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Abstract Background Tuberculosis (TB) is a chronic infectious disease caused by the Mycobacterium tuberculosis complex (MTBC), which is the leading cause of death from infectious diseases. The rapid and accurate microbiological detection of the MTBC is crucial for the diagnosis and treatment of TB. Metagenomic next-generation sequencing (mNGS) has been shown to be a promising and satisfying application of detection in infectious diseases. However, relevant research about the difference in MTBC detection by mNGS between bronchoalveolar lavage fluid (BALF) and lung biopsy tissue specimens remains scarce. Methods We used mNGS to detect pathogens in BALF and lung biopsy tissue obtained by CT-guide percutaneous lung puncture (CPLP) or radial endobronchial ultrasound transbronchial lung biopsy (R-EBUS-TBLB) from 443 hospitalized patients in mainland China suspected of pulmonary infections between May 1, 2019 and October 31, 2021. Aim to evaluate the diagnostic performance of mNGS for detecting MTBC and explore differences in the microbial composition in the 2 specimen types. Results Among the 443 patients, 46 patients finally were diagnosed with TB, of which 36 patients were detected as MTBC positive by mNGS (8.93%). Striking differences were noticed in the higher detection efficiency of lung biopsy tissue compared with BALF (P = 0.004). There were no significant differences between the 2 specimen types in the relative abundance among the 27 pathogens detected by mNGS from the 36 patients. Conclusions This study demonstrates that mNGS could offer an effective detection method of MTBC in BALF or lung tissue biopsy samples in patients suspected of TB infections. When it comes to the situations that BALF samples have limited value to catch pathogens for special lesion sites or the patients have contraindications to bronchoalveolar lavage (BAL) procedures, lung biopsy tissue is an optional specimen for MTBC detection by mNGS. However, whether lung tissue-mNGS is superior to BALF-mNGS in patients with MTBC infection requires further prospective multicenter randomized controlled studies with more cases.

Abstract. Background:. As a non-invasive and effective diagnostic method for small intestinal bacterial overgrowth (SIBO), wild-use of breath test (BT) has demonstrated a high comorbidity rate in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and SIBO. Patients overlapping with SIBO respond better to rifaximin therapy than those with IBS-D only. Gut microbiota plays a critical role in both of these two diseases. We aimed to determine the microbial difference between IBS-D overlapping with/without SIBO, and to study the underlying mechanism of its sensitivity to rifaximin. Methods:. Patients with IBS-D were categorized as BT-negative (IBSN) and BT-positive (IBSP). Healthy volunteers (BT-negative) were enrolled as healthy control. The patients were clinically evaluated before and after rifaximin treatment (0.4 g bid, 4 weeks). Blood, intestine, and stool samples were collected for cytokine assessment and gut microbial analyses. Results:. Clinical complaints and microbial abundance were significantly higher in IBSP than in IBSN. In contrast, severe systemic inflammation and more active bacterial invasion function that were associated with enrichment of opportunistic pathogens were seen in IBSN. The symptoms of IBSP patients were relieved in different degrees after therapy, but the symptoms of IBSN rarely changed. We also found that the presence of IBSN-enriched genera (Enterobacter and Enterococcus) are unaffected by rifaximin therapy. Conclusions:. IBS-D patients overlapping with SIBO showed noticeably different fecal microbial composition and function compared with IBS-D only. The better response to rifaximin in those comorbid patients might associate with their different gut microbiota, which suggests that BT is necessary before IBS-D diagnosis and use of rifaximin. Registration:. Chinese Clinical Trial Registry, ChiCTR1800017911.

ABSTRACT: Objective: This is a prospective, single-arm, phase Ib study to evaluate the safety and efficacy of camrelizumab combined with chemotherapy and apatinib as neoadjuvant therapy for locally advanced thoracic esophageal squamous cell carcinoma (ESCC). Methods: The regimen encompassed 2–4 cycles of neoadjuvant camrelizumab, nab-paclitaxel, nedaplatin, and apatinib to treatment-naive patients with resectable locally advanced ESCC. The treatment was repeated every 14 days. Initially, six patients were planned to receive two cycles of neoadjuvant therapy as safety assessment, and then 24 patients received four cycles of neoadjuvant therapy, followed by esophagectomy after 4–8 weeks. The primary endpoint was safety. The key secondary endpoints were pathologic complete response (pCR) and major pathologic response (MPR). Results: This study enrolled 30 patients, among whom, five patients received two cycles of neoadjuvant therapy, and one patient missed the second cycle of therapy due to grade 3 elevated alanine transaminase (ALT) level. The remaining 24 patients received four planned cycles of neoadjuvant therapy. Eleven patients (36.7%) developed grade 3 neoadjuvant treatment-related adverse events (TRAEs). No patient developed grade 4 or 5 TRAEs. Neutropenia (23.3%) was the most common grade 3 TRAE. Twenty-nine patients underwent esophagectomy after neoadjuvant therapy. Among them, 15 patients (51.7%) achieved MPR, including seven patients with pCR (24.1%). Radiographic analyses established a significant correlation between maximal standardized uptake value (SUVmax) reduction and pathologic regression (P = 0.00095). Conclusions: Neoadjuvant camrelizumab combined with chemotherapy plus apatinib demonstrated a manageable safety profile for patients with locally advanced ESCC, and an encouraging efficacy was observed in most of the treated patients. A decrease in SUVmax of the primary tumor may be a predictor of pathologic response to neoadjuvant camrelizumab combined with chemotherapy plus apatinib in ESCC.

SETD2 methylates histone H3K36me3 in gene bodies in mammalian cells. Here the authors show H3K36me3 is also enriched at the promoter regions, and that this methylation is carried out by SMYD5, which is recruited by RNA polymerase II. They furthermore show SMYD5 is elevated in liver cancer and is correlated with changes in gene expression.

Abstract Background Most retroperitoneal sarcoma (RPS) operations require combined multi-organ resection, and the proportion of unplanned reoperation is high. However, there are no relevant studies on reoperation for RPS. Methods Patients who underwent at least once unplanned reoperation at Shanghai Public Health Clinical Center, Fudan University, China, from August 2009 to December 2021 were retrospectively analyzed. The baseline characteristics, primary surgery, and reoperation information, postoperative complications, and survival were analyzed. Results A total of 51 patients were included. Among them, 21 (41.2%) were male and 30 (58.8%) were female. The median age was 51 (interquartile range [IQR], 49-63) years. Most (88.3%) had a history of abdominal surgery. Dedifferentiated liposarcoma, well-differentiated liposarcoma, leiomyosarcoma, and others accounted for 50.9%, 21.6%, 15.7%, and 11.8%, respectively. The conditions of the primary operation were as follows: 35 (68.6%) patients achieved complete surgical resection, 48 patients had combined organ resection, and a median of 3 (IQR, 2–4) organs was removed, of which 5 (9.9%) were combined with pancreaticoduodenectomy. The median operative time was 330 (IQR, 245–440) min, and the median estimated blood loss was 1500 (IQR, 500–2600) ml. The median postoperative hospital stay was 42 (IQR, 23–82) days. For reoperation, the most common reasons were bleeding (31.3%), complications related to intestinal anastomosis (27.4%), and intestinal perforation (19.9%). The mortality rate after reoperation was 39.2% (20/51). Twelve (23.5%) patients underwent reoperation at least twice. Conclusions Unplanned reoperation among retroperitoneal sarcoma correlates with established measures of surgical quality.

BackgroundDue to the aging population, there is a need for monitoring well-being and safety while living independently. A low-intrusive monitoring system is based on a person’s use of energy or water. ObjectiveThe study's objective was to provide a systematic overview of studies that monitor the health and well-being of older people using energy (eg, electricity and gas) and water usage data and study the outcomes on health and well-being. MethodsCENTRAL, Embase, MEDLINE (Ovid), Scopus, Web of Science, and Google Scholar were searched systematically from inception until November 8, 2021. The inclusion criteria were that the study had to be published in English, have full-text availability, target independent-living people aged 60 years and older from the general population, have an observational design, and assess the outcomes of a monitoring system based on energy (ie, electricity, gas, or water) usage on well-being and safety. The quality of the studies was assessed by the QualSyst systematic review tool. ResultsThe search strategy identified 2920 articles. The majority of studies focused on the technical algorithms underlying energy usage data and related sensors. One study was included in this review. This study reported that the smart energy meter data monitoring system was considered unobtrusive and was well accepted by the older people and professionals involved. Energy usage in a household acted as a unique signature and therefore provided useful insight into well-being and safety. This study lacked statistical power due to the small number of participants and the low number of observed events. In addition, the quality of the study was rated as low. ConclusionsThis review identified only 1 study that evaluated the impact of an energy usage monitoring system on the well-being and safety of older people. The absence of reliable evidence impedes any definitive guidance or recommendations for practice. Because this emerging field has not yet been studied thoroughly, many questions remain open for further research. Future studies should focus on the further development of a monitoring system and the evaluation of the implementation and outcomes of these systems. Trial RegistrationPROSPERO CRD42022245713; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=245713

Abstract Background N6‐methyladenosine (m6A) RNA modification is known as a common epigenetic regulation form in eukaryotic cells. Emerging studies show that m6A in noncoding RNAs makes a difference, and the aberrant expression of m6A‐associated enzymes may cause diseases. The demethylase alkB homologue 5 (ALKBH5) plays diverse roles in different cancers, but its role during gastric cancer (GC) progression is not well known. Methods The quantitative real‐time polymerase chain reaction, immunohistochemistry staining and western blotting assays were used to detect ALKBH5 expression in GC tissues and human GC cell lines. The function assays in vitro and xenograft mouse model in vivo were used to investigate the effects of ALKBH5 during GC progression. RNA sequencing, MeRIP sequencing, RNA stability and luciferase reporter assays were performed to explore the potential molecular mechanisms involved in the function of ALKBH5. RNA binding protein immunoprecipitation sequencing (RIP‐seq), RIP and RNA pull‐down assays were performed to examine the influence of LINC00659 on the ALKBH5–JAK1 interaction. Results ALKBH5 was highly expressed in GC samples and associated with aggressive clinical features and poor prognosis. ALKBH5 promoted the abilities of GC cell proliferation and metastasis in vitro and in vivo. The m6A modification on JAK1 mRNA was removed by ALKBH5, which resulted in the upregulated expression of JAK1. LINC00659 facilitated ALKBH5 binding to and upregulated JAK1 mRNA depending on an m6A‐YTHDF2 manner. Silencing of ALKBH5 or LINC00659 disrupted GC tumourigenesis via the JAK1 axis. JAK1 upregulation activated the JAK1/STAT3 pathway in GC. Conclusion ALKBH5 promoted GC development via upregulated JAK1 mRNA expression mediated by LINC00659 in an m6A‐YTHDF2‐dependent manner, and targeting ALKBH5 may be a promising therapeutic method for GC patients.

Endometriosis is closely associated with ectopic focal inflammation and immunosuppressive microenvironment. Multiple types of pattern recognition receptors (PRRs) are present in the innate immune system, which are able to detect pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) in both intracellular and external environments. However, the exact role of PRRs in endometriosis and the underlying molecular mechanism are unclear. PRRs are necessary for the innate immune system to identify and destroy invasive foreign infectious agents. Mammals mainly have two types of microbial recognition systems. The first one consists of the membrane-bound receptors, such as toll-like receptors (TLRs), which recognize extracellular microorganisms and activate intracellular signals to stimulate immune responses. The second one consists of the intracellular PRRs, including nod-like receptors (NLRs) and antiviral proteins retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5) with helix enzyme domain. In this review, we mainly focus on the key role of PRRs in the pathological processes associated with endometriosis. PRRs recognize PAMPs and can distinguish pathogenic microorganisms from self, triggering receptor ligand reaction followed by the stimulation of host immune response. Activated immune response promotes the transmission of microbial infection signals to the cells. As endometriosis is characterized by dysregulated inflammation and immune response, PRRs may potentially be involved in the activation of endometriosis-associated inflammation and immune disorders. Toll-like receptor 2 (TLR2), toll-like receptor 3 (TLR3), toll-like receptor 4 (TLR4), nod-like receptor family caspase activation and recruitment domain (CARD) domain containing 5 (NLRC5), nod-like receptor family pyrin domain containing 3 (NLRP3), and c-type lectin receptors (CLRs) play essential roles in endometriosis development by regulating immune and inflammatory responses. Absent in melanoma 2 (AIM2)-like receptors (ALRs) and retinoic acid-inducible gene I-like receptors (RLRs) may be involved in the activation of endometriosis-associated immune and inflammation disorders. PRRs, especially TLRs, may serve as potential therapeutic targets for alleviating pain in endometriosis patients. PRRs and their ligands interact with the innate immune system to enhance inflammation in the stromal cells during endometriosis. Thus, targeting PRRs and their new synthetic ligands may provide new therapeutic options for treating endometriosis.

BackgroundHypoxia-inducible factor 1-alpha (HIF-1α) stability and transcriptional action are reduced by the hypoxia-inducible factor 1-alpha subunit suppressor (HIF1AN). Its inappropriate expression is associated with the development of cancer and immune control. It is yet unknown how HIF1AN, clinical outcomes, and immune involvement in breast cancer (BC) are related.MethodsUsing the GEPIA, UALCAN, TIMER, Kaplan-Meier plotter, and TISIDB datasets, a thorough analysis of HIF1AN differential expression, medical prognosis, and the relationship between HIF1AN and tumor-infiltrating immune cells in BC was conducted. Quantitative real-time PCR (qRT−PCR) analysis of BC cells were used for external validation.ResultsThe findings revealed that, as compared to standard specimens, BC cells had significantly lower levels of HIF1AN expression. Good overall survival (OS) for BC was associated with higher HIF1AN expression. Additionally, in BC, the expression of HIF1AN was closely associated with the chemokines and immune cell infiltration, including neutrophils, macrophages, T helper cells, B cells, Tregs, monocytes, dendritic cells, and NK cells. A high correlation between HIF1AN expression and several immunological indicators of T-cell exhaustion was particularly revealed by the bioinformatic study.ConclusionsHIF1AN is a predictive indicator for breast tumors, and it is useful for predicting survival rates.

BackgroundNeonatal sclerosing cholangitis (NSC) is a rare and severe autosomal recessive inherited liver disease with mutations in DCDC2, commonly requiring liver transplantation (LT) for decompensated biliary cirrhosis in childhood.MethodsThe information of four Chinese patients with NSC caused by mutations in DCDC2 from Children's Hospital of Fudan University were gathered. The four patients' clinicopathological and molecular features were summarized by clinical data, liver biopsy, immunohistochemical, and molecular genetic analysis.ResultsAll patients presented with jaundice, hepatosplenomegaly, hyperbilirubinemia and bile embolism, and high serum γ-glutamyl transferase activity (GGT). Liver biopsies revealed varying degrees of bile duct hyperplasia, portal-tract inflammation, and/or fibrosis. Whole-exome sequencing (WES) found novel heterozygous variants of c.1024-1G > T /p.? and c.544G > A /p. Gly182Arg in the DCDC2.ConclusionThis study expands the genetic spectrum of DCDC2 in NSC.

Postmenopausal osteoporosis (PMOP) is a common bone disease characterized by decreased bone density and increased bone fragility due to decreased estrogen levels. Qiangguyin (QGY) is transformed from the famous traditional Chinese medicine BuShen Invigorating Blood Decoction. In this study, we used QGY to treat PMOP. We observed that QGY significantly reduced fat accumulation in the chondro-osseous junction. However, its specific mechanism of action remains unclear. To determine the specific molecular mechanism of QGY, we explored the pharmacological mechanism by which QGY reduces fat accumulation in the chondro-osseous junction through network pharmacological analysis. The active components and targets related to PMOP and QGY were screened from different databases, forming a composition-target-disease network. Next, a comprehensive analysis platform including protein-protein interaction (PPI) network, Gene Ontology (GO) enrichment analysis, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were established. The results revealed that QGY inhibits adipogenic differentiation by activating the mitogen-activated protein kinase (MAPK) signaling pathway, thus reducing the accumulation of fat in the chondro-osseous junction. For further verification. In vitro and in vivo experiments were carried out. Our data showed that QGY significantly reversed the high expression of fatty acid binding protein 4 (FABP4) and peroxisome proliferator-activated receptor γ (PPARγ). Further, QGY prevents fat accumulation by inhibiting the expression of p38. In summary, the results of this study suggested that QGY-induced phenotypic changes are related to the activation of the p38 MAPK signaling pathway.

Summary: Overall survival (OS) is considered the standard clinical endpoint to support effectiveness claims in new drug applications globally, particularly for lethal conditions such as cancer. However, the source and reliability of OS in the setting of clinical trials have seldom been doubted and discussed. This study first raised the common issue that data integrity and reliability are doubtful when we collect OS information or other time-to-event endpoints based solely on simple follow-up records by investigators without supporting material, especially since the 2019 COVID-19 pandemic. Then, two rounds of discussions with 30 Chinese experts were held and 12 potential source scenarios of three methods for obtaining the time of death of participants, including death certificate, death record and follow-up record, were sorted out and analysed. With a comprehensive assessment of the 12 scenarios by legitimacy, data reliability, data acquisition efficiency, difficulty of data acquisition, and coverage of participants, both short-term and long-term recommended sources, overall strategies and detailed measures for improving the integrity and reliability of death date are presented. In the short term, we suggest integrated sources such as public security systems made available to drug inspection centres appropriately as soon as possible to strengthen supervision. Death certificates provided by participants’ family members and detailed standard follow-up records are recommended to investigators as the two channels of mutual compensation, and the acquisition of supporting materials is encouraged as long as it is not prohibited legally. Moreover, we expect that the sharing of electronic medical records and the legal disclosure of death records in established health registries can be realized with the joint efforts of the whole industry in the long-term. The above proposed solutions are mainly based on the context of China and can also provide reference for other countries in the world.

Abstract Background Angiitis-induced critical limb ischaemia (AICLI) patients, who are usually young and have a high amputation rate, always lose their ability to return to the labour force. Return to work (RTW) not only indicates patients’ physical health, showing that they could undertake the work, but also demonstrates their psychological well-being. While cell transplantation showed satisfactory efficacy in limb salvage, few studies of AICLI patients’ RTW after transplantation have been reported. Methods From May 2009 to May 2021, AICLI patients who underwent cell transplantation and completed no less than 12 months of follow-up were retrospectively enrolled. The primary endpoint was RTW. Patient demographics and characteristics of the ischaemic limbs were reviewed to analyse independent risk factors for RTW. Results A total of 171 AICLI patients (170 males) were enrolled with a mean age of 41.9 ± 9.6 years (range: 20–57 years). The 12-month and 24-month RTW cumulative rates were 69.4% (95% confidence interval [CI] 61.6–75.6%) and 70.1% (95% CI 62.3–76.2%), respectively. Age

Tumor-associated macrophages (TAMs) exert integrated effects in all aspects of tumor progression, including tumor cell proliferation, angiogenesis, invasion, and metastasis. Recently, considerable preclinical and clinical trials have demonstrated that TAM-targeted therapy is an effective antitumor therapeutic approach, especially as a complementary strategy in combination with conventional chemotherapy, radiotherapy, or emerging immunotherapy. Here, we review all of the current clinical trials targeting TAMs worldwide up to May 2021 and highlight instances of the synergetic therapeutic efficacy of TAM-targeted combined therapeutic strategies. In total, 606 clinical trials were conducted, including 143 tested products. There has been explosive growth in macrophage-targeted therapy around the world during the past decade. Most trials were at early phase, and two-thirds used macrophage-targeting therapy as part of a combination approach. The most common combination is that of traditional chemotherapy with TAM-targeted therapy, followed by immune checkpoint inhibitors and targeted drugs. TAM-targeted therapeutic approaches are a newly emerging but rapidly developing area of anticancer therapy, especially as a combinatorial therapeutic approach. Further investigation of promising combination strategies will pave the way to more effective anticancer therapies.

Abstract Circular RNAs are an important kind of noncoding RNAs and involved in cancerogenesis, but the specific mechanism between gastric cancer and circRNAs needs further study. Hsa_circ_0007967 was selected by RNA sequencing. Here, hsa_circ_0007967 was highly expressed in gastric cancer tissues than adjacent normal tissues. Overexpressing hsa_circ_0007967 promoted gastric cancer cell proliferation in vitro and in vivo, while suppression of hsa_circ_0007967 inhibited gastric cancer cell proliferation in vitro and in vivo. Mechanistically, hsa_circ_0007967 sponged miR-411-5p to increase MAML3 expression. Overall, hsa_circ_0007967 is a promising biomarker for gastric cancer diagnosis and a potential molecule for gastric cancer treatment.

Abstract Backgrounds Patients with AICLI constitute a considerable proportion of NO-CLI patients and cannot be treated with surgical or endovascular treatment. Although cell therapy has shown satisfactory results in treating AICLI, research comparing the efficacy of treatment with the 2 kinds of cell products is rare. The aim of this study was to report the 5-year outcomes of a randomized single-blinded noninferiority trial (Number: NCT 02089828) on peripheral blood mononuclear cells (PBMNCs) and purified CD34+ cells (PCCs) transplantation for treating angiitis-induced critical limb ischemia (AICLI). Methods A randomized single-blinded non-inferiority trial (Number: NCT 02089828) was performed. Fifty patients were randomized 1:1 to the PBMNCs and PCCs groups. Efficacy outcomes, safety outcomes and patients’ work conditions were analyzed. The primary efficacy outcomes included major amputation and total amputation over 60 months. Results During the 60-month follow-up, 1 patient was lost to follow-up, 1 died, and 2 underwent major amputation. The major amputation-free survival rate (MAFS) was 92.0% (95% confidence interval [CI] 82.0%-100.0%) in the PBMNCs group and 91.7% (95% CI 81.3%-100.0%) in the PCCs group (P = 0.980). Compared with the PCCs group, the PBMNCs group had a significantly higher 5-year new lesion-free survival rate (100.0% vs. 83.3% [95% CI 69.7–99.7%], P = 0.039). All patients lost their ability to work before transplantation, and the 5-year cumulative return to work (RTW) rates were 88.0% in the PBMNCs group and 76.0% in the PCCs group (P = 0.085). Conclusion The long-term follow-up outcomes of this trial not only demonstrated similar efficacy and safety for the 2 types of autoimplants but also showed a satisfactory cumulative RTW rate in AICLI patients who underwent cell transplantation. Trial registration: ClinicalTrials.gov, number NCT 02089828. Registered 14 March 2014, https://clinicaltrials.gov/ct2/show/record/NCT02089828 .

Background: Pyroptosis is a programmed cell death related to caspase-1, accompanied by the secretion of pro-inflammatory cytokines. Objectives: To explore the effects of LPS on the P2X7R/NLRP3 pathway in macrophages, and hepatocytes pyroptosis in mice. Methods: LPS was used to establish an animal model of the acute liver injury. The macrophage RAW264.7 was induced by LPS to establish a cell model. The P2X7R inhibitor A438079 and agonist BZATP were added. RAW264.7 was co-cultured with AML-12 cells. Pyroptosis and the ratio of CD11b+CD86+/CD11b+CD206+ were analyzed by flow cytometry. ELISA, WB, and qRT-PCR were applied to analyze factors involved in the P2X7R/NLRP3 pathway. Results: LPS induced liver damage in mice, promoted cell pyroptosis and increased the levels of IL-18, IL-1β, ALT, AST, and TBIL. P2X7R, GSDMD, and GSDMD-N expressions also increased in the LPS group. LPS induced macrophage activation in vivo. NLRP3, ASC, P2X7R, and caspase-1 expressions in vitro promoted. ELISA confirmed that the IL-1β and IL-18 levels repressed in the BZATP (P2X7R agonist) group, while the trend was opposite in the A438079 (P2X7R inhibitor) group. LPS activated the P2X7R/NLRP3 pathway in macrophages. After RAW264.7 was co-cultured with AML-12 cells, the pyroptosis of AML-12 cells promoted but the proliferation decreased in the BZATP group. GSDMD and GSDMD-N expressions promoted in the BZATP group, while the trend was opposite in the A438079 group. Conclusion: LPS activated macrophages via P2X7R activation of NLRP3 and induced hepatocyte pyroptosis, which provided novel potential targets for the liver injury treatment.

Abstract The neoadjuvant and adjuvant anti-PD-1/PD-L1 treatment has been increasingly noticed. To summarize the global landscape of these clinical trials will provide essential data for all the stakeholders of drug development. Based on the Trialtrove database, a total of 668 clinical trials initiated by the end of 2020 were retrospectively analyzed. We found that a rising capability of global neoadjuvant and adjuvant anti-PD-1/PD-L1 clinical development has been achieved. High prevalent cancer types were extensively studied though the priorities in China and the United States were different. However, a lack of phase III trials and industry-sponsored trials was addressed. The confirmatory neoadjuvant trials were particularly insufficient, and the combination strategy mainly focused on chemotherapy. Thus, more public funding and accelerated regulatory strategies are needed in this field. Efforts should be made to confirm the benefit of neoadjuvant treatment and explore novel combination strategies.

Objective: Heme oxygenase-1 (HO-1) is a protein involved in the inflammatory response following ischemia-reperfusion injury (IRI). Evidence suggests that pyroptosis plays an important role in IRI. However, the underlying mechanism between HO-1 and pyroptosis in IRI requires further investigation. Methods: Using the “two-cuff” method, a Sprague Dawley rat model of liver transplantation (LT) was established using livers from donors after circulatory death. An automatic biochemical analyzer was used to detect serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels and evaluate liver function. Paraffin sections of the rat liver were stained with hematoxylin-eosin (HE) to observe the degree of pathological damage. An enzyme-linked immunosorbent assay was used to detect serum levels of interleukin (IL)-1β and IL-18. Moreover, western blotting was used to analyze the expression of HO-1, pro-caspase-1, p22, full-gasdermin D (GSDMD), and cleaved-N-GSDMD in the liver. Immunohistochemistry was used to detect NLRP3 expression. Results: HO-1 expression was time-dependent with IRI. HE staining and Suzuki score showed that necrosis was more severe at 6 h after IRI than in controls. Reactive oxygen species (ROS), ALT, and AST levels in the reperfusion were significantly higher at 6 h after IRI. Similar to HO-1 expression, pro-caspase-1, p22, and GSDMD expression in the reperfusion was time-dependent and was significantly higher at 6 h. Compared with the HO-1-shRNA (short hairpin RNA) group, the HO-1 overexpression group significantly inhibited ROS, p22, GSDMD, IL-1β, IL-18, ALT, and AST. Immunohistochemistry revealed that NLRP3 levels were the highest in the HO-1 overexpression group. Conclusions: HO-1 improved the survival rate and IRI recovery after LT in rats. This study demonstrates that HO-1 inhibits hepatocyte pyroptosis, thereby reducing IRI after LT.

This paper proposes a low-noise amplifier (LNA) for terahertz communication systems. The amplifier is designed based on 90 nm InP high-electron-mobility transistor (HEMT) technology. In order to achieve high gain of LNA, the proposed amplifier adopts a five-stage amplification structure. At the same time, the use of staggered tuning technology has achieved a large bandwidth of terahertz low-noise amplification. In addition, capacitors are used for interstage isolation, sector lines are used for RF bypass, and Microstrip is used to design matching circuits. The entire LNA circuit was validated using accurate electromagnetic simulation. The simulation results show that at 140 GHz, the small signal gain is 25 dB, the noise figure is 4.4 dB, the input 1 dB compression point is −19 dBm, and the 3 dB bandwidth reaches 60 GHz (110–170 GHz), which validates the effectiveness of the design.

Research on manufacturing components for electric vehicles plays a vital role in their development. Furthermore, significant advancements in additive manufacturing processes have revolutionized the production of various parts. By establishing a system that enables the recovery, processing, and reuse of metal powders essential for additive manufacturing, we can achieve sustainable production of electric vehicles. This approach holds immense importance in terms of reducing manufacturing costs, expanding the market, and safeguarding the environment. In this study, we developed an additive manufacturing system for recycled metal powders, encompassing powder variety, properties, processing, manufacturing, component properties, and applications. This system was used to create a knowledge graph providing a convenient resource for researchers to understand the entire procedure from recycling to application. To improve the graph’s accuracy, we employed ChatGPT and BERT training. We also demonstrated the knowledge graph’s utility by processing recycled 316 L stainless steel powders and assessing their quality through image processing. This experiment serves as a practical example of recycling and analyzing powders using the established knowledge graph.

This study aimed to investigate the associations between COVID-19 vaccination status and self-reported SARS-CoV-2 infection among children and adolescents aged 3–17 years during a massive COVID-19 outbreak after China changed its zero COVID policy. A cross-sectional online survey was conducted between 1 and 9 March 2023. Participants were the parents of children studying in kindergartens, primary schools, or secondary schools in Shenzhen. Convenient sampling was used. All kindergartens, primary schools, and secondary schools in the Longhua District of Shenzhen invited the parents of children and adolescents attending the schools. Interested parents completed an online survey. Multivariate logistic regression was fitted. Among 8538 participants, 40.9% self-reported that their children had SARS-CoV-2 infection after 7 December 2022, where 92.9% of them received two doses of the COVID-19 vaccines, and 74.6% received their second dose for more than six months. In multivariate analysis, children who received their second dose of the COVID-19 vaccination for no more than three months had a lower SARS-CoV-2 infection rate compared to unvaccinated children (

This systematic review and meta-analysis summarises the literature on parental acceptance, parental hesitancy, uptake, and the associated factors of seasonal influenza vaccination (SIV) among children aged 6–59 months. Studies were sourced from the following platforms: PubMed, Web of Science, MEDLINE, and EMBASE databases. A random-effects model was used to evaluate the prevalence and 95% confidence intervals (CI) of parental acceptance, parental hesitancy, and SIV uptake in the last flu season and lifetime among children. A total of 36 studies were included for analysis. The overall prevalence was 64% for parental acceptance (95% CI: 51–75%), 34% for parental hesitancy (95% CI: 22–48%), 41% for SIV uptake in the last flu season (95% CI: 33–50%), and 46% for SIV uptake in a lifetime (95% CI: 20–74%). Associated factors of parental acceptance/hesitancy and uptake included the age of the children or parents, parental education level, household income level, ethnicity, and other modifiable factors, including perceived benefits, perceived barriers, perceived severity, perceived susceptibility, and cues to action related to SIV. Meta-regression analyses revealed regional differences in parental acceptance (Americas: 79% vs. Asia: 60%). The results provided implications informing us of the development of intervention programs targeting parents to improve SIV coverage among young children.

Bacterial panicle blight, bacterial leaf streak, and bacterial brown stripe are common bacterial diseases in rice that represent global threats to stable rice yields. In this study, we used the rice variety HZ, Nekken and their 120 RIL population as experimental materials. Phenotypes of the parents and RILs were quantitatively analyzed after inoculation with Burkholderia glumae, Xanthomonas oryzae pv. oryzicola, and Acidovorax avenae subsp. avenae. Genetic SNP maps were also constructed and used for QTL mapping of the quantitative traits. We located 40 QTL loci on 12 chromosomes. The analysis of disease resistance-related candidate genes in the QTL regions with high LOD value on chromosomes 1, 3, 4, and 12 revealed differential expression before and after treatment, suggesting that the identified genes mediated the variable disease resistance profiles of Huazhan and Nekken2. These results provide an important foundation for cloning bacterial-resistant QTLs of panicle blight, leaf streak, and brown stripe in rice.

With the rapid development of Social Networking Services (SNSs), linking online user IDs is becoming increasingly important to internet service providers. Existing methods can achieve matching adjacent IDs between different services, where adjacent IDs mean the IDs that send message loggings at the same physical location. However, nonadjacent IDs also need to be matched in reality, which is a key challenge. In this paper, a new method based on users social behaviors and contact graph is put forward to realize linking of IDs across domains. This method can be used for matching both adjacent IDs and nonadjacent IDs. Specifically, all the IDs are mapped to contact graph. And we utilize a set matching algorithm based on the contact graph to find out the set of candidate IDs and generate confidence score by means of this algorithm to select the most appropriate matching. Our experimental results show that our algorithm is capable of identifying not only the set of adjacent IDs that belong to one same user but also the set of nonadjacent IDs that belong to one same user.

This study aimed to estimate the latest magnitudes and temporal trends of melanoma burden at the national, regional, and global levels. The data on melanoma incidence, deaths, and disability-adjusted life-years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease 2019 Study. Estimated annual percentage change (EAPC) was calculated to depict the temporal trends and Spearman rank correlation was used to analyze the influential factors of EAPC. From 1990 to 2019, the incident cases of melanoma increased by 170% to 289,950, death increased by 90% to 62,840, and DALYs increased by 67% to 1,707,800 globally. The age-standardized incidence rate (ASIR) of melanoma increased globally by an average of 1.13 [95% confidence interval (CI): 0.93–1.32], while the age-standardized rates of death and DALYs both declined with the EAPC of −0.27 (95% CI: −0.36 to −0.19) and −0.49 (95% CI: −0.57 to −0.41). In 2019, the highest burden of melanoma was observed in Australasia, followed by high-income North America and Europe regions, which all presented an incremental growth in ASIR. The positive association between the EAPC in ASIR and socio-demographic index (SDI) in 2019 (ρ = 0.600, P

Abstract Aim Media use may strengthen parents’ capacities to deal with parenting issues. This study examined which factors are associated with media use for parenting information. Design Cross‐sectional data of 658 parents of children aged 0–8 years, gathered in the CIKEO cohort study in the Netherlands, were analysed. Methods Multivariable logistic regression models were used to examine which factors were associated with media use for parenting information. Results The mean age of the participants was 33.8 years (SD = 5.0); 94.7% were mothers; 77.4% used media for parenting information. Parents with more questions or concerns (OR: 1.40, 95% CI: 1.23, 1.59), and parents who received parenting information from their social contacts (OR: 5.57, 95% CI: 3.22, 9.61), had higher odds of media use for parenting information. Older parents (OR: 0.95, 95% CI: 0.91, 1.00), and parents of older children (OR: 0.84, 95% CI: 0.74, 0.95), had lower odds of media use for parenting information.

We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma‐free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next‐generation sequencing before and after operation. Whole‐exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre‐ and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow‐up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time‐points was associated with significantly shorter recurrence‐free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real‐time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC.

Soil moisture (SM) estimation is a critical part of environmental and agricultural monitoring, with satellite-based microwave remote sensing being the main SM source. However, the limited spatial resolution of most current remote sensing SM products reduces their utility for many applications, such as evapotranspiration modeling and agriculture management. In this article, to address this issue, we propose a Bayesian deep image prior (BDIP) downscaling approach to estimate the high-resolution SM from satellite products. More specifically, the high-resolution SM estimation problem is formulated as a maximum a posteriori problem, and solved via a neural network comprising of a deep fully convolutional neural network (FCNN) for modeling the prior spatial correlation distribution of the underlying high-resolution SM variables, and a forward model characterizing the SM map degeneration process for modeling the data likelihood. As such, the proposed BDIP approach provides a statistical framework that integrates deep learning with forward modeling in a coherent manner for combining different sources of information, i.e., the knowledge in the forward model, the spatial correlation prior in FCNN architecture, and the remote sensing data and products. Experiments on the downscaling of SM active passive SM products using the moderate resolution imaging spectroradiometer products show that SM maps estimated using the proposed method provide greater spatial detail information than other downscaling methods, with the SM estimates very close to in situ measurements.

Faster diagnosis of Coronavirus disease 2019 (COVID-19) is crucial for surveillance, prompt implementation of infection control measures and adequate patient care among older adults. This study investigated the behavioral intention to use Rapid Antigen Tests (RAT) and associated factors among older adults in Hong Kong for health monitoring and when having COVID-19-like symptoms. This was a population-based cross-sectional random telephone survey of 370 Chinese-speaking adults aged ≥65 years. The behavioral intention to use RAT was the main outcome, and logistic regression models were used to assess the associated factors, using SPSS (version 26.0.). Results indicate that among the participants, 90.3% had used RAT, of which 21.6% obtained positive results. The common challenges faced when using RAT included: difficulty choosing the right RAT kit, uncertainty about how to use RAT, and not knowing what to do after getting a positive result. Additionally, 27.3% intended to use RAT regularly for health status monitoring without any symptoms, while 87.0% if they had COVID-19-like symptoms. After adjustment for significant background characteristics, positive attitudes, perceiving Hong Kong government and their children and/or other family members would support them using RAT, belief that RAT health promotion materials were helpful to understand how to use RAT and thoughtful consideration of the veracity of COVID-19 specific information were associated with higher behavioral intention to use RAT both when having no symptoms and in presence of COVID-19-like symptoms. Having negative attitudes toward RAT was associated with a lower intention of RAT use only when having no symptoms. Addressing difficulties faced when using RAT, strengthening positive attitudes, involving significant others and empowering with adequate information-veracity evaluating skills are potentially vital strategies to increase RAT use among older adults.

BackgroundCOVID-19 has had an impact on physical activity (PA) among older adults; however, it is unclear whether this effect would be long-lasting, and there is a dearth of studies assessing the changes in barriers to performing PA among older adults before and after entering the “postpandemic era.” ObjectiveThe aim of this study was to compare the levels and barriers of PA among a random sample of community-dwelling older adults recruited during (February to April 2022) and after the fifth wave of the COVID-19 outbreak (May to July 2022) in Hong Kong. In addition, we investigated factors associated with a low PA level among participants recruited at different time points. MethodsThis study involved two rounds of random telephone surveys. Participants were community-dwelling Chinese-speaking individuals aged 65 years or above and having a Hong Kong ID card. Household telephone numbers were randomly selected from the most updated telephone directories. Experienced interviewers carried out telephone interviews between 6 PM and 10 PM on weekdays and between 2 PM and 9 PM on Saturdays to avoid undersampling of working individuals. We called 3900 and 3840 households in the first and second round, respectively; for each round, 640 and 625 households had an eligible older adult and 395 and 370 completed the telephone survey, respectively. ResultsAs compared to participants in the first round, fewer participants indicated a low level of PA in the second round (28.6% vs 45.9%, P

To compare the safety and efficacy of endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangial drainage (PTCD) in the treatment of malignant obstructive jaundice, a systematic review and meta-analysis of published studies was undertaken to assess the differences between the two procedures in terms of efficacy and safety. From November 2000 to November 2022, the Embase, PubMed, MEDLINE, and Cochrane databases were searched for randomized controlled trials (RCTs) on the treatment of malignant obstructive jaundice with ERCP or PTCD. Two investigators independently assessed the quality of the included studies and extracted the data. Six RCTs, including 407 patients, were included. The results of the meta-analysis showed that the overall technical success rate in the ERCP group was significantly lower than that in the PTCD group (Z=3.19, P=0.001, OR=0.31 (95% CI: 0.15-0.64)), but with a higher overall procedure-related complication incidence rate (Z=2.57, P=0.01, OR=0.55 (95% CI: 0.34-0.87)). The incidence of procedure-related pancreatitis in the ERCP group was higher than that in the PTCD group (Z=2.80, P=0.005, OR=5.29 (95% CI: 1.65-16.97)), and the differences were statistically significant. No significant difference was observed between the two groups when the clinical efficacy, postoperative cholangitis, and bleeding rate were compared.Both treatments for malignant obstructive jaundice were efficacious and safe. However, the PTCD group had a greater technique success rate and a lower incidence of postoperative pancreatitis.The present meta-analysis has been registered in PROSPERO

Visceral leishmaniasis is a vector-borne infection by the Leishmania spp., a parasite. Although the overall incidence of visceral leishmaniasis is low, the disease still occurs frequently in some high-risk areas. In our study, two patients were admitted to the hospital with an unprovoked and recurrent high fever, and the condition was not improved after antibiotics administration. Meanwhile, bone marrow aspiration smears failed to find out any pathogen. Finally, Leishmania-specific nucleic acid sequences were successfully detected in the peripheral blood of two patients through metagenomic next-generation sequencing (mNGS), which was further confirmed by bone marrow smear microscopy and antibody tests. After targeted treatment for visceral leishmaniasis in the patients, mNGS reported a decrease in the reads number of Leishmania sequence. The results indicate the feasibility of mNGS in detecting Leishmania spp. in peripheral blood samples. Its therapeutic effect evaluation may be achieved through a comparative analysis of the number of reads before and after the treatment.

Rare tumor has a huge unmet medical need without standard regimens, calling for novel therapeutic interventions. The National Cancer Center of China identified a threshold of incidence for rare tumor as 2.5/100,000, based on the characteristics of Chinese population. Molecular profiles for rare tumor patients in China further provided prospects for precise and individualized targeted treatment. An ongoing phase II clinical trial, the PLATFORM study, is the first trial tailored for rare solid tumors in China, featured by molecule‐guided therapeutics. With the promulgation of supportive policies to encourage the development of innovative drugs for rare tumors in China, opportunities will be provided for these patients and the gap will be filled in the treatment of rare tumors.

Objective To evaluate the predictive value of vesical imaging-reporting and data system (VI-RADS) based on multi-parameter magnetic resonance imaging (MRI) for muscle invasive bladder cancer. Methods Clinical data of 278 patients undergoing transurethral resection of bladder tumor (TURBT) or radical cystectomy in our hospital from January 2017 to March 2021 were collected in this study. After VI-RADS score was assessed by 2 radiologists independently, Kappa test was used for the consistency of the obtained scores. Chi-square test was employed to analyze the consistency of VI-RADS score with pathological results. Receiver operating characteristic (ROC) curve was drawn to analyze the efficacy of VI-RADS scores in the diagnosis of muscle invasive bladder cancer. The consistency of VI-RADS score with pathological Results of tissues obtained by different surgical Methods was analyzed with Chi-square test. Results The VI-RADS scores of the 2 radiologists were consistent with each other (coincidence rate: 79.86%, kappa value: 0.750 8, P < 0.001). ROC curve analysis showed that the area under curve (AUC), Yodon index, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.774, 54.78%, 96.16%, 58.62%, 58.14% and 96.23%, respectively, when predicting muscular invasion with VI-RADS score ≥3 as the threshold. The study also found that the coincidence rate between the pathological Results of radical cystectomy and VI-RADS score was 92.85%, which was significantly higher than that of TURBT (79.81%, P < 0.05). Conclusion VI-RADS score based on preoperative multi-parameter MRI has good consistency and stability, and is highly consistent with the Results of postoperative pathology. VI-RADS score ≥3 has predictive diagnostic value for muscular-invasive bladder cancer and can guide the selection of clinical surgical methods.

Radical cystectomy plus pelvic lymph node dissection is the gold standard treatment for muscle invasive bladder cancer. However, the patients with severe medical complications cannot tolerate the operation, and the incidence rates of short- and long-term postoperative complications are quite high. In order to achieve good tumor control while preserve bladder function and maintain good quality of life, bladder preservation treatment is actively explored in China and at abroad. At present, triple or multiple combination therapy, including maximum transurethral bladder tumor resection, chemotherapy and external irradiation and radiotherapy, is mostly adopted. Studies have shown that its long-term tumor control effect is similar to that of cystectomy, and it has been recommended as an effective treatment option for muscle invasive bladder cancer by domestic and foreign specialized diagnosis and treatment guidelines. In the course of comprehensive treatment for bladder preservation, the efficacy of the treatment is currently evaluated by liquid biopsy, radiography, cystoscopic biopsy or surgical thoroughness of transurethral bladder tumor resection, and timely salvage radical resection can be performed for the patients with poor response. In addition, neoadjuvant chemotherapy may have no effect on the overall survival of the patients after bladder preservation combination therapy, but it can be used as a screening method for treatment response, and early radical surgery is recommended for patients with poor response. There is no standard treatment plan for bladder preservation combination therapy, and it is difficult to determine the best treatment population. Randomized controlled studies and long-term follow-up trial of the combination treatment in comparison with radical bladder resection need to be carried out. In view of the breakthrough efficacy of immune checkpoint inhibitors in the treatment of advanced uroepithelial carcinoma, the combination of immune checkpoint inhibitors and radiotherapy and chemotherapy may also be the direction of future research.

Objective To investigate the role and mechanism on how M2 macrophages promote epithelial-mesenchymal transition (EMT) of bladder cancer cells via clauding10 (CLDN10)-mediated signaling pathway. Methods Ten pairs of fresh bladder cancer tissues and corresponding para-tumor tissues were collected in Chongqing University Cancer Hospital during March and September 2020. Immunohistochemical (IHC) assay was used to detect the expression of macrophages' membrane markers. The genes regulated by macrophages were screen out with transcriptome sequencing together with immune scores based on IHC assay in bladder tissues. CCK-8 assay, cellular colony and Western blotting were employed to observe the effect of CLDN10 on the growth and proliferation of bladder cancer cells. Results Macrophages' characteristic marker CD68 and M2 macrophages' CD163 were highly expressed in bladder cancer tissues. Gene sequencing indicated that CLDN10 was significantly expressed in the tumor tissues, and its expression was positively correlated with the infiltration of macrophages in bladder tissues. The Results of Western blotting showed that the CLDN10 expression were higher in cancer tissues compared to adjacent normal tissues (P < 0.05). Knockdown of CLDN10 decreased the growth ability of T24 cells and decreased the number of colonies than the untreated cells (198.0±10.3 vs 145.0±8.4, P < 0.05). Additionally, the protein levels of snail, twist and vimentin were significantly decreased, whereas that of Ecadherin was increased after CLDN10 knockdown. Conclusion Macrophages upregulate CLDN10 expression in bladder cancer cells, and thus promotes EMT and progression of the cancer cells.

Abstract Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.

Abstract Background Alcohol screening and brief intervention (SBI) is recommended to be implemented in primary care settings to intervene against hazardous/harmful drinking. However, studies showed that the uptake rate was low in many regions/countries. This systematic review presented current findings on the facilitators and barriers of SBI implemented by health professionals in primary care settings using the Consolidated Framework for Implementation Research (CFIR). Methods We included qualitative, quantitative, and mixed-method studies identified through four electronic databases (PubMed, MEDLINE, PsycInfo, and Web of Science) from inception to June 2020. Included articles had to address barriers and facilitators of SBI implementation and provide sufficient details that the CFIR domains could be identified and data were abstracted using a standardized extraction form. Results A total of 74 studies published from 1985 to 2019 were finally analysed and summarized. The most common facilitators were knowledge and positive beliefs about SBI (characteristics of the individuals) and available resources (inner setting). In contrast, the most common barriers were cost related to implementing SBI (intervention characteristics), negative beliefs about SBI (characteristics of the individuals), and lack of self-efficacy in implementing SBI (characteristics of the individuals). It could be observed that factors related to the inner setting and characteristics of individuals were extensively studied whilst the process received the least attention. Conclusions Most of the facilitators and barriers are modifiable. Additionally, most literature focused on various kinds of available assets to implement SBI. To promote the spread of SBI implementation, more high-quality studies on the implementation process are needed. This systematic review could serve as a reference framework for health authorities to devise strategies for improving the implementation of SBI in primary care settings. Trial registration This systematic review was registered in PROSPERO ( CRD42021258833 ).

Extracellular vesicles (EVs) that act as messengers mediate communication between parent and recipient cells through their contents, including nucleic acids, proteins, and lipids. These endogenous vesicles have emerged as a novel cell-free strategy for the treatment of diseases. EVs can be released by various types of cells with unique biological properties. Recent studies have shown that native EVs are used as therapeutic agents to promote tissue repair by delivering various growth factors and trophic factors including VEGF, EGF, TFN-α, IL-1β, and TGF-β to participate in all physiological processes of wound healing. Furthermore, to improve their specificity, safety, and efficiency for wound healing, the content and surface of EVs can be designed, modified, and engineered. The engineering strategies of EVs are divided into parent cell modification and indirect modification of EVs. The therapeutic potential of current EVs and engineered EVs for wound healing still requires the exploration of their large-scale clinical applications through innovative approaches. Herein, we provide an overview of the current biological knowledge about wound healing and EVs, as well as the application of native EVs in promoting wound healing. We also outline recent advances in engineering EV methodologies to achieve ideal therapeutic potential. Finally, the therapeutic applications of engineered EVs in wound healing are reviewed, and the challenges and prospects for the translation of engineered EVs to clinical applications are discussed.

BackgroundNo consensus on whether physical activity (PA) is related to physical and mental health among pediatric population remains has been reached to date. To further explore their association, our study assessed the effect of PA on physical and mental health of children and adolescents through a systematic review and meta-analysis of randomized controlled studies (RCTs).MethodsSeveral databases(Web of science, PubMed, Embase, Cochrane Central register of controlled trials, CINAHL) were searched from inception to 1st, December 2020 without language restrictions.Results38,236 records were identified primitively and 31 included studies with 1,255 participants eventually met our inclusion criteria, all of which exhibited a relatively low-moderate risk of bias of overall quality. In regard to mental health, the administration of PA, compared with the control group, led to moderate improvements in Autism Spectrum Disorder(ASD)[Standard mean difference (SMD) = −0.50, Confidence interval(CI): −0.87, −0.14)] and depression(SMD = −0.68, CI: −0.98, −0.38) among children and adolescents. Similarly, significant result was observed in obesity (SMD = −0.58, CI: −0.80, −0.36). No significant differences were observed in Attention deficit hyperactivity disorder (ADHD) (SMD = −0.29, CI: −0.59, 0.01).ConclusionAltogether, PA may have a beneficial effect on children and adolescents with ASD, depression and obesity; nevertheless, there is insufficient evidence to confirm its efficacy in ADHD. More large-scale population based randomized controlled trials are needed to explore more reliable evidence between them.

IntroductionPreoperative evaluation of the mitotic index (MI) of gastrointestinal stromal tumors (GISTs) represents the basis of individualized treatment of patients. However, the accuracy of conventional preoperative imaging methods is limited. The aim of this study was to develop a predictive model based on multiparametric MRI for preoperative MI prediction.MethodsA total of 112 patients who were pathologically diagnosed with GIST were enrolled in this study. The dataset was subdivided into the development (n = 81) and test (n = 31) sets based on the time of diagnosis. With the use of T2-weighted imaging (T2WI) and apparent diffusion coefficient (ADC) map, a convolutional neural network (CNN)-based classifier was developed for MI prediction, which used a hybrid approach based on 2D tumor images and radiomics features from 3D tumor shape. The trained model was tested on an internal test set. Then, the hybrid model was comprehensively tested and compared with the conventional ResNet, shape radiomics classifier, and age plus diameter classifier.ResultsThe hybrid model showed good MI prediction ability at the image level; the area under the receiver operating characteristic curve (AUROC), area under the precision–recall curve (AUPRC), and accuracy in the test set were 0.947 (95% confidence interval [CI]: 0.927–0.968), 0.964 (95% CI: 0.930–0.978), and 90.8 (95% CI: 88.0–93.0), respectively. With the average probabilities from multiple samples per patient, good performance was also achieved at the patient level, with AUROC, AUPRC, and accuracy of 0.930 (95% CI: 0.828–1.000), 0.941 (95% CI: 0.792–1.000), and 93.6% (95% CI: 79.3–98.2) in the test set, respectively.DiscussionThe deep learning-based hybrid model demonstrated the potential to be a good tool for the operative and non-invasive prediction of MI in GIST patients.

Macrophage polarization followed by myocardial infarction (MI) is essential for wound healing. Tripartite motif-containing protein 21 (TRIM21), a member of E3 ubiquitin ligases, is emerging as a mediator in cardiac injury and heart failure. However, its function in modulating post-MI macrophage polarization remains elusive. Here, we detected that the levels of TRIM21 significantly increased in macrophages of wild-type (WT) mice after MI. In contrast, MI was ameliorated in TRIM21 knockout (TRIM21-/-) mice with improved cardiac remodeling, characterized by a marked decrease in mortality, decreased infarct size, and improved cardiac function compared with WT-MI mice. Notably, TRIM21 deficiency impeded the post-MI apoptosis and DNA damage in the hearts of mice. Consistently, the accumulation of M1 phenotype macrophages in the infarcted tissues was significantly reduced with TRIM21 deletion. Mechanistically, the deletion of TRIM21 orchestrated the process of M1 macrophage polarization at least partly via a PI3K/Akt signaling pathway. Overall, we identify TRIM21 drives the inflammatory response and cardiac remodeling by stimulating M1 macrophage polarization through a PI3K/Akt signaling pathway post-MI.

Abstract Background Demand for eye care has increased in recent decades in China due to rapid socioeconomic development and demographic shift. Knowledge of output and productivity of ophthalmic services would allow policymakers to optimize resource allocation, and is therefore essential. This study sought to map the landscape of ophthalmic services available in Shanghai, China. Methods In 2018, a government-led survey was conducted of all 86 tertiary/secondary hospitals and five major private hospitals providing eye care in Shanghai in the form of electronic questionnaire, which encompassed ophthalmic services (outpatient and emergency room [ER] visit, inpatient admissions, and surgical volume) and service productivity in terms of annual outpatient and ER visits per doctor, inpatient admissions per bed, and surgical volume per doctor. Comparisons were made among different levels of hospitals with categorical variables tested by Chi-square analysis. Results The response rate was 85.7%. The Eye and Ear, Nose, and Throat (EENT) Hospital was the largest tertiary specialty hospital, and alone contributed to the highest 21.0% of annual ophthalmic outpatient and ER visits (visits per doctor: 5460), compared with other 26 tertiary hospitals, 46 secondary hospitals and five private hospitals (visits per doctor: 3683, 4651 and 1876). The annual inpatient admission was 20,103, 56,992, 14,090, and 52,047 for the EENT Hospital, all the other tertiary hospitals, secondary hospitals and five private hospitals, respectively. Turnover rates were highest for the EENT Hospital and private hospitals. The average surgical volume at the EENT Hospital was 72,666, exceeding that of private (15,874.8) and other tertiary hospitals (3366.7). The EENT Hospital and private hospitals performed 16,982 (14.2%) and 55,538 (46.6%) of all cataract surgeries. Proportions of both complicated cataractous cases and complicated cataract surgeries at the EENT Hospital was the highest, followed by other tertiary and secondary/private hospitals (P

A localized Wnt3a signal has been shown to induce asymmetric division of mouse embryonic stem cells. Here the authors develop SET-seq, an approach to jointly profile epigenome and transcriptome in the same single cell and use it to provide mechanistic insights into the gene regulatory programs for maintaining and resetting stem cell fate during differentiation.

Background: The role of autophagy in the formation of hypertrophic scars (HS) remains unclear. This study aimed to explore the role and potential mechanism of autophagy during the development of HS. Methods: RNA and protein expression levels of Beclin-1, p62, and LC3II in normal skin tissues and HS specimens from different patients were examined. Autophagy inducers and inhibitors were used to cure established HS in rabbit ears, and the expression of Beclin-1, p62, and LC3II at the RNA and protein level was determined. Lastly, the effects of autophagy inducers and inhibitors on HS development were analyzed. Results: Compared to normal skin tissues, the expression of LC3Ⅱ and Beclin-1 was higher (P

To compare the safety and immunogenicity of lyophilized PVRV under Zagreb and Essen regimen. A post-marketing parallel control clinical trial was conducted. Totally 240 subjects were assigned to two groups randomly, immunized with lyophilized PVRV under Zagreb and Essen schedule. Solicited adverse events were observed after each dose and unsolicited adverse events were collected. Serum samples were collected on days 0, 7, 14, 42, 180 and 365 to be used to determine immunogenicity level. No severe adverse events (SAE) were observed. The incidence of adverse events under Zagreb and Essen were similar and there was no significant difference between the two groups and within all age groups. Fever and pain were the most frequently reported systemic and local adverse events (AEs) respectively. There were no differences in the GMT and the positive seroconversion rate between these two groups. All participants in the Zagreb group obtained protective effect on day 14, while 99.16% of the subjects obtained in the Essen group. Both groups showed similar enduring immunity. Immunizations under Zagreb and Essen regimens showed similar safety and immunogenicity. For lyophilized PVRV, Zagreb was non-inferior to Essen to patients of all age groups.