinal mucosal barrier maintenance, providing a basis for understanding the role of mesenchymal cells in the pathophysiological function of the intestine.

Cancer-associated fibroblasts nurture LGR5 marked liver tumor-initiating cells and promote their tumor formation, growth, and metastasis.

BACKGROUND & AIMS: In liver cancer, leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) compartment represents an important tumor-initiating cell (TIC) population and served as a potential therapeutic target. Cancer-associated fibroblasts (CAFs) is a critical part of the tumor microenvironment, heavily influenced TIC function and fate. However, deeply investigations have been hindered by the lack of accurate preclinical models to investigate the interaction between CAFs and TIC. Organoids model have achieved major advancements as a precious research model for recapitulating the morphological aspects of organs, and thus also serving as a candidate model to investigate the mutual interaction between different cell types. Consequently, this study aimed to construct a three-dimensional (3D) co-culture organoid model of primary LGR5-expressing tumor stem cells from primary murine liver tumors with CAFs to investigate the impact of CAFs on LGR5 marked TICs in liver cancer. MATERIALS AND METHODS: First, both of the transgenic LGR5-diphtheria toxin receptor (DTR)-GFP knock-in mice and transgenic Rosa26-mT mice developed primary liver tumors by diethylnitrosamine (DEN) administration. Tumor organoids and CAFs were generated from those primary liver cancer separately. Second, LGR5-expressing TICs organoid with CAFs were established ex vivo based on cell-cell contact or trans-well co-culture system, and the mutual influence between those two types of cells was further investigated. Subsequently, immunodeficient mouse-based xenograft model was further adopted to evaluate the influence of CAFs to LGR5 tumor stem cell, tumor formation, and metastasis. RESULTS: The co-culture organoid model composed of murine liver tumor LGR5+ tumor-initiating cells and CAFs in 3D co-culture was successfully established, with the intention to investigate their mutual interaction. The existence of CAFs upon engrafting tumor organoids resulted in dramatic higher number of LGR5+ cells in the neoplasia when compared with engrafting tumor organoids alone. Furthermore, ex vivo culture of isolated LGR5+ cells from tumors of co-engrafted mice formed significantly larger size of organoids than mono-engrafted. Our results also indicated significantly larger size and number of formed organoids, when LGR5+ cells co-cultured with CAF in both cell-cell contact and paracrine signaling in vitro, comparing to LGR5+ cells alone. Furthermore, we found that specific knockout of LGR5 expressing cells suppressed CAF-mediated promotion of tumor formation, growth, and metastasis in the experimental mice model. CONCLUSIONS: Altogether, in a 3D co-culture type of murine liver LGR5+ cells and cancer-associated fibroblasts, we have demonstrated robust effects of CAFs in the promotion of LGR5 marked liver TICs. We also further revealed the influence of tumor microenvironment on stem cell-related therapy, suggesting the possibility of combing CAF-targeted and tumor stem cell targeted therapy in treating liver cancer.

miR-142-3p encapsulated in T lymphocyte-derived tissue small extracellular vesicles induces Treg function defect and thyrocyte destruction in Hashimoto's thyroiditis.

BACKGROUND: Hashimoto's thyroiditis (HT) is an organ-specific autoimmune disease characterized by lymphocyte infiltration that destroys thyrocyte cells. The aim of the present study was to elucidate the role and mechanisms of tissue small extracellular vesicle (sEV) microRNAs (miRNAs) in the pathogenesis of HT. METHODS: Differentially expressed tissue sEV miRNAs were identified between HT tissue and normal tissue by RNA sequencing in the testing set (n = 20). Subsequently, using quantitative real-time polymerase chain reaction (qRT‒PCR) assays and logistic regression analysis in the validation set (n = 60), the most relevant tissue sEV miRNAs to HT were verified. The parental and recipient cells of that tissue sEV miRNA were then explored. In vitro and in vivo experiments were further performed to elucidate the function and potential mechanisms of sEV miRNAs that contribute to the development of HT. RESULTS: We identified that miR-142-3p encapsulated in T lymphocyte-derived tissue sEVs can induce Treg function defect and thyrocyte destruction through an intact response loop. Inactivation of miR-142-3p can effectively protect non-obese diabetic (NOD).H-2h4 mice from HT development display reduced lymphocyte infiltration, lower antibody titers, and higher Treg cells. Looking at the mechanisms underlying sEV action on thyrocyte destruction, we found that the strong deleterious effect mediated by tissue sEV miR-142-3p is due to its ability to block the activation of the ERK1/2 signaling pathway by downregulating RAC1. CONCLUSIONS: Our findings highlight the fact that tissue sEV-mediated miR-142-3p transfer can serve as a communication mode between T lymphocytes and thyrocyte cells in HT, favoring the progression of HT.

Ageing and non-liver comorbidities in population with chronic hepatitis B infection in the western pacific region from 1990 to 2019.

Objectives: This study examined the age structure and burden of non-liver noncommunicable diseases in population with chronic hepatitis B virus (HBV) infection in the Western Pacific Region (WPR) from 1990 to 2019. Methods: We estimated ageing trends and the prevalence of non-liver NCDs among the HBV-infected population and the general population in 31 countries/areas in the Western Pacific Region from 1990 to 2019 based on the Global Burden of Disease 2019 dataset. Results: The proportion of individuals aged 60 or older among the HBV-infected population has increased at a faster rate compared to the general population, whereas the proportion of individuals younger than 19 years has decreased rapidly over the past three decades. Among the HBV-infected population, the prevalence of most (29/31) NCDs increased from 1990 to 2019, with the top three most significant increases found for non-Hodgkin's lymphoma (789.94% increase), prostate cancer (512.40% increase), and kidney cancer (411.34% increase). The prevalence of NCDs among the HBV-infected population increased faster than in the general population over the past three decades, especially in countries with rapid population ageing. Conclusion: This study highlights the increasing burden of non-liver comorbidities among the HBV-infected population. The integrated management of non-liver NCDs among this population should be implemented.

The effectiveness of the first dose COVID-19 booster vs. full vaccination to prevent SARS-CoV-2 infection and severe COVID-19 clinical event: a meta-analysis and systematic review of longitudinal studies.

Background: The effectiveness of full Coronavirus Disease 2019 (COVID-19) vaccination against COVID-19 wanes over time. This study aimed to synthesize the clinical effectiveness of the first dose of COVID-19 booster by comparing it to the full vaccination. Methods: Studies in PubMed, Web of Science, Embase, and clinical trials databases were searched from 1 January 2021 to 10 September 2022. Studies were eligible if they comprised general adult participants who were not ever or currently infected with SARS-CoV-2, did not have impaired immunity or immunosuppression, and did not have severe diseases. The seroconversion rate of antibodies to S and S subunits and antibody titers of SARS-CoV-2, frequency, phenotype of specific T and B cells, and clinical events involving confirmed infection, admission to the intensive care unit (ICU), and death were compared between the first booster dose of COVID-19 vaccination group and full vaccination group. The DerSimonian and Laird random effects models were used to estimate the pooled risk ratios (RRs) and corresponding 95% confidence intervals (CIs) for the outcomes of clinical interest. While a qualitative description was mainly used to compare the immunogenicity between the first booster dose of COVID-19 vaccination group and full vaccination group. Sensitivity analysis was used to deal with heterogenicity. Results: Of the 10,173 records identified, 10 studies were included for analysis. The first dose COVID-19 booster vaccine could induce higher seroconversion rates of antibodies against various SAS-CoV-2 fragments, higher neutralization antibody titers against various SARS-CoV-2 variants, and robust cellular immune response compared to the full vaccination. The risk of SARS-CoV-2 infection, the risk of admission to the ICU, and the risk of death were all higher in the non-booster group than those in the booster group, with RRs of 9.45 (95% CI 3.22-27.79; total evaluated population 12,422,454 vs. 8,441,368; I2 = 100%), 14.75 (95% CI 4.07-53.46; total evaluated population 12,048,224 vs. 7,291,644; I2 = 91%), and 13.63 (95% CI 4.72-39.36; total evaluated population 12,385,960 vs. 8,297,037; I2 = 85%), respectively. Conclusion: A homogenous or heterogeneous booster COVID-19 vaccination could elicit strong humoral and cellular immune responses to SARS-CoV-2. Furthermore, it could significantly reduce the risk of SARS-CoV-2 infection and severe COVID-19 clinical events on top of two doses. Future studies are needed to investigate the long-term clinical effectiveness of the first booster dose of the COVID-19 vaccine and compare the effectiveness between homogenous and heterogeneous booster COVID-19 vaccination. Systematic review registration: https://inplasy.com/inplasy-2022-11-0114/, identifier: INPLASY2022110114.

Understanding the Uptake and Outcomes of Non-occupational Postexposure Prophylaxis Use Through an Online Medical Platform in China: Web-Based Cross-sectional Study.

BACKGROUND: To date, non-occupational postexposure prophylaxis (PEP) has been widely accepted as a safe and effective intervention for HIV in many countries, yet it remains an underutilized prevention strategy in China. Evidence indicated a high demand for PEP among Chinese men who have sex with men, but the uptake and access to PEP service remain limited. In an era of rapid development of web-based technology, online medical platforms in China hold great promise in facilitating PEP provision and delivery by addressing problems such as accessibility, convenience, privacy protection, and antidiscrimination by integrating online and offline resources. However, there is a paucity of data concerning the uptake and outcomes of online PEP in China. OBJECTIVE: The aim of this study is to explore online PEP service provision and understand PEP uptake and outcome through a web-based cross-sectional study. METHODS: From January 2020 to June 2021, we conducted a retrospective web-based survey among those seeking online PEP services via the internet medical platform "HeHealth" using a structured questionnaire. Participants were surveyed on sociodemographic characteristics, sexual and drug-related behaviors, history of preexposure prophylaxis (PrEP) usage, and PEP uptake. Statistical analysis included descriptive analysis, chi-square test, and multivariable logistic regression. P values <.05 were deemed statistically significant. RESULTS: No HIV seroconversions were observed among 539 PEP users. Our sample demonstrated that most participants seeking online PEP services were gay (397/539, 73.7%), single (470/539, 87.2%), having an education of more than 12 years (493/539, 91.5%), and with an average monthly income of 7000 RMB (1 RMB=US $0.14) or more (274/539, 50.8%). Sexual exposures accounted for 86.8% (468/539) of the cases, with anal sex being the most common indication (389/539, 72.2%) for seeking PEP use. Among 539 participants, 60.7% (327/539) sought online PEP for relatively low-risk exposures, whereas 39.3% (212/539) were considered high-risk exposures. Nearly all (537/539, 99.6%) initiated PEP within 72 hours and 68.6% (370/539) within 24 hours of exposure. All users (539/539) were prescribed a 3-drug regimen, with most comprising 3TC/TDF+DTG (lamivudine, tenofovir disoproxil fumarate, and dolutegravir; 293/539, 54.4%), followed by FTC/TDF+DTG (emtricitabine, tenofovir disoproxil fumarate, and dolutegravir; 158/539, 29.3%). The adjusted model showed that greater odds of PrEP usage were associated with an age of 35 years or older versus the age group of 25-34 years (adjusted odds ratio [AOR] 2.04, 95% CI 1.24-3.37), having an education of 17 years or more versus an education of 12 years or less (AOR 3.14, 95% CI 1.29-7.62), average monthly income of 20,000 RMB or more versus less than 3000 RMB (AOR 2.60, 95% CI 1.09-6.23), and having high-risk sexual behavior during PEP treatment (AOR 2.20, 95% CI 1.05, 3.69). CONCLUSIONS: The 0% infection rate in this study demonstrated that online PEP could be a valuable risk-reduction option to improve HIV prevention service within China. However, further research is needed to better facilitate PrEP transition among online PEP users.

Different clinical guidelines, common goal: To reduce COVID-19 mortality.

The tendency of the Omicron variant to rapidly became the dominant SARS-CoV-2 strain and its weaker virulence than other strains worldwide has prompted many countries to adjust their public health strategies. This work summarizes all appropriate clinical interventions to reduce the public health burden caused by COVID-19 according to guidelines from the World Health Organization and 10 countries, i.e., the United States of America (USA), India, France, Germany, Brazil, South Korea, Japan, Italy, the United Kingdom (UK), and China. Five stages of COVID-19 were identified: asymptomatic infection and mild, moderate, severe, and critical illness. Most guidelines recommend antivirals starting with mild cases for those from Germany and India. Since more drugs are being developed and are becoming available to COVID-19 patients, guidelines are increasingly being updated with new pharmacological intervention strategies. Thus, a global view needs to be adopted to provide helpful options and precise treatment strategies during the lasting fight against the COVID-19 pandemic.

Estimating global prevalence, incidence, and outcomes of non-alcoholic fatty liver disease from 2000 to 2021: systematic review and meta-analysis.

BACKGROUND: The increasing burden of non-alcoholic fatty liver disease (NAFLD) worldwide imposes an emerging public health issue. We perform the current study to estimate the global prevalence, incidence, disease progression, and clinical outcomes of NAFLD. METHODS: A systematic search was conducted in Medline, Embase, Web of Science, Google Scholar, and Cochrane CENTRAL that screened articles in English language published from January 2000 to December 2021. NAFLD prevalence, incidence, rate of disease progression, and outcomes were calculated with the DerSimonian-Laird random effects model with arcsine transformation. RESULTS: Our search identified 59,156 records, of which 578 studies fulfilled our inclusion criteria. The overall prevalence of NAFLD was 29.38% (95% confidence interval [CI] 28.09-30.69) regardless of the diagnostic techniques. Looking at the group in which the diagnosis was made by ultrasound exclusively, the pooled prevalence was 30.49% (95% CI 29.55-31.43). NAFLD has become more prevalent during the year 2011-2021 (31.63%, 95% CI 30.23-33.04) compared with year 2000-2010 (27.94%, 95% CI 26.23-29.69). The pooled estimation of non-alcoholic steatohepatitis prevalence was 8.26% (95% CI 1.13-21.01), 46.49% (95% CI 35.93-57.20), and 46.72% (95% CI 37.57-55.98) in general population, NAFLD patients, and severe/morbidly obese patients, respectively. Based on a total of 110,142 newly developed NAFLD patients, the pooled incident rate was estimated as 46.24 cases per 1000 person-years (95% CI 43.21-49.30). In patients with NAFLD, the incident rate of hepatocellular carcinoma was 1.46 (95% CI 0.90-2.03) cases per 1000 person-years. The overall pooled estimate of NAFLD related mortality was 23.91 (95% CI 13.55-37.18) death per 1000 person-years. CONCLUSIONS: The prevalence of NAFLD is increasing globally. It is contributing to poor clinical outcomes including hepatocellular carcinoma and death. Rising awareness and urgent actions are warranted to control the NAFLD pandemic across the globe. REGISTRATION: PROSPERO, No. CRD42020171104.

Biodegradable and Antioxidant DNA Hydrogel as a Cytokine Delivery System for Diabetic Wound Healing.

Impaired diabetic wound healing is associated with the persistence of chronic inflammation and excessive oxidative stress, which has become one of the most serious clinical challenges. Wound dressings with anti-inflammatory and reactive oxygen species (ROS)-scavenging properties are desirable for diabetic wound treatment. In this study, a shape-adaptable, biodegradable, biocompatible, antioxidant, and immunomodulatory interleukin-33 (IL-33)-cytogel is developed by encapsulating IL-33 into physically cross-linked DNA hydrogels and used as wound dressings to promote diabetic wound healing. The porous microstructures and biodegradable properties of the IL-33-cytogel ensure the local sustained-release of IL-33 in the wound area, where the sustained-release of IL-33 is maintained for at least 7 days. IL-33-cytogel can induce local accumulation of group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs), as well as M1-to-M2 transition at the wound sites. Additionally, the antioxidant and biocompatible characteristics of DNA hydrogels promote the scavenging of intracellular ROS without affecting cell viability. As a result, local inflammation in the diabetic wound area is resolved upon IL-33-cytogel treatment, which is accompanied by improved granulation tissue regeneration and accelerated wound closure. This study demonstrates a promising strategy in tissue engineering and regenerative medicine by incorporating DNA hydrogels and cytokine immunotherapy for promoting diabetic wound healing.

Higher Risk of Dyslipidemia With Coformulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide than Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate Among Antiretroviral-Naive People Living With HIV in China.

BACKGROUND: We aimed to examine the evolution of blood lipids and compare the risk of dyslipidemia between antiretroviral-naive people living with HIV who received tenofovir disoproxil fumarate (TDF), lamivudine (3TC), and efavirenz (EFV) (TDF + 3TC + EFV) and those who received coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (E/C/F/TAF). METHODS: We retrospectively reviewed the medical records of 2343 antiretroviral-naive people living with HIV who initiated TDF + 3TC + EFV or E/C/F/TAF. A propensity score matching method was used to compare longitudinal changes of blood lipids between the 2 groups. RESULTS: By using 1:3 matching ratio, we included 253 and 91 matched patients in TDF + 3TC + EFV group and E/C/F/TAF group, respectively. The levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol were higher in E/C/F/TAF group than those in TDF + 3TC + EFV group at 3, 6, 9, and 12 months (Wilcoxon test, all Ps < 0.05), except for high-density lipoprotein cholesterol at 9 and 12 months. The cumulative rates of hypercholesterolemia, hypertriglyceridemia, and high LDL-C in PLWH with normal lipid levels in E/C/F/TAF group were higher than those in TDF + 3TC + EFV group (hypercholesterolemia, 59.7% vs 21.5%, P < 0.001; hypertriglyceridemia, 69.5% vs 46.3%, P < 00.001; and high LDL-C, 41.5% vs 14.2%, P < 0.001). Multivariate analysis showed treatment with E/C/F/TAF was associated with a significantly higher risk of hypercholesterolemia [adjusted hazard ratio (HR), 4.12; 95% confidence interval (CI): 2.65 to 6.41], hypertriglyceridemia (adjusted HR, 1.69; 95% CI: 1.18 to 2.43), and high LDL-C (adjusted HR, 4.60; 95% CI: 2.66 to 7.97). CONCLUSIONS: We concluded that treatment with E/C/F/TAF resulted in higher risks of dyslipidemia compared with TDF + 3TC + EFV.

Total dietary flavonoid intake and risk of cardiometabolic diseases: A dose-response meta-analysis of prospective cohort studies.

Several epidemiological studies have suggested that flavonoid intake is associated with a decreased risk of cardiometabolic disease. However, the results remained inconsistent and there is no dose-response meta-analysis for specific outcomes. We conducted a meta-analysis to synthesize the knowledge about their associations and to explore their dose-response relationships. We comprehensively searched the PubMed, Embase, and Web of Science databases for prospective cohort studies published up to December 1, 2021. Summary relative risks (RR) and 95% confidence intervals (CI) were pooled for the association between flavonoid intake and cardiometabolic disease. Evaluations of linear or nonlinear dose-response were presented by restricted cubic splines. We identified 47 articles, including 1,346 676 participants and 127,507 cases in this meta-analysis. The summary of RR per 500 mg/d increase in flavonoid intake was 0.93 (95% CI 0.88-0.98) for cardiovascular disease, 0.89 (95% CI 0.84-0.94) for diabetes, and 0.97 (95% CI 0.94-0.99) for hypertension, respectively. We also found a linearity dose-response association between total flavonoid intake and cardiovascular disease (p nonlinearity = 0.541), and diabetes (p nonlinearity = 0.077). Our finding based on quantitative data suggested that a higher level of flavonoid intake is beneficial for the prevention of cardiometabolic diseases.