Whole-brain connectivity to the bed nucleus of the stria terminalis calretinin-expressing interneurons in male mice.

The bed nucleus of the stria terminalis (BNST) is a neuropeptide-enriched brain region that modulates a wide variety of emotional behaviours and states, including stress, anxiety, reward and social interaction. The BNST consists of diverse subregions and neuronal ensembles; however, because of the high molecular heterogeneity within BNST neurons, the mechanisms through which the BNST regulates distinct emotional behaviours remain largely unclear. Prior studies have identified BNST calretinin (CR)-expressing neurons, which lack neuropeptides. Here, employing virus-based cell-type-specific retrograde and anterograde tracing systems, we mapped the whole-brain monosynaptic inputs and axonal projections of BNST CR-expressing neurons in male mice. We found that BNST CR-expressing neurons received inputs mainly from the amygdalopiriform transition area, central amygdala and hippocampus and moderately from the medial preoptic area, basolateral amygdala, paraventricular thalamus and lateral hypothalamus. Within the BNST, plenty of input neurons were primarily located in the oval and interfascicular subregions. Furthermore, numerous BNST CR-expressing neuronal boutons were observed within the BNST but not in other brain regions, thus suggesting that these neurons are a type of interneuron. These results will help further elucidate the neuronal circuits underlying the elaborate and distinct functions of the BNST.

Augmented Reality for Enhanced Visualization of MOF Adsorbents.

Augmented reality (AR) is an emerging technique used to improve visualization and comprehension of complex 3D materials. This approach has been applied not only in the field of chemistry but also in real estate, physics, mechanical engineering, and many other areas. Here, we demonstrate the workflow for an app-free AR technique for visualization of metal-organic frameworks (MOFs) and other porous materials to investigate their crystal structures, topology, and gas adsorption sites. We think this workflow will serve as an additional tool for computational and experimental scientists working in the field for both research and educational purposes.

Analyzing drop coalescence in microfluidic devices with a deep learning generative model.

Predicting drop coalescence based on process parameters is crucial for experimental design in chemical engineering. However, predictive models can suffer from the lack of training data and more importantly, the label imbalance problem. In this study, we propose the use of deep learning generative models to tackle this bottleneck by training the predictive models using generated synthetic data. A novel generative model, named double space conditional variational autoencoder (DSCVAE) is developed for labelled tabular data. By introducing label constraints in both the latent and the original space, DSCVAE is capable of generating consistent and realistic samples compared to the standard conditional variational autoencoder (CVAE). Two predictive models, namely random forest and gradient boosting classifiers, are enhanced on synthetic data and their performances are evaluated based on real experimental data. Numerical results show that a considerable improvement in prediction accuracy can be achieved by using synthetic data and the proposed DSCVAE clearly outperforms the standard CVAE. This research clearly provides more insights into handling imbalanced data for classification problems, especially in chemical engineering.

Accurate identification and measurement of the precipitate area by two-stage deep neural networks in novel chromium-based alloys.

The performance of advanced materials for extreme environments is underpinned by their microstructure, such as the size and distribution of nano- to micro-sized reinforcing phase(s). Chromium-based superalloys are a recently proposed alternative to conventional face-centred-cubic superalloys for high-temperature applications, e.g., Concentrated Solar Power. Their development requires the determination of precipitate volume fraction and size distribution using Electron Microscopy (EM), as these properties are crucial for the thermal stability and mechanical properties of chromium superalloys. Traditional approaches to EM image processing utilise filtering with a fixed contrast threshold, leads to weak robustness to background noise and poor generalisability to different materials. It also requires an enormous amount of time for manual object measurements on large datasets. Efficient and accurate object detection and segmentation are therefore highly desired to accelerate the development of novel materials like chromium-based superalloys. To address these bottlenecks, based on YOLOv5 and SegFormer structures, this study proposes an end-to-end, two-stage deep learning scheme, DT-SegNet, to perform object detection and segmentation for EM images. The proposed approach can thus benefit from the training efficiency of CNNs at the detection stage (i.e., a small number of training images required) and the accuracy of the ViT at the segmentation stage. Extensive numerical experiments demonstrate that the proposed DT-SegNet significantly outperforms the state-of-the-art segmentation tools offered by Weka and ilastik regarding a large number of metrics, including accuracy, precision, recall and F1-score. This model forms a useful tool to aid alloy development microstructure examinations, and offers significant advantages to address the large datasets associated with high-throughput alloy development approaches.

The Nrf2/HMGB1/NF-κB axis modulates chondrocyte apoptosis and extracellular matrix degradation in osteoarthritis.

Osteoarthritis (OA) is a degenerative or posttraumatic condition of the joints. In OA chondrocytes, Nrf2 functions as a stress response regulator with antioxidant and anti-inflammatory effects. This study aims to investigate the role of Nrf2 and its downstream pathway in the development of osteoarthritis. IL-1ß treatment suppresses Nrf2, aggrecan, and COL2A1 levels and cell viability but promotes apoptosis in chondrocytes. IL-1ß stimulation induces cell apoptosis, upregulates the mRNA expression of inflammatory factors, decreases aggrecan, COL2A1, and Bcl-2 levels but increases ADAMTS-5, ADAMTS-4, MMP13, cleaved caspase 3, and BAX levels, and promotes p65 phosphorylation. Nrf2 overexpression exerts opposite effects on IL-1ß-treated chondrocytes, as demonstrated by the significant attenuation of IL-1ß-induced changes in chondrocytes. By binding to the HMGB1 promoter region, Nrf2 suppresses HMGB1 expression. Similar to Nrf2 overexpression, HMGB1 knockdown also attenuates IL-1ß-induced changes in chondrocytes. Notably, under IL-1ß stimulation, the effects of Nrf2 overexpression or tert-butylhydroquinone (TBHQ, an activator of Nrf2) on apoptosis, inflammatory factor expression, ECM and apoptosis, and NF-κB pathway activity in chondrocytes are remarkably reversed by HMGB1 overexpression or recombinant HMGB1 (rHMGB1). Similarly, rHMGB1 could partially counteract the curative effect of TBHQ on OA damage in mice. In OA cartilage tissue samples, the level of Nrf2 is lower, while the levels of HMGB1, apoptotic, and inflammatory factors are increased compared to normal cartilage tissue samples. In conclusion, for the first time, the Nrf2/HMGB1 axis was found to modulate apoptosis, ECM degradation, inflammation and activation of NF-κB signaling in chondrocytes and OA mice.

Pharmacokinetics and bioequivalence study of two ciprofloxacin hydrochloride tablets in healthy Chinese subjects under fasting and fed conditions: A randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover study.

OBJECTIVE: The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under fasting and fed conditions. MATERIALS AND METHODS: The study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg ciprofloxacin hydrochloride. Blood samples were collected from 1 hour before dosing to 36 hours after administration with 16 timepoints in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including Cmax, AUC0-t, and AUC0-∞. RESULTS: A total of 48 subjects were enrolled in the fasting and fed studies, and 1 of the subjects was excluded before drug administration. In the fasting study, the 90% CIs for the test/reference geometric mean ratios (GMRs) of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 85.41 - 100.97%, 95.40 - 100.27%, and 95.48 - 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0-t, and AUC0-∞ were 90.15 - 113.75%, 99.10 - 103.77%, and 99.11 - 103.80%, respectively. These values all fell within the standard acceptance range of 80 - 125%. CONCLUSION: In the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after single-, oral-dose administration under fasting and fed conditions.

Implementation of flipped classroom combined with case- and team-based learning in residency training.

The core problem of Chinese resident doctor training is that medical educators present content in an attractive teaching mode to make students more motivated to learn and improve their clinical thinking ability, humanistic care, and practical ability. The traditional classroom mode of teaching cannot meet the needs of modern medical education. The purpose of this study is to explore the benefits and challenges of the flipped classroom (FC) combined with case- and team-based learning (FC-CTBL) for residency training. In this study, 60 junior surgical residents of Xiangya Medical College were enrolled. "Diabetic foot" was selected as the content of this study. Residents were divided into an FC-CTBL group and an FC group. FC-CTBL and FC were compared on the basis of residents' feedback questionnaires, residents' learning burden, test scores from a pre-quiz, and objective structured clinical examinations (OSCE). Residents were more satisfied with the FC-CTBL model compared with FC. In the FC-CTBL group, more participants said that the course improved their teamwork skills, analytical skills and their confidence in tackling unfamiliar problems. Residents in the FC-CTBL group also spent significantly less time preparing for class and performed better in the OSCE than those in the FC group. FC-CTBL stimulates residents' learning motivation, decreases their workload, improves their performance in the OSCE and may help to enhance clinical thinking and teamwork skills. The FC-CTBL approach is a good option for residency training.

Genetic polymorphisms of histone methyltransferase SETD2 predicts prognosis and chemotherapy response in Chinese acute myeloid leukemia patients.

BACKGROUND: SETD2, the single mediator of trimethylation of histone 3 at position lysine 36, has been reported associated with initiation progression and chemotherapy resistance in acute myeloid leukemia (AML). Whether polymorphisms of SETD2 affect prognosis and chemotherapy response of AML remains elusive. METHODS: Three tag single-nucleotide polymorphisms (tagSNPs) of SETD2 were genotyped in 579 AML patients by using Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, overall survival (OS) and relapse-free survival (RFS) were analyzed. RESULT: Survival analysis indicated that SETD2 rs76208147 TT genotype was significantly associated with poor prognosis of AML (TT vs. CC + CT hazard ratio: HR = 1.838, 95% confidence interval (CI) 1.005-3.360, p = 0.048). After adjusting for the known prognostic factors including risk stratification, age, allo-SCT, WBC count and LDH count, rs76208147 TT genotype was still associated with OS in the multivariate analysis (TT vs. CC + CT HR = 1.923, 95% CI 1.007-3.675, p = 0.048). In addition, after adjusting by other clinical features, patients with rs4082155 allele G carries showed higher rate of complete remission which indicated by CR rate (AG + GG vs. AA odd ratio (OR) = 0.544, 95% CI 0.338-0.876, p = 0.012). CONCLUSIONS: SETD2 genetic polymorphism is associated with AML prognosis and chemotherapy outcome, suggesting the possibility for development in AML diagnostics and therapeutics towards SETD2.

Influence of DNMT3A R882 mutations on AML prognosis determined by the allele ratio in Chinese patients.

BACKGROUND: The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations. METHODS: DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed. RESULTS: DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10-4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035). CONCLUSION: Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.

miR-223/Hsp70/JNK/JUN/miR-223 feedback loop modulates the chemoresistance of osteosarcoma to cisplatin.

Osteosarcoma (OS) is a primary bone malignancy with a five-year survival rate of 60%; the chemoresistance of OS still remains a huge challenge. Heat shock protein 70 (Hsp70), a member of HSP family, is overexpressed in OS cell lines and involved in the resistance of OS cell lines. In addition, miRNAs have been involved in the carcinogenesis and chemoresistance of OS; of them, miR-223 has been reported to be underexpressed and serve as a tumor suppressor in OS through targeting Hsp90B1, also a member of HSP family. Herein, online tools predicted that Hsp70 might be a direct target of miR-223. In the present study, miR-223 expression was down-regulated in OS tissues and cell lines; miR-223 overexpression enhanced the cellular effects of cisplatin (CDDP) on OS cell lines. Through binding to the HSPA1A 3'UTR, miR-223 could regulate Hsp70 protein levels and downstream JNK/JUN signaling pathway, thus modulating OS cell apoptosis through Hsp70 under CDDP stress. Finally, JUN, a downstream transcription factor of JNK signaling, could bind to the promoter region of miR-223 to promote its transcription. In summary, miR-223, Hsp70 and downstream JNK/JUN formed a feedback loop to modulate the chemoresistance of OS to CDDP.

Influence of UGT1A1 polymorphisms on the outcome of acute myeloid leukemia patients treated with cytarabine-base regimens.

BACKGROUNDS: UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver. METHODS: UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated. RESULTS: After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10-4) and better overall survival (HR = 0.787, 95% CI 0.627-0.990, P = 0.040) as compared with homozygotes for both polymorphisms. CONCLUSION: Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML).

BACKGROUND: Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP. METHODS: A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients. CONCLUSION: Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

Green tea polyphenol EGCG suppresses osteosarcoma cell growth through upregulating miR-1.

(-)-Epigallocatechin-3-gallate (EGCG), the most abundant and active polyphenol in green tea, has been demonstrated to have anticancer effects in a wide variety of human cancer. MicroRNAs (miRNAs) are a class of short noncoding RNAs and play important role in gene regulation and are critically involved in the pathogenesis and progression of human cancer. This study aims to investigate the effects of EGCG on osteosarcoma (OS) cells and elucidate the underlying mechanism. Cellular function assays revealed that EGCG inhibited cell proliferation, induced cell cycle arrest and promoted apoptosis of OS cells in vitro, and also inhibited the growth of transplanted tumors in vivo. By miRNA microarray and RT-qPCR analysis, miR-1 was found to be significantly upregulated in MG-63 and U-2OS treated by EGCG in dose- and time-dependent manners, and miR-1 downregulation by inhibitor mimics attenuated EGCG-induced inhibition on cell growth of OS cells. We also confirmed that miR-1 was also frequently decreased in clinical OS tumor tissues. Moreover, both EGCG and miR-1 mimic inhibited c-MET expression, and combination treatment with EGCG and c-MET inhibitor (crizotinib) had enhanced inhibitory effects on the growth of MG-63 and U-2OS cells. Taken together, these results suggest that EGCG has an anticancer effect on OS cells, at least partially, through regulating miR-1/c-MET interaction.

Cerebral protective effect of in situ and remote ischemic postconditioning on ischemic stroke rat via the TGFß1-Smad2/3 signaling pathway.

Patients with acute ischemic stroke achieve inadequate benefit due to the short therapeutic window for thrombolysis and the risk of ischemia/reperfusion (IR) injury. Ischemic postconditioning induces endogenous cerebral protection for acute ischemic stroke, although the protective mechanisms associated with ischemic postconditioning haven't been well clarified. In present study, the rat models of ischemic cerebral stroke with in situ and remote ischemic postconditioning (ISP and RIP) were established successfully. The Zea Longa and the modified neurological severity scoring (mNSS) were carried out to evaluate neurological function in the rats, while the open field test was explored to estimate their autonomic athletic ability. The 2,3,5-riphenyltetrazolium chloride (TTC) staining method was used to measure the size of the infarcts. TUNEL and Nissl's staining were used to detect the apoptosis rate of cells in the ischemic penumbra, with the expression of TGFß1, Smad2, and Smad3 in the ischemic penumbra and serum detected by immunohistochemical staining, qRT-PCR, Western blots, and ELISA analysis. We showed that application of both types of ischemic postconditioning had cerebral protective effects for the ischemic stroke rats, that included effective reduction in the volume of cerebral infarction, alleviation of apoptosis and inflammation in the ischemic penumbra, and promotion of recovery of neurological function. These effects included significantly enriched gene ontology (GO) terms after RIP intervention that were related to TGFß1, increased protein levels of TGFß1 and decreased levels of p-Smad2/3 and smad3 following RIP intervention. We showed that the TGFß1-Smad2/3 signaling pathway was associated with the cerebral protection of ischemic postconditioning.

Efficacy and Safety of Different Doses of Rivaroxaban and Risk Factors for Bleeding in Elderly Patients with Venous Thromboembolism: A Real-World, Multicenter, Observational, Cohort Study.

INTRODUCTION: Venous thromboembolism (VTE) consists of deep vein thrombosis (DVT) and pulmonary embolism (PE). Rivaroxaban is a direct oral anticoagulant (DOAC) inhibiting activated coagulation factor X (FXa), and exerts several advantages in the treatment of VTE compared to conventional therapy. However, the efficacy and safety of rivaroxaban in elderly patients with VTE was still poorly understood. METHODS: The study was carried out using an observational and non-interventional approach. A total of 576 patients aged ≥ 60 years with newly diagnosed VTE were included in the study. All patients received rivaroxaban with recommended treatment duration of ≥ 3 months for secondary prevention. In addition, 535 elderly patients with various diseases except VTE were included in the study in a retrospective and randomized way. RESULTS: The total bleeding rate was 12.2% (70/576). Major bleeding and non-major clinically relevant (NMCR) bleeding occurred in 4 (0.69%) patients and 5 (0.87%) patients, respectively. The rate of recurrent VTE was 5.4%. The mean level of D-dimers was increased by 467.2% in the elderly patients with VTE compared with the elderly patients without VTE. The elderly patients with VTE receiving rivaroxaban at a dose of 10 mg once daily (n = 134) had lower risk for bleeding (3.7% vs 14.7%; P = 0.001) and a similar rate of recurrent VTE (4.5% vs 5.7%; P = 0.596) as compared to the elderly patients with VTE receiving rivaroxaban at higher doses including 15 mg once daily and 20 mg once daily (n = 442). In addition, age, concomitant aspirin, hemoglobin, activated partial thromboplastin time (APTT), and rivaroxaban doses were independent predictive factors for bleeding events. CONCLUSIONS: The study suggested that a dose of 10 mg once daily should be the priority in elderly patients with VTE receiving long-term rivaroxaban anticoagulation therapy in view of reduced bleeding risk.

Platelet-to-Lymphocyte Ratio (PLR), Neutrophil-to-Lymphocyte Ratio (NLR), Monocyte-to-Lymphocyte Ratio (MLR), and Eosinophil-to-Lymphocyte Ratio (ELR) as Biomarkers in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD).

Purpose: The study comprehensively evaluated the prognostic roles of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and eosinophil-to-lymphocyte ratio (ELR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Patients and Methods: Six hundred and nineteen patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics of the patients with AECOPD and the complete blood counts (CBCs) of the healthy volunteers were collected. The associations of PLR, NLR, MLR, BLR, and ELR with airflow limitation, hospital length of stay (LOS), C-reactive protein (CRP), and in-hospital mortality in patients with AECOPD were analyzed. Results: Compared with the healthy volunteers, PLR, NLR, MLR, BLR, and ELR were all elevated in COPD patients under stable condition. PLR, NLR, MLR, and BLR were further elevated while ELR was lowered during exacerbation. In the patients with AECOPD, PLR, NLR, and MLR were positively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more severe airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while elevated ELR was associated with decreased in-hospital mortality. Binary logistic regression analysis showed that smoking history, FEV1% predicted, pneumonia, pulmonary heart disease (PHD), uric acid (UA), albumin, and MLR were significant independent predictors ofin-hospital mortality. These predictors along with ELR were used to construct a nomogram for predicting in-hospital mortality in AECOPD. The nomogram had a C-index of 0.850 (95% CI: 0.799-0.901), and the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) further demonstrated its good predictive value and clinical applicability. Conclusion: In summary, PLR, NLR, MLR, and ELR served as useful biomarkers in patients with AECOPD.

A systematic review of vascular endothelial growth factor expression as a biomarker of prognosis in patients with osteosarcoma.

Vascular endothelial growth factor (VEGF) plays an important role in the tumor angiogenesis, and its expression has been supposed to be a biomarker of prognosis in patients with osteosarcoma. There are many studies assessing the prognostic role of VEGF expression in osteosarcoma, and no consistent outcomes are reported. To provide a comprehensive assessment of the prognostic role of VEGF expression, we performed a systematic review and meta-analysis of published studies. We assessed the effect of VEGF expression on the overall survival rate and the disease-free survival rate by calculating the pooled odds ratio (OR) with corresponding 95 % confidence interval (95 %CI). Finally, 12 studies with a total of 559 osteosarcoma patients were included into the systematic review and meta-analysis. Compared with osteosarcoma patients with low or negative VEGF expression, patients with high VEGF expression were obviously associated with lower disease-free survival (OR=0.25, 95 %CI 0.11-0.58, P=0.001, I (2) =56.4 %). In addition, patients with high VEGF expression were obviously associated with lower overall survival (OR=0.22, 95 %CI 0.13-0.35, P<0.001, I (2) =0.0 %). Therefore, the findings from this systematic review suggest that VEGF expression is an effective biomarker of prognosis in patients with osteosarcoma.

Efficacy and safety evaluation of Azvudine in the prospective treatment of COVID-19 based on four phase III clinical trials.

Azvudine (FNC) is a synthetic nucleoside analog used to treat adult patients living with human immunodeficiency virus-1 (HIV-1) infection with high viral load. After phosphorylation, Azvudine inhibits RNA-dependent RNA polymerase, leading to the discontinuation of RNA chain synthesis in viruses. In addition, Azvudine is the first dual-target nucleoside oral drug worldwide to simultaneously target reverse transcriptase and viral infectivity factors in the treatment of HIV infection. On 9 August 2022, Azvudine was incorporated into the Guidelines for the Diagnosis and Treatment of Coronavirus Disease 2019 (version ninth) issued by the National Health Commission and the National Administration of Traditional Chinese Medicine. The recommended oral dose of Azvudine for the treatment of moderate coronavirus disease 2019 (COVID-19) is 5 mg once daily, and the duration of Azvudine treatment should not exceed 14 days. Four phase III clinical trials were performed during 2020-2022 to evaluate the efficacy and safety of Azvudine in the treatment of COVID-19. The results revealed that Azvudine could reduce nucleic acid-negative conversion time, viral load, and time to improvement in clinical conditions in patients with moderate COVID-19. In addition, Azvudine exhibited good safety and tolerance. Thereafter, Azvudine was incorporated into the Chinese guidelines and expert consensus for the treatment of COVID-19 and was highly approbated. Furthermore, Azvudine was also included in the Chinese guidelines for HIV infection.

Why is it necessary to improve COVID-19 vaccination coverage in older people? How to improve the vaccination coverage?

In accordance with the COVID-19 surveillance data from Hong Kong, over 95% fatal cases were elderly patients aged ≥60 years, and the median age of the dead cases was 86 years in the fifth COVID-19 wave. COVID-19 case fatality rates increased with age, vaccinations offered notable protection against COVID-19 death, and the protection was enhanced as the doses of vaccinations increased. The data fully demonstrated that elderly people were the main group of victims in the COVID-19 pandemic, and the vaccination was a vital weapon against COVID-19 in elderly people. In light of the experience of China's COVID-19 response, the measures to improve COVID-19 vaccination coverage in older people were shown as follows: dispatching volunteers into residential communities to urge older people to complete COVID-19 vaccinations; ascertaining the vaccination status of elderly people suffering from underlying diseases; mobilizing various public institutions to participate in COVID-19 response; releasing a great deal of news via mass media every day to educate the elderly about COVID-19 prevention and control measures; assisting elderly people in rural and remote areas through drug distribution and emergency reserves.

Deuremidevir and Simnotrelvir-Ritonavir for the Treatment of COVID-19.

Deuremidevir hydrobromide tablets and simnotrelvir tablets/ritonavir tablets (co-packaged) were approved by the Chinese National Medical Products Administration for the treatment of mild to moderate COVID-19 in January 2023. Both formulations contain small-molecule anti-SARS-CoV-2 agents. Deuremidevir, an oral nucleoside analog, is a broad-spectrum virus replication inhibitor targeting the highly conserved RNA-dependent RNA polymerase. Simnotrelvir-ritonavir is a co-packaged combination drug consisting of simnotrelvir tablets and ritonavir tablets. Simnotrelvir is an oral antiviral agent targeting the 3-chymotrypsin-like protease, which is essential for SARS-CoV-2 viral replication. Previous clinical trials revealed that both deuremidevir and simnotrelvir-ritonavir were effective and well tolerated in the treatment of COVID-19.